Textbook of Palliative Medicine and Supportive Care [3 ed.] 0367642034, 9780367642037

Citation preview

TEXTBOOK OF PALLIATIVE MEDICINE AND SUPPORTIVE CARE THIRD EDITION Edited by Eduardo Bruera, MD, FAAHPM

Professor and Chair, Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Irene J. Higginson, OBE, BMedSci, BMBS, PhD, FMedSci, FRCP, FFPHM Professor and Director, Cicely Saunders Institute of Palliative Care, Policy and Rehabilitation, King’s College London, UK

Charles F. von Gunten, MD, PhD

Vice President, Medical Affairs, Hospice and Palliative Medicine, OhioHealth, Columbus, Ohio, USA

Tatsuya Morita, MD

Director, Department of Palliative and Supportive Care, Seirei Mikatahara General Hospital, Hamamatsu, and Adjunct Professor, Kyoto University, Japan

Third edition published 2021 by CRC Press 6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487-2742 and by CRC Press 2 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN © 2021 Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, LLC This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. The publishers wish to make clear that any views or opinions expressed in this book by individual editors, authors or contributors are personal to them and do not necessarily reflect the views/opinions of the publishers. The information or guidance contained in this book is intended for use by medical, scientific or health-care professionals and is provided strictly as a supplement to the medical or other professional’s own judgement, their knowledge of the patient’s medical history, relevant manufacturer’s instructions and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, procedures or diagnoses should be independently verified. The reader is strongly urged to consult the relevant national drug formulary and the drug companies’ and device or material manufacturers’ printed instructions, and their websites, before administering or utilizing any of the drugs, devices or materials mentioned in this book. This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole responsibility of the medical professional to make his or her own professional judgements, so as to advise and treat patients appropriately. The authors and publishers have also attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, access www.copyright.com or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. For works that are not available on CCC please contact [email protected] Trademark notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Names: Bruera, Eduardo, editor. | Higginson, Irene, editor. | Von Gunten, Charles F., 1956- editor. | Morita, Tatsuya, editor. Title: Textbook of palliative medicine and supportive care / edited by Eduardo Bruera, Professor and Chair, Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA, Irene Higginson, OBE, BMedSci, BMBS, PhD, FMedSci, FRCP, FFPHM Professor and Director, Cicely Saunders Institute of Palliative Care, Policy and Rehabilitation, King’s College London, UK, Charles F. von Gunten, MD, PhD, Vice President, Medical Affairs, Hospice and Palliative Medicine, OhioHealth, Columbus, Ohio, USA, Tatsuya Morita, MD, Director, Department of Palliative and Supportive Care, Seirei Mikatahara General Hospital, Hamamatsu, and Adjunct Professor, Kyoto University, Japan. Description: Third edition. | Boca Raton : CRC Press, 2021. | Summary: “This new edition provides the essential clinical guidance both for those embarking upon a career in palliative medicine and for those already established in the field. A team of international experts here distil what every practitioner needs to know into a practical and reliable resource”-- Provided by publisher. Identifiers: LCCN 2020049406 (print) | LCCN 2020049407 (ebook) | ISBN 9780367642037 (hardback) | ISBN 9780429275524 (ebook) Subjects: LCSH: Palliative treatment. Classification: LCC R726.8 .T464692 2021 (print) | LCC R726.8 (ebook) | DDC 616.02/9--dc23 LC record available at https://lccn.loc.gov/2020049406 LC ebook record available at https://lccn.loc.gov/2020049407 ISBN: 978-0-367-64203-7 (hbk) ISBN: 978-0-429-27552-4 (ebk) ISBN: 978-0-367-22546-9 (pbk) Typeset in Warnock Pro by KnowledgeWorks Global Ltd.

CONTENTS List of contributors�������������������������������������������������������������������������������� vi

18. Home palliative care................................................................137 Heather Grant and Dana Lustbader

1. The development of hospice and palliative care.................. 1 Kate Kirk

19. Palliative care unit.................................................................... 143 Karen Macmillan, Kelley Fournier, Beth Tupala, and Kim Crowe Mackinnon

2. Palliative care as a public health issue................................... 7 Irene J. Higginson and Massimo Costantini 3. Palliative care as a primary care issue................................. 17 Scott A. Murray, Sebastien Moine, and Kirsty Boyd 4. The future of palliative medicine...........................................25 Charles F. Von Gunten and Irene J. Higginson 5. Palliative care and supportive care....................................... 33 Eduardo Bruera 6. Ethics in the practice of palliative care................................ 39 Nelia Jain and James A. Tulsky 7. Undergraduate education in palliative medicine............. 47 Linh My Thi Nguyen 8. Graduate education for nonspecialists................................ 51 Fiona Rawlinson and Ilora G. Finlay 9. Challenges of research in palliative and supportive medicine......................................................................................... 61 Irene J. Higginson 10. The population: Who are the subjects in palliative medicine research?..................................................................... 71 Claudia Bausewein and Fliss E.M. Murtagh 11. Study designs in palliative medicine....................................77 Massimo Costantini 12. Outcome measurement in palliative care........................... 85 Joan M. Teno 13. Ethics in palliative care research........................................... 95 Jonathan Koffman and Emel Yorganci 14. Adoption of palliative care: The engineering of organizational change.............................................................107 Winford E. (Dutch) Holland and Eduardo Bruera 15. Principles of measuring the financial outcomes of specialist palliative care programs......................................115 J. Brian Cassel and Thomas J. Smith 16. Population-based needs assessment for patients and those important to them, such as families............... 119 Irene J. Higginson and Richard Harding 17. Models of palliative care delivery........................................127 Eduardo Bruera and Jessica H. Brown

20. Multidimensional patient assessment............................... 149 Marvin Omar Delgado-Guay and Alexander Harding 21. Tools for pain and symptom assessment...........................167 Victor T. Chang 22. Quality of life assessment in palliative care.....................189 Richard Sawatzky and S. Robin Cohen 23. Pathophysiology of chronic pain.........................................199 Sebastiano Mercadante 24. Causes and mechanisms of pain in palliative care patients................................................................................207 Michal Kubiak, Marieberta Vidal, and Suresh K. Reddy 25. Opioid analgesics......................................................................221 Geana Paula Kurita, Stein Kaasa, and Per Sjøgren 26. Assessment and management of opioid side effects......235 Shalini Dalal 27. Adjuvant analgesic medications..........................................249 Jessica Geiger 28. Alternative routes for systemic opioid delivery..............255 Raffaele Giusti, Monica Bosco, Maurizio Lucchesi, and Carla Ida Ripamonti 29. Interventional pain procedures in palliative care..........271 Po-Yi Paul Su, Ann Cai Shah, and Sarah Gebauer 30. Pain management in pediatrics............................................285 Kevin Madden 31. Pain in the older adult.............................................................293 Linh My Thi Nguyen and Michelle Peck 32. Neuropathic pain......................................................................301 Paolo Marchettini, Fabio Formaglio, and Marco Lacerenza 33. Bone cancer pain and skeletal complications..................313 Yoko Tarumi 34. Breakthrough (episodic) pain in cancer patients...........323 Shirley H. Bush 35. Somatic symptoms, symptom clusters, and symptom burden.......................................................................333 David V. Nelson and Diane M. Novy

iii

iv 36. Pain in patients with alcohol and drug dependence.................................................................................337 Leah Couture, Malisa Dang, and Danielle Noreika

Contents 54. Infections in palliative care...................................................525 Rudolph M. Navari

37. Cachexia–anorexia syndrome...............................................343 Paul Zelensky, Mallika Dammalapati, and Egidio Del Fabbro

55. Pediatric palliative wound care: The unique anatomy and physiology of neonatal skin......................................................................... 531 Ann Marie Nie and Joyce M. Black

38. Nausea/vomiting.......................................................................357 Sebastiano Mercadante

56 Mouth care..................................................................................539 Flavio Fusco

39. Constipation...............................................................................365 Charu Agrawal and Karina Shih

57. Fistulas.........................................................................................547 Maurizio Lucchesi, Fabio Fulfaro, Raffaele Giusti, and Carla Ida Ripamonti

40. Jaundice........................................................................................375 Nathan I. Cherny 41. Malignant bowel obstruction................................................381 Carla I. Ripamonti, Alexandra M. Easson, and Hans Gerdesh 42. Endoscopic treatment of digestive symptoms.....................................................................................395 Pasquale Spinelli 43. Mechanism, assessment, and management of fatigue......................................................................................401 Sean Hutchinson and Sriram Yennurajalingam 44. Breathlessness............................................................................421 Claudia Bausewein and Sara Booth 45. Other respiratory symptoms (cough, hiccup, and secretions)...........................................................................433 Regina M. Mackey and Francisco Loaiciga 46. Depression/anxiety..................................................................441 Tatsuo Akechi 47. Delirium.......................................................................................455 Yesne Alici and William S. Breitbart 48. Sleep disturbances in advanced cancer patients.........................................................................................467 Delmer A. Montoya and Sriram Yennurajalingam 49. Counseling in palliative care...............................................477 Sophie A. McGilvray and David W. Kissane

58. Assessment and management of lymphedema................553 Ying Guo and Mark V. Schaverien 59. Hypercalcemia...........................................................................563 Kimberson Tanco and Saima Rashid 60. Hemorrhage................................................................................569 Timothy Fuller, Kencee Graves, and Jen-Yu Wei 61. Spinal cord compression.........................................................579 Maitry Patel, Adrian Cozma, Edward Chow, and Srinivas Raman 62. Clinical features and management of superior vena cava syndrome..................................................................587 Álvaro Sanz, María Luisa del Valle, and Carlos Centeno 63. Acute pain and management.................................................593 Mellar P. Davis 64. Suicide.......................................................................................... 613 Daniel C. McFarland, Yesne Alici, and William S. Breitbart 65. Cancer: Radiotherapy..............................................................623 Adrian Cozma, Maitry Patel, Edward Chow, and Srinivas Raman 66. Chemotherapy, hormonal therapy, targeted agents, and immunotherapy.................................................................639 David Hui

50. Hope in end-of-life care.........................................................485 Cheryl L. Nekolaichuk

67. Integrative medicine in supportive and palliative care.....................................................................649 Gabriel Lopez, Santhosshi Narayanan, Wenli Liu, and Lorenzo Cohen

51. Dehydration and rehydration...............................................493 Robin L. Fainsinger

68. Neurological diseases..............................................................655 Tobias Walbert and Joel Phillips

52. Fever, sweats, and hot flashes................................................501 Ahsan Azhar and Shalini Dalal

69. End-stage congestive heart failure......................................663 Sam Straw, Klaus K. Witte, and Mark T. Kearney

53. Pruritus........................................................................................ 515 Michael Tang, Katie Taylor, and Andrew Thorns

70. Geriatric palliative care..........................................................669 Kimberson Tanco and Maxine De La Cruz

Contents 71. Advanced chronic obstructive pulmonary disease..........................................................................................677 Daisy J.A. Janssen, Lynn F. Reinke, and J. Randall Curtis 72. Other infectious diseases: Malaria, rabies, tuberculosis................................................................................687 Richard Harding, Rene Krause, and Sue Marsden 73. Practical resources for palliative care development in countries with limited resources: An IAHPC perspective.......................................697 Liliana De Lima 74. Prognostic indicators of survival.........................................705 Morena Shkodra, Augusto T. Caraceni, Marco Maltoni, and Caterina Modonesi 75. Palliative sedation.................................................................... 717 Nathan I. Cherny A.M. 76. Staff stress and burnout in palliative care........................727 Aimee E. Anderson and Eduardo Bruera 77. Spiritual care..............................................................................735 Marvin Omar Delgado-Guay and Alexander Harding 78. Family caregivers and cultural sensitivity........................743 Rony Dev and Ali Haider 79. Bereavement............................................................................... 761 Victoria H. Raveis 80. Children of palliative care patients.....................................769 Estela Beale and Sujin Ann-Yi

v 86. Peripheral neuropathy and neurotoxicity......................... 811 Sheetal Shroff, Akhil Shivaprasad, and Ivo W. Tremont-Lukats 87. Sex and sexuality....................................................................... 819 Mary K. Hughes 88. Managing communication challenges with patients and families................................................................825 Anthony L. Back 89. Supportive and palliative care for patients with HIV infection....................................................................831 Richard Harding, Elizabeth J. Chuang, and Peter A. Selwyn 90. Implantable cardiac devices..................................................841 Laura J. Morrison 91. Supportive care for patients with advanced chronic kidney disease............................................................861 Sara N. Davison 92. Palliative care in the emergency department..................873 Travis DeVader and Tammie Quest 93. Optimal Symptom Management in Hematopoietic Stem Cell Transplantation.....................................................879 Katie N. Kanter, Allison Kestenbaum, Thomas W. LeBlanc, and Eric J. Roeland 94. The end of therapy: Building the psychosocial and spiritual bridges to survivorship.................................897 Marvin Omar Delgado-Guay and Paige Farinholt

81. Neutropenic fever.....................................................................777 Hiroshi Ishiguro and Harumi Gomi

95. Rehabilitation in the acute and chronic care setting..................................................................................909 George J. Francis and Ki Y. Shin

82. Side effects of radiation therapy...........................................783 Michael Wang, Elizabeth Barnes, and Alysa Fairchild

96. Long-term cognitive function...............................................913 Asao Ogawa

83. Cardiac and pulmonary toxicities of treatments..............................................................................791 Marieberta Vidal

97. Gonadal functions and reproductive health.................... 919 Koji Kawai, Miyuki Harada, Yutaka Osuga, and Hiroyuki Nishiyama

84. Oral complications of cancer therapies.............................795 Siri Beier Jensen and Deborah P. Saunders

98. Pulmonary rehabilitation......................................................925 Ryo Kozu

85. Dermatologic side effects.......................................................803 Jen-Yu Wei and Michael Goodblatt

Index......................................................................................................929

LIST OF CONTRIBUTORS Charu Agrawal Oncology Supportive Medicine Baylor College of Medicine Houston, TX, USA

Joyce M. Black College of Nursing University of Nebraska Medical Center Omaha, NE, USA

Tatsuo Akechi Department of Psychiatry and Cognitive-Behavioral Medicine Nagoya City University Graduate School of Medical Sciences Nagoya, Japan

Sara Booth Department of Palliative Care Addenbrookes Hospital Cambridge University Hospitals NHS Foundation Trust Cambridge, UK

Yesne Alici Department of Psychiatry and Behavioral Sciences Memorial Sloan Kettering Cancer Center New York, NY, USA

Monica Bosco U.O. Cure Palliative-Dipartimento Cure Primarie AUSL Piacenza, Piacenza, Italy

Aimee E. Anderson Department of Palliative Care MD Anderson Cancer Center Houston, TX, USA Sujin Ann-Yi Department of Palliative Care MD Anderson Cancer Center Houston, TX, USA Ahsan Azhar Department of Palliative, Rehabilitation, and Integrative Medicine The University of Texas MD Anderson Cancer Center Houston, TX, USA Anthony L. Back Fred Hutchinson Cancer Research Center University of Washington Seattle, WA, USA Elizabeth A. Barnes Department of Radiation Oncology University of Alberta and Cross Cancer Institute Edmonton, Alberta, Canada Claudia Bausewein Cicely Saunders Institute of Palliative Care, Policy & Rehabilitation King’s College London, UK Estela Beale Philadelphia, PA, USA

vi

Kirsty Boyd Primary Palliative Care Research Group Usher Institute of Population Health Sciences and Informatics University of Edinburgh, UK William S. Breitbart Department of Psychiatry and Behavioral Sciences Memorial Sloan Kettering Cancer Center New York, NY, USA Jessica H. Brown Scientific Development Team Department of Palliative Care MD Anderson Cancer Center Houston, TX, USA Shirley H. Bush Department of Medicine Division of Palliative Care University of Ottawa Bruyère Research Institute Ottawa Hospital Research Institute Bruyère Continuing Care Ottawa, Canada Augusto T. Caraceni Palliative Care, Pain Therapy and Rehabilitation Unit Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy J. Brian Cassel Division of Hematology, Oncology & Palliative Care Virginia Commonwealth University School of Medicine Richmond, VA, USA

Carlos Centeno Palliative Medicine Clínica Universidad de Navarra University of Navarra Pamplona, Spain Victor T. Chang VA New Jersey Health Care System Rutgers New Jersey Medical School NJ, USA Nathan I. Cherny Cancer Pain and Palliative Medicine Service Department of Medical Oncology Shaare Zedek Medical Center Jerusalem, Israel Edward Chow Department of Radiation Oncology Odette Cancer Centre Sunnybrook Health Sciences Centre Toronto, ON, Canada Elizabeth J. Chuang Department of Family and Social Medicine Montefiore Medical Center Albert Einstein College of Medicine Bronx, NY, USA Lorenzo Cohen Department of Palliative, Rehabilitation, and Integrative Medicine The University of Texas MD Anderson Cancer Center Houston, TX, USA S. Robin Cohen Program in Palliative Care Departments of Oncology and Medicine McGill University Montreal, Quebec, Canada Massimo Costantini Azienda USL-IRCCS di Reggio Emilia Reggio Emilia, Italy Leah Couture Division of Hematology, Oncology and Palliative Care Virginia Commonwealth University Richmond, VA, USA Adrian Cozma University of Toronto Toronto, ON, Canada

List of contributors

vii

J. Randall Curtis University of Washington School of Nursing Department of Biobehavioral Nursing and Health Informatics Cambia Palliative Care Center of Excellence Harborview Medical Center, and Department of Medicine University of Washington School of Medicine Seattle, WA, USA

María Luisa del Valle Radiotherapy Hospital Clínico Universitario de Valladolid Valladolid, Spain

Fabio Formaglio Centro di Medicina del Dolore Istituto Scientifico and Ospedale San Raffaele Milan, Italy

Marvin Omar Delgado-Guay Department of Palliative, Rehabilitation, and Integrative Medicine The University of Texas MD Anderson Cancer Center Houston, TX, USA

Kelley Fournier Tertiary Palliative Care Unit Grey Nuns Community Hospital Covenant Health Edmonton, Alberta, Canada

Shalini Dalal Department of Palliative, Rehabilitation, and Integrative Medicine The University of Texas MD Anderson Cancer Center Houston, TX, USA

Rony Dev Department of Palliative, Rehabilitation and Integrative Medicine Division of Cancer Medicine MD Anderson Cancer Center Houston, TX, USA

Mallika Dammalapati Support Services Virginia Commonwealth University Massey Richmond, VA, USA Malisa Dang Division of Hematology, Oncology and Palliative Care Virginia Commonwealth University Richmond, VA, USA Mellar P. Davis Palliative Services Geisinger Medical Center Danville, PA, USA Sara N. Davison Department of Medicine University of Alberta Edmonton, Alberta, Canada Maxine De La Cruz Department of Palliative, Rehabilitation, and Integrative Medicine The University of Texas MD Anderson Cancer Center Houston, TX, USA

Travis DeVader Department of Emergency Medicine and Department of Palliative Medicine Stormont-Vail HealthCare Topeka, KS, USA Alexandra M. Easson Department of Surgery University of Toronto General Surgery and Surgical Oncology Mount Sinai Hospital and Princess Margaret Cancer Centre Toronto, Ontario, Canada Robin L. Fainsinger Department of Oncology University of Alberta Edmonton, Canada Alysa Fairchild Department of Radiation Oncology University of Alberta and Cross Cancer Institute Edmonton, Alberta, Canada

George J. Francis Department of Clinical Neurosciences and Department of Oncology Cumming School of Medicine University of Calgary Calgary, Alberta, Canada Fabio Fulfaro Department of Clinical Oncology Policlinico “Paolo Giaccone” University Hospital Palermo, Italy Timothy Fuller Internal Medicine University of Utah Health Salt Lake City, UT, USA Flavio Fusco Struttura Semplice Dipartimentale Cure Palliative Sistema Sanatorio Regione Liguria, Genova, Italy Sarah Gebauer Department of Anesthesia and Perioperative Care UCSF San Francisco, CA, USA Jessica Geiger Hematology and Medical Oncology Cleveland Clinic Cleveland, OH, USA

Liliana De Lima International Association for Hospice and Palliative Care Houston, TX, USA

Paige Farinholt Department of Palliative, Rehabilitation, and Integrative Medicine The University of Texas MD Anderson Cancer Center Houston, TX, USA

Hans Gerdesh Weill Cornell Medical College Department of Medicine and Gastrointestinal Endoscopy Unit Memorial Hospital for Cancer and Allied Diseases New York, NY, USA

Egidio Del Fabbro Palliative Care Virginia Commonwealth University Massey Cancer Center Richmond, VA, USA

Ilora G. Finlay Department of Pharmacology, Radiology, Oncology and Palliative Medicine University of Cardiff, UK

Raffaele Giusti Medical Oncology Unit Azienda Ospedaliero Universitaria Sant’Andrea Roma, Italy

List of contributors

viii Harumi Gomi Center for Global Health Mito Kyodo General Hospital University of Tsukuba Tsukuba, Japan Michael Goodblatt Palliative Care Providence St Peter Hospital Olympia, WA, USA Heather Grant OPTUM Supportive Care New York, NY, USA Kencee Graves Internal Medicine University of Utah Health Salt Lake City, UT, USA Ying Guo Department of Palliative, Rehabilitation, and Integrative Medicine The University of Texas MD Anderson Cancer Center Houston, TX, USA Ali Haider Department of Palliative, Rehabilitation and Integrative Medicine Division of Cancer Medicine MD Anderson Cancer Center Houston, TX, USA Miyuki Harada Department of Obstetrics and Gynecology Faculty of Medicine The University of Tokyo, Japan Alexander Harding Department of Palliative, Rehabilitation, and Integrative Medicine The University of Texas MD Anderson Cancer Center Houston, TX, USA Richard Harding Cicely Saunders Institute of Palliative Care, Policy & Rehabilitation King’s College London, UK Winford E. (Dutch) Holland Holland Management Consulting Houston, TX, USA Mary K. Hughes Psychiatry Department The University of Texas MD Anderson Cancer Center Houston, TX, USA

David Hui Associate Professor Department of Palliative Care, Rehabilitation, and Integrative Medicine Department of General Oncology The University of Texas MD Anderson Cancer Center Houston, TX, USA

Koji Kawai Department of Urology Institute of Clinical Medicine University of Tsukuba Ibaraki, Japan

Sean Hutchinson Department of Palliative, Rehabilitation and Integrative Medicine Division of Cancer Medicine MD Anderson Cancer Center Houston, TX, USA

Allison Kestenbaum University of California San Diego La Jolla, CA, USA

Hiroshi Ishiguro Department of Medical Oncology International University of Health and Welfare Hospital Tochigi, Japan

David W. Kissane Cunningham Centre for Palliative Care Research University of Notre Dame Australia St Vincent’s Hospital Sydney Sacred Heart Hospital and Palliative Care Service Darlinghurst, NSW, Australia

Nelia Jain Department of Psychosocial Oncology and Palliative Care Dana-Farber Cancer Institute, and Division of Palliative Medicine Brigham and Women’s Hospital Boston, MA, USA Daisy J.A. Janssen Department of Research & Education CIRO, Centre of expertise for chronic organ failure Department of Health Services Research CAPHRI School for Public Health and Primary Care Faculty of Health Medicine and Life Sciences Maastricht University Maastricht, the Netherlands Siri Beier Jensen Department of Dentistry and Oral Health Faculty of Health Aarhus University Aarhus, Denmark Stein Kaasa Institute of Cancer Research and Molecular Medicine Norwegian University of Science and Technology and European Palliative Care Research Centre Trondheim, Norway Katie N. Kanter Massachusetts General Hospital Cancer Center Boston, MA, USA

Mark T. Kearney Leeds University School of Medicine Leeds, UK

Kate Kirk Cambridge, UK

Jonathan Koffman Cicely Saunders Institute of Palliative Care, Policy and Rehabilitation King’s College London, UK Ryo Kozu Department of Rehabilitation Medicine Nagasaki University Hospital, Japan Rene Krause School of Public Health and Family Medicine University of Cape Town, South Africa Michal Kubiak Internal Medicine at Centegra Rosalind Franklin University of Medicine and Science Chicago, IL, USA Geana Paula Kurita Multidisciplinary Pain Centre Rigshospitalet Copenhagen University Hospital Copenhagen, Denmark Marco Lacerenza Centro di Medicina del Dolore Istituto Scientifico and Ospedale San Raffaele Milan, Italy

List of contributors Thomas W. LeBlanc Duke Cancer Institute Durham, NC, USA Wenli Liu Department of Palliative, Rehabilitation, and Integrative Medicine The University of Texas MD Anderson Cancer Center Houston, TX, USA Francisco Loaiciga Michael E. Debakey VA Medical Center Texas Houston, TX, USA

ix Marco Maltoni Palliative Care Unit Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS Meldola, Italy Paolo Marchettini Centro di Medicina del Dolore Istituto Scientifico and Ospedale San Raffaele Milan, Italy Sue Marsden Hospice North Shore Auckland, New Zealand

Gabriel Lopez Department of Palliative, Rehabilitation, and Integrative Medicine The University of Texas MD Anderson Cancer Center Houston, TX, USA

Daniel C. McFarland Department of Psychiatry and Behavioral Sciences Memorial Sloan Kettering Cancer Center New York, NY

Maurizio Lucchesi Oncology and Hematology Unit Nuovo Ospedale delle Apuane Massa Pulmunology Unit – Pneumo-Oncology Service Azienda Ospedaliero-Universitaria Pisana Pisa, Italy

Sophie A. McGilvray Cunningham Centre for Palliative Care Research University of Notre Dame Australia St Vincent’s Hospital Sacred Heart Hospital and Palliative Care Service Darlinghurst, NSW, Sydney, Australia

Dana Lustbader OPTUM Supportive Care New York, NY, USA Regina M. Mackey Family Medicine Mayo Clinic Rochester, MN, USA Kim Crowe Mackinnon Tertiary Palliative Care Unit Grey Nuns Community Hospital Covenant Health Edmonton, Alberta, Canada Karen Macmillan Tertiary Palliative Care Unit Grey Nuns Community Hospital Covenant Health Edmonton, Alberta, Canada Kevin Madden Department of Palliative, Rehabilitation and Integrative Medicine Division of Cancer Medicine MD Anderson Cancer Center Houston, TX, USA

Sebastiano Mercadante Pain Relief and Palliative Care La Maddalena Cancer Center Palermo, Italy Caterina Modonesi UOC ONCOLOGIA-Azienda ULSS6 EUGANEA (Veneto) Ospedali Riuniti Padova Sud Padova, Italy Sebastien Moine Primary Palliative Care Research Group Usher Institute of Population Health Sciences and Informatics University of Edinburgh, UK Delmer A. Montoya Aultman Hospital Canton, OH, USA Laura J. Morrison Hospice and Palliative Medicine Yale University School of Medicine and Yale-New Haven Hospital New Haven, CT, USA

Scott A. Murray Emeritus Professor of Primary Palliative Care University of Edinburgh, UK Fliss E.M. Murtagh Cicely Saunders Institute of Palliative Care, Policy & Rehabilitation King’s College London, UK Santhosshi Narayanan Department of Palliative, Rehabilitation, and Integrative Medicine The University of Texas MD Anderson Cancer Center Houston, TX, USA Rudolph M. Navari Division of Hematology Oncology University of Alabama at Birmingham School of Medicine Experimental Therapeutics Program UAB Comprehensive Cancer Center Birmingham, AL, USA Cheryl L. Nekolaichuk Department of Oncology University of Alberta Edmonton, Canada David V. Nelson Department of Psychology and Philosophy Sam Houston State University Huntsville, TX, USA Linh My Thi Nguyen Department of Internal Medicine Division of Geriatric and Palliative Medicine McGovern Medical School Houston, TX, USA Ann Marie Nie College of Nursing University of Nebraska Medical Center Omaha, NE, USA Hiroyuki Nishiyama Department of Urology Institute of Clinical Medicine University of Tsukuba Ibaraki, Japan

List of contributors

x Danielle Noreika Inpatient Palliative Care Services Hospice and Palliative Medicine Fellowship Division of Hematology, Oncology and Palliative Care Virginia Commonwealth University Richmond, VA, USA Diane M. Novy Department of Pain Medicine Division of Anesthesiology, Critical Care, and Pain Medicine MD Anderson Cancer Center Houston, TX, USA Asao Ogawa National Cancer Center Hospital East National Cancer Center Tokyo, Japan Yutaka Osuga Department of Obstetrics and Gynecology Faculty of Medicine The University of Tokyo, Japan

Victoria H. Raveis New York University New York, NY, USA Fiona Rawlinson School of Medicine University Hospital of Wales Chair Specialty Training Committee for Wales Palliative Medicine Consultant in Palliative Medicine for City Hospice Cardiff, UK Suresh K. Reddy Department of Palliative, Rehabilitation and Integrative Medicine Division of Cancer Medicine MD Anderson Cancer Center Houston, TX, USA

Maitry Patel Radiation Oncology Princess Margaret Cancer Center Toronto, ON, Canada

Lynn F. Reinke Department of Veterans Affairs Puget Sound Health Care System Health Services R&D University of Washington School of Nursing Department of Biobehavioral Nursing and Health Informatics Seattle, WA, USA

Michelle Peck Department of Internal Medicine Division of Geriatric and Palliative Medicine McGovern Medical School Houston, TX, USA

Carla Ida Ripamonti ssd Oncologia-Cure di Supporto al paziente Fondazione IRCCS Istituto Nazionale dei Tumori Milan, Italy

Joel Phillips Henry Ford Health System Detroit, MI, USA

Eric J. Roeland Massachusetts General Hospital Cancer Center Boston, MA, USA

Tammie Quest Department of Emergency Medicine Division of Geriatrics and Gerontology Emory University School of Medicine Atlanta, GA, USA Srinivas Raman Odette Cancer Centre Sunnybrook Health Sciences Centre University of Toronto Toronto, ON, Canada Saima Rashid Department of Supportive Care Medicine, Moffitt Cancer Center Tampa, FL, USA

Álvaro Sanz Medical Oncology Hospital Universitario del Rio Hortega Valladolid, Spain Deborah P. Saunders Health Sciences North North East Regional Cancer Center Department of Dental Oncology Northern Ontario School of Medicine Sudbury, Ontario, Canada Richard Sawatzky Trinity Western University School of Nursing Langley, BC, USA

Mark V. Schaverien Department of Palliative, Rehabilitation, and Integrative Medicine The University of Texas MD Anderson Cancer Center Houston, TX, USA Peter A. Selwyn Department of Family and Social Medicine Montefiore Medical Center Albert Einstein College of Medicine Bronx, NY, USA Ann Cai Shah Pain Management Center UCSF San Francisco, CA, USA Karina Shih MD Anderson Cancer Center Houston, TX, USA Ki Y. Shin Department of Palliative, Rehabilitation, and Integrative Medicine The University of Texas MD Anderson Cancer Center Houston, TX, USA Akhil Shivaprasad Stanley H. Appel Department of Neurology Houston Methodist-Weill Cornell College of Medicine Houston, TX, USA Morena Shkodra Palliative Care, Pain Therapy and Rehabilitation Unit Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Milan, Italy Sheetal Shroff Stanley H. Appel Department of Neurology Houston Methodist-Weill Cornell College of Medicine Texas A&M College of Medicine Houston, TX, USA Per Sjøgren Multidisciplinary Pain Centre Rigshospitalet Copenhagen University Hospital Copenhagen, Denmark

List of contributors Thomas J. Smith Sidney Kimmel Comprehensive Cancer Center Johns Hopkins Medical Institutions Baltimore, MD, USA Pasquale Spinelli International Medical System and Services Milan, Italy Sam Straw Leeds University School of Medicine Leeds, UK Po-Yi Paul Su Department of Anesthesia and Perioperative Care UCSF San Francisco, CA, USA Kimberson Tanco Department of Palliative, Rehabilitation, and Integrative Medicine The University of Texas MD Anderson Cancer Center Houston, TX, USA Michael Tang Department of Palliative, Rehabilitation and Integrative Medicine Division of Cancer Medicine MD Anderson Cancer Center Houston, TX, USA

xi Joan M. Teno Division of General Internal Medicine and Geriatrics School of Medicine Oregon Health Sciences University Portland, OR, USA Andrew Thorns Palliative Medicine Pilgrims Hospices Canterbury, UK Ivo W. Tremont-Lukats Department of Neuro-Oncology MD Anderson Cancer Center The University of Texas Houston, TX, USA James A. Tulsky Department of Psychosocial Oncology and Palliative Care Dana-Farber Cancer Institute, and Division of Palliative Medicine Brigham and Women’s Hospital Boston, MA, USA Beth Tupala Tertiary Palliative Care Unit Grey Nuns Community Hospital Covenant Health Edmonton, Alberta, Canada

Yoko Tarumi Department of Oncology Division of Palliative Care Medicine University of Alberta Edmonton, Alberta, Canada

Marieberta Vidal Department of Palliative, Rehabilitation and Integrative Medicine Division of Cancer Medicine MD Anderson Cancer Center Houston, TX, USA

Katie Taylor Hospice in the Weald Tunbridge Wells, UK

Tobias Walbert Henry Ford Health System Detroit, MI, USA

Michael Wang Department of Radiation Oncology University of Alberta and Cross Cancer Institute Edmonton, Alberta, Canada Jen-Yu Wei Internal Medicine University of Utah Health Salt Lake City, UT, USA Klaus K. Witte Leeds University School of Medicine Leeds, UK Sriram Yennurajalingam Department of Palliative, Rehabilitation and Integrative Medicine Division of Cancer Medicine MD Anderson Cancer Center Houston, TX, USA Emel Yorganci Cicely Saunders Institute of Palliative Care, Policy and Rehabilitation King’s College London, UK Paul Zelensky Palliative Care Virginia Commonwealth University Massey Cancer Center Richmond, VA, USA

1

THE DEVELOPMENT OF HOSPICE AND PALLIATIVE CARE

Kate Kirk

Contents The “ready minds”..................................................................................................................................................................................................................2 Global growth of the modern hospice movement...........................................................................................................................................................3 Recognition.............................................................................................................................................................................................................................4 The need remains...................................................................................................................................................................................................................4 References................................................................................................................................................................................................................................5 In May 2014, WHO World Health Assembly Resolution 67.19 called for palliative care to be strengthened “as a component of comprehensive care throughout the life course.”1 This was the first global resolution on palliative care, and the call to integrate it into national health policies and programs was adopted unanimously by the representatives of the 194 Member States attending the Geneva meeting. The resolution meant that palliative care was now included in the definition of universal health coverage, and in the WHO Global Monitoring Framework and action plan for the prevention and control of noncommunicable diseases 2013–2020. It also meant that medications typically used for pain and symptom control in palliative care would be included in WHO’s Model Essential Medicines lists for both adults and children. From policies to education, and from funding to basic support, Resolution 67.19 called for Member States to integrate palliative care across all aspects of their health systems, and for the Director-General of WHO to drive the necessary programs and projects to help Member States to support implementation. Prior to this, palliative care had become a recognized human right when the UN Committee on Economic, Social and Cultural Rights adopted General Comment No. 14 in 2000. This General Comment asserted the right to “attention and care for chronically and terminally ill persons, sparing them avoidable pain and enabling them to die with dignity.” 2 The WHO definition of palliative care, as revised two years later (see Box 1.1), included the family, underscoring a concept familiar to those working in the field, that of “total pain.” For a medical specialty barely 25 years old where it is recognized, and still unrecognized in many countries, the 2014 WHO Resolution was a major step. And yet, the origins of hospice and palliative care go back centuries. The first hospices were simply places for pilgrims to rest. Given the rigors of the journeys these guests were undertaking, caring for the sick became an integral part of the comfort hospices provided. The idea of a hospice being a home for the “incurable” took root in the 19th century, when such homes were first established in France and Ireland. So while palliative care has only recently taken its rightful place in the world of medicine, the hospice care it is intimately linked with and derives from is hardly new. But what is new is the modern hospice, and indeed the invention of the term “palliative care” to encompass all aspects of caring for patients with life-limiting conditions—not just cancer (although that is typically the assumption for hospices) but also

WHO DEFINITION OF PALLIATIVE CARE (REVISED 2002) Palliative care is an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial, and spiritual. Palliative care: • provides relief from pain and other distressing symptoms; • affirms life and regards dying as a normal process; • intends neither to hasten or postpone death; • integrates the psychological and spiritual aspects of patient care; • offers a support system to help patients live as actively as possible until death; • offers a support system to help the family cope during the patients illness and in their own bereavement; • uses a team approach to address the needs of patients and their families, including bereavement counseling if indicated; • will enhance quality of life, and may also positively influence the course of illness; • is applicable early in the course of illness, in conjunction with other therapies that are intended to prolong life, such as chemotherapy or radiation therapy, and includes those investigations needed to better understand and manage distressing clinical complications. 3 conditions such as heart failure, respiratory and neurological diseases, and HIV/AIDS. As with many leaps of progress, an idea starts to take root in a number of different places and in the minds of different people at around the same time. But it takes a particular individual to shake things up—to challenge the fundamental assumptions around an area of practice or scientific enquiry and cause the necessary paradigm shift by pointing researchers in a new direction and to new sources of evidence. 1

Textbook of Palliative Medicine and Supportive Care

2 The history of hospice and palliative care is one such paradigm shift that did, indeed, start to grow in several places in the 1950s. However, it is impossible to write about how the field developed without focusing on the work of my late aunt, Dame Cicely Saunders OM, DBE, FRCP, FRCN. In his Foreword to a selection of her published letters, Professor Balfour Mount asserted that “Dame Cicely … has been the catalyst for a paradigm shift in global health care.”4 When accepting the Templeton Prize in 1981, Cicely herself pointed out that “[t] here are not too many original ideas around but there is often a new pattern to be discovered if we search with ready minds and ask some questions.”5 Asking questions, as Cicely did enthusiastically throughout her life, underpins the development of what we recognize as hospice and palliative care today.

The “ready minds” Looking back, it is easy to see a chain of events that led logically, indeed inexorably, to World Health Assembly Resolution 67.19, but without the “ready minds” and questioning stance of a few key individuals, the chain may never have been completed. Indeed, without Cicely’s unusual career path, it might never have been started. Cicely initially went up to Oxford University in 1938 to study Politics, Philosophy and Economics, but at the outbreak of World War II, she left her studies and trained as a nurse at the Nightingale Home and Training School at St. Thomas’ hospital in London. To her great disappointment, her nursing career was cut short by an increasingly aggravated back injury, and in 1944 she went back to Oxford to finish her degree. After graduating, realizing she could not go back to the nursing she loved, she qualified as what she saw as the next best thing, a Lady Almoner, or Medical Social Worker, and began working in this new role in St. Thomas’ in 1947. The next key moment was in 1948, when she met David Tasma, a Polish Jew who had come to England shortly before war broke out, but was now dying of cancer. He was alone, having lost contact with his family back in Poland, and Cicely spent considerable time with him. A bond formed between them over lengthy and far-ranging conversations, particularly over how the dying were cared for, and how much better things could be. A vision of a place where death was not a medical failure but instead part of a journey, and deserving of equal care, was born. When he died, Tasma left Cicely a sum of money toward her vision, apparently telling her that “I will be a window in your home.”6 After Tasma’s death, Cicely added two more important pieces to her journey and both would inform her next step. First, she started volunteering at St. Luke’s Hospital for Advanced Cases in London. As a Lady Almoner, she had occasionally had to send patients to what were often referred to as “homes for the dying,” and St. Luke’s was one of them. Her nursing vocation remained, and volunteering reconnected her to that vocation. It also gave her time to investigate more closely how dying patients were cared for. In particular, she saw what could be done with different regimes for pain-killing drugs, and the use of the so-called Brompton cocktail, an undefined mixture of morphine, codeine, sodium amytal, alcohol, and other ingredients. The second crucial change at this time was to combine her duties as an Almoner with acting as medical secretary to Norman “Pasty” Barrett, a consultant thoracic surgeon who played a pivotal role. Cicely discussed her observations from St. Luke’s with Barrett and explained that she was thinking of going back into

nursing to test her ideas. He pointed out the obvious, that a nurse would not be able to challenge the establishment, and that “it is doctors who desert the dying.” 7 If she wanted to change things, she should go to medical school. Cicely was the oldest in her class by almost a decade when she began training as a doctor in 1951, once more at St. Thomas’. During her training, she began monitoring and recording her observations of, and conversations with, dying patients. Most of her “foundational” patients, as she termed them, were suffering from cancer. Her experience as a nurse, social worker, and now trainee doctor gave her unique insights into the constraints and problems around their care, and the wider ramifications of their situation. In 1958, an article by Cicely entitled “Dying of Cancer” was published in the St. Thomas’s Hospital Gazette. In it, she detailed the cases of four dying patients and the issues associated with their care, good and bad. She concluded with her thoughts on the care of the dying and an early vision of how modern hospice care might evolve. It appears to me that many patients feel deserted by their doctors at the end. Ideally the doctor should remain the centre of a team who work together to relieve where they cannot heal, to keep the patient’s own struggle within his compass and to bring hope and consolation to the end.8 Once qualified, Cicely took a position as physician at St. Joseph’s Hospice, another of London’s homes for the dying, where she worked for the next seven years. Over that time, she started to do more detailed research into the use of painkillers. She interviewed and recorded notes on over one thousand patients, building a formidable set of qualitative and quantitative data, and began to write about the benefits of giving regular doses of painkillers in contrast to the established practice of either waiting until the patient could bear the pain no longer or sticking to a strict timetable. She also began to develop relationships with other workers in the field, both in the UK and internationally, principally North America, writing to and talking to as many people as possible about her ideas. These included her concept of total pain—that the dying patient, and their family, should have not only their medical needs addressed, but also their psychological, social, and spiritual needs as well—which reflected her rare combined experience as a nurse, social worker, and now physician. As she wrote in 1966: …a patient, trying to describe her pain, says simply, “It began in my back, but now it seems that all of me is wrong.” This kind of “total” pain has physical, mental, social and spiritual elements. Neither she in her words nor we in our approach and treatment can deal with any of these separately.9 With David Tasma’s legacy still waiting to be spent, Cicely was increasingly focused on how she could establish her own hospice, one where she could combine the best possible care with research and teaching. In 1963, she was awarded a nursing fellowship, which she used to travel to the US, where she visited the National Institutes of Health in Maryland and a number of hospitals, talking to professionals from all parts of the medical spectrum. As she wrote in her report of the trip: I found it a great asset that I was able to go in my threefold capacity of nurse, social worker and doctor. It made

The Development of Hospice and Palliative Care

3

my own approach a broad one and also made me “one of them” when I discussed problems with each of the different professions.10

and then go back. Well, I won’t have it. I’ll tell you what, leave your wife at home; be prepared to come for a week, role up your sleeves and get to work, and I’ll have you.12

An additional grant from the Ella Lyman Cabot Trust enabled Cicely to extend her 1963 tour—crucially giving her the time to meet some other “ready minds,” including Florence Wald, dean of the Yale School of Nursing. Subsequent trips to the US included a six-week lectureship at Yale in 1966, which included two more important meetings. She renewed her acquaintance with psychiatrist Colin Murray Parkes, who would add crucial expertise to her plans. She also met Elisabeth Kübler-Ross, who was already conducting the interviews that would inform her seminal 1969 work, On Death and Dying. Kübler-Ross would note in her book:

Mount visited St. Christopher’s as soon as it could be arranged, and went back again the following year for a longer stay. Having undertaken a review of the care of the dying in his own hospital, the Royal Victoria in Montreal, Mount wanted to develop a way of bringing hospice care into the hospital setting. Eventually, in 1975 Mount set up a pilot project in the Royal Victoria that introduced the term, “palliative care.” The hospital’s Palliative Care Service was the first of its kind. David Clark points out in his biography of Cicely that, although initially unconvinced by the term, she soon changed her mind and:

It may not be a coincidence that one of the doctors best known for the total care of the dying patient, Cicely Saunders, started her work as a nurse and is now physician attending the terminally ill in a hospital set-up especially designed for their care.11

…quickly embraced [the term] in the coming years and readily cited Mount and Montreal as its source … the neologism was to prove hugely consequential as it entered into use across the world and sounded out the message that hospice principles could be practised in many contexts. It was not the setting that was important, but rather the approach to care that was being adopted.13

That “hospital set-up” that Kübler-Ross referred to was St. Christopher’s Hospice in Sydenham, South London. Fired up by the publication of a 1960 report to the UK Government on the care of the terminally ill by Glyn Hughes, Cicely had redoubled her efforts to raise funds and gather support from a broad range of stakeholders in order to realize her vision. St. Christopher’s Hospice admitted its first patients in July, 1967. Funded by various philanthropic organizations and individuals, and with a contribution from the UK’s National Health Service, research and education were at the heart of activities from the beginning. Cicely continued the research she had begun at St. Joseph’s, and brought in others to develop new projects. One of these was Robert Twycross, who joined St. Christopher’s as a Clinical Research Fellow in Therapeutics in 1971. Twycross undertook a series of seminal studies documenting the use of oral morphine, as given to patients in the Brompton cocktail, and also comparing the efficacy of morphine, diamorphine, and methadone in controlling pain. For the first time, there was robust, evidence-based confirmation that controlled doses of morphine could be used to replace the Brompton cocktail. Many other key developments in the field came after visits to St. Christopher’s. These included that of Florence Wald, who spent four weeks working there in 1969. After going back to the US, Wald and a few colleagues joined forces to plan and develop the Hospice Home Care program in New Haven, Connecticut, which launched in 1974. This first hospice program in the US was initially concerned solely with providing home care but opened its first in-patient beds in 1980. Canadian physician Balfour Mount was another early visitor to St. Christopher’s. He was inspired to make contact after organizing a discussion group for his church to talk about the Kübler-Ross book, On Death and Dying. The description of St. Christopher’s in the book intrigued him and he determined to visit. Cicely famously tried to put him off when he telephoned her in September, 1973. First of all, she refused to take his call, saying she was just going for lunch and he could call her back later. When that didn’t deter and Mount persisted in calling again, she told him: I know you. You want to come over to London with your wife, see a few plays, have a quick run around the hospice

Apart from the many visitors to St. Christopher’s itself who went away inspired to “do their bit” for the care of the dying, there are numerous other incidences where a meeting with Cicely, a lecture she gave, even singing in the same choir, had an impact on the development of palliative care. When Mary Baines (a contemporary of Cicely’s at medical school and one of the first physicians at St. Christopher’s), surveyed a group of doctors prior to attending a Wellcome Trust Witness Seminar on the development of palliative medicine in the UK, she found that half of them had chosen their career in palliative medicine after meeting Cicely.14 Not surprisingly, therefore, it is impossible to name all of the people who were inspired by Cicely and went on to contribute to the expansion of the modern hospice movement and the subsequent development of palliative medicine. The previous edition of this book provides many more names and details, but it, too, is far from complete.

Global growth of the modern hospice movement St. Christopher’s served as a model modern hospice, but Cicely never intended it to be copied exactly. Instead, she encouraged any who expressed a desire to create something similar to spend time at St. Christopher’s and then go away and tailor provision to local conditions. Today, there are around 220 hospices in the UK.15 Most are independent and rely on charitable funding for over two-thirds of their operating costs. In the US, there were over 3,000 hospice programs by the time of Florence Wald’s death in 2008. The introduction of Medicare hospice benefits in 1980 was a key trigger for the growth of in-patient provision, and in 2017, the National Hospice and Palliative Care Organization recorded 4,515 Medicare-certified hospices operating in the US. It also reported that 1.49 million Medicare beneficiaries had one day or more of hospice care in the same year, over half those days of care were delivered in the home, and around 65% of the recipients were 80 years of age or over.16 The 2012 Atlas of Palliative Care in Latin America cited an overall figure of 44 in-patient beds per million inhabitants across

Textbook of Palliative Medicine and Supportive Care

4 the 19 countries in the region.17 This ranged from a high of 11 per million population in Argentina to zero in Cuba, El Savador, Honduras, Nicaragua, Panama, and Peru. Similarly, eight countries had no home care provision, and very few had any provision in community centers. A 2017 review of end-of-life care in Latin America found national palliative laws in four countries, and that six countries still had no hospice.18 Looking more broadly, the 2014 joint Worldwide Palliative Care Alliance and WHO Global Atlas of Palliative Care at the End of Life assessed end-of-life-care provision under 4 categories and found that 75 countries were in Group 1, with no known hospice or palliative care activity. Many of these were islands where populations were small and overall health provision challenging, but the list also included countries such as Liechtenstein, Monaco, and Syria.19 A further 23 countries were in the “capacity building” phase, but only 20 countries had reached category 4b, advanced integration of hospice and palliative care.

Recognition Hospices are, of course, only part of the picture. In fact, it is the growing recognition of palliative care as not only a human right but also a medical specialism that has arguably had the greatest effect on the care of the dying worldwide. As with any other medical specialty, in order to be recognized, palliative medicine had to develop the foundations of a profession, including research, peer-reviewed journals, associations of practitioners, education, and certification. In the UK, the Association of Palliative Care and Hospice Doctors was formed in 1985, and palliative medicine was first recognized as a sub-specialty by the Royal College of Physicians in 1987. Seven years of research, education, and development later, it became a specialty in its own right. Established in 1991, the position of Sainsbury Professor of Palliative Medicine at the United Medical Schools of Guys and St. Thomas’ Hospitals in London was the first Chair in Palliative Medicine in Europe.20 By 2005 there were nine such positions throughout the UK, and three Chairs had been created for palliative care within social sciences. The UK’s National Institute for Clinical Excellence published its first guidance on palliative care, for patients with cancer, in 2004. Its most recent set of quality standards for end-of-life care include not only various forms of cancer but also COPD, chronic heart failure, chronic kidney disease, and dementia.21 The European Association for Palliative Care was established at an international congress in Milan in December 1988 and recognized as a nongovernmental organization of the Council of Europe 10 years later. By this time, palliative care was beginning to appear in legislation in several European countries, and in 2003, the Council of Europe incorporated recommendations for the provision of palliative care. The American Academy of Hospice and Palliative Medicine (originally the Academy of Hospice Physicians) was also founded in 1988 and now claims over 5,000 members. In the 2006 edition of this book, Ryndes and Von Gunten pointed out that, as of 2004, the US was awaiting a decision on whether palliative care would be considered a medical specialism. A combination of various programs and initiatives supported the claim, and the authors commented that “[f]ormal recognition is seen as likely” at a meeting of the American Board of Medical Specialities in that year.22 In fact, it was two years later, in 2006,

when palliative medicine was finally recognized as a subspecialty of internal medicine.23 Although the first Canadian Chair of Palliative Medicine was established at the University of Alberta in 1987, an application to confirm palliative care as a specialty in Canada was turned down in 1995. It was only in 2017 that legislation in Canada led to the publication of the Framework on Palliative Care in Canada by Health Canada in 2018. The report pointed out that, while there were a number of programs aimed at delivering and improving palliative care in place across the provinces and territories of Canada, there was no national strategy, despite the appointment of a minister with special responsibility for Palliative and Endof-Life Care in 2001.24 The report also noted that the Canadian Institutes of Health Research had put $16.5 million into palliative care research between 2004 and 2009, and a further $494 million in funding for aging research between 2012 and 2017 included some funds directed to palliative care. Nevertheless, a fundamental weakness in the advancement of palliative care as a profession remains: Unfortunately, the core palliative care competencies of skilled communication, expert pain and symptom management, and psychosocial assessment remain, at best, a small part of most medical school and residency training programs in Canada.25 Elsewhere, progress is equally variable. The African Palliative Care Association, launched in 2004, reports that 21 out of 47 African countries have “no identified hospice or palliative care activity,” and only four countries “could be classified as having services approaching some measure of integration with mainstream service providers.”26 Similarly, the Asia-Pacific region sees progress in some countries but barriers in others, particularly associated with availability of opioids. However, there is some encouragement to be drawn from efforts to at least improve education and training, especially for those in low- and middle-income countries. Online and distance courses, such as the Stanford Palliative Care Always program, aimed at cancer specialists, and projects such as that established by the Lien Collaborative for Palliative Care, to train trainers in order to build capacity,27 at least keep progress moving in the right direction.

The need remains Despite efforts by national and international bodies to put palliative and hospice care on the health agenda, the unmet need is still high. WHO estimates that “worldwide, only about 14% of people who need palliative care currently receive it.”28 The same WHO Factsheet also points to the increased demand for palliative care as populations around the world age and greater numbers of people live with complex conditions in their later years. There is still a shortage of academic leaders for capacity building, and research remains challenging for a number of reasons, including ethical considerations, difficulty of predicting time to dying, frailty of patients, and the subjectivity of measuring factors such as quality of life. The Cicely Saunders Institute, opened in 2010 in London, strives to address all of these challenges in a multidisciplinary organization that reflects the origins of the specialty in nursing, social work, and medicine, but despite efforts here and elsewhere, much remains to be done.

The Development of Hospice and Palliative Care Speaking personally, I feel that Cicely would be pleased at how far we’ve come but also frustrated at how far we still have to go. As anyone who met her would know, she would also be rolling up her sleeves alongside us and encouraging us to get on with it.

References





1. World Health Organization. Strengthening of Palliative Care as a Component of Comprehensive Care Throughout the Life Course. SixtySeventh United Nations World Health Assembly, 2014. http://apps. who.int/gb/ebwha/pdf_files/WHA67/A67_R19-en.pdf 2. Committee on Economic, Social and Cultural Rights (CESCR), 2000. CESCR General Comment No. 14: The Right to the Highest Attainable Standard of Heatlh (Art. 12). Office of the High Commissioner for Human Rights. Para 25. https://www.refworld.org/pdfid/4538838d0. pdf 3. WHO Definition of Palliative Care. https://www.who.int/cancer/ palliative/definition/en/ 4. Clark D. Cicely Saunders, Founder of the Hospice Movement, Selected Letters 1959–1999. Oxford: Oxford University Press, 2002, p. v. 5. Saunders C. Templeton Prize Speech. In: Saunders C, ed. Cicely Saunders: Selected Writings 1958–2004. Oxford: Oxford University Press, 1981, p. 158. 2006. 6. Saunders C. A place to die. Crux 1973–1974;11(3):24–27. In: Saunders C, ed. Cicely Saunders: Selected Writings 1958–2004. Oxford: Oxford University Press, 1973, p. 125, 2006. 7. Clark D. Cicely Saunders: A Life and Legacy. Oxford: Oxford University Press, 2018, p. 72. 8. Saunders C. Dying of cancer. St Thomas’s Hosp Gaz 1958;56(2):37–47. In: Saunders C, ed. Cicely Saunders: Selected Writings 1958–2004. Oxford: Oxford University Press, p. 11. 9. Saunders C. The last frontier. Frontier, Autumn 1966, pp. 183–186. In Saunders C, ed. Cicely Saunders: Selected Writings 1958–2004. Oxford: Oxford University Press, 1958, p. 87, 2006. 10. Saunders C. Report of tour in the United States of America (Spring), unpublished. In Clark D. Cicely Saunders: A Life and Legacy. Oxford: Oxford University Press, 1963, p. 171, 2018. 11. Kübler-Ross E. On Death and Dying. 50th anniversary ed. New York: Scribner, 1969, p. 234. 12. Mount BM. Snapshots of Cicely: Reflections at the end of an era. J Palliat Care 2005;21(3):133–135. 13. Clark D. Cicely Saunders: A Life and Legacy. Oxford: Oxford University Press, 2018, p. 218. 14. Overy C, Tansey EM, eds. Palliative medicine in the UK c. 1970–2010. Wellcome Witness to Twentieth Century Medicine, vol. 45. London: Queen Mary, University of London, 2013, p. 9. http://www.histmodbiomed.org/ sites/default/files/92239.pdf

5 15. Hospice UK, 2019. Hospice UK highlights 2017–2018. p. 2. https://www. hospiceuk.org/docs/default-source/about-us-documents-and-files/ hospiceuk_highlights-2018_web.pdf?sfvrsn=0 16. NHCPO, 2019. NHCPO Facts and Figures 2018 edition (Revised 7-2-2019) (no page numbers). https://39k5cm1a9u1968hg74aj3x51w pengine.netdna-ssl.com/w p-content/uploads/2019/07/2018 _ NHPCO_Facts_Figures.pdf 17. Pastrana T, De Lima L, Wenk R, et al. Atlas of Palliative Care in Latin America. International Association for Hospice and Palliative Care, 2012, p. 8. https://cuidadospaliativos.org/uploads/2013/12/Atlas%20 of%20Palliative%20Care%20in%20Latin%20America.pdf 18. Soto-Perez-de-Celis, E, Chavarri-Guerra Y, Pastrana T, Ruiz-Mendoza R, Bukowski A, Goss PE. End-of-life care in Latin America. J Global Oncol 2017;3(3):261–270. https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC5493222/ 19. Worldwide Palliative Care Alliance. Global Atlas of Palliative Care. WPCA, 2014, p. 36. 20. Overy C, Tansey EM, eds. Palliative Medicine in the UK c. 1970–2010. Wellcome Witness to Twentieth Century Medicine, vol. 45. London: Queen Mary, University of London, 2013, p. 115. http://www.histmodbiomed.org/sites/default/files/92239.pdf 21. NICE, 2017. End of life care for adults. Quality Standard: Related Quality Standards. NICE. https://www.nice.org.uk/guidance/qs13/chapter/ related-nice-quality-standards#related-nice-quality-standards 22. Ryndes T, Von Gunten, CF. The development of palliative medicine in the USA. In: Bruera E, et al. eds. 2006. Textbook of Palliative Medicine. London: Hodder Arnold, 2006, p. 33. 23. American Board of Medical Specialities, 2006. ABMS establishes New Subspecialty Certificate in Hospice and Palliative Medicine. Press release, October 6, 2006. https://web.archive.org/ web/20101116144358/http://abms.org/News_and_Events/downloads/ NewSubcertPalliativeMed.pdf 24. Health Canada, 2018. Framework on Palliative Care in Canada. https:// w w w.canada.ca/en/health-canada/services/health-care-system/ reports-publications/palliative-care/framework-palliative-care-canada. html 25. Morrison RS. A national palliative care strategy for Canada. J Palliative Med 2017;20(Suppl 1):S-63–S-75. https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC5733738/ 26. African Palliative Care Association, 2019. Frequently Asked Questions. https://www.africanpalliativecare.org/foot-menu/faqs/ 27. Spruyt O. The status of palliative care in the Asia-Pacific region. Asia-Pac J of Oncol Nurs 2018;5:12–14. https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC5763429/ 28. WHO, 2018. Palliative Care. https://www.who.int/en/news-room/ fact-sheets/detail/palliative-care

2

PALLIATIVE CARE AS A PUBLIC HEALTH ISSUE

Irene J. Higginson and Massimo Costantini

Contents Introduction............................................................................................................................................................................................................................7 What is public health?...........................................................................................................................................................................................................7 Public health: New approaches.....................................................................................................................................................................................7 Public health approach to palliative care...........................................................................................................................................................................8 Patient and public involvement as part of the public health response..................................................................................................................8 Moving to palliative care as a human rights issues and the need for universal health coverage to include palliative care........................8 Public health challenges in palliative and supportive care............................................................................................................................................9 Escalating global palliative care need...........................................................................................................................................................................9 Response to population aging in the context of palliative care.............................................................................................................................10 Palliative care during epidemics and pandemics.....................................................................................................................................................10 Inequities.........................................................................................................................................................................................................................11 Poverty and deprivation..........................................................................................................................................................................................11 Extending palliative care beyond cancer.............................................................................................................................................................11 Other disadvantaged groups..................................................................................................................................................................................11 Effectiveness and cost-effectiveness of palliative care............................................................................................................................................12 Research...........................................................................................................................................................................................................................12 Concluding thoughts: Addressing palliative care through an expanding public health paradigm.....................................................................13 References..............................................................................................................................................................................................................................13

Introduction Palliative care is increasingly recognized as an important public health issue.1-5 Public health is the science of protecting and improving the health of people and their communities. This is achieved by promoting healthy lifestyles, researching disease and injury prevention, and detecting, preventing, and responding to common diseases and health concerns. Overall, public health is concerned with protecting the health of entire populations. These populations can be as small as a local neighborhood, or as big as an entire country or region of the world. Death and the end of life affect everyone in society. Despite the continuing advances in prevention and curative treatments, everyone will eventually die. Despite this, until recently palliative care received very little attention in the field of public health. This may be because public health focused on infectious diseases, and on preventing illness and premature deaths. However, the rise in non-communicable and chronic infectious diseases, variations in access to care, evidence of inequities, and the escalating need make palliative care a crucial public health issue that requires response. Our societies are aging with changes in population structures, and an increasing number of older people with complex needs and chronic illness. This requires a response that mobilizes communities, takes preventative measures, and increases access to services, broadening the focus of palliative care from patients and families to include a societal approach. This is set in the context where care at the end of life comprises a large component of health-care resources; depending on the methods used, around 20% of total health-care costs are spent in the last year of life.6–8 Costs increase toward the end of life,

especially the last 3 months of life when, in many high income countries, 80% of health-care costs are spent in the hospital.9 This chapter provides an introduction to the core principles of public health and provides examples of public health solutions to challenges of palliative care development.

What is public health? The definition of public health as “the art and science of preventing disease, prolonging life and promoting health through the organized efforts of society,” first introduced in England in 1988,10 has been used by the World Health Organization (WHO) and others since. Public health has further been interpreted as “…a collective action of State and Civil Society to protect and improve the health of individuals. It is a notion that goes beyond population or community-based interventions and includes the responsibility of ensuring access by citizens to quality health care. It does not approach public health as an academic discipline but rather as an interdisciplinary social practice.”11 The key element that distinguishes public health from clinical care is being accomplished through social and political action, as opposed to action targeted at the individual or family level. Examples of public health include vaccination programs, smoking awareness campaigns, professional education, reform of public laws impacting health (such as alcohol tax), and many other societal interventions.

Public health: New approaches

The definition of what constitutes a public health issue has evolved with time. Because public health focuses on major causes of morbidity and mortality, it must evolve as the causes of morbidity and 7

Textbook of Palliative Medicine and Supportive Care

8 mortality change. For example, public health approaches in the 18th and 19th century focused on sanitary and environmental reforms, and antibacterial therapies to curb transmission of communicable diseases—like cholera, tuberculosis and malaria— which were the main causes of morbidity. In its earliest western incarnation, after John Snow closed the famous London water pump and ended a cholera outbreak, public health’s ambition did not extend much beyond what is now considered basic infectious disease epidemiology. The epidemiological transition to noncommunicable diseases in the 20th century necessitated the development of new public-health approaches to addressing the problems posed by these killers of the new age. As understanding of the determinants of health became more sophisticated, so did public health practice. Disciplines of health services research, sociology, economics, psychology, nutrition, anthropology, and others are now considered by many to be important in understanding the health of individuals and, hence, populations and societies. The 1988 Acheson Report, commissioned by the UK Minister of Health to review and summarize health inequalities and to recommend priority areas for policy development and interventions to reduce them, noted that their work was based on a socioeconomic model of health that recognized that main determinants of health could be described as layers of environmental and social influence over the fixed individual constitutional factors. Similarly, the US Institute of Medicine in their seminal report on the Future of Public Health defines health as a “public good” because “many aspects of human potential such as employment, social relationships, and political participation are contingent upon it.”12 One area of action identified by this report was to adopt a population health approach that considers multiple determinants of health. The aging of societies and challenges of maintaining health and function in a mostly older population, together with antibiotic resistances and new epidemics of poor health and illnesses due to obesity, pollution, and other concerns, as we see in the 21st century, requires a further evolution of public health. New public health has emerged with one of its main themes being that interventions be conducted with people rather than on people. One main difference between the new and old public health is that the professional dominance of those from the outside—assuming that that they knew what is best for the community—was challenged. For example, in old public health, health professionals adopted an institutionalized view toward hospice and end-of-life care (viewing death and dying as experiences requiring “containment”). However, the ideas of the new public health and community empowerment promote moving away from the focus on “containment” to highlighting social and collective responsibility.

Public health approach to palliative care As a health issue that affects everyone is amenable to populationbased and public sector interventions, and has the potential to reduce suffering on a massive scale, palliative and end-of-life care is an important public health issue. The disciplines of palliative and supportive care, with their understanding of the interrelationships between physical, spiritual, emotional, and practical domains of human existence and suffering, fit quite comfortably into an approach to population health that recognizes multiple biopsychosocial determinants of health and enduring health problems. It has made this philosophy the cornerstone of clinical practice for decades.

Patient and public involvement as part of the public health response

The current public health approach to palliative care includes these ideas and is an integral part of the wider global health promotion campaign. New initiatives are currently being developed which aim not only to promote the involvement of the community in their care, but also to involve them in research. An example of such initiatives is the “patient, family and public involvement (PPI) in palliative care research” initiative at the Cicely Saunders Institute in London. The aims of the PPI initiative are primarily to improve the quality impact, and clinical relevance of palliative-care research, and to demystify preconceptions, and raise awareness of palliative care and palliativecare research.13–16 Public involvement in palliative care has evolved from a view that patients were too ill to be involved, to innovative methods including face-to-face events, and on-line fora.17

Moving to palliative care as a human rights issues and the need for universal health coverage to include palliative care

Palliative care encompasses, but extends beyond, end-of-life care. WHO has defined palliative care as “…an approach which improves quality of life of patients and their families facing lifethreatening illness through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychological and spiritual.”18 A palliative approach then should be applied along all stages of serious illness regardless of the immediacy of death. To do otherwise can rightly be considered a failure to provide quality care. In this light, the public health mandate of palliative care becomes even larger and more complex: the target for palliative interventions is not just the result of a calculation based on incidence of death but, rather, on prevalence of lifethreatening and serious disease in a defined population or geographic area. Early initiatives outlined the principles and practice of palliative care as a human right.19 WHO guidance, such as Palliative Care for Older People, and Palliative Care: the Solid Facts, provided the foundations for a wider evidence-based public health approach to palliative care, supporting the growing recognition of palliative care as a human right.18,20,21 The guidance provided an imperative for governments in many countries to address palliative care as part of universal health coverage and include it within public health strategies.18,20–22 In 2014, the Worldwide Palliative Care Alliance produced the Global Atlas of Palliative Care.23 The Atlas calculated global palliative care needs and charted the response in different countries. It reaffirmed that access to palliative care, including access to pain relief, is a human right. The Atlas noted that palliative care is highly effective at relieving the pain and suffering of people living with and affected by life-limiting illness, greatly enhancing their ability to live to the fullest until the end of life, and yet without increasing health-care costs. It highlighted that millions of people worldwide cannot access this type of care, resulting in grave suffering, and recommended: 1. Development of a research agenda to map and improve the evidence base around palliative care. Special attention should be afforded to populations such as children, older people, and marginalized groups.

Palliative Care as a Public Health Issue

9

2. Comprehensive analysis to identify gaps in existing guidance on palliative care across levels of care in health and community systems and disease groups. 3. Scale-up, leadership, and accountability, with palliative care becoming a part of universal health care, with measurable benchmarks. The Sixty-seventh World Health Assembly, in 2014, considered and approved resolution WHA67.19, to strengthen palliative care as a component of integrated treatment throughout the life course. Member States were urged to develop, strengthen, and implement “palliative care policies to support the comprehensive strengthening of health systems to integrate evidencebased, cost-effective and equitable palliative care services in the continuum of care, across all levels, with emphasis on primary care, community and home-based care, and universal coverage schemes.” 24 This has prompted further initiatives to recognize palliative care as a public health challenge, which must be addressed. 5,25

Public health challenges in palliative and supportive care Escalating global palliative care need

The world’s population is growing. It is expected to grow from 7.79 billion in 2020, by a rate of 1.05% (2020) to 0.67% (2039) per year, reaching 9.20 billion in 2040. Population growth is predicted to slow slightly each year ranging 0.37–0.66% per year, reaching 10.15 billion population by 2060. Most of the population increase will be in what are currently considered lower and middle income countries.26 Note that we cannot assume that country incomes in 2020 will remain the same by 2040 or 2060. While the growth of the world’s population is well recognized, the projected growth in the number of annual deaths is only recently being recognized. In 2008 Gomes et al. published the first landmark predictions that identified that not only was the population growing but the numbers of deaths annually were predicted to grow from around 2018 onward.27 This change was brought about by earlier “delaying of deaths” into later life with a fall in annual deaths up to around 2003, and a surge in births during the 1950s, increasing the population in certain age groups. Subsequent research led to projections, which by 2019 gave a much better picture of the likely future needs for palliative and end-of-life care in many countries and globally.28–32 The total number of deaths worldwide is predicted to increase by 79% from 57 million in 2016 to over 101 million in 2060

according to the WHO global mortality predictions.28 Assuming that each death affects at least 5 other people, we have calculated that end-of-life issues are estimated to affect at least 3.6% of the world’s population each year in 2020, and 5% (i.e., 1 in 20 people) each year in 2060. There are predicted increases in the numbers of deaths and in need for palliative care in many countries, such as by 2040 a 25% increase in England, 33 by 2050 a 26% increase in Germany, 32 and by 2060 a 70% increase in Brazil, 34 see Table 2.1 for summary examples. The causes and nature of death have changed, altering the provision of care and impacting health-care systems. There are three important changes driving an increasing role for palliative care, with a public health approach. First, more people are dying from chronic diseases rather than from acute illnesses. In 1900 in many countries, the leading causes of death were communicable diseases, including tuberculosis and diarrheal diseases in children. Nowadays, the top predicted causes of death are usually heart disease, cerebrovascular disease/stroke, dementias, chronic respiratory disease, respiratory infections, and lung cancer. Noncommunicable diseases and the later more chronic phases of some communicable diseases (notably HIV/AIDS) are ever more prevalent, requiring symptom relief and emotional, social, and spiritual support. Second, people are living longer with these chronic or multimorbid conditions, suggesting that they require palliative care, symptom management, support for decision-making and for those important to them and their families for longer periods that in the past. Third, people are dying increasingly at older ages and this is projected to increase. Some countries, such as Portugal and Japan already have a high proportion of older people in their societies.26,31,35 In England and Wales by 2040, 53.6% of those who die will be aged 85 years and over, compared with only 38.8% in 2014. The projections research have produced estimates of need for palliative care, showing increases in need ranging from 42% to 112% depending on the region and methods of calculation.28–34 These increases in need have implications for where and how care is provided, in particular the number of hospice, community and hospital beds, and support for patients at home. In many countries, there has been a trend away from hospital death to more home and care home deaths. However, for these trends to continue, the numbers of deaths at home and in care homes will increase, with the majority of people supported outside hospital by 2040. This leads to priorities relevant to public health: (1) to increase and upskill a community health and social care workforce through education, training, and valuing of care work; (2) to build community care capacity through informal caregiver

TABLE 2.1  Growth in Numbers of Who Will Die and in Need for Palliative Care, Selection of Published Modeled Projections Time Period

Increase in Number of Annual Deaths

England and Wales England and Wales

2014–2040 2014–2040

25.4% 26.8%

Scotland

2016–2040

15.9%

Portugal Germany Brazil Global

2010–2030 2009–2050 2000–2040 2016–2060

NA 26.0% 70.0% 79.0%

Country/Region

Sources: Source data used from Refs. [28–34].

Modeled Impacts

Authors and Reference

A 42.4% increase in need for palliative care Need to provide services for 134,390 more deaths each year A 60% increase in community and social care provision is needed Hospital deaths will increase by 27.7–52.1% Implications for hospital care 76% increase in palliative care need 87% increase in serious health related suffering

Etkind et al.33 Bone et al.30 Finucane et al.29 Sarmento et al.31 Simon et al.32 Santos et al.34 Sleeman et al.28

10 support and community engagement; and (3) to stimulate a realistic public debate on death, dying, and sustainable funding.29,30 Projections of the future burden of serious health-related suffering suggest that by 2060, 48 million people will need direct palliative care each year.28 This approach uses the Lancet Commission on Palliative Care and Pain Relief definitions of serious health-related suffering, 36 combined with WHO mortality projections (2016–2060) and estimates of physical and psychological symptom prevalence in 20 conditions most often associated with symptoms requiring palliative care.28 This projection of 48 million people represents 47% of all deaths globally and is an 87% increase from 26 million people in 2016. Further, 83% of these deaths will occur in what are currently low-income and middle-income countries. Serious health-related suffering will increase in all regions, with the largest proportional rise in low-income countries (155% increase between 2016 and 2060). Globally, serious health-related suffering will increase most rapidly among people aged 70 years or older (183% increase between 2016 and 2060). In absolute terms, it will be driven by rises in cancer deaths (16 million people, 109% increase between 2016 and 2060). The condition with the highest proportional increase in serious-related suffering will be dementia (6 million people, 264% increase between 2016 and 2060).28 If a different definition, based on a more comprehensive approach to determine palliative care needs are applied, where 63–82% of all deaths have palliative care needs37 (rather than only 48%), the escalation in need is much more marked. In these instances the numbers of deaths are growing annual, due to prolonged survival and an earlier boom in births, leading to 15–30% increases in annual deaths by 2040.29,33

Response to population aging in the context of palliative care

Life expectancy is increasing in most countries, and populations are living longer and are on average older. In 2018, for the first time in history, persons aged 65 or above outnumbered children under five years of age globally. Projections by the United Nations suggest that the number of people aged 80 years and over worldwide will triple, from 143 million in 2019 to 426 million in 2050. By 2050, one in six people in the world will be over age 65 (16%), up from one in 11 in 2019 (9%). Regions where the share of the population aged 65 years or over is projected to double between 2019 and 2050 include Northern Africa and Western Asia, Central and Southern Asia, Eastern and South-Eastern Asia, and Latin America and the Caribbean. By 2050, one in four persons living in Europe and Northern America could be aged 65 or over.26 While the number of deaths is expected to increase, the potential support ratio, which compares numbers of persons at working ages to those over age 65, is falling around the world. In Japan this ratio is 1.8, the lowest in the world. An additional 29 countries, mostly in Europe and the Caribbean, already have potential support ratios below three. By 2050, 48 countries, mostly in Europe, Northern America, and Eastern and South-Eastern Asia, are expected to have potential support ratios below two. These low values underscore the potential impact of population aging on the labor market and economic performance, as well as the fiscal pressures that many countries will face in the coming decades as they seek to build and maintain public systems of health care, pensions, and social protection for older persons.26 This will place pressures on health and social care systems to provide care and support. The number of informal caregivers may also decrease. This is in part due to women, who have traditionally been relied on to

Textbook of Palliative Medicine and Supportive Care care for people at the end of life, more frequently being in formal employment. Social changes such as smaller family size, dispersed families, and increased divorce rates have made informal caregiver availability less self-evident. Research from different countries and in different conditions finds that informal caregivers provide considerable care at the end of life, often more than formal care. 38–42 If the activities and support of informal caregivers needed to be paid for, this could lead to an increase of 250% (for people with advanced illness and breathlessness)40 or 300% (in the case of people with early onset dementia). 39 Given this unprecedented global aging it is vital to align health and social care for older populations to support the dual priorities of living well, while also experiencing increasing or fluctuating illnesses and ultimately the end of life.5 This objective is not in conflict with those of palliative care in its origins, as Dame Cicely Saunders said, “we will do all we can to help you live well, even at the end of life.” It is also important to remember that many older people continue to make substantial contributions to society, and continue in good health until a very old age. Nevertheless, it is imperative to develop and evaluate new models of care that respond to the changing (and often very elderly) populations needing palliative care that are effective, appropriate, and affordable. A review recently identified two overarching classifications of service models but with different target outcomes: Integrated Geriatric Care, emphasizing physical function, and Integrated Palliative Care, focusing mainly on symptoms and concerns. Areas of synergy across the overarching classifications included person-centered care, education, and a multiprofessional workforce.43 Both approaches highlight the urgency to integrate the care continuum, with service involvement triggered by the patient’s needs and likelihood of benefits. Economic analyses that span health and social care and take a societal approach to care costs, including informal caregivers, are critical. New models of care, such as short-term integrated palliative care, appear promising for these populations and have effectiveness and cost-effectiveness in randomized trials44–49 and appear to promote patient and family dignity.48

Palliative care during epidemics and pandemics

Palliative care is an important component of health care in epidemics and pandemics, contributing to symptom control, psychological support, and supporting triage and complex decision-making.50 The hospice and palliative care sector are capable of responding flexibly and rapidly to epidemics and pandemics. This has been evident in the SARS, MERS, Ebola, and COVID-19 epidemics and pandemics.51 A useful framework is to consider the availability and response in terms of systems (policies, training and protocols, communication and coordination, and data), staff (deployment, skill mix, and resilience), space (community provision and use of technology), and stuff (medicines and equipment as well as personal protective equipment).51 Palliative care services do not have capacity to care for all those in need but can help by ensuring protocols for symptom management are available, and training non-specialists in their use; being involved in triage; considering shifting resources into the community; considering redeploying volunteers to provide psychosocial and bereavement care; facilitating camaraderie among staff and adopting measures to deal with stress; using technology to communicate with patients and caregivers; and adopting standardized data collection systems to inform operational changes and improve care. It is essential that public health services,

Palliative Care as a Public Health Issue planners, and governments recognize the essential contribution of hospice and palliative care to epidemics and pandemics, especially in instances where the disease is not curable. While prevention and treatment are of course important, care and symptom management for those affected are also vital. The 2020 COVID-19 pandemic is a particular instance where palliative care was even more vital. The population most affected was older, frailer people, and in some countries, such as the UK, especially those in care homes.52,53 The excess deaths and suffering may not only relate to the number of people known to have the disease. As was seen in many countries, excess mortality was far greater than would be expected from the number of people affected by the disease and may have been double the number of reported deaths.54 This may be due to missed diagnoses, and also the consequences of measures to control infection or strain on health-care services. Thus, there is a need to ensure that palliative care is integrated into the health-care system response. However, essential equipment, including availability of personal protective equipment, syringe drivers, appropriate medicines, and settingspecific guidance are essential.

Inequities Poverty and deprivation

Evidence suggests that people in the lowest socio-economic class tend to die younger, with poorer quality of life than those in higher socio-economic classes.55–57 Also, there are more hospital deaths in areas of high socio-economic deprivation, despite preferences to the contrary.56–58 Perhaps because it tends to be more difficult to raise charitable funds for home and hospice care in deprived areas, the level of palliative care provision may be inversely proportional to the level of need—the inverse care law. In addition to the complex range of factors that contribute toward the inverse care law, knowledge and awareness of palliative care and related services also appear to be important here. Koffman et al. surveyed 252 cancer patients at 2 hospitals in London and found that the least materially deprived patients were significantly more likely to recognize and describe the term palliative care (OR = 8.4; p = 0.002) and understand the role of Macmillan nurses (OR = 6.68; p < 0.0001)—when compared with their most deprived peers.59 People with lower education levels also have poorer access to palliative care.60 A recent systematic review analyzed data from 209 studies from a wide diversity of countries. Compared to people living in the least deprived neighborhoods, people living in the most deprived neighborhoods were more likely to die in hospital versus home (OR 1.30, 95% CI 1.23–1.38, p < 0.001), to receive acute hospital-based care in the last 3 months of life (OR 1.16, 95% CI 1.08–1.25, p < 0.001), and to not receive specialist palliative care (OR 1.13, 95% CI 1.07–1.19, p < 0.001). For every quintile increase in area deprivation, hospital versus home death was more likely (OR 1.07, 95% CI 1.05–1.08, p < 0.001), and not receiving specialist palliative care was more likely (OR 1.03, 95% CI 1.02–1.05, p < 0.001). Compared to the most educated (qualifications or years of education completed), the least educated people were more likely to not receive specialist palliative care (OR 1.26, 95% CI 1.07–1.49, p = 0.005).61 Although the observational nature of the studies included and the focus on high-income countries limit the conclusions of this review, the results bear out the social inequity of access to palliative care, which still needs addressing after it was first identified in 1994.62,63 Worryingly, Sleeman’s recent analysis of access to inpatient hospices suggests that the trend may be heading in the wrong direction in the UK.64 People who are homeless also seem to have poorer access to palliative care.65

11 Extending palliative care beyond cancer

Although early studies of the need for people at the end of life included different diseases, the response of palliative care is often more focused in cancer in most countries.66 This leads to inequities, where people with non-cancer conditions, but similar levels of symptoms, often miss out on the best in palliative care. For example, research shows that patients with many different progressive chronic diseases have similar symptom profiles. Five symptoms—pain, breathlessness, fatigue, anorexia, worry—are common among more than 50% of patients with advanced cancer, acquired immune deficiency syndrome, chronic heart failure, end-stage renal disease, chronic obstructive pulmonary disease, multiple sclerosis, motor neuron disease, Parkinson’s disease, and dementia; 9–11 different symptoms are prevalent across all these conditions.67,68 There appeared to be a common pathway toward death for malignant and non-malignant diseases. Despite this, access for patients with diseases other than cancer is often limited. For example, people with progressive lung diseases have poorer access to palliative care, despite having similar problems with symptoms, need for information and support.69,70 A similar pattern is for patients with neurological disease, such as Parkinson’s disease or multiple sclerosis,71–73 heart disease,74–77 renal and liver failure,78–81 HIV/AIDS,82,83 and many other conditions. In recent years, dementia has become a major health challenge worldwide and accounts for increasing health resource use, particularly in developed countries.84 In 2005, the global prevalence of dementia was estimated to be 23.4 million, with an incidence of 4.6 cases annually (a new case every second).85 The prevalence of dementia is expected to reach 81.1 million people by 2040, most of whom will live in developing countries (60% in 2001, rising to 71% by 2040).85 Research suggests that symptoms of dementia are similar to those of cancer; however, patients with dementia experience these symptoms for longer periods than those with cancer.86 “Patients with dementia often receive poor end-of-life care, with inadequate pain control and without access to the palliative care services that patients with cancer are offered.”87

Other disadvantaged groups

Age is linked to disadvantaged groups by diagnosis, as people with non-cancer conditions tend to be older. In many countries, older patients and their caregivers do not have equal access to palliative care when compared with younger patients.88 This may partly be accounted for by the fact that the majority of patients receiving palliative care are cancer patients—who, on average, are younger—but age appears to be an independent factor, both in place of death and access to specialist care. A systematic review by Burt and company on the effect of age on referral to specialist palliative care reported that “older people were less likely to be referred to, or to use, specialist palliative care.”89 Although this direct age discrimination is important, the main concern is perhaps that of indirect discrimination through failure to provide adequate palliative care to older people in the hospital. A European population-based survey by Gomes et al. found that between 51% and 84% of people across seven countries would prefer to die at home if they had advanced cancer.90 Despite this, 34–63% of deaths occurred in hospital, and older people were found to be more likely to die in the hospital when compared with their younger counterparts.91 Furthermore, a UK national end-of-life care survey of 473 bereaved informal caregivers found that 75.6% of the under 85s were reported to have had an official record of preference for place of death, but this was only true for

12 39% of the oldest old (people aged 85 years and over).92 The study also found that being over the age of 85 was associated with a 64% reduction in the odds of dying at home (OR = 0.36).92 Other disadvantaged groups include black and minority ethnic groups;93–95 people with learning disabilities; lesbian, gay, bisexual, and transgender groups;96 prisoners; refugees, asylum seekers, and others.97 There is also regional variation in access to palliative care.97

Effectiveness and cost-effectiveness of palliative care

The effectiveness of palliative care can be considered at two levels. There is the general issue of the effectiveness of expert palliative care services and approaches, and there is also the effectiveness of individual new interventions, services, or approaches, including those that train those less experienced in palliative care. There is now quite good evidence to support expert (or specialist) palliative care multiprofessional teams. High-quality and randomized trial evidence reveals that palliative care services improve outcomes and are effective, cost-effective, and high value (outcomes/costs).1–4 These appear to improve symptom control, reduce depression and psychological distress, in some instances improve patient quality of life, and may improve survival.4,98–103 They also can reduce caregiver burden.46 However, it should be stressed that these studies were carried out on services staffed usually by experts trained in palliative care. Therefore, it is important that as palliative care services develop more widely, outcomes are assessed on a routine basis—to ensure that the palliative care services continue to achieve high-quality outcomes for patients and families. Otherwise, there may be a temptation for funders and commissioners of services to cut corners.104,105 There is, however, less evidence that specific training programs or pathways adapted from hospices and palliative care services and provided to generalists can improve care. The Liverpool care pathway failed to provide evidence of significant patient or caregiver benefits in a cluster randomized controlled trial.106 Many other training systems are in development but are not yet well evaluated. Equally, new techniques and treatments often need evaluation. It is important for palliative care interventions to be routinely subjected to economic evaluation for at least two reasons. First, economic evaluation can enable comparisons between palliative care services to determine the most efficient use of currently allocated resources. “Services that can be shown to be relatively ineffective and costly can be replaced by those that achieve more for less.”107 Second, and most importantly, palliative care will always compete with other health-care services for the same funds. It is the responsibility of health policy makers to consider “value for money” when deciding what services to fund. Arguing for special consideration based on an intrinsic value of a service is rarely sufficient. Failure to demonstrate the cost-effectiveness of interventions can result in weak arguments in the competition for scarce resources.107 Moreover, the WHO resolution on palliative care urges member states to develop and implement policies, which support the integration of cost-effective and equitable palliative care services in the continuum of care, across all levels.108 Therefore, to enable health policy makers to provide the resources required to meet the needs of dying patients, it is necessary for the palliative care community to provide information on the “value for money” of palliative care. Economic evaluation using cost-utility analysis—which compares interventions in terms of their cost per quality-adjusted life years (QALYs) gained—is a common means of providing such information.109,110

Textbook of Palliative Medicine and Supportive Care However, economic evaluations, particularly cost-utility analysis of palliative care, are relatively rare, partly due to the difficulties of estimating costs and outcomes. For example, a 2014 review of the cost-effectiveness of palliative care found that the majority of studies focused only on costs (cost analysis), only one study reported cost-effectiveness analysis, and none of the studies report cost-utility analysis.111 The authors conclude that in most cases, palliative care was significantly cheaper than comparators.111 “Economic evaluation of palliative interventions poses some challenges, both for palliative medicine and for economics.”107 A major challenge around measuring cost in palliative care is that it is difficult to attribute true costs (and outcomes) to one particular service or intervention because, within a single episode of illness, palliative-care patients are usually cared for by various providers in different settings, simultaneously.112 Also, because palliative-care patients have complex needs and demands, it is necessary to adjust for need and complexity (case-mix) when comparing costs between providers. It is reassuring that in a number of countries, palliative care funding models which account for case-mix are being developed, such as the Australian National Sub-acute and Non-acute Patient system,113,114 and the current development work on a palliative-care “currency” in the UK.115 Although issues exist around measuring cost, the measurement of outcomes is arguably more challenging in the context of economic evaluations—particularly cost-utility analysis—of palliative care. This may partly be because some of the goals of palliative care—such as improving the quality of the experience of death—may be incompatible with how the QALY is estimated (i.e., centered around maximizing healthy or quality-adjusted life-years). There has been a lot of debate on the appropriateness of the QALY as an outcome measure in cost-utility analyses of palliative care services.107,116–120 A major criticism of the QALY framework is that standard tools, such as the EQ-5D121,122 and SF-6D122—which have preference weights that enable the estimation of QALYs—are “generic” in nature, and so, do not capture specific domains that are important to palliative care.117,119 Several validated palliative-care-specific outcome measures exist, such as the Palliative Care Outcome Scale (POS),123 and the McGill Quality of Life Questionnaire,124 which capture important palliative care domains. Recent research with the POS is developing preference weights, so that this can be used as an economic measure.125

Research

Clearly, tracking the scope of pain and suffering should be a vital concern that benefits public health and the public good. There is a clear need to develop an evidence base for policy and programs.126,127 Documenting chronic illness, pain, and symptoms and their management through epidemiologic and demographic and health surveys should be integral in high, middle, and low income countries.128 Research is needed to identify salient characteristics of successful palliative care programs.127 Studies must be performed that describe and analyze practice, policy, and advocacy to inform future developments and research for building programs that achieve the varied goals of palliative care—that is, achieving the best quality of life for patients and their families. To minimize risk of failure, it is important that new or expanding palliative care projects in developing countries understand both the successes and failures of existing programs. Several issues recently identified as research topics for investigation include availability of pain-relieving drugs, pain and symptom control,

Palliative Care as a Public Health Issue access to services, education and training, identification of relevant needs and determination of outcomes for care at the community level, and evaluation of the impact of education of policy makers and program directors about palliative care. Given the magnitude of palliative care required by people living in developing regions of the world, programs must also consider coverage and not simply strive to provide high-quality care to a few patients. End-of-life and palliative care research is currently allocated a minute proportion of research funding (e.g., 0.24% of cancer research funding in the UK and 1% in the United States).129 To ensure high-quality research outputs, investment in end-of-life care research is urgently needed.

Concluding thoughts: Addressing palliative care through an expanding public health paradigm Public health focuses on health promotion and prevention of disease and has often seen pain and suffering as removed from the public health paradigm, left to be addressed by tertiary care in a biomedical/clinical model. Although WHO and others have long argued a broadening of the concept of health that includes how well people are able to perform their daily tasks, only recently has daily functioning begun to be included routinely in the assessment of people’s health status through measures of health-related quality of life. Simple measures have been tested and adapted for use in a wide variety of settings including lower income settings.123,130–136 Investigators are going beyond the traditional paradigm that views health only in terms of adherence to or deviation from physical or biochemical markers. Instead, they are including in their assessment of health people’s own reports of their sense of well-being and their ability to perform valued social roles. Indeed, there is some evidence that these more patient-centered

KEY LEARNING POINTS • Palliative care is now recognized as a core public health issue. • The need for palliative care is escalating, with rising numbers of deaths annually across the globe, population aging and changes in chronic diseases and multimorbidity. • Estimates of growth in palliative care need range from 40% to 87% between now and 2060. • Although palliative care is now recognized as a core human right, and should be part of universal health care (with a World Health Assembly declaration in 2014), there are still inequities in access. • Inequities in access to palliative care in particular affect groups, such as those with socioeconomic disadvantage, non-cancer diagnosis, elderly, cultural minorities, those with lower education, homelessness, and those who are lesbian, gay, bisexual, or transgender. • There is good evidence that palliative care is effective, cost-effective, and adds value (costs/ outcomes), but new models may need to evolve to respond to the populations of the future.

BK-TandF-BRUERA_9780367642037-200160-Chp02.indd 13

13 measures are better markers of illness than traditional biological measures.137 Therefore, pain and suffering should be measured through epidemiological and social science methods as a critical health condition that should be tracked just as we track infectious diseases. By expanding the public health paradigm to include and promote palliative care, we further the goals of public health—prevention of disease and prolonging life in society. As life expectancy increases and medical advances are being made, people are living longer with chronic diseases. Therefore, an integrated model of palliative care has practical and pragmatic implications for public health universally. Marginalizing those in need of palliative care services to clinical specialists or ignoring them entirely creates a society in dire need of public health action and intervention.

References





1. Brighton LJ, Miller S, Farquhar M, et al. Holistic services for people with advanced disease and chronic breathlessness: A systematic review and meta-analysis. Thorax 2019;74(3):270–281. 2. May P, Normand C, Cassel JB, et al. Economics of palliative care for hospitalized adults with serious illness: A meta-analysis. JAMA Intern Med 2018;178(6):820–829. 3. Gaertner J, Siemens W, Meerpohl JJ, et al. Effect of specialist palliative care services on quality of life in adults with advanced incurable illness in hospital, hospice, or community settings: Systematic review and meta-analysis. BMJ 2017;357:j2925. 4. Higginson IJ, Evans CJ. What is the evidence that palliative care teams improve outcomes for cancer patients and their families? Cancer J 2010;16(5):423–435. 5. De Lima L, Pastrana T. Opportunities for palliative care in public health. Annu Rev Public Health 2016;37:357–374. 6. Duncan I, Ahmed T, Dove H, Maxwell TL. Medicare cost at end of life. Am J Hosp Palliat Care 2019;36(8):705–710. 7. Marie Curie Cancer Care. Understanding the Cost of End of Life Care in Different Settings. London: Marie Curie Cancer Care, 2012. 8. Menec V, Lix L, Steinbach C, Ekuma O, Sirski M, Dahl M, Soodeen RA. Patterns of Health Care Use and Cost at the End of Life. Winnipeg, Canada: Manitoba Centre for Health Policy, 2004. 9. Yi D, Johnston BM, Ryan K, et al. Drivers of care costs and quality in the last 3 months of life among older people receiving palliative care: A multinational mortality follow-back survey across England, Ireland and the United States. Palliat Med 2020;34(4):513–523. doi: 10.1177/0269216319896745. [Epub ahead of print]. 10. Acheson D. Public Health in England. London: HMSO, 1988. 11. PHPPO. Available from http://www.phppo.cdc.gov/dphsdr/whoccphp/ documents/Instrument.doc. 12. National Academy of Sciences. The Future of Public Health in the 21st Century. Washington, DC: National Academies Press [Internet], 2003. 13. Cicely Saunders Institute. Public Involvement Forum. 2017. 14. O’Hara JK, Lawton RJ. At a crossroads? Key challenges and future opportunities for patient involvement in patient safety. BMJ Quality Saf 2016;25(8):565–568. 15. Daveson BA, de Wolf-Linder S, Witt J, et al. Results of a transparent expert consultation on patient and public involvement in palliative care research. Palliat Med 2015;29(10):939–949. 16. Hughes RA, Down K, Sinha A, Higginson IJ, Leigh PN. Building user involvement in motor neurone disease: Key lessons. J Interprof Care 2004;18(1):80–81. 17. Brighton LJ, Pask S, Benalia H, et al. Taking patient and public involvement online: Qualitative evaluation of an online forum for palliative care and rehabilitation research. Res Involv Engagem 2018;4:14. 18. Hall S, Petkova H, Tsouros AD, Costantini M, Higginson IJ. Palliative Care for Older People: Better Practices. Copenhagen: World Health Organization, 2011. 19. Seymour J. Changing times: Preparing to meet palliative needs in the 21st Century. Br J Community Nurs 2011;16(1):18. 20. Davies E, Higginson IJ. Palliative Care: The Solid Facts. Copenhagen: World Health Organization, 2004. 21. Davies E, Higginson IJ. Better Palliative Care for Older People. Copenhagen: World Health Organization, 2004.

24/06/21 11:43 AM

14 22. Morrissey MB, Herr K, Levine C. Public health imperative of the 21st century: Innovations in palliative care systems, services, and supports to improve health and well-being of older Americans. Gerontologist 2015;55(2):245–51. 23. Connor SR, Sepulveda Bermedo MC. Global Atlas of Palliative Care at the End of Life. Geneva: World Palliative Care Alliance, World Health Organization, 2014. 24. WHO. Sixty-seventh World Health Assembly: Strengthening of palliative care as a component of integrated treatment throughout the life course (document A67/31). 2014. http://apps.who.int/gb/e/e_wha67. html (Accessed 02 Jun 2014). 25. World Health Organization. Palliative care for non-communicable diseases: A global snapshot. Geneva: World Health Organization; 2019. 26. United Nations DoEaSA, Population Division. World Population Prospects. New York: United Nations, 2019. 27. Gomes B, Higginson IJ. Where people die (1974–2030): Past trends, future projections and implications for care. Palliat Med 2008;22(1):33–41. 28. Sleeman KE, de Brito M, Etkind S, et al. The escalating global burden of serious health-related suffering: Projections to 2060 by world regions, age groups, and health conditions. Lancet Glob Health 2019;7(7):e883–e892. 29. Finucane AM, Bone AE, Evans CJ, et al. The impact of population ageing on end-of-life care in Scotland: Projections of place of death and recommendations for future service provision. BMC Palliat Care 2019;18(1):12. 30. Bone AE, Gomes B, Etkind SN, et al. What is the impact of population ageing on the future provision of end-of-life care? Population-based projections of place of death. Palliat Med 2018;32(2):329–336. 31. Sarmento VP, Higginson IJ, Ferreira PL, Gomes B. Past trends and projections of hospital deaths to inform the integration of palliative care in one of the most ageing countries in the world. Palliat Med 2016;30(4):363–373. 32. Simon ST, Gomes B, Koeskeroglu P, Higginson IJ, Bausewein C. Population, mortality and place of death in Germany (1950–2050): Implications for end-of-life care in the future. Public Health 2012;126(11):937–946. 33. Etkind SN, Bone AE, Gomes B, et al. How many people will need palliative care in 2040? Past trends, future projections and implications for services. BMC Med 2017;15(1):102. 34. Santos CED, Campos LS, Barros N, Serafim JA, Klug D, Cruz RP. Palliative care in Brasil: Present and future. Rev Assoc Med Bras (1992) 2019;65(6):796–800. 35. Shinkai S, Yoshida H, Taniguchi Y, et al. Public health approach to preventing frailty in the community and its effect on healthy aging in Japan. Geriatr Gerontol Int 2016;16(Suppl 1):87–97. 36. Knaul FM, Farmer PE, Krakauer EL, et al. Alleviating the access abyss in palliative care and pain relief-an imperative of universal health coverage: The Lancet Commission report. Lancet 2018;391(10128):1391–1454. 37. Murtagh FE, Bausewein C, Verne J, Groeneveld EI, Kaloki YE, Higginson IJ. How many people need palliative care? A study developing and comparing methods for population-based estimates. Palliat Med 2014;28(1):49–58. 38. Brick A, Smith S, Normand C, et al. Costs of formal and informal care in the last year of life for patients in receipt of specialist palliative care. Palliat Med 2017;31(4):356–368. 39. Bakker C, de Vugt ME, van Vliet D, et al. The use of formal and informal care in early onset dementia: Results from the NeedYD study. Am J Geriatr Psychiatry 2013;21(1):37–45. 40. Dzingina MD, Reilly CC, Bausewein C, et al. Variations in the cost of formal and informal health care for patients with advanced chronic disease and refractory breathlessness: A cross-sectional secondary analysis. Palliat Med 2017;31(4):369–377. 41. Farre M, Kostov B, Haro JM, et al. Costs and burden associated with loss of labor productivity in informal caregivers of people with dementia: Results from Spain. J Occup Environ Med 2018;60(5):449–456. 42. Joling KJ, Schope J, van Hout HP, van Marwijk HW, van der Horst HE, Bosmans JE. Predictors of societal costs in dementia patients and their informal caregivers: A two-year prospective cohort study. Am J Geriatr Psychiatry 2015;23(11):1193–1203. 43. Evans CJ, Ison L, Ellis-Smith C, et al. Service delivery models to maximize quality of life for older people at the end of life: A rapid review. Milbank Q 2019;97(1):113–175.

Textbook of Palliative Medicine and Supportive Care 44. Bone AE, Morgan M, Maddocks M, et al. Developing a model of shortterm integrated palliative and supportive care for frail older people in community settings: Perspectives of older people, carers and other key stakeholders. Age Ageing 2016;45(6):863–873. 45. Higginson IJ, Costantini M, Silber E, Burman R, Edmonds P. Evaluation of a new model of short-term palliative care for people severely affected with multiple sclerosis: A randomised fast-track trial to test timing of referral and how long the effect is maintained. Postgrad Med J 2011;87(1033):769–775. 46. Higginson IJ, McCrone P, Hart SR, Burman R, Silber E, Edmonds PM. Is short-term palliative care cost-effective in multiple sclerosis? A randomized phase II trial. J Pain Symptom Manage 2009;38(6):816–826. 47. Reilly CC, Bausewein C, Pannell C, Moxham J, Jolley CJ, Higginson IJ. Patients’ experiences of a new integrated breathlessness support service for patients with refractory breathlessness: Results of a postal survey. Palliat Med 2016;30(3):313–322. 48. Gysels M, Reilly CC, Jolley CJ, et al. Dignity through integrated symptom management: Lessons from the breathlessness support service. J Pain Symptom Manage 2016;52(4):515–524. 49. Higginson IJ, Bausewein C, Reilly CC, et al. An integrated palliative and respiratory care service for patients with advanced disease and refractory breathlessness: A randomised controlled trial. Lancet Respir Med 2014;2(12):979–987. 50. Costantini M, Sleeman KE, Peruselli C, Higginson IJ. Response and role of palliative care during the COVID-19 pandemic: A national telephone survey of hospices in Italy. Palliat Med 2020:34(7):889–895 (preprint at https://www.medrxiv.org/content/10.1101/2020.03.18. 20038448v1; doi: 10.1101/2020.03.18.20038448). 51. Etkind SN, Bone AE, Lovell N, et al. The role and response of palliative care and hospice services in epidemics and pandemics: A rapid review to inform practice during the COVID-19 pandemic. J Pain Symptom Manage 2020;60(1):e31–e40. 52. Lovell N, Maddocks M, Etkind SN, et al. Characteristics, symptom management and outcomes of 101 patients with COVID-19 referred for hospital palliative care. J Pain Symptom Manage 2020;60(1):e77–e81. 53. Kunz R, Minder M. COVID-19 pandemic: Palliative care for elderly and frail patients at home and in residential and nursing homes. Swiss Med Wkly 2020;150:w20235. 54. Montagano C. COVID-19: Excess mortality figures in Italy. A comparison between official COVID-19 deaths and mortality in Lombardy. Towards Data Sci 2020. https://towardsdatascience.com/ covid-19-excess-mortality-figures-in-italy-d9640f411691?gi=cbcfa620 700a. 55. Gao W, Ho YK, Verne J, Glickman M, Higginson IJ, on behalf of the GCp. Changing patterns in place of cancer death in England: A population-based study. PLoS Med 2013;10(3):e1001410. 56. Decker SL, Higginson IJ. A tale of two cities: Factors affecting place of cancer death in London and New York. Eur J Public Health 2007;17(3):285–290. 57. Higginson IJ, Jarman B, Astin P, Dolan S. Do social factors affect where patients die: An analysis of 10 years of cancer deaths in England. J Public Health Med 1999;21(1):22–28. 58. Sims A, Radford J, Doran K, Page H. Social class variation in place of cancer death. Palliat Med 1997;1(5):369–373. 59. Koffman J, Burke G, Dias A, et al. Demographic factors and awareness of palliative care and related services. Palliat Med 2007;21(2):145–153. 60. Beccaro M, Costantini M, Merlo DF. Inequity in the provision of and access to palliative care for cancer patients. Results from the Italian survey of the dying of cancer (ISDOC). BMC Public Health 2007;7:66. 61. Davies JM, Sleeman KE, Leniz J, et al. Socioeconomic position and use of healthcare in the last year of life: A systematic review and metaanalysis. PLoS Med 2019;16(4):e1002782. 62. Higginson I, Webb D, Lessof L. Reducing hospital beds for patients with advanced cancer. Lancet 1994;344(8919):409. 63. Davies J, Higginson I, Sleeman K. Time to go beyond observing the problem. Response to: Dying in hospital: Socioeconomic inequality trends in England, doi: 10.1177/1355819616686807. J Health Serv Res Policy 2018. doi: 10.1177/1355819617750184. 64. Sleeman KE, Davies JM, Verne J, Gao W, Higginson IJ. The changing demographics of inpatient hospice death: Population-based cross-sectional study in England, 1993–2012. Palliat Med 2016;30(1):45–53. 65. Henry B, Dosani N, Huynh L, Amirault N. Palliative care as a public health issue: Understanding disparities in access to palliative care for the homeless population living in Toronto, based on a policy analysis. Curr Oncol 2017;24(3):187–191.

Palliative Care as a Public Health Issue 66. Higginson I. Palliative care: A review of past changes and future trends. J Public Health Med 1993;15(1):3–8. 67. Solano JP, Gomes B, Higginson IJ. A comparison of symptom prevalence in far advanced cancer, AIDS, heart disease, chronic obstructive pulmonary disease and renal disease. J Pain Symptom Manage 2006;31(1):58–69. 68. Moens K, Higginson IJ, Harding R, Euro I. Are there differences in the prevalence of palliative care-related problems in people living with advanced cancer and eight non-cancer conditions? A systematic review. J Pain Symptom Manage 2014;48(4):660–677. 69. Bausewein C, Booth S, Gysels M, Kuhnbach R, Haberland B, Higginson IJ. Understanding breathlessness: Cross-sectional comparison of symptom burden and palliative care needs in chronic obstructive pulmonary disease and cancer. J Palliat Med 2010;13(9):1109–1118. 70. Bajwah S, Koffman J, Higginson IJ, et al. ‘I wish I knew more …’ the end-of-life planning and information needs for end-stage fibrotic interstitial lung disease: Views of patients, carers and health professionals. BMJ Support Palliat Care 2013;3(1):84–90. 71. Saleem TZ, Higginson IJ, Chaudhuri KR, Martin A, Burman R, Leigh PN. Symptom prevalence, severity and palliative care needs assessment using the Palliative Outcome Scale: A cross-sectional study of patients with Parkinson’s disease and related neurological conditions. Palliat Med 2013;27(8):722–731. 72. Kumpfel T, Hoffmann LA, Pollmann W, et al. Palliative care in patients with severe multiple sclerosis: Two case reports and a survey among German MS neurologists. Palliat Med 2007;21(2):109–114. 73. Voltz R, Borasio GD. Palliative therapy in the terminal stage of neurological disease. J Neurol 1997;244:S2–S10. 74. Klindtworth K, Oster P, Hager K, Krause O, Bleidorn J, Schneider N. Living with and dying from advanced heart failure: Understanding the needs of older patients at the end of life. BMC Geriatr 2015;15:125. 75. Malik FA, Gysels M, Higginson IJ. Living with breathlessness: A survey of caregivers of breathless patients with lung cancer or heart failure. Palliat Med 2013;27(7):647–656. 76. Harding R, Selman L, Beynon T, et al. Meeting the communication and information needs of chronic heart failure patients. J Pain Symptom Manage 2008;36(2):149–156. 77. Selman L, Harding R, Beynon T, et al. Improving end-of-life care for patients with chronic heart failure: “Let’s hope it’ll get better, when I know in my heart of hearts it won’t”. Heart 2007;93(8):963–967. 78. Mazzarelli C, Prentice WM, Heneghan MA, Belli LS, Agarwal K, Cannon MD. Palliative care in end-stage liver disease: Time to do better? Liver Transpl 2018;24(7):961–968. 79. Kane PM, Vinen K, Murtagh FE. Palliative care for advanced renal disease: A summary of the evidence and future direction. Palliat Med 2013;27(9):817–821. 80. Murtagh FE, Addington-Hall JM, Higginson IJ. End-stage renal disease: A new trajectory of functional decline in the last year of life. J Am Geriatr Soc 2011;59(2):304–308. 81. Murtagh FE, Higginson IJ. Death from renal failure eighty years on: How far have we come? J Palliat Med 2007;10(6):1236–1238. 82. Namisango E, Harding R, Atuhaire L, et al. Pain among ambulatory HIV/AIDS patients: Multicenter study of prevalence, intensity, associated factors, and effect. J Pain 2012;13(7):704–713. 83. Harding R, Easterbrook P, Higginson IJ, Karus D, Raveis VH, Marconi K. Access and equity in HIV/AIDS palliative care: A review of the evidence and responses. Palliat Med 2005;19(3):251–258. 84. Comas-Herrera A, Wittenberg R, Pickard L, Knapp M. Cognitive impairment in older people: Future demand for long-term care services and the associated costs. Int J Geriatr Psychiatry 2007;22(10):1037–1045. 85. Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: A Delphi consensus study. Lancet 2005;366(9503):2112–2117. 86. McCarthy M, Addington-Hall J, Altmann DAN. The experience of dying with dementia: A retrospective study. Int J Geriatr Psychiatry 1997;12(3):404–409. 87. Sampson EL, Ritchie CW, Lai R, Raven PW, Blanchard MR. A systematic review of the scientific evidence for the efficacy of a palliative care approach in advanced dementia. Int Psychogeriatr 2005;17(1):31–40. 88. Lock A, Higginson I. Patterns and predictors of place of cancer death for the oldest old. BMC Palliat Care 2005;4:6. 89. Burt J, Raine R. The effect of age on referral to and use of specialist palliative care services in adult cancer patients: A systematic review. Age Ageing 2006;35(5):469–476.

15 90. Gomes B, Higginson IJ, Calanzani N, et al. Preferences for place of death if faced with advanced cancer: A population survey in England, Flanders, Germany, Italy, the Netherlands, Portugal and Spain. Ann Oncol 2012;23(8):2006–2015. 91. Cohen J, Bilsen J, Addington-Hall J, Lofmark R, et al. Populationbased study of dying in hospital in six European countries. Palliat Med 2008;22(6):702–710. 92. Hunt KJ, Shlomo N, Addington-Hall J. End-of-life care and preferences for place of death among the oldest old: Results of a population-based survey using VOICES-Short Form. J Palliat Med 2014;17(2):176–182. 93. Price RA, Parast L, Haas A, Teno JM, Elliott MN. Black and Hispanic patients receive hospice care similar to that of white patients when in the same hospices. Health Aff (Millwood) 2017;36(7):1283–1290. 94. Calanzani N, Koffman J, Higginson IJ. Palliative and End of Life Care for Black, Asian and Minority Ethnic Groups in the UK. London: Marie Curie Cancer Care, 2013. 95. Koffman J, Higginson IJ. Accounts of carers’ satisfaction with health care at the end of life: A comparison of first generation black Caribbeans and white patients with advanced disease. Palliat Med 2001;15(4):337–345. 96. Bristowe K, Hodson M, Wee B, et al. Recommendations to reduce inequalities for LGBT people facing advanced illness: ACCESSCare national qualitative interview study. Palliat Med 2018;32(1):23–35. 97. Wee B. Models of delivering palliative and end-of-life care in the UK. Curr Opin Support Palliat Care 2013;7(2):195–200. 98. Gomes B, Calanzani N, Curiale V, McCrone P, Higginson IJ. Effectiveness and cost-effectiveness of home palliative care services for adults with advanced illness and their caregivers. Cochrane Database Syst Rev 2013;6:CD007760. 99. Paiva CE, Faria CB, Nascimento MSDA, et al. Effectiveness of a palliative care outpatient programme in improving cancer-related symptoms among ambulatory Brazilian patients. Eur J Cancer Care (Engl) 2012;21(1):124–130. 100. Harding R, List S, Epiphaniou E, Jones H. How can informal caregivers in cancer and palliative care be supported? An updated systematic literature review of interventions and their effectiveness. Palliat Med 2012;26(1):7–22. 101. Gomez-Batiste X, Porta-Sales J, Espinosa-Rojas J, Pascual-Lopez A, Tuca A, Rodriguez J. Effectiveness of palliative care services in symptom control of patients with advanced terminal cancer: A Spanish, multicenter, prospective, quasi-experimental, pre-post study. J Pain Symptom Manage 2010;40(5):652–660. 102. Higginson IJ, Finlay IG, Goodwin DM, et al. Is there evidence that palliative care teams alter end-of-life experiences of patients and their caregivers? J Pain Symptom Manage 2003;25(2):150–168. 103. Finlay IG, Higginson IJ, Goodwin DM, et al. Palliative care in hospital, hospice, at home: Results from a systematic review. Ann Oncol 2002;13(Suppl 4):257–264. 104. Teno JM, Casarett D, Spence C, Connor S. It is “too late” or is it? Bereaved family member perceptions of hospice referral when their family member was on hospice for seven days or less. J Pain Symptom Manage 2012;43(4):732–738. 105. Teno JM, Gozalo PL, Lee IC, et al. Does hospice improve quality of care for persons dying from dementia? J Am Geriatr Soc 2011;59(8):1531–1536. 106. Costantini M, Romoli V, Leo SD, et al. Liverpool care pathway for patients with cancer in hospital: A cluster randomised trial. Lancet 2014;383(9913):226–237. 107. Normand C. Economics and evaluation of palliative care. Palliat Med 1996;10(1):3–4. 108. WHO. Strengthening of palliative care as a component of integrated treatment within the continuum of care. In: 134th Session: Document EB134.R7, 2014. http://apps.who.int/gb/e/e_eb134.html (Accessed 03 Jun 2014). 109. Earnshaw J, Lewis G. NICE guide to the methods of technology appraisal: Pharmaceutical industry perspective. PharmacoEconomics 2008;26(9):725–727. 110. Drummond MF, Sculpher MJ, Torrance GW, O’Brien BJ, Stoddart GL. Methods for the Economic Evaluation of Health Care Programmes, third ed. Oxford: Oxford University Press, 2005. 111. Smith S, Brick A, O’Hara S, Normand C. Evidence on the cost and cost-effectiveness of palliative care: A literature review. Palliat Med 2014;28(2):130–150.

16 112. Murtagh FEM, Groeneveld IE, Kaloki YE, Calanzani N, Bausewein C, Higginson IJ. Capturing activity, costs, and outcomes: The challenges to be overcome for successful economic evaluation in palliative care. Progress Palliat Care 2013;21(4):232–235. 113. Gordon R, Eagar K, Currow D, Green J. Current funding and financing issues in the Australian hospice and palliative care sector. J Pain Symptom Manage 2009;38(1):68–74. 114. Palmer KS, Agoritsas T, Martin D, et al. Activity-based funding of hospitals and its impact on mortality, readmission, discharge destination, severity of illness, and volume of care: A systematic review and metaanalysis. PLoS One 2014;9(10):e109975. 115. Team NEFSFP. Developing a new approach to palliative care funding: A first draft for discussion, 2014. http://www.england.nhs.uk/wp-content/ uploads/2014/10/pall-care-fund-new-appr-fin.pdf (Accessed 25 Oct 2014). 116. Gomes B, Harding R, Foley KM, Higginson IJ. Optimal approaches to the health economics of palliative care: Report of an international think tank. J Pain Symptom Manage 2009;38(1):4–10. 117. Normand C. Measuring outcomes in palliative care: Limitations of QALYs and the road to PalYs. J Pain Symptom Manage 2009;38(1):27–31. 118. Round J. Is a QALY still a QALY at the end of life? J Health Econ 2012;31(3):521–527. 119. Hughes J. Palliative care and the QALY problem. Health Care Anal 2005;13(4):289–301. 120. Coast J, Smith RD, Lorgelly P. Welfarism, extra-welfarism and capability: The spread of ideas in health economics. Soc Sci Med 2008;67(7):1190–1198. 121. Gusi N, Olivares PR, Rajendram R. The EQ-5D health-related quality of life questionnaire. In: Preedy V, Watson R, eds. Handbook of Disease Burdens and Quality of Life Measures. New York: Springer, 2010, pp. 87–99. 122. Marra CA, Woolcott JC, Kopec JA, et al. A comparison of generic, indirect utility measures (the HUI2, HUI3, SF-6D, and the EQ-5D) and disease-specific instruments (the RAQoL and the HAQ) in rheumatoid arthritis. Soc Sci Med 2005;60(7):1571–1582. 123. Hearn J, Higginson IJ. Development and validation of a core outcome measure for palliative care: The palliative care outcome scale. Palliative care core audit project advisory group. Qual Health Care 1999;8(4):219–227. 124. Albers G, Echteld MA, de Vet HC, Onwuteaka-Philipsen BD, van der Linden MH, Deliens L. Evaluation of quality-of-life measures for use in palliative care: A systematic review. Palliat Med 2010;24(1):17–37. 125. Dzingina M, Higginson IJ, McCrone P, Murtagh FEM. Development of a patient-reported palliative care-specific health classification system: The POS-E. Patient 2017;10(3):353–365.

Textbook of Palliative Medicine and Supportive Care 126. Cassel JB, Kerr KM, Kalman NS, Smith TJ. The business case for palliative care: Translating research into program development in the U.S. J Pain Symptom Manage 2015;50(6):741–749. 127. Evans CJ, Harding R, Higginson IJ. ‘Best practice’ in developing and evaluating palliative and end-of-life care services: A meta-synthesis of research methods for the MORECare project. Palliat Med 2013;27(10):885–898. 128. Harding R, Selman L, Powell RA, et al. Research into palliative care in sub-Saharan Africa. Lancet Oncol 2013;14(4):e183–e188. 129. Sleeman KE, Gomes B, Higginson IJ. Research into end-of-life cancer care–investment is needed. Lancet 2012;379(9815):519. 130. Murtagh FE, Ramsenthaler C, Firth A, et al. A brief, patient- and proxyreported outcome measure in advanced illness: Validity, reliability and responsiveness of the Integrated Palliative care Outcome Scale (IPOS). Palliat Med 2019;33(8):1045–1057. 131. Guo P, Gao W, Higginson IJ, Harding R. Implementing outcome measures in palliative care. J Palliat Med 2018;21(4):414. 132. Bausewein C, Daveson BA, Currow DC, et al. EAPC white paper on outcome measurement in palliative care: Improving practice, attaining outcomes and delivering quality services—Recommendations from the European Association for Palliative Care (EAPC) task force on outcome measurement. Palliat Med 2016;30(1):6–22. 133. Harding R, Selman L, Agupio G, et al. Validation of a core outcome measure for palliative care in Africa: The APCA African palliative outcome scale. Health Qual Life Outcomes 2010;8:10. 134. Eisenchlas JH, Harding R, Daud ML, Perez M, De Simone GG, Higginson IJ. Use of the palliative outcome scale in Argentina: A crosscultural adaptation and validation study. J Pain Symptom Manage 2008;35(2):188–202. 135. Veronese S, Rabitti E, Costantini M, Valle A, Higginson I. Translation and cognitive testing of the Italian Integrated Palliative Outcome Scale (IPOS) among patients and healthcare professionals. PLoS One 2019;14(1):e0208536. 136. Ellis-Smith C, Higginson IJ, Daveson BA, Henson LA, Evans CJ, BuildCare. How can a measure improve assessment and management of symptoms and concerns for people with dementia in care homes? A mixed-methods feasibility and process evaluation of IPOS-Dem. PLoS One 2018;13(7):e0200240. 137. Ramsenthaler C, Gao W, Siegert RJ, Schey SA, Edmonds PM, Higginson IJ. Longitudinal validity and reliability of the Myeloma Patient Outcome Scale (MyPOS) was established using traditional, generalizability and Rasch psychometric methods. Qual Life Res 2017;26(11):2931–2947.

3

PALLIATIVE CARE AS A PRIMARY CARE ISSUE

Scott A. Murray, Sebastien Moine, and Kirsty Boyd

Contents Primary palliative care has a sixfold potential to deliver better end-of-life care.....................................................................................................17 First potential of palliative care in primary care: Caring for people with all life-threatening conditions..........................................................17 Second potential of palliative care in primary care: An integrated palliative care approach from diagnosis of life-threatening conditions rather than toward the end............................................................................................................................................................................18 Third potential of palliative care in primary care: Meeting all dimensions of need (physical, psychological, social, and spiritual)............19 Rapid functional decline...............................................................................................................................................................................................19 Intermittent, fluctuating decline.................................................................................................................................................................................20 Gradual decline...............................................................................................................................................................................................................20 Fourth potential of palliative care in primary care: Making a difference in the community................................................................................20 Fifth potential of palliative care in primary care: Reaching to all in need in economically poorer countries and learning from them about bringing death back to life............................................................................................................................................................................21 Sixth potential of palliative care in primary care: Supporting family caregivers in their time of caring and subsequent bereavement.....21 Facilitating factors for strong primary palliative care...................................................................................................................................................22 Caring for all in the last year or phase of life..................................................................................................................................................................22 References..............................................................................................................................................................................................................................22

BOX 3.1  DEFINITIONS USED IN THIS CHAPTER Key worker: Health or social care professional with responsibility for organizing the care of an individual patient. Palliative care approach: An approach that generalist health and social care providers can adopt whereby they consider all dimensions of the person’s care and life experience and plan holistic care for the future as well as the present with them. Primary palliative care1: Primary palliative care is palliative care practiced by primary health-care workers, who are the principal providers of integrated health care for people in local communities throughout their life. It includes early identification and triggering of palliative care as part of integrated and holistic chronic disease management, collaborating with specialist palliative care services where they exist, and strengthening underlying professional capabilities in primary care. Specialist palliative care: Services whose core activity is the provision of palliative care. The main role of specialist palliative care is to manage patients and families with more complex and challenging needs while supporting and training generalist palliative care providers. Terminal care: Care in the last days or week of life or care in the dying phase. Transition in care: A change in setting or place of care or a change in the focus of care from being largely curative to being more supportive and palliative.

Primary palliative care has a sixfold potential to deliver better end-of-life care The first potential is to identify and treat people with any serious or life-threatening condition taking palliative care beyond cancer and adapting it to meet the diverse needs of the growing numbers of people dying with non-malignant conditions. The second potential is to help people earlier rather than later, not just in the very terminal stage but from diagnosis of a life-threatening illness. The third potential is to care for all aspects of the person, all dimensions—physical, psychological, social, and spiritual— as good family practitioners already do. The fourth potential is to have reliably good palliative care available in all community settings: residential and care homes and people’s own home. The fifth potential is making end-of-life care available for people in all nations, especially the poorer countries. Finally, primary care

teams can support family caregivers in their time of caring and subsequent bereavement, as they are frequently cared for by the same primary care team.

First potential of palliative care in primary care: Caring for people with all life-threatening conditions In more economically developed countries, most people die after a longish period of disability with the top three causes of death now being cancer, organ failure, and frailty/dementia.2 This can be illustrated by noting that a family physician in the UK, who has on average about 1,800 patients on his or her registered list, has 18 deaths on average per year. If we only take into account the underlying cause of death (i.e., the disease or injury leading directly to death), then five of these deaths are from cancer, seven from organ 17

18

Textbook of Palliative Medicine and Supportive Care

Second potential of palliative care in primary care: An integrated palliative care approach from diagnosis of life-threatening conditions rather than toward the end

FIGURE 3.1  The three main trajectories of decline at the end of life. Number of deaths in each trajectory, out of the average 18 deaths each year per UK general practice list of 1,800 patients. (Adapted from Murray SA and Sheikh A, BMJ 2008; 336:958–959.) failure (such as chronic obstructive pulmonary disease, heart failure, liver failure, renal failure), and four from frailty or progressive neurological conditions (including dementia). The presence of multimorbidity is now normal3: it is included in annual mortality data as contributing causes of death but most people still follow one of three typical trajectories of decline. Only about 2 out of the 18 are likely to die totally unexpectedly (Figure 3.1).4 So around 90% of deaths are in people with progressive conditions and primary care teams have the opportunity to adopt a palliative care approach with most of these people in a timely way. For these three main categories of dying, the implications for palliative care provision are quite different as the patients’ needs differ. The rapid trajectory (typically cancer) follows a more predictable course with a short decline toward the end. Hospice care fits well with people dying with cancer and can meet their needs.5 Conversely, patients with an intermittent trajectory (typically organ failure) may have a gradual decline over 2–5 years, but during that period, there are acute episodes and frequent hospital admissions. Such patients may die rapidly at any time but, in contrast with advanced cancer, are not expected to die in the next few months. Prognostic uncertainty and funding constraints mean such patients rarely benefit from specialist palliative care except close to death and usually when in hospital. The gradual frailty trajectory is variable and may last for many years from the onset of difficulties in functional activities of daily living and/or cognitive impairment associated with dementia. The needs of this group are for holistic care and long-term support at home, caregiver support, and nursing care at home or in care homes. In many countries, support for this group is inconsistent. Therefore, to meet the end-of-life needs of all patients reliably, we must provide support to people with all illnesses, and primary care is uniquely placed to identify patients with one or more advanced progressive conditions. There is a challenge for specialist palliative care to redesign services so that they are configured to meet the typical needs of people on the three archetypal trajectories, providing access based on needs not diagnosis. An emphasis on education and integrating with primary care are the obvious ways to take this forward.

With cancer, traditionally there was a period when a cure was the aim and then, when this was no longer possible, palliative care intervened. The new and better concept is that supportive and palliative care should start at diagnosis of a life-threatening illness and gradually increase while disease-modifying management may change its focus or decrease (Figure 3.2). This model and understanding can be applied to all people with progressive conditions including organ failure and frailty.6,7 As debility increases, from specific illnesses or general frailty, people can be considered for a palliative approach while continuing with disease-modifying treatment. Provision of palliative care should be triggered not by diagnosis, or even prognosis, but by a growing burden of illness and related needs. Another specific trigger for considering a holistic palliative approach might be admission to a residential or nursing care home, as this transition is to increase supportive care. Alternatively, for people at home the need for more practical care and support for the patient and or caregiver can be a trigger for review of overall care and care planning. In the organ failure and frailty trajectories, it can be more difficult to conceptualize and decide when a palliative care approach might be clinically appropriate. However, examining a typical organ failure trajectory, it is evident that events or triggers such as a hospital admission might be utilized to consider moving from a chronic disease management approach (stage 1) to a proactive, supportive, and palliative care approach (stage 2). Then when the patient reaches the last days of life, terminal care can be planned in stage 3, as illustrated in Figure 3.3. Alternatively, there might be clinical indicators such as breathlessness at rest or other persistent symptoms despite optimal disease management to trigger stage 2. Some clinicians use the surprise question to help them identify when care goals might need review. This question is

FIGURE 3.2  Supportive and palliative care should start at diagnosis of life-threatening disease. (From Murray, S.A., Kendall, M., Boyd, K., and Sheikh, A, Illness trajectories and palliative care, BMJ, 330, 1007–1011,2005, Copyright 2005, with permission from BMJ Publishing Group Ltd.)

Palliative Care as a Primary Care Issue

19

FIGURE 3.3  Caring for people with organ failure: Three progressive stages in advanced illnesses. commonly stated as: “Would I be surprised if this patient were to die in the next year?” If the answer is “no,” this means that the patient is probably sufficiently at risk of dying and is ready for anticipatory care planning to be started just in case. Research has shown that patients are living with both preparation for death and hopes for the future, as they often describe dual narratives of illness.8 Several tools have been developed for use in primary care to help doctors and community nurses identify patients as they transition to a point when a supportive and palliative care approach is beneficial.9 A tool used increasingly in primary care and other care settings around the world is the Supportive and Palliative Care Indicator Tool (SPICT). It consists of evidencebased clinical indicators of deteriorating health, both condition specific and generic. These point to a growing burden of illnessrelated suffering such that introducing palliative care would be of benefit. SPICT is available for download from an open access website (http://www.spict.org.uk). There are translations in 10 languages and a free application is also available (https://www. spict.org.uk/spictapp/). SPICT can be used opportunistically at patient consultations or by scanning patient disease registers or primary care records to identify such patients for a comprehensive needs assessment and a palliative care approach including proactive future care planning.10,11 SPICT also offers guidance on communication and care planning. Treatments and potentially distressing interventions that are no longer of benefit late in the course of all these types of illnesses, when the person is in the last days of life, can be prevented by diagnosing imminent death and caring for the patient and family using an individualized, holistic, end-oflife care plan. This approach ensures that communication with patient and family is central, goals of care are clear, and treatments and tests that are not consistent with the agreed care goals or are of greater burden than benefit are stopped. Plans are made to manage any symptoms or problems that might develop, including as needed prescription of medications. Family, spiritual, religious, cultural, and other needs are considered and addressed. Earlier discussions in primary care about thinking ahead and planning for when a person deteriorates and might die can reduce the risks of over-treatment and having to make such decisions in a crisis.

Third potential of palliative care in primary care: Meeting all dimensions of need (physical, psychological, social, and spiritual) Family physicians are skilled at providing patient-centered care in the context of family and community and are trained in person-centered communication. When the doctor–patient relationship is well established, the trust and mutual understanding that are essential to the therapeutic relationship are already present. This also helps patients receive support and care starting from the time of diagnosis of the potentially fatal illness, when psychological and existential distress may be especially acute.12–14 It is now recognized that everyone has spiritual needs when faced with serious life-threatening illness. An internationally accepted definition states, “spiritual needs are needs that relate to the meaning and purpose of life.”8 People may or may not use religious vocabulary to express such needs. If the spiritual issue or need causes the person distress, it becomes spiritual distress. Each of the above typical trajectories of physical decline has different patterns of multidimensional distress illustrated below (see Figures 3.4–3.6).14

Rapid functional decline

In people with advanced cancer, social functioning typically declines in parallel with physical decline, whereas psychological and spiritual wellbeing often fall together at four key times: around diagnosis, at discharge after initial treatment, as the illness progresses, and in the terminal phase (Figure 3.4). Patients and family members report that the time around diagnosis is one of the most traumatic, psychologically and existentially, with further emotional turmoil as the patient gets more ill. Thus, all people whose cancer is life-limiting, but still treatable, should be considered for palliative care from diagnosis. Patients report finding it supportive for professionals to simply acknowledge that this initial adjustment time can be very challenging. Some, but not all, value being able to talk about the likely course of events for people with their condition. Waiting for physical decline later on misses the opportunity to provide well-coordinated palliative care integrated with other treatments.

20

Textbook of Palliative Medicine and Supportive Care

FIGURE 3.4  Wellbeing trajectories in patients with rapid functional decline (typically progressive cancer).

Intermittent, fluctuating decline

person-centered, early palliative care. Anticipating likely changes and planning future care can reduce distress while promoting a realistic understanding of normal ageing. Understanding multidimensional trajectories can help family practitioners address difficult questions such as “How long have I got?” which patients sometimes ask early in the illness trajectory. A response could be “It’s hard to know how long, but can we talk about what might happen and how we support people as things change?” If uncertainty is acknowledged and worries are explored, patients and caregivers can ask for information and feel empowered by knowing more about what the future may hold.

Gradual decline

Fourth potential of palliative care in primary care: Making a difference in the community

In people with life-limiting, long-term conditions or multiple illnesses, social and psychological decline both tend to track the physical decline, while spiritual distress fluctuates more and is modulated by other influences, including the person’s capacity to remain resilient (Figure 3.5). People may die suddenly during an exacerbation or when still functioning relatively well, so death is often perceived as unexpected, although it has been predictable as a risk for some years. During the increasingly frequent exacerbations of heart, lung, liver, or renal failure, patients and their caregivers are anxious, need information, and often have social problems. Support for these needs might reduce or shorten hospital admissions. People who have frailty or a progressive neurological disease typically experience a gradual physical decline from a lower baseline15 Psychological and existential wellbeing sometimes fall in response to changes in social circumstances or an acute physical illness but a decrease in social, psychological, or existential wellbeing can herald global physical decline or death (Figure 10.6). Some older people reach a tipping point when they feel unable to live usefully or with dignity and experience increasing psychological and existential distress before dying. Actions to promote optimum physical health should be combined with help to engage with social support and care that lets people maintain a sense of self and purpose. Allowing people to raise and discuss their greatest fears—of losing independence, developing dementia, or being a burden to others—is

In many economically developed countries, only about 20–25% of people die at home. However, surveys indicate that many more people would prefer to die at home, if possible. The Gold Standards Framework, developed in the UK, is being used by many primary care teams there and in other countries to deliver primary palliative care in the community. It gives a framework for general practitioners and community nurses to organize and coordinate care within their practices. In the UK National Health Service, all patients are registered with a specific practice, and this framework is based on creating a register of all patients identified for supportive or palliative care within each practice. It highlights the 7Cs, seven aspects that are vital for quality palliative and

FIGURE 3.5  Wellbeing trajectories in patients with intermittent decline (typically organ failure or multimorbidity).

Palliative Care as a Primary Care Issue

21

FIGURE 3.6  Wellbeing trajectories in patients with gradual decline (typically frailty or cognitive decline).

end-of-life care in the community: communication, coordination, control of symptoms, continuity of care, continued learning, caregiver support, and care in the dying phase.16 The three main steps of the Gold Standards Framework approach and indeed of primary palliative care are the following: • Identify which patients would benefit from more support. • Assess their current and future clinical and personal/family needs. • Plan their future care. This framework has been adapted for nursing care homes, and this is also associated with positive outcomes such as less hospital admissions in the last weeks of life and more frequent documentation of advance care plans and resuscitation status information. Other interventions that have improved palliative care in the community include case conferencing with specialist palliative care.17,18 Training of family residents in palliative care in Canada has proved effective.19 Work in Australia led by practice nurses has resulted in much improved care planning. 20 Groundwork for what successful integration of primary delivery of palliative care in primary care practices might entail in the USA is reported.15

development known as health promoting palliative care is starting to make dying much more than a “medical” issue. This calls for community involvement in end-of-life care and encourages people and the community to talk more openly and be more involved in many aspects of care at the end of life. This approach argues that if death and dying were brought more into the open, it would be much easier to plan for a good death. Such an approach can be cultivated by family practitioners in their local communities, or hospices in their localities.22

Sixth potential of palliative care in primary care: Supporting family caregivers in their time of caring and subsequent bereavement Family caregivers are frequently cared for by the same primary care team as the patient. Research has revealed that family caregivers of patients with lung cancer can experience a similar dynamic pattern of needs as the people they care for, so this must be acknowledged and addressed23 (Figure 3.7). In the UK, general practitioners are encouraged to identify and keep registers of people who have a significant caring role and to assess their needs and support them.24

Fifth potential of palliative care in primary care: Reaching to all in need in economically poorer countries and learning from them about bringing death back to life As primary care is the only level of care available to most people in less developed countries, its potential must be maximized and enhanced, ideally by international collaborations to let end-of-life care reach most people there. In Africa, few countries have palliative care services integrated within their national health services, although Uganda, Kenya, and Rwanda lead the way.21 But most African countries have vibrant communities where members visit the dying to comfort and support them practically. Economically developed countries can learn much from talking about death and dying, visiting people, and supporting our friends and neighbors in the community at the end of life. Initially in Australia and now developing internationally in India, Canada, and some European countries, an exciting

FIGURE 3.7  Trajectories of physical, social, psychological, and spiritual wellbeing in family caregivers of patients with progressive lung cancer, from diagnosis to death.

Textbook of Palliative Medicine and Supportive Care

22

Facilitating factors for strong primary palliative care Factors that facilitate palliative care in the community include a strong primary care system with large group practices where primary care physicians, nurses, and other professionals work together. Such practices can identify patients eligible for palliative care proactively and provide multidisciplinary care to people living at home. There should be a reimbursement system that values home visits, rapid access to telephone support, and longer appointments for people with complex needs. Integration with hospital and emergency care is vital to promote continuity of care and information throughout the 24 hours. Given adequate training (adapted to the constraints and the context of primary care), resources, and access to specialist support, family practitioners can provide end-of-life care to most patients. Providing primary palliative care can help fast-track the extension of the palliative care approach to people with non-malignant conditions. A toolkit to help establish palliative care by primary care professionals in their own country or state or region is available on the web page of the European Association for Palliative Care Primary Care Reference Group at: https://www.eapcnet.eu/eapc-groups/ reference/primary-care.25 Recent WHO initiatives have strongly supported palliative care to be integrated in chronic disease management.26 Furthermore, palliative care has been recognized as one of the core components of universal health coverage, and it should be available for those in need at the primary level.27 Recommendations for the integration into primary health care with guidance on how to do so are detailed in a guide published by the WHO.28

earlier rather than later, when input is strategic and formative and when emotional needs are often acute. Third, we can help patients with all dimensions of need in the community, going beyond the physical to the social, psychological, and spiritual. Fourth, we can help more people live and then die where they want to be, often at home or in a familiar care home. Fifth, we can assist lower income countries in setting up systems and training community staff to meet substantial needs for good pain and symptom control while learning from them how to talk more openly about dying and how to promote wellbeing in the face of death. Finally, palliative care based in the community can take the lead in supporting family caregivers and engaging and encouraging local communities to be actively involved in caring for friends and neighbors in the last phase of life.22

References

Caring for all in the last year or phase of life



So, palliative care can address many of its most pressing challenges through primary care. It can first go beyond cancer and help people at the end of life no matter what the illness. We shouldn’t offer palliative care according to diagnosis or even prognosis but based on need for holistic care and care planning. The second challenge primary palliative care can meet is to help





KEY LEARNING POINTS • There is great potential for palliative care to be delivered in the community, by primary care doctors and community nurses. • Primary care teams can reach many more people with palliative care needs than can specialists and also earlier in the course of the illness. • Palliative care specialists should prioritize delivering training, advice, and support for hospital and community generalists. • Primary care is well placed to provide high-quality palliative care for patients: • With all life-limiting conditions • From early in the course of the illness • With all dimensions of need • In care homes and at home • In all countries, including lower income settings • And to support family caregivers







1. Munday D, Boyd K, Jeba J, et al. Defining primary palliative care for universal health coverage. Lancet 2019;394:621–622. doi: 10.1016/ S0140-6736(19)31830-6. 2. Lunney JR, Lynn J, Foley DS, Lipson S, Guralnik JM. Patterns of functional decline at the end-of-life. JAMA 2003;289:2387–2392. 3. Aiden H. Multimorbidity. Understanding the challenge. A report for the Richmond Group of Charities. London: The Richmond Group of Charities, 2018. 4. Murray SA, Sheikh A. Making a difference campaign. BMJ 2008;336:958–959. 5. Murray SA, Kendall M, Boyd K, Sheikh A. Illness trajectories and palliative care: Clinical review. BMJ 2005;330(7498):1007–1011. 6. World Health Organization. Palliative Care: The Solid Facts. Copenhagen, Denmark: WHO, 2004. 7. Murray SA. Meeting the challenge of palliation beyond cancer. Eur J Palliat Care 2008;15:213. 8. Murray SA, Kendall M, Grant E, Boyd K, Barclay S, Sheikh A. Patterns of social psychological and spiritual decline towards the end-of-life in lung cancer and heart failure. JPSM 2007;34:393–402. 9. Maas EAT, Murray SA, Engels Y, Campbell C. What tools are available to identify patients with palliative care needs in primary care: A systematic literature review and survey of European practice. BMJ Support Palliat Care 2013;3(4):444–451. doi: 10.1136/bmjspcare-2013-000527. 10. Mason B, Boyd K, Steyn J, Kendall M, Macpherson S, Murray SA. Computer screening for palliative care needs in primary care: A mixed-methods study. Br J Gen Pract 2018;68(670):e360–e369. 11. Boyd K and Murray SA. Recognising and managing key transitions in end of life care. BMJ 2010;341:649–652. 12. Cavers D, Hacking B, Erridge SE, Kendall M, Morris PG, Murray SA. Social, psychological and existential well-being in patients with glioma and their caregivers: A qualitative study. CMAJ 2012;184(7):E373– E382. doi: 10.1503/cmaj. 111622. 13. Kendall M, Cowey E, Mead G, Barber M, McAlpine C, Stott DJ. Outcomes, experiences and palliative care in major stroke: a multicentre, mixed-method, longitudinal study. CMAJ 2018;190(9): E238–E246. 14. Murray SA, Kendall M, Mitchell G, Moine S, Amblàs-Novellas J, Boyd K. Palliative care from diagnosis to death. BMJ 2017;356:j878. doi: 10.1136/bmj.j878. 15. Nowels D, Jones J, Nowels CT, Matlock D. Perspectives of primary care providers toward palliative care for their patients. J Am Board Fam Med 2016;29:748–758. 16. Gold Standards Framework (GSF) Prognostic Indicator Guide (PIG). http://www.goldstandardsframework.org.uk/ 2012 (Accessed 24 Oct 2019). 17. Hollingworth S, Zhang J, Vaikuntam BP, Jackson C, Mitchell G. Case conference primary-secondary care planning at end of life can reduce the cost of hospitalisations. BMC Palliat Care 2016;15:84. doi: 10.1186/ s12904-016-0157-9. 18. Arora S, Smith T, Snead J, Zalud-Cerrato S, Marr L, Watson M. Project ECHO: An effective means of increasing palliative care capacity. AJMC 2017. Available from: https://www.ajmc.com/journals/evidencebased-oncology/2017/june-2017/project-echo-an-effective-means-ofincreasing-palliative-care-capacity.

Palliative Care as a Primary Care Issue 19. Pereira J, Palacios M, Collin T, Wedel R, Galloway L, Murray A. The impact of a hybrid online and classroom-based course on palliative care competencies of family medicine residents. Palliat Med 2008. 22(8):929–937. doi: 10.1177/0269216308094561. 20. The Advance Project. The Advance Project Toolkit, 2019. Available from: https://www.theadvanceproject.com.au/. (Accessed 24 Oct 2019). 21. Grant L, Downing J, Luyirika E, Murphy M, Namukwaya L, Kiyange F. Integrating palliative care into national health systems in Africa: A multi-country intervention study. J Glob Health 2017;7:010419. doi: 10.7189/jogh.07.0104. 22. Sallnow L, Richardson H, Murray SA, Kellehear A. The impact of a new public health approach to end-of-life care: A systematic review. Palliat Med 2015;30(3):200–211. doi: 10.1177/0269216315599869. 23. Murray SA, Kendall M, Boyd K, Grant L, Highet G, Sheikh A. Archetypal trajectories of social, psychological, and spiritual wellbeing and distress in family care givers of patients with lung cancer: Secondary analysis of serial qualitative interviews. BMJ 2010;340:c2581. doi:10.1136/ bmj.c2581.

23 24. Carduff E, Jarvis A, Highet G, Finucane A, Kendall M, Harrison N. Piloting a new approach in primary care to identify, assess and support carers of people with terminal illnesses: A feasibility study. BMC Fam Pract 2016;17(1):1–9. 25. Murray S, Moine S. Toolkit for the Development of Palliative Care in Primary Care, EAPC, WONCA, 2019. Available from the web page of the EAPC Primary Care Reference Group: https://www.eapcnet.eu/ eapc-groups/reference/primary-care. 26. World Health Assembly. Strengthening of palliative care as a component of comprehensive care throughout the life course. Resolution WHA67.19 adopted by the sixty-seventh World Health Assembly. Geneva: WHO, 2014. Available from: http://apps.who.int/gb/ebwha/ pdf_files/wha67/a67_r19-en.pdf 27. World Health Organization, United Nations International Children’s Fund. Declaration of Astana. Global Conference on Primary Health Care. Astana, Kazakhstan, October 25–26, 2018. Geneva and New York: WHO and UNICEF, 2018. 28. World Health Organization. Integrating Palliative Care and Symptom Relief into Primary Health Care. Geneva: WHO, 2018.

4

THE FUTURE OF PALLIATIVE MEDICINE

Charles F. Von Gunten and Irene J. Higginson

Contents Introduction..........................................................................................................................................................................................................................25 Palliative medicine now......................................................................................................................................................................................................25 Future of palliative medicine.............................................................................................................................................................................................27 Meeting individual patient and family needs...........................................................................................................................................................27 Responding to demographic changes of escalating need.......................................................................................................................................27 Developing a unique physician role............................................................................................................................................................................27 Distinct body of knowledge....................................................................................................................................................................................27 Publication of scholarly research..........................................................................................................................................................................28 Graduate medical education..................................................................................................................................................................................28 Professional association..........................................................................................................................................................................................28 Practice patterns and professional role................................................................................................................................................................28 Challenges for the future....................................................................................................................................................................................................29 Health-care policy..........................................................................................................................................................................................................29 Professional boundaries................................................................................................................................................................................................29 Developing new and appropriate models of care in response to the different trajectories of illness and diseases and to new diseases.....29 Fund-raising and/or remaining part of statutory funded care....................................................................................................................................30 Training............................................................................................................................................................................................................................30 Research...........................................................................................................................................................................................................................30 Summary................................................................................................................................................................................................................................31 References..............................................................................................................................................................................................................................31

Introduction A reliable forecast for the future requires a hard look at the present. Therefore, we will structure this chapter in three parts. First, we will broadly summarize the current state of palliative medicine in the world. Details of the development of palliative medicine in various parts of the world have been described in other chapters in this textbook. Second, we will summarize the case for a future that rests on a response to three features: the needs of patients and families, demographic changes, and the physician role in palliative medicine as a distinct subspecialty. Third, we will describe the challenges that palliative medicine must face in the future if it is to prosper.

Palliative medicine now The need for palliative care in the world is immense. Of 57 million deaths in 2016 worldwide, 6 of the top 10 were from noncommunicable diseases.1 The vast majority will suffer from pain and other symptoms as well as psychosocial or spiritual problems that palliative care will address. Surely, the governments of the world will want to ensure that palliative medicine is part of the health system response to their public’s needs.2 The current state of that response around the world can be summarized as highly variable. Part of the issue is that there isn’t a common language to describe palliative care services or the physician role. 3 Another is that each country has a different approach to the provision of health care for its citizens.4 In some countries, the field is a recognized specialty or subspecialty with

organized programs for clinical care, education, and research. In many others, a broad program of clinical care has emerged without the official recognition that grounds the discipline in the academic foundation of health care or the financing of health care. In the poorest nations, the most basic tools for the relief of suffering are unavailable. This lack of progress is despite the fact that in 2014, at the World Health Assembly, all member countries voted in favor of and together passed resolution 67.19 (2014). This resolution is that countries integrate palliative care into national health policies—by revising laws and processes to improve access to opioids and provide palliative care services through primary health care as well as through community settings with adequate resources. 5 The number of countries speaking strongly for the resolution was impressive. However, a review published in 2019 by the World Health Organization found that by 2017, only 56% of countries reported that their national non-communicable disease policy includes palliative care, with this figure ranging from 37% of countries in the Western Pacific region to 82% of countries in the South-East Asia region. Some countries did not have a national non-communicable disease policy. Just over two-thirds (68%) of countries reported they had funding for palliative care, with this proportion much higher in high-income countries (93%) than low-income countries (29%).5 One way to look at this is from an institutional change model. In such a model, an innovation (such as palliative medicine) is developed in one location (such as England, Ireland, Australia, Singapore, Canada, or the United States) and then gradually spreads to other institutions as its merits become known. There is 25

26 good evidence for this. From a handful of hospices worldwide in the 1970s and 1980s, the number of hospices and palliative care programs has grown to involve every continent of the world in more than 100 countries. The total number of hospice or palliative care initiatives is in excess of 8,000 and includes hospice inpatient units, hospital-based palliative care services, community-based teams, and day-care centers. In England and Wales, over 100,000 new patients were cared for by the 288 palliative home care teams in 2014, and 40,000 were cared for in one of the 193 inpatient hospice or palliative care units, with 2,881 beds. Of those cared for in inpatient hospices, just below 90% had cancer; of those cared for by home care teams, the proportion was around 86%, with 14% having conditions other than cancer. The mean length of stay in inpatient units was around two weeks.6 Trend analysis found that the number of annual inpatient hospice deaths increased from 17,440 in 1993 to 26,032 in 2012, accounting for 3.4% of all deaths in 1993 and 6.0% in 2012. Half of hospice decedents were men; mean age was 69.9 (standard deviation: 12.4) years. Just 5.2% of all hospice decedents had non-cancer diagnoses, and even though the likelihood of non-cancer conditions increased slightly over time, absolute numbers remained small. The proportions admitted to hospices from the more deprived areas fell slightly over time.7 Just below half (44%) of patients who are admitted are discharged from inpatient care when their reasons for admission are addressed. This is usually to homes, where many receive ongoing support. In the same year, the number of cancer deaths in England was around 140,000, suggesting that around 65% of patients with cancer receive care from a palliative care/hospice home care team, and 18% die in a hospice.6 In addition, over 85,000 new patients are seen by hospital palliative care teams each year; many of these go on to receive home care and/or hospice care. Hospital palliative care teams see more patients with non-cancer conditions—on average, around 22% of patients are cared for, but this ranges from 0% to almost 50%.8 The 2019 EAPC Atlas identified 803 specialized palliative care services for adults in the United Kingdom, and 6,388 specialized services across all Europe (a median of 0.8 adult services per 100,000 inhabitants).9 Note, however, that the number of services per inhabitant is difficult to interpret, as this does not take account of the size of the services. In the United States, where hospice care is delivered by teams primarily in patient’s homes, an estimated 1.1 million patients who died received hospice care in 2011.10 This corresponds with about 45% of all deaths in the United States. In contrast with England, 38% of patients served by hospice programs have cancer; the remainder dies from heart disease, lung disease, or other conditions. The number of hospitals in the United States who report a palliative care team has increased to 66%.6 Another way to look at the current state of affairs is from an economic point of view. Those countries that have most developed palliative care are comparatively wealthy countries where palliative care is paid for after other services are covered. Even in countries where palliative care and hospice are widely developed, such as the United Kingdom, much remains to the charitable sector. This may in part explain why the areas with higher deprivation have lower in-patient hospice access,7 as in these areas charitable hospices are more difficult to establish. In the United Kingdom, 75% of the inpatient hospices are managed by charities, with the National Health Service covering on average 34% of their costs. In the United Kingdom, place of death varies considerably according to patient characteristics. Multivariable analysis found that hospital deaths for all causes combined were

Textbook of Palliative Medicine and Supportive Care more likely for people aged 75+ years, those who lived in London, those who were divorced, single and widowed, those who lived in more deprived areas, and those who died in autumn, winter or at New Year.11 This variation by region, age, marital status, and area deprivation suggests that inequities exist, which services and better care planning could seek to address. In poorer countries where it hasn’t yet developed, health-care funds are spent in other ways. In this worldview, any money spent on palliative care in developing countries can be construed as a failure to provide the standard health care available in other countries. In other words, patients who can’t get standard health care are given morphine in order to ease their otherwise preventable death. An international comparison of formal care costs (health and social care) in the last three months of life in three high-income countries found that hospital care accounted for >80% of total care costs; community care 6–16%, palliative care 1–15%, despite all those included in the study having some access to specialist palliative care. The total mean care costs per person with cancer/non-cancer were US$37,250/US$37,376 (the United States), US$29,065/US$29,411 (Ireland), US$15,347/US$16,631 (England). Formal care costs differed markedly between the countries, as did cost distributions. Costs were most homogeneous in England. Interestingly 10% of decedents used ˜30% of total care costs. Poverty and poor home care appeared to drive high costs in the last three months of life.12 This suggests that improving community palliative care may improve care value, especially as palliative care expenditure was low. Finally, the development of palliative medicine can be viewed from a public health point of view. An argument can be made that the most significant health-care developments of the past century relate to health promotion (e.g., nutrition), prevention (e.g., sanitation, smoking cessation), and palliation (e.g., pain relief). The universality of end of life needs (it is something that happens to everyone, like birth) and the variation in palliative care access are two main reasons why palliative care is increasingly regarded as a public health issue (see Chapter 20). In this model, palliative medicine is fundamental to health care and even the poorest countries should assure their citizens with it. A further way to consider palliative medicine is the extent that it remains relevant during periods of major strain on health and social care. The role of palliative care during epidemics, pandemics, or similar such events, such during as the COVID-19 pandemic, can highlight this. There is quite limited understanding and research into the role of palliative care in epidemics or pandemics. A rapid review conducted at the start of the COVID-19 pandemic identified only 10 observational studies.13 Countries involved in this research were mainly: West Africa, Taiwan, Hong Kong, Singapore. There were only two studies outside of these regions, one from the USA, which was based on simulated experiences, and a survey from Italy, conducted at the start of the pandemic to understand the “readiness” of hospice and palliative care services.14 There is a great risk that during pandemics and epidemics, or other crises, palliative care is overlooked. Indeed, as was pointed out in the Lancet, palliative care was not mentioned in the World Health Organization response.15,16 This overlooks the fact that the relief of suffering, supporting complex decision-making, and managing clinical uncertainty are key attributes of palliative care and are also essential components of the response to epidemics and pandemics.13 However, several of the public health measures implemented during a pandemic, which are designed to slow the spread of the virus, also in crease barriers for families and limit

The Future of Palliative Medicine interdisciplinary support.17–20 There is a risk of shortage of medicines supply, equipment such as syringe drivers and personal protective equipment, and potentially staff, if staff become unwell due to infection themselves, which all limit the response.13,21,22 The bereavement issues are also potentially immense. In the context of a new disease, research and international collaboration are essential. Early data described some of the challenges faced by patients with COVID-19. The most prevalent symptoms seemed to be breathlessness (67%), agitation (43%), drowsiness (36%), pain (23%), and delirium (24%). More than half of the patients in one palliative care service needed subcutaneous infusions to control symptoms, frequently opioids and a benzodiazepine.23 International collaboration and a minimum data set would accelerate finding answers to new questions as any new disease or pandemic develops.

Future of palliative medicine The future of palliative medicine rests on the responses to three features.

Meeting individual patient and family needs

People with serious chronic illness, and their families, experience a remarkably similar set of needs that are relatively independent of the specific disease or diseases from which they suffer. These can be categorized in the physical, psychological (emotional), social (practical), and spiritual (existential) domains. The prevalence of symptoms such as pain, breathlessness, and fatigue ranges from 50% to 80%.24 Psychological conditions such as depression and anxiety affect both patient and family. The effect of the social domain, including family and community relationships and support, and the need for services can be provided. This includes the patient’s and family’s need for information and training. Finally, the spiritual or existential domain that involves the search for meaning is often affected by serious illness. Fortunately, there is growing evidence that palliative care is an effective response to these needs. When pain and symptoms are controlled, information is shared, family and caregivers are supported, services are coordinated, and health-care outcomes are improved at a reasonable cost.

Responding to demographic changes of escalating need

People in both the developed and developing world are aging. People live longer and the proportion of those living more than 65 years into very old age is also increasing rapidly. The pattern of disease from which these people die is now characterized by chronic progressive illnesses, including the frailty syndrome of advanced age. This means there will be more people needing health care toward the end of life. There are three significant changes driving this escalating need. The first is the predicted rise in the number of annual deaths from non-communicable diseases, with increases of around 15–30% in the next 15 years in many countries.25–28 This crescendo in annual deaths is brought about by both a delaying of deaths until later life due to earlier prevention, and a 1950s boom of births in many countries. The second is that people are living longer with their chronic diseases, with increasing multimorbidity, symptoms, and problems, experienced for longer periods of time.25 The third is the increasing evidence that specialist palliative care earlier in the course of illness, integrated with existing services, can prevent problems, is effective and valued by patients and those important to them, and may lead to cost-savings.29–34

27 The imperative question is, what is the correct response to this increased need? Especially when the rise in people needing palliative care will pressurize existing community and hospital services even further.28,35 Palliative medicine is likely to have a critical role in (1) helping to increase and upskill a community health and social care workforce through education, training, and valuing of care work; (2) building community care capacity through informal caregiver support and community engagement; and (3) to stimulate a realistic public debate on death, dying and sustainable funding.28 This will require evidence of effectiveness, in particular of new models of care designed to respond to the populations of tomorrow. These would need to be implemented in different contexts with an available workforce. Models such as early short term palliative care, and increasingly an integration with rehabilitation approaches, are likely to be needed for these populations.29,36,37 Recent evidence also suggests that palliative care is particularly effective when needs are complex and multimorbidity is prevalent. 38 At the same time as this growth of people who need care, there is a decrease in the number of both formal and informal caregivers. Innovative ways of providing care are needed. One component of that plan is palliative care.

Developing a unique physician role

The development of the palliative medicine role within the multiprofessional teams who deliver palliative care within hospitals, inpatient units, nursing facilities, or patient’s homes is a significant development of the past 50 years. The future of palliative medicine rests on the strength of the case for the field as a distinct specialty. The specialty of palliative medicine has moved from an emerging discipline to a recognized area of expertise in some parts of the world. It is formally recognized as a distinct specialty in a growing number of countries, for example, in Great Britain, Ireland, Poland, Australia, Canada, and the United States. Subspecialty recognition is also increasing, but levels of training vary. Around half (29/51) of the European countries considered in the 2019 European Association for Palliative Care (EAPC) Atlas of Palliative Care have an official accreditation process for physicians in palliative medicine organized by national competent authorities. However, this varies from palliative medicine being recognized as a separate specialty in a handful of countries (such as Great Britain, Ireland, Poland), to a sub-specialty (11/51) or as a special field of competence (13/51) with quite short training programs.9,39 We can expect similar recognition in other countries for the following reasons.40–42

Distinct body of knowledge

A distinct body of scientific knowledge in palliative medicine has accumulated over the past 40 years.43 The emergence of specialized journals, well-regarded textbooks, and formal curricula is an indicator. This textbook is but one repository. That knowledge is expressed in a variety of scientific and academic endeavors. For instance, the Cochrane Collaboration has a pain, palliative care, and supportive care review group that has produced over 270 reviews.44 In 2004, the UK government published guidance from the National Institute of Clinical Excellence on supportive and palliative care in cancer.45 The guidance had reviewed the evidence for the effectiveness of 13 areas of supportive and palliative care, including communication, information, psychological support, specialist palliative care, end-of-life care, and rehabilitation.46 In 2018, the National Consensus Project for Quality Palliative Care published its fourth revision of the clinical practice guidelines

28 for quality palliative care based on an extensive evidence review and consensus process with the major US palliative care organizations.47 Addressing the needs of policy makers, the World Health Organization’s European Office produced an evidencebased guidance on palliative care in two complementary booklets. Palliative Care: The Solid Facts48 dealt with general palliative care issues, future needs, and evidence, and Better Palliative Care for Older People49 dealt with the need to address the demographic changes in society and take a public health approach to palliative care. Most recently, the Institute of Medicine in the United States is revisiting its landmark report from 1997 on the state of end-oflife care in the United States and in 2019 undertook a consensus study to explore current state and barriers to advance progress.50 The EAPC and National Associations within Europe have developed white papers and guidance on many aspects of care and policy as have other national and international organizations based in Taiwan, Australia, Singapore, New Zealand, Canada, Africa, India, and many other regions. The major skills central to palliative medicine are the assessment and management of physical, psychological, and spiritual suffering faced by patients with life-limiting illnesses and their families. Communication and teamwork are also critical skills in palliative medicine.

Publication of scholarly research

New knowledge is being discovered at an expanding rate. Research in the area of palliative medicine appears in at least eight international specialized peer-reviewed journals: Journal of Palliative Care, Journal of Pain and Symptom Management (including supportive and palliative care, the United States), Journal of Palliative Medicine (the United States), Palliative Medicine (the United Kingdom), American Journal of Hospice and Palliative Care (the United States), Palliative and Supportive Care (the United States), Progress in Palliative Care (Australia), BMC Palliative Care (a web-based rapid publication from biomedcentral.com, an international group), and Supportive Care in Cancer (Switzerland). More than one curriculum for palliative medicine has been published.51–54 Models to guide clinical palliative care have been disseminated, 55 and a number of well-regarded textbooks are now available56–58 of which the Oxford Textbook of Palliative Care is now in its fourth edition. In fact, the Oxford University Press has prioritized being a market leader in publishing in palliative care, with Oxford Scholarship Online-palliative care as a search tool.59

Graduate medical education

New specialties are characterized by defined training programs that prepare the holder of an undergraduate medical degree for independent practice. Specialty training programs are usually of 3–4 years length after general medical training. In the United Kingdom, individuals begin the four-year training program in palliative medicine once they have completed their medical degree and around three years of general medical posts, including hospital medicine. The Association for Palliative Medicine of Great Britain and Ireland has over 1,000 physician members, of which 450 are in training, 100 are associate members registered in other medical specialties or general practice, and the rest are consultants (fully qualified) or associate specialists (completing a shorter program60). There is a national training program, with regionally organized advertising and monitoring. In Great Britain, Palliative Medicine is one of the larger medical specialties, now being the 12th largest specialty within medicine, with a

Textbook of Palliative Medicine and Supportive Care similar number of physicians to oncologists.40 However, palliative care and palliative medicine are minute in terms of clinical academic training or established academic positions, opportunities, new knowledge, or priority for policy makers.41,42 In the United States, there are 85 programs in operation with a total of 234 physicians in training.61 In Australia, palliative medicine specialists are Fellows of the Royal Australasian College of Physicians and have completed the College’s training program in palliative medicine, a Fellow of the Australasian Chapter of Palliative Medicine, or both. The College’s training program comprises three years of full-time equivalent (FTE) training in either a pediatric or adult setting under the supervision of a Palliative Care physician. Successful trainees are accredited as a palliative medicine physician in Australia or New Zealand. In Australia, medical practitioners may also complete a six-month Clinical Diploma in Palliative Medicine, but this qualification does not result in specialist accreditation. In 2017, there were 249 specialist palliative medicine physicians employed in Australia, representing 1 in 140 employed medical specialists, and 1.0 FTE per 100,000 population, respectively. 39

Professional association

New specialties are also characterized by professional associations. The American Academy of Hospice and Palliative Medicine (AAHPM) is the professional association for physicians in palliative medicine. AAHPM currently has 5,000 physician members.61 The Association for Palliative Medicine of Great Britain and Ireland has over 1,000 members. The EAPC is a membership organization composed, in part, by members of the national associations of countries throughout western and central Europe. Palliative Care Australia is the national peak body for palliative care in Australia representing all those who work toward highquality palliative care for all Australians. The body works closely with consumers, its Member Organizations, and the palliative care workforce, to improve access to, and promote the need for, palliative care. Palliative Care Australia was launched in 1998, developing from the Australian Association for Hospice and Palliative Care Inc., which started in 1991. Similar associations have formed in Southeast Asia, Africa, South America, and most parts of the globe.

Practice patterns and professional role

The 1997 Institute of Medicine report, Approaching Death: Improving Care at the End of Life, delineated a three-tiered structure for professional competence: 1. A basic level of competence in the care of the dying patient for all practitioners. 2. An expected level of palliative and humanistic skills considerably beyond this basic level. 3. A cadre of superlative professionals to develop and provide exemplary care for those approaching death, to guide others in the delivery of such care, and to generate new knowledge to improve care of the dying.52 These three levels correspond to the primary, secondary, and tertiary levels around which medical care is commonly organized. Primary palliative care (a term used mainly in the United States; in the United Kingdom and much of the rest of Europe, the term used is the palliative care approach, or generalist palliative care, and here, primary palliative care refers to palliative care in the

The Future of Palliative Medicine primary care setting, i.e., the community, organized by general practitioners and family doctors) is the responsibility of all physicians. This includes basic approaches to the relief of suffering and improving quality of life for the whole person and his or her family. Secondary (referred to also as specialist) palliative care is the responsibility of specialists and hospital or community-based palliative care or hospice programs. The role of the secondary specialist or program is to provide consultation and assist the managing service. Tertiary palliative care is the province of academic centers where new knowledge is created through research, and new knowledge is disseminated through education, as well as providing a clinical service. The major competencies of the specialist level palliative medicine practitioner can be summarized under the broad patientcentered goals of • relief of symptom and suffering • promotion of quality of life for patients and families in the context of life-threatening illness • promotion of the development and growth possible at the end of life While the knowledge domains and skills of palliative medicine overlap to some extent with the knowledge, attitudes, and skills that characterize other disciplines that care for patients with advanced illnesses, the specialty practice of palliative medicine is distinguished from other disciplines by its focus on the common features and symptoms associated with life-limiting disease. Palliative medicine reaches across many disease categories and organ systems to concentrate on relieving the burden of illness. The palliative medicine specialist acquires and applies (1) a higher level of clinical expertise in addressing the multidimensional needs of patients with life-threatening illnesses, including a practical skill set in symptom control interventions; (2) a high level of expertise in both clinical and nonclinical issues related to death and dying; (3) a commitment to an interdisciplinary team approach; and (4) the strong focus on the patient and family as the unit of care. The specialist level competency required of practitioners in palliative medicine complements the core competency that should be maintained by other disciplines.

Challenges for the future There are a number of challenges that confront the future of the field. These include the response of health-care policy makers, the definition of the boundaries of the specialty, and the training of the new physicians that are needed.

Health-care policy

The future of palliative medicine requires a social and political impetus that is beyond the scope of medicine and firmly in the sphere of government. For palliative medicine to prosper, healthcare policy must place much greater emphasis on the care of people of all ages who are living with and dying from a range of serious chronic diseases. The structure of health care as if these prevalent illnesses are acute and curable must be changed. Therefore, publicly funded palliative care services as a core part of health care is needed; it cannot be an add-on extra. Those services must meet the needs in the rural and urban community dwelling public as well as in nursing homes and hospitals, including intensive care. Those services must be based on need rather than on specific diseases or prognosis. Finally, health-care policy must provide for

29 the development of new knowledge through research. Despite the prevalence of palliative care need, national research budgets are paltry. Surely, we don’t want to be using the same tools and treatments in 50 years that we have now. The low level of investment in research—less than 1% of research funding in cancer is spent on palliative or end of life care, and this percentage is likely even lower in other conditions41—limits growth here. There is an urgent need for palliative care practitioners, hospice and palliative care services, charities, and governments to prioritize highquality research and invest in this. The example of Australia is particularly insightful here. In Australia, resourcing of palliative care has moved to a needs-based approach, with services receiving core funding and not having to rely on charitable income for the bulk of their day-to-day running costs. However, moving toward more core funding will bring with it a responsibility for specialist palliative care services to monitor and report their outcomes and to show the additional quality of care provided and complexity of patients and families cared for.

Professional boundaries

A significant issue that confronts the future of the field is whether it focuses on a condition (the dying patient) or relates to a broader set of competencies that can be integrated across the spectrum of serious and chronic illness. The roots of palliative medicine in hospice care for the dying would lend itself to the former. The experiences of hospital-based and outpatient office-based palliative medicine physicians suggest that the skills are more broadly applicable than just for the dying. Furthermore, good symptom management and psychosocial care require earlier palliative care intervention. Many patients and families should not have to wait until they are confirmed to be at the end of life to be offered the palliative care expertise in symptom control or emotional, social, or spiritual support. New models of palliative care are exploring how it can be integrated with other specialties, so that patients can receive potentially life-extending treatment at the same time as symptom relief and psychosocial and spiritual support. Palliative medicine is practiced within the context of a team. Some would say it cannot be practiced without a team. Yet, the broad interdisciplinary nature of palliative medicine makes it more challenging to define the boundaries of the specialty than for those with a disease focus (such as oncology), an organ focus (such as cardiology), or a technical skill (such as surgery). As with other fields, there are areas of overlap with other specialties and subspecialties. Delineating and negotiating those boundaries are an important aspect of the maturation of the discipline. There is little argument that palliative medicine is primarily a consulting specialty to the other primary disciplines. There is no agenda, expressed or implied, that all suffering and dying patients be cared for by physicians board certified in palliative medicine.

Developing new and appropriate models of care in response to the different trajectories of illness and diseases and to new diseases Although the symptom and problem profile of patients with different chronic progressive conditions are similar, the trajectory of diseases is likely to vary. In addition, caring for older people, an increasing part of the palliative care population, has specific challenges—notably iatrogenic disease, multiple pathology, and difficulties in prognostication. The early models of palliative care may have to evolve to care for these patients. In particular, the model

Textbook of Palliative Medicine and Supportive Care

30 of consultation and palliative care offered for periods throughout the illness, rather than at a particular prognostic point, may have to develop. It will be a challenge for palliative medicine to develop and test such models of care while maintaining existing services. Some new models, such as short-term palliative care, are being developed and tested. These test ways to offer palliative care earlier in the course of the illness, but in the short term, integrated with other services. Evidence to date is preliminary but suggests benefits. For example, a randomized trial of early palliative care in oncology for patients with lung cancer found quality of life and survival benefits. 34 Early palliative care for people severely affected by multiple sclerosis appeared to have benefits in terms of reduced caregiver burden and improved symptom control and lower overall costs, without worsening, and possibly improving, survival. 37 The Salzburg Global Seminar on “Rethinking Care Toward the End of Life” brought together 66 health leaders from 14 countries to engage in cross-cultural and collaborative discussions across several future focused themes including patient/family/ caregiver engagement, integrating health and community-based social care, eliciting and honoring patient preferences, building an evidence base for palliative care, learning from system failures, and delivering end-of-life care in low-resource countries. Lessons learned from this seminar include proposals for learning from low-resource countries, wider use of existing evidence-based quality measures, improving research, training and education, and respecting the personal agency of patients and their families.62 The COVID-19 pandemic, and future pandemics, highlights the need for palliative care and hospice services to respond rapidly to changing needs of patients and in society.13,14,63–65 A framework for rapid adaptation could include consideration of systems (e.g., policies, training), staff (employed and volunteers), space (community versus inpatient, technology), and resources (medicines and equipment).13,64,66 To that we would add evidence (from research into problems and evaluation of solutions).

Fund-raising and/or remaining part of statutory funded care Currently, much of palliative care is provided within the voluntary sector and not-for-profit organizations. These have a continued battle to raise funds to stand still—and provide a continued service to the community. The charitable sector is set to become more competitive in years to come and is subject to fluctuations in response to economic changes. Becoming part of the statutory sector or receiving increased statutory funds removes some of the freedom of previously voluntary units, although it provides more security. Achieving the right balance here can be a challenge, especially as national charity organizations in some countries (e.g., the charity commission in the United Kingdom) provide guidance that charities should not undertake tasks that should be provided by statutory services. Perhaps more and more, the role of charitable organizations will be to innovate and discover better treatments and ways to care, while they advocate for the statutory sector to pick up the funding of the services they have proven, through good research, as effective and cost effective.

Training

Another challenge to the field is to build enough capacity within training programs to train the next generation of specialists.

The current interest in developing training programs is heartening, but financial resources are scarce and competition for them is strong. In England, palliative care posts can go unfilled for want of trained specialists. In the United States and many other countries, where the field is emerging, there are similar shortages. This will remain the case unless the field is recognized and sufficient capacity built into national and international programs for training medical professionals. There is an inherent challenge here, because the field needs the best dedicated and bright clinicians who have undergone sufficient training. Therefore, a balance needs to be struck between filling posts and filling them with sufficiently experienced and qualified individuals who have the ability to deliver the services and development, and to engage in the research and education needed. Palliative medicine clinicians often find themselves in leadership roles and so have to not only provide clinical care but be versed in managing and motivating staff, strategically developing their services, engage in the implementation and generation of new knowledge, and often negotiating contracts and teaching other doctors. They also need to educate others, as there are not sufficient palliative care clinicians to meet all the needs. Burnout is likely to be a problem in palliative care, especially if clinicians are isolated and asked to cover services 24 hours, without backup or peer support, as well as to deal with issues of staff management and service development (see the Burnout chapter in this book). Equally, problems can arise in clinical academic posts, where filling posts with individuals without sufficiently robust trackrecords or from fields outside of palliative medicine can lead to loss of respect for the field or a distraction of effort away from palliative medicine patients. International networks for capacity building and support might help to improve and motivate individuals within the field, but they would require resourcing.

Research

A major challenge for the future of palliative medicine is to become a strong specialty for the future. Robust knowledge has to be a central key to this. The COVID-19 pandemic also highlighted the need for international research collaboration, and having a research infrastructure so that new knowledge about any new condition could be quickly generated. During the pandemic this was a challenge for palliative care. If the specialty is to contribute to the future care of patients and families, then the evidence base for the treatment of many symptoms and problems needs to be improved. Unfortunately, research has been and continues to be relatively neglected. There has been inadequate funding in all countries, a hesitancy on the part of some ethics committees and Institutional Review Boards to fully support research, and a reluctance of some staff, who entered the specialty because they felt it did not involve research. There are problems too because of the nature of research in palliative care, which is often difficult because of ethical concerns, the intangible nature of many aspects to be measured (e.g., fatigue, quality of life, quality of death), and the fact that patients are ill and difficult to interview. They may live for unpredictable times. Weighed against this, we should recognize that there have been enormous achievements in research in palliative medicine in the last decades, despite these problems and the lack of resources. This is a tribute to the few centers and individuals who are researching the field. In the future, an improved training in appraising and participating in research is needed for doctors and nurses entering the field. There is now evidenced-based guidance and statements on the conduct and

The Future of Palliative Medicine reporting of research in palliative care, such as the Medical Research Council generate guidance, MORECare.67 MORECare includes additional recommendations such as on ethical issues encountered in research, 68 how and when to measure outcomes, 69 how to manage missing data,70 and how to integrate and publish mixed methods.67 The MORECare guidance is listed on the EQUATOR network to improve the conduct and reporting of health research are increasingly being used by editors, researchers, clinicians, and academics.71 It is not expected that everyone will conduct research, but all will need to appraise it and may increasingly be part of large studies organized in tertiary centers.72

Summary In summary, there can be a bright future for palliative medicine. There is a widespread need within society and this is set to escalate in the future. There is now a body of good-quality evidence that shows that palliative medicine within palliative care programs can meet the need. The challenge is clear. The field needs to grow to sufficient size to be a sustainable response. It also needs to develop mechanisms to meet the challenge of the changing population and in particular the increase in the elderly population and changed trajectory of illness; it needs to continually improve the caliber and skills of those in the field, through training, and to invest substantially in research to discover and test better methods of care and treatment, and to build research capacity.

KEY LEARNING POINTS • Palliative medicine is highly variable in the world. • The evidence base supports the effectiveness of palliative care. • The demographic changes in the world’s populations (living longer with more chronic ultimately fatal disease and increasing numbers of deaths) require expanded palliative care services. • Research in palliative care is vital. This was highlighted especially during the COVID-19 pandemic, where responses to a new disease resulted in a need for evidence to be gathered urgently. • It is vital in the coming years that palliative care moves from being an add-on extra to become a core component of health care. To do this, it will have to become needs-based, evidence-based, and report its outcomes. The development of a unique palliative medicine role for the physician within multiprofessional teams is a phenomenon likely to develop in most countries. • Expanding clinical services to meet the needs of patients and families will require modifications in patterns of care and new models of care and expansion of the numbers of trained physicians and other professionals needed to provide palliative care. • Collection of internationally agreed data on outcomes and the issues faced by patients and families will be key for the field in the future.

31

References

1. World Health Organization. 2019. whoint/news-room/fact-sheets/ detail/the-top-10-causes-of-death (Accessed 19 Aug 2019). 2. Radbruch L, de Lima L, Lohmann D, Gwyther E, Payne S. The Prague Charter: Urging government to relieve suffering and ensure the right to palliative care. Palliat Med 2012;25:101–102. 3. von Gunten CF. Humpty-Dumpty syndrome. Palliat Med 2007;21:461–462. 4. Centeno C, Clark D, Lynch T, et al. Facts and indicators on palliative care development in 52 countries of the WHO European region: Results of an EAPC Task Force. Palliat Med 2007;21:463–471. 5. World Health Organization. Palliative Care for Non-communicable Diseases: A Global Snapshot. World Health Organization, 2019. ● 6. National Council for Palliative Care: Minimum Data Set. National Survey of Patient Activity Data for Specialist Palliative Care Services. London, UK: National Council for Palliative Care, 2019. http:// w w w.endof lifecare-intelligence.org.uk/resources/publications/ mdsreport2014 (Accessed 19 Aug 2019). 7. Sleeman KE, Davies JM, Verne J, Gao W, Higginson IJ. The changing demographics of inpatient hospice death: Population-based crosssectional study in England, 1993–2012. Palliat Med 2016;30(1):45–53. 8. Palliative Care Information—UK, 2014. http://www.helpthehospices. org.uk/about-hospice-care/facts-figures/ (Accessed 21 July 2014). 9. Arias A, Garralda E, Rhee J, et al. EAPC Atlas of Palliative Care. Europe Vilvoorde: EAPC Press, 2019. 10. NHPCO Facts and Figures: Hospice Care in America. 2018 addition, 2019. https://www.nhpco.org/wp-content/uploads/2019/07/2018_ NHPCO_Facts_Figures.pdf (Accessed 19 Aug 2019). 11. Gao WHY, Verne J, Gordon E, Higginson IJ. Geographical and temporal understanding in place of Death in England (1984–2010): Analysis of trends and associated factors to improve end-of-life Care (GUIDE Care). Health Serv Deliv Res 2014;2(42):1–104. 12. Yi D, Johnston BM, Ryan K, et al. Drivers of care costs and quality in the last 3 months of life among older people receiving palliative care: A multinational mortality follow-back survey across England, Ireland and the United States. Palliat Med 2020;34(4):513–523. doi: 10.1177/0269216319896745. 13. Etkind S, Bone AE, Nea L. The role and response of palliative care and hospice services in epidemics and pandemics: A rapid review to inform practice during the COVID-19 pandemic. J Pain Symptom Manage 2020;60(1): e31–e40. doi: 10.1016/j.jpainsymman.2020.03.029. 14. Costantini M, Sleeman KE, Peruselli C, Higginson IJ. Response and role of palliative care during the COVID-19 pandemic: A national telephone survey of hospices in Italy. Palliat Med 2020;34(7):889–895 (preprint at https://www.medrxiv.org/content/10.1101/2020.03.18.200 38448v1; doi: 10.1101/2020.03.18.20038448). 15. Radbruch L, Knaul FM, de Lima L, de Joncheere C, Bhadelia A. The key role of palliative care in response to the COVID-19 tsunami of suffering. Lancet 2020;395(10235);1467–1469. 16. The Lancet. Palliative care and the COVID-19 pandemic. Lancet 2020;395(10231):1168. 17. Fusi-Schmidhauser T, Preston NJ, Keller N, Gamondi C. Conservative management of COVID-19 patients-emergency palliative care in action. J Pain Symptom Manage 2020;60(1):e27–e30. 18. Hendin A, La Riviere CG, Williscroft DM, O’Connor E, Hughes J, Fischer LM. End-of-life care in the emergency department for the patient imminently dying of a highly transmissible acute respiratory infection (such as COVID-19). CJEM 2020;22(4):1–4. 19. Koh MYH. Palliative care in the time of COVID-19: Reflections from the frontline. J Pain Symptom Manage 2020;60(1):e3–e4. 20. Kunz R, Minder M. COVID-19 pandemic: Palliative care for elderly and frail patients at home and in residential and nursing homes. Swiss Med Wkly 2020;150:w20235. 21. Bajwah S, Wilcock A, Towers R. Managing the supportive care needs of those affected by COVID-19. Eur Respir J 2020. doi: 10.1183/13993003.00815-2020 (online). 22. Borasio GD, Gamondi C, Obrist M, Jox R, for the Covid-Task Force of Palliative Collaborators. COVID-19: Decision making and palliative care. Swiss Med Wkly 2020;150:w20233. 23. Lovell N, Maddocks M, Etkind SN, et al. Characteristics, symptom management and outcomes of 101 patients with COVID-19 referred for hospital palliative care. J Pain Symptom Manage 2020;60(1):e77–e81. ● 24. Solano JP, Gomez B, Higginson IJ. A comparison of symptom prevalence in far advanced cancer, AIDS, heart disease, chronic obstructive pulmonary disease (COPD) and renal disease. JPSM 2005;31:58–69.

32 25. Etkind SN, Bone AE, Gomes B, et al. How many people will need palliative care in 2040? Past trends, future projections and implications for services. BMC Med 2017;15(1):102. 26. Sleeman KE, de Brito M, Etkind S, et al. The escalating global burden of serious health-related suffering: Projections to 2060 by world regions, age groups, and health conditions. Lancet Glob Health 2019;7(7):e883–e892. 27. Sarmento VP, Higginson IJ, Ferreira PL, Gomes B. Past trends and projections of hospital deaths to inform the integration of palliative care in one of the most ageing countries in the world. Palliat Med 2016;30(4):363–373. 28. Finucane AM, Bone AE, Evans CJ, et al. The impact of population ageing on end-of-life care in Scotland: Projections of place of death and recommendations for future service provision. BMC Palliat Care 2019;18(1):112. 29. Higginson IJ, Bausewein C, Reilly CC, et al. An integrated palliative and respiratory care service for patients with advanced disease and refractory breathlessness: A randomised controlled trial. Lancet Respir Med 2014;2(12):979–987. 30. May P, Normand C, Cassel JB, et al. Economics of palliative care for hospitalized adults with serious illness: A meta-analysis. JAMA Intern Med 2018;178(6):820–829. 31. Brighton LJ, Miller S, Farquhar M, et al. Holistic services for people with advanced disease and chronic breathlessness: A systematic review and meta-analysis. Thorax 2019;74(3):270–281. 32. Farquhar MC, Prevost AT, McCrone P, et al. Is a specialist breathlessness service more effective and cost-effective for patients with advanced cancer and their carers than standard care? Findings of a mixed-method randomised controlled trial. BMC Med 2014;12:194. 33. Bakitas MA, El-Jawahri A, Farquhar M, et al. The TEAM approach to improving oncology outcomes by incorporating palliative care in practice. J Oncol Pract 2017;13(9):557–566. 34. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non–small-cell lung cancer. N Engl J Med 2010;363(8):733–742. 35. Bone AE, Gomes B, Etkind SN, et al. What is the impact of population ageing on the future provision of end-of-life care? Population-based projections of place of death. Palliat Med 2018;32(2):329–336. 36. Bone AE, Morgan M, Maddocks M, et al. Developing a model of shortterm integrated palliative and supportive care for frail older people in community settings: Perspectives of older people, carers and other key stakeholders. Age Ageing 2016;45(6):863–873. 37. Higginson IJ, McCrone P, Hart SR, Burman R, Silber E, Edmonds PM. Is short-term palliative care cost-effective in multiple sclerosis? A randomized phase II trial. J Pain Symptom Manage 2009;38(6):816–826. 38. May P, Garrido MM, Cassel JB, et al. Palliative care teams’ cost-saving effect is larger for cancer patients with higher numbers of comorbidities. Health Aff (Millwood) 2016;35(1):44–53. 39. Australian Institute of Health and Welfare. Palliative Care Services in Australia. Australia Government, 2019. https://www.aihw.gov.au/ reports/palliative-care-services/palliative-care-services-in-australia/ contents/palliative-care-workforce (Accessed 21 Feb 2020). 40. Royal College of Physicians. Focus on Physicians: 2018–19 Census (UK Consultants and Higher Specialty Trainees). London: Royal College of Physicians, 2019. 41. Sleeman KE, Gomes B, Higginson IJ. Research into end-of-life cancer care—Investment is needed. Lancet 2012;379(9815):519. 42. Sleeman KE, Leniz J, Higginson IJ, Bristowe K. Is end-of-life care a priority for policymakers? Qualitative documentary analysis of health care strategies. Palliat Med 2018;32(9):1474–1486. 43. von Gunten CF, Lupu D. Development of a medical subspecialty in palliative medicine: Progress report. J Palliat Med 2004;7(2):209–219. ♦ 44. http://papas.cochrane.org/palliative-care-database, 2019 (Accessed 19 Aug 2019). ⋆ 45. National Institute of Clinical Excellence (NICE). Improving Supportive and Palliative Care for Adults with Cancer—The Manual. London, UK: National Institute of Clinical Excellence, 2004. ♦ 46. Gysels M, Higginson IJ. Improving Supportive and Palliative Care for Adults with Cancer: Research Evidence. London, UK: National Institute of Clinical Excellence, 2004. www.nice.org.uk/pdf/csgsresearchevidence.pdf (Accessed 7 Sept 2013). ⋆ 47. National Consensus Project for Quality Palliative Care. Clinical Practice Guidelines for Quality Palliative Care, 2019. https://www. nationalcoalitionhpc.org/ncp/ (Accessed 19 Aug 2019).

Textbook of Palliative Medicine and Supportive Care 48. Davies E, Higginson IJ. Palliative Care: The Solid Facts. Denmark: World Health Organization, 2004. 49. Davies E, Higginson IJ. Better Palliative Care for Older People. Denmark: World Health Organization, 2004. 50. National Academy of Sciences, 2019. Nationalacademies.org/hmd/ Activities/Aging/TransformingEndofLife.aspx (Accessed 19 Aug 2019). 51. Billings JA, Block SD, Finn JW, et al. Initial voluntary program standards for fellowship training in palliative medicine. J Palliat Med 2002;5(1):23–33. ♦ 52. Field MJ, Cassel CK, eds. Approaching Death: Improving Care at the End of Life. Washington, DC: National Academy Press, 1997, p. 208. ♦ 53. Emanuel LL, von Gunten CF, Ferris FD, eds. The Education for Physicians on End-of-life Care (EPEC) Curriculum, 1999. www.epec. net (Accessed 3 Apr 2013). 54. Schonwetter RS, Hawke W, Knight CF, eds. Hospice and Palliative Medicine Core Curriculum and Review Syllabus. American Academy of Hospice and Palliative Medicine. Dubuque, IA: Kendall/Hunt Publishing Company, 1999. 55. Ferris F, Balfour H, Bowen K, et al. A model to guide patient and family care: Based on nationally accepted principles and norms of practice. J Pain SymptManage 2002;24(2):106–123. 56. Berger AM, Portenoy RK, Weissman DE. Principles and Practice of Palliative Care and Supportive Oncology. Philadelphia, PA: LippincottRaven, 2002. 57. Doyle D, Hanks GW, MacDonald N, eds. Oxford Textbook of Palliative Medicine, 3rd edn. Oxford, England: Oxford University Press, 2003. 58. Portenoy RK, Bruera EB, eds. Topics in Palliative Care, Vol. 5. New York: Oxford University Press, 2001. 59. Oxford University Press, 2019. https://global.oup.com/academic/product/oxford-scholarship-online—palliative-care-9780199642748?cc= us&lang=en& (Accessed 19 Aug 2019). 60. Association for Palliative Medicine. 2012 Accounts. Southampton, UK: Association of Palliative Medicine, 2013 (Accessed 7 Sept 2013). 61. American Academy of Hospice and Palliative Medicine, 2013. www. AAHPM.org/fellowship/directory.html (Accessed 4 Apr 2013). 62. Bangerter LR, Griffin JM, Eagan A, et al. Recommendations from the Salzburg global seminar on rethinking care toward the end of life. Int J Qual Health Care 2018;30(5):408–413. 63. Adams C. Goals of care in a pandemic: Our experience and recommendations. J Pain Symptom Manage 2020;60:e15-e17. 64. Arya A, Buchman S, Gagnon B, Downar J. Pandemic palliative care: Beyond ventilators and saving lives. CMAJ 2020;192(15):E400–E404. 65. Chidiac C, Feuer D, Naismith J, Flatley M, Preston N. Emergency palliative care planning and support in a COVID-19 pandemic. J Palliat Med 2020;23(6):752–753. 66. Fausto J, Hirano L, Lam D, et al. Creating a palliative care inpatient response plan for COVID-19: The UW medicine experience. J Pain Symptom Manage 2020;60(1):e21–e26. 67. Higginson IJ, Evans CJ, Grande G, et al. Evaluating complex interventions in end of life care: The MORECare statement on good practice generated by a synthesis of transparent expert consultations and systematic reviews. BMC Med 2013;11:111. doi: 10.1186/1741-7015-11-111(111). 68. Gysels M, Evans CJ, Lewis P, et al. MORECare research methods guidance development: Recommendations for ethical issues in palliative and end-of-life care research. Palliat Med 2013;27(10):908–917. 69. Evans CJ, Benalia H, Preston NJ, et al. The selection and use of outcome measures in palliative and end-of-life care research: The MORECare International Consensus Workshop. J Pain Symptom Manage. 2013;46(6):925–937. 70. Preston NJ, Fayers P, Walters SJ, et al. Recommendations for managing missing data, attrition and response shift in palliative and end-of-life care research: Part of the MORECare research method guidance on statistical issues. Palliat Med 2013;27(10):899–907. 71. Oriani A, Dunleavy L, Sharples P, Perez Algorta G, Preston NJ. Are the MORECare guidelines on reporting of attrition in palliative care research populations appropriate? A systematic review and meta-analysis of randomised controlled trials. BMC Palliat Care 2020;19(1):6. 72. Center to Advance Palliative Care. 2019. www.capc.org (Accessed 19 Aug 2019).

5

PALLIATIVE CARE AND SUPPORTIVE CARE

Eduardo Bruera

Contents Introduction..........................................................................................................................................................................................................................33 Palliative medicine as an emerging medical specialty..................................................................................................................................................33 Role of supportive care.......................................................................................................................................................................................................34 Interdisciplinary nature of palliative medicine..............................................................................................................................................................34 Levels of palliative medicine..............................................................................................................................................................................................35 Conclusions...........................................................................................................................................................................................................................36 References..............................................................................................................................................................................................................................36 Web Resources......................................................................................................................................................................................................................37

Introduction Palliative care programs have three distinct characteristics: • Multidimensional assessment and management. This includes the assessment and management of a large number of physical symptoms, psychosocial distress, and functional, spiritual, financial, and family concerns. • Interdisciplinary care. This includes the pivotal role of a team including physicians, nurses, social workers, pastoral caregivers, occupational therapists and physiotherapists, pharmacists, counselors, dieticians, and volunteers who work together in an integrated fashion for the delivery of care. • Emphasis on caring for patients and their families. In the first palliative care programs, it was realized that the majority of physical and emotional care near the end of life is provided by the patient’s family. Thus, programs were developed that aimed to support those families with counseling, education, respite, and bereavement care. Physicians have had a major role in the development of palliative care programs in the United Kingdom and other areas of the world. They came from multiple specialties including family medicine, oncology, pain medicine, surgery, neurology, psychiatry, and geriatrics. These physicians are integrated with the other medical disciplines to establish palliative care teams in programs that were mostly based in the community. During the first two decades of the development of palliative care, there was an impressive and global expansion of clinical programs. It soon became clear that some of the most seriously ill patients died in acute care hospitals and cancer centers, and palliative care programs progressively expanded from the community into major academic centers. The body of knowledge of palliative care started to progressively develop and the need for research became apparent. The growth in clinical programs, the variety of settings where palliative care was delivered, and the expanding body of knowledge and need for research led to the development of the specialty of palliative medicine.

Palliative medicine as an emerging medical specialty Dr. Cicely Saunders started the modern hospice movement in the 1960s at St. Christopher’s Hospice in the United Kingdom, focusing on improving care for patients at the end of life. With increasing clinical knowledge and research, this led to the establishment of a professional discipline with expertise in symptom management, psychosocial spiritual care, patient–clinician communication, complex health-care decision making, and caregiver support.1 In the 1970s, Dr. Baulfor Mount coined the term palliative care to describe his hospice program in Canada, and this term has since gained worldwide acceptance.2 To date, palliative medicine has achieved specialty or subspecialty status in the United Kingdom (since 1987), the United States, Canada, and Australia. In addition, there are active efforts to establish palliative medicine as a subspecialty in many European countries and several countries in Latin America and Asia. The move toward accreditation is highly important because it allows palliative care practitioners to obtain standardized training and to be recognized for their expertise, clinical programs to set benchmarks for their operations, institutions, and governments to allocate health-care resources, and researchers to properly evaluate the structures, processes, and outcomes associated with palliative care services. The only nation where the specialty of palliative medicine has existed long enough to allow for some evaluation of its impact is the United Kingdom, where physicians need to complete four years of specialty training to be qualified as palliative medicine consultants. Hospice and palliative medicine have been an accredited specialty in the United States since 2009, requiring physicians to complete a one-year clinical fellowship program with an optional second year focusing on research. The consensus among physician groups in most of the world is that the development of the specialty of palliative medicine is of great importance for the further development of the field, particularly in acute care institutions and universities.

33

Textbook of Palliative Medicine and Supportive Care

34

FIGURE 5.1  Conceptual framework for supportive care, palliative care, and hospice care.

Role of supportive care The term supportive care first emerged in the early 1990s and was defined by Page et al. as the following: The provision of the necessary services for those living with or affected by cancer to meet their informational, emotional, spiritual, social or physical need during their diagnostic treatment or follow-up phases encompassing issues of health promotion and prevention, survivorship, palliation and bereavement.… In other words, supportive care is anything one does for the patient that is not aimed directly at curing his disease but rather is focused at helping the patient and family get through the illness in the best possible condition. Clearly this type of help would need to be broad in scope and as varied as the individuals requiring it. 3 Others have used supportive care in a narrower sense to describe the management of treatment-related adverse effects, such as chemotherapy-induced nausea and vomiting, oral mucositis, peripheral neuropathy, and skin rash.4 For instance, the Multinational Association of Supportive Care in Cancer has traditionally focused on the treatment of antineoplastic therapyrelated adverse effects and has now expanded its scope to include palliative care domains such as psychosocial/spiritual care and communication, as well as survivorship care. Given the significant overlap and confusion around the description of supportive care, palliative care, and hospice care, 5 we recently completed a systematic review to identify defining features for these three terms and developed a preliminary conceptual framework unifying these terms along the continuum of care (Figure 5.1).4 Hospice care focuses on providing care for patients at the end of life (i.e., last six months) predominantly in the community setting. Palliative care includes not only hospice care services, but also acute care programs in hospitals providing care for patients with advanced diseases. Supportive care is the most encompassing term that spans survivorship care services to bereavement programs for patients throughout the disease trajectory. Given that supportive care includes palliative care, it is sometimes used interchangeably to describe palliative care programs or services. We recently surveyed oncologists and mid-level providers about their perception of palliative care and supportive care.6 A majority of the respondents reported that supportive care

was less likely to cause distress in patients and families compared to palliative care and that they were more likely to refer patients to a supportive care service. Based on this finding, we changed our program name to supportive care in 2007.7 In a before and after name change comparison, we found that the name change to supportive care was associated with more inpatient referrals, as well as earlier referrals in the outpatient setting.8 There is strong evidence that early access to palliative care improves multiple clinical, quality, and financial outcomes.9,10 Consult teams and outpatient centers with the name supportive care are perceived by physicians as less likely to reduce patient and family hope and more likely to result in early referrals.11

Interdisciplinary nature of palliative medicine Figure 5.2 illustrates the main disciplines involved in the palliative circle of care. Each of these disciplines is responsible for developing its own body of knowledge and for contributing to the integration of this body of knowledge with that of the other

FIGURE 5.2  Palliative circle of care.

Palliative Care and Supportive Care

35

FIGURE 5.3  Main medical and nonmedical disciplines that influenced the body of knowledge in palliative medicine. disciplines within the circle. The effective growth and interactions of these disciplines result in increased knowledge in palliative care, which in turn improves care for patients and families. In this theoretical model, palliative medicine is the medical component of the multidimensional and interdisciplinary domain known as palliative care. Figure 5.3 shows that there are many important contributors to the body of knowledge of palliative medicine. These contributors have not only included subspecialties of medicine, but a large contribution to the knowledge of medicine has also been made by disciplines such as nursing, rehabilitation, psychology, social work, pastoral care, and nutrition.12 It is desirable to have representatives of these disciplines as part of the research and education in palliative care. It is likely that with the regular interaction as part of the palliative care circle, these disciplines will continue to influence the growth of palliative medicine in the future.

Levels of palliative medicine As palliative care matures into a professional discipline with specialized knowledge and skills, the practice of palliative care can be divided into three categories based on the level of involvement

in clinical care, education, and research.13 Box 5.1 summarizes the similarities and differences between primary, secondary, and tertiary palliative care. Palliative medicine specialists are not necessarily expected to see all patients with progressive, incurable diseases or their families. In most cases, the physician in charge of the primary care of the patient, either their family physicians (such as in Canada, the United Kingdom, and Australia4) or their primary specialists (such as in the United States,14,15 most of continental Europe,16 and the developing world17), can deliver the principles of palliative care assessment and management. These primary care physicians can access a number of other palliative care disciplines for the patient including nursing, social work, pastoral care, counseling, rehabilitation, or volunteer services. To ensure a high base level of primary palliative care delivery, we need to increase the intensity of palliative care training among medical students and postgraduate trainees. When patients present with physical or psychosocial distress that cannot be appropriately controlled by their primary care physician, involvement of secondary palliative care by a specialized team is advised. They can provide episodic care, such as consultations, or collaborative care by following up with the patient in an integrated manner with the primary physician.18,19

BOX 5.1  PRIMARY, SECONDARY, AND TERTIARY PALLIATIVE CARE

Personnel Roles Settings

Complexity of patient cases Involvement in palliative care education Involvement in palliative care research

Primary palliative care

Secondary palliative care

Tertiary palliative care

Primary care or specialists (e.g., oncologists, cardiologists) Provision of primary care and basic palliative care Community, hospitals, academic centers

Specialist palliative care teams

Specialist palliative care teams Provision of specialist palliative care and primary care Academic centers (palliative care units)

+ –

Provision of specialist palliative care as consultants Hospitals (palliative care clinics and palliative care inpatient consultations) ++ +/–

–

+/–

+++

+++ +++

36 The palliative medicine specialist will then be able to access all other members of the palliative care team as required. A small percentage of patients are severely distressed, and this requires that the palliative medicine specialist becomes the primary care physician. This will take place both in the ambulatory care setting and particularly in palliative care units.20–22 In many cases, the most important contribution of the palliative medicine specialist is to provide the sophisticated assessment and correct management plan that will help the team develop the most effective interventions. Tertiary palliative care specialists are not only active in the provision of complex care, but also active in educating the next generation of clinicians and conducting palliative care research.23 These different levels of delivery of palliative care are not different from the role of other medical specialists in the management of different diseases. For example, it would not be reasonable to expect that cardiologists provide primary care to all patients with arterial hypertension or that endocrinologists provide primary care to all patients with type 2 diabetes. In most countries in the world, their own primary care physicians provide the majority of care for these patients. However, the specialist is available for consultation for a major proportion of these patients and for primary delivery of care in the most refractory situations. The degree of use of the palliative medicine specialist as a consultant will be linked to the level of expertise of the primary physician. Some primary physicians will have acquired enough education and experience in palliative care to be able to resolve a large proportion of clinical problems, whereas others will have a much lower threshold for consultation. The best indicator for the appropriate utilization of palliative medicine specialty services will be the level of physical and psychosocial distress in patients and families in each institution and/or region. Palliative medicine specialists are extremely important for undergraduate and postgraduate education.24–27 They are also responsible for the continuing medical education of those primary care physicians already working in the community. The adoption of new assessments and pharmacological and non-pharmacological interventions by primary care physicians will heavily depend on the clinical and educational leadership of palliative medicine specialists in every community. Physicians adopt new diagnostic tests, medications, and procedures mostly as a result of the clinical leadership and education of those who have specialized in these specific areas of knowledge. Finally, palliative medicine specialists are responsible for the development of the body of knowledge that will result in changes in the assessment and treatment of patients and families.26 Although most physicians will use analgesics, antiemetics, and drugs for the management of delirium on a regular basis, there is a huge need for a small number of specialists with great dedication to the discovery of new assessments and treatments for pain, emesis, and delirium in palliative care. Individuals who are fully focused on palliative care research will ensure that there is progress in this field.29 In summary, palliative medicine specialists are able to deliver clinical care to those patients and families with the most difficult problems, to educate colleagues about the appropriate delivery of palliative care, and to actively conduct research on new developments in assessment and management of clinical problems. Ideally, a significant proportion of palliative medicine specialists should operate within academically organized departments in medical schools. Such departments already exist in a number of universities in the United Kingdom, North America, and Europe.

Textbook of Palliative Medicine and Supportive Care KEY LEARNING POINTS • Palliative care programs have three main characteristics: multidimensional assessment and management, interdisciplinary care, and emphasis on the patient and their families. • Palliative medicine was initially established as a specialty in the United Kingdom in 1987. • Palliative medicine specialists integrate with multiple other disciplines in the delivery of palliative care. • Palliative medicine specialists provide clinical care in the most complex situations, graduate and postgraduate education, and research. The university affiliation will allow palliative medicine specialists to have the necessary protected time for conducting academic activities, the possibility to influence the development of undergraduate and postgraduate curricula, and the possibility to establish research teams by interacting with experts in methodology, content, and biostatistics affiliated with different universities.

Conclusions Since the establishment of the specialty of palliative medicine in the United Kingdom in 1987, similar efforts have been made in a number of countries. Palliative medicine specialists have been instrumental in the development of scientific organizations and meetings, peer-reviewed journals, and textbooks, and in the development of a curriculum for the undergraduate and postgraduate teaching of palliative medicine for physicians. These specialists have also linked with other health-care professionals and volunteers to maintain the multidimensional and interdisciplinary nature of palliative care. The nature and content of the teaching curriculum, the financial viability of the different palliative specialist positions in different countries, and the overall body of knowledge are not completely defined for this young medical specialty. As palliative medicine is progressively adopted by acute care facilities and academic institutions, the need for palliative medicine specialists is likely to grow exponentially during the next decade in most parts of the world. Unfortunately, the vast majority of universities and large medical centers don’t have independent clinical and academic palliative care departments; therefore, research and education progress have been much slower for this emerging specialty compared to the traditional biomedical disease-centered specialties.

References 1. Saunders C. Introduction: History and challenge. In: Saunders C, Sykes N, eds. The Management of Terminal Malignant Disease. London, Great Britain: Hodder and Stoughton, 1993, pp. 1–14. 2. Mount BM. The problem of caring for the dying in a general hospital: The palliative care unit as a possible solution. CMAJ 1976;115(2):119–121. 3. Page B. What is supportive care? Can Oncol Nurs J 1994;4:62–63. 4. Hui D, De La Cruz M, Mori M, et al. Concepts and definitions for “supportive care,” “best supportive care,” “palliative care,” and “hospice care” in the published literature, dictionaries, and textbooks. Support Care Cancer 2013;21(3):659–685. 5. Hui D, Mori M, Parsons H, et al. The lack of standard definitions in the supportive and palliative oncology literature. J Pain Symptom Manage 2012;43(3):582–592.

Palliative Care and Supportive Care 6. Fadul N, Elsayem A, Palmer JL, et al. Supportive versus palliative care: what’s in a name? A survey of medical oncologists and midlevel providers at a comprehensive cancer center. Cancer 2009;115(9):2013–2021. 7. Bruera E, Hui D. Conceptual models for integrating palliative care at cancer centers. J Palliat Med 2012;15(11):1261–1269. 8. Dalal S, Palla S, Hui D, et al. Association between a name change from palliative to supportive care and the timing of patient referrals at a comprehensive cancer center. Oncologist 2011;16(1):105–111. 9. Hui D, Hannon BL, Zimmermann C, Bruera E. Improving patient and caregiver outcomes in oncology: Team-based, timely, and targeted palliative care. CA Cancer J Clin 2018;68:356–376. 10. Hui D, Bruera E. Integrating palliative care into the trajectory of cancer care. Nat Rev Clin Oncol 2016;13:159–171. 11. Wong A, Vidal M, Prado B, et al. Patients perspective of timeliness and usefulness of an outpatient supportive care referral at a comprehensive cancer center. J Pain Symptom Manage 2019;58(2):275–281. 12. Hui D, Parsons HA, Damani S, et al. Quantity, design, and scope of the palliative oncology literature. Oncologist 2011;16:694–703. 13. von Gunten CF. Secondary and tertiary palliative care in U.S. hospitals. JAMA 2002;287(7):875–881. 14. Morrison RS, Meier DE. Clinical practice: Palliative care. N Engl J Med 2004;350(25):2582–2590. 15. White KR, Cochran CE, Patel UB. Hospital provision of end-of-life services: Who, what, and where? Med Care 2002;40(1):17–25. 16. Centeno C, Gomez-Sancho M. Models for the delivery of palliative care: The Spanish model. In: Bruera E, Portenoy RK, eds. Topics in Palliative Care. Oxford, UK: Oxford University Press, 2001, pp. 25–38. 17. Wenk R, Bertolino M. Models for the delivery of palliative care: The Argentine model. In: Bruera E, Portenoy RK, eds. Topics in Palliative Care. Oxford, UK: Oxford University Press, 2001, pp. 39–54. 18. Yennurajalingam S, Atkinson B, Masterson J, et al. The impact of an outpatient palliative care consultation on symptom burden in advanced prostate cancer patients. J Palliat Med 2012;15(1):20–24. 19. Yennurajalingam S, Urbauer DL, Casper KL, et al. Impact of a palliative care consultation team on cancer-related symptoms in advanced cancer patients referred to an outpatient supportive care clinic. J Pain Symptom Manage 2010;41(1):49–56.

37 20. Hui D, Elsayem A, Li Z, De La Cruz M, Palmer JL, Bruera E. Antineoplastic therapy use in patients with advanced cancer admitted to an acute palliative care unit at a comprehensive cancer center: A simultaneous care model. Cancer 2010;116(8):2036–2043. 21. Hui D, Elsayem A, Palla S, et al. Discharge outcomes and survival of patients with advanced cancer admitted to an acute palliative care unit at a comprehensive cancer center. J Palliat Med 2010;13(1):49–57. 22. Elsayem A, Swint K, Fisch MJ, et al. Palliative care inpatient service in a comprehensive cancer center: Clinical and financial outcomes. J Clin Oncol 2004;22(10):2008–2014. 23. Hui D, Elsayem A, De la Cruz M, et al. Availability and integration of palliative care at U.S. cancer centers. JAMA 2010;303(11):1054–1061. 24. LeGrand SB, Walsh D, Nelson KA, Davis MP. A syllabus for fellowship education in palliative medicine. Am J Hosp Palliat Care 2003;20(4):279–289. 25. Oneschuk D. Undergraduate medical palliative care education: A new Canadian perspective. J Palliat Med 2002;5(1):43–47. 26. Oneschuk D, Fainsinger R, Hanson J, Bruera E. Assessment and knowledge in palliative care in second year family medicine residents. J Pain Symptom Manage 1997;14(5):265–273. 27. Oneschuk D, Hanson J, Bruera E. An international survey of undergraduate medical education in palliative medicine. J Pain Symptom Manage 2000;20(3):174–179. 28. Bruera E, Hui D. Palliative care research: Lessons learned by our team over the last 25 years. Palliat Med 2013;27(10):939–951. 29. Rodgers EM. Adoption of Innovation Theory: Diffusion of Innovation, 4th edn. New York: Free Press, 1995.

Web Resources Edmonton Regional Palliative Care Program: www.palliative.org International Association of Hospice Care: www.hospicecare.com

6

ETHICS IN THE PRACTICE OF PALLIATIVE CARE

Nelia Jain and James A. Tulsky

Contents Disclosure and truth telling...............................................................................................................................................................................................39 Advance care planning........................................................................................................................................................................................................40 Requests for treatment of unproven, limited or no benefit.........................................................................................................................................41 Responding to intractable terminal suffering.................................................................................................................................................................42 Conclusion.............................................................................................................................................................................................................................43 References..............................................................................................................................................................................................................................44 Excellent palliative care demands careful attention to diagnostic, prognostic, and therapeutic challenges. The palliative care clinician must demonstrate sensitivity to psychosocial and spiritual concerns and thoughtful, empathic communication with patients and families. Yet, even when these are skillfully done, patients and providers may still meet ethical dilemmas along the journey through serious illness. Some dilemmas are subtle and, perhaps, not recognized. Others are easily apparent and may lead to conflict. This chapter will discuss several of the more common and vexing ethical issues that arise in the care of patients with advanced serious illness. These include truth telling; when and how to engage in advance care planning; responding to requests for treatments of unproven, limited, or no benefit; and, finally, consideration of aggressive measures for responding to intractable suffering. The following case raises each of these dilemmas. The case is typical, and the problems are not profound. Yet, they reflect the thorny issues that arise in the real daily practice of palliative care. S.K. is a 68-year-old retired, Korean born, university professor who is admitted to the hospital with pneumonia and chest pain. Chest CT reveals a 4 cm lesion obstructing the right upper bronchus and several rib lesions suspicious for malignancy. As the physician approaches the patient’s hospital room, he is pulled aside by Mr. K’s son and daughter who wish to know the result of the CT scan. They request that the doctor not share the results with their father if it means he might have cancer.

Disclosure and truth telling Truth telling is fundamental to respectful patient care and a necessary component of informed consent. By fully including patients in all decision-making, health-care professionals honor patient autonomy. Truth telling also engenders trust in the medical profession and promotes shared decision-making. Surveys consistently show that most patients wish to receive as much information as possible,1,2 perhaps as a way to cope with uncertainty. 3,4 In one typical survey of 2,850 British patients, over 1,000 of them receiving palliative care, nearly 90% stated they would like to be told most or all information about their illness. 5 Information allows patients to plan their futures and to make decisions. Lack of information may heighten their fear and anxiety, as the truth is

often not as bad as what might be imagined, and they may lose the opportunity to achieve important goals prior to death. In addition, the secrecy and collusion necessary to withhold information may present a significant challenge to clinicians and families. Yet, patients also desire an individualized approach to receiving bad news and discussing prognosis.6 Furthermore, clinicians should anticipate variations in patients’ informational needs throughout the course of their illness.7 Most patients prefer to participate actively in decision-making yet also wish to receive a physician’s advice regarding recommended options. Physicians must strike a balance between conveying the ambiguity that clouds medical decision-making and helping patients find the best options for themselves. Disclosure of serious diagnoses and their repercussions appears to vary widely. Physicians do not always share prognosis, and when they do, they tend to bias optimistically.8 Although withholding information or providing an overly optimistic assessment of illness may be deceptive, legitimate reasons for the practice also exist. Patients may find it too difficult to hear bad news or may consciously defer all decision-making to their families. While such perspectives may challenge notions of patient autonomy, in fact, autonomy dictates that patients also have the right to not hear or to defer responsibility to others. Cultural issues also impact patient expectations and the importance of individual autonomy. While in most Western societies, common practice is to answer patients’ questions honestly and to share relevant information about their medical condition, prognosis, and therapeutic options, significant variation exists worldwide.9,10 In many societies, decision-making is localized in the family and individual autonomy is not recognized. Blackhall surveyed members of four distinct ethnic groups in the United States and found widely disparate perspectives on whether a patient should be told a diagnosis of metastatic cancer. Only 47% of first-generation Korean Americans and 65% of firstgeneration Mexican Americans believed that patients should be told, whereas European Americans (87%) and African Americans (88%) were more likely to want to hear this news directly themselves.11 In some cultures, the delivery of bad news may determine how patients confront illness and being told the wrong information can cause harm. For example, in Navajo society, the concept of hozho or living in beauty may be considered to be violated by statements that are viewed as negative.12 Such observations imply that, in different cultures, personal autonomy carries different 39

Textbook of Palliative Medicine and Supportive Care

40 levels of importance. That said, patients’ preferences are not simply a reflection of their ethnic background, and there are no identifiable predictors of such preferences. To avoid assuming patients’ preferences inaccurately, clinicians should ask patients directly, “How much information are you interested in hearing about your illness?” Patients can specify what they wish to hear and subsequently receive only the amount of information they desire. If a patient expresses ambivalence, clinicians should offer information that fulfills the reasonable patient standard, conveying the information a reasonable patient would need to know to make rational decisions.13 Regardless of the extent of information desired, clinicians should convey medical facts and recommendations in an empathic manner. Attending to the emotional responses evoked by patients and families during these conversations will help the clinician determine the pace at which information should be delivered.

Advance care planning Mr. K. is treated for his pneumonia and biopsy reveals non-small cell lung cancer, metastatic to rib. He receives radiation to his lung and ribs and feels much better. He is seen six weeks later in his doctor’s office, and the physician wonders whether this would be a good opportunity to begin advance care planning. Advance care planning is the process by which patients, together with their families and health-care providers, consider their values and goals and articulate preferences for future care.14 Although it could refer simply to signing a form in a lawyer’s or doctor’s office, ideally, advance care planning creates an opportunity for patients to explore their own values, beliefs, and attitudes regarding quality of life and medical interventions, particularly as their condition changes. Patients may speak with loved ones, physicians, spiritual advisers, and others during the process. This reflective work can help patients learn more about what they can expect as their disease progresses and gain a sense of control over their medical care and their future.15 An important aspect of advance care planning is the process of naming a surrogate, also referred to as a health-care proxy. Patients with serious illness are at risk for losing decisional capacity at any stage of their illness, with greater risk in more advanced stages. Decisional capacity should be assessed using a systematic framework, evaluating a patient’s ability to comprehend medical information regarding one’s condition, apply relevant information to one’s situation, demonstrate a logical reasoning process in making medical decisions, and express a clear choice that is consistent with previously expressed values and beliefs.16,17 Assumptions regarding a patient’s decisional capacity should not be made based on underlying or comorbid conditions (e.g., depression or cognitive impairment). Patient ambivalence may be expected, particularly in later stages of illness, and does not reflect a lack of decisional capacity.18 Furthermore, the burden of proof required to establish a patient’s decisional capacity is proportionate to the level of risk and consequence of decision at stake, with higher stakes decisions such as those regarding life-sustaining interventions occurring more frequently in the care of seriously ill patients.19 Earlier conversations with patients ensure that patients have the ability to directly express their values and preferences in the context of their illness as well as identify trusted surrogate decision makers. When a patient loses decision-making capacity, health-care teams turn to surrogate decision makers to assist with medical decision-making. The ethical standard expected to be met by health-care proxies is one of substituted judgments,

where the surrogate’s understanding of the patient’s values and preferences is used to guide medical decision-making. Clinicians and loved ones who have been involved in the advance care planning process know the patient’s goals and values better and make medical decisions that are more likely to align with the patient’s values and preferences. Written advance directives formalize patient preferences and values elicited from advance care planning conversations and include living wills or other statements of patient preferences, as well as durable powers of attorney for health care, which name health-care proxies. Do-not-attempt resuscitation orders are written by physicians to operationalize one specific set of preferences articulated by patients and their proxies. More recently, a newer directive, often referred to as Physician Orders for LifeSustaining Treatment (POLST), has been initiated in many US states as a way of ensuring that patient preferences are enacted in practice.20 POLST documents are actual medical orders, respected by emergency medical services and local health-care institutions, which implement a scope of treatment for a particular patient. Advance care planning and documentation has been promoted widely in the United States and other countries, particularly in response to high-profile cases in which patients in a vegetative state have been kept alive despite a presumption that such treatment violated their preferences.21 When the patient’s illness has progressed to its final stages, health-care providers can use the groundwork from these earlier discussions to make specific plans about what is to be done when the inevitable worsening occurs. Engaging in advance planning affords patients reassurance that they will be cared for at the end of life in a manner that is consistent with their preferences. Although patients and families agree that advance care planning is important, clinicians are often reluctant to raise the subject with their patients and often do so later than patients may desire.22 While clinicians are often worried that patients will be put off by a discussion about advance care plans, most patients want to discuss these issues early in the course of their disease and believe the doctor should raise the topic.23 The root cause of much of physicians’ reluctance stems from lack of training in how to have these discussions. With training, physicians can feel more comfortable having these discussions, can learn how to deal with patients’ emotional responses, and can have effective discussions that the physician will find truly helpful in caring for patients.24,25 Clinicians also struggle with the timing of initiating such conversations as they attempt to balance patients’ and families’ readiness for conversations against other factors such as a patient’s risk for loss of decisional capacity further downstream in the illness trajectory.26,27 By introducing conversations early, and shifting the focus away from specific medical interventions toward an exploration of patients’ values and goals, clinicians may find patients and families more willing to engage in these discussions. Clinicians also cite time constraints as a barrier to conducting advance care planning conversations. While time constraints are difficult to overcome, there are multiple strategies that clinicians may implement. Patients and families are often receptive to advance care-planning discussions with multiple members of the health-care teams. Enlisting nurses and social workers to initiate these conversations, particularly those with longstanding relationships with the patients and families, can help increase the frequency of advance care planning discussions and offload the responsibility from any one particular team member.28,29 The use of booklets, videos, and other tools to introduce the concepts involved in advance care planning may help physicians efficiently use their time to

Ethics in the Practice of Palliative Care answer specific questions patients may have and to guide patients through the process.30,31 Finally, the introduction of advance care planning billing codes allows physicians to dedicate clinic and hospital visits to addressing advance care planning.32 Advance care planning conversations can result in increased patient and family satisfaction, higher rates of known and followed end-of-life care wishes, and decreased anxiety, stress, and depression among their family members. 33 In addition, advance care planning can lead to increased completion of advance directives, decreased utilization of aggressive treatments in late stages of illness, and improved quality of life and prioritization of comfort-focused care at the end of life. 34,35 Unfortunately, the impact of advance directives on actual resuscitation events remains unclear, with most of the older literature showing minimal effect. 36–43 This may be due to several causes. Discussions often do not occur or are not recorded in ways that may have a lasting effect.44 Some of the barriers to successful implementation have been procedural when, for example, documents are not available when needed. More importantly, problems arise with deciding in advance about specific interventions,45 the adequacy of communication,46 the willingness of health-care providers to follow patient preferences,41,44 and patient and family misunderstandings about the process. More recent data including utilization of POLST forms to reflect patient wishes suggest higher rates of patients receiving goal-concordant care.47 Entering these conversations may feel awkward, but if they are viewed as conversations about hopes, fears, and goals rather than decisions for specific preferences, they may be easier to engage. For example, Mr. K. could be asked how he has been doing since his hospitalization, his response to learning his diagnosis, and the impact on his hopes and worries for the future. By careful exploration of patients’ values, health-care providers can help patients discover their preferences. From such discussions, health-care providers can help patients consider specifically whether there are certain treatments that they might wish to forgo and to think about the circumstances under which they might forgo them. Nevertheless, there will be some patients who are not ready to discuss advance directives. Health-care providers must be sensitive to these patients. Advance care planning is a process that should be offered to patients, not forced upon them.

Requests for treatment of unproven, limited or no benefit Mr. K. chooses to undergo chemotherapy and receives carboplatin and gemcitabine. However, he experiences a significant decline and his tumor progresses. He then tries nivolumab but is hospitalized with shortness of breath and hypoxia, and nivolumab is stopped due to concerns for immune-mediated pneumonitis. At this point, his oncologist tells him that there are no more proven treatments left and that he would not suggest more treatment given his age and poor responses to previous agents. Mr. K asks, “isn’t there anything else? What about an experimental drug?” Mr. K. has exhausted the proven treatments for his cancer. Even though he has experienced significant side effects from his treatment, he does not want to die and is willing to consider other options. Such options range in efficacy from unproven or questionable benefit to limited benefit to clear lack of benefit. Clinicians will often be in the position of making recommendations about treatments of unclear benefit, raising the question of how to best

41 engage patients in informed consent. The principle of therapeutic proportionality may serve as a useful guide to clinicians facing this quandary. Clinicians should take into consideration the level of aggressiveness and invasiveness of the intervention in question along with the severity of risks imposed on the patient and weigh these against the patient’s prognosis and any potential benefit. Treatments of unproven benefit such as phase I clinical trials are not meant to be therapeutic and, historically, approximately 5% of patients enrolled in such trials for cancer agents achieve a response.48,49 Nevertheless, most patients enroll with the intent of achieving therapeutic benefit.50,51 This may be due, in part, to a lack of adequate disclosure practices by trial investigators.52 As treatment intent shifts from emergent to elective to experimental, the standards for disclosure are higher. Increasingly, it is recognized that patients choosing to enroll in phase I trials may have different values than those who do not enroll, and although they understand the prognostic data presented to them, they maintain a more optimistic perspective and believe that they will be the ones to gain benefit.53,54 In fact, many now argue that hospice care and phase I trials ought to coexist simultaneously.55,56 In addition to clinical trials, there are other medical advances such as high flow oxygen therapy or total parental nutrition that are more routinely utilized in the care of seriously ill patients that may confer some benefit; however, the amount of benefit with respect to quality of life and quantity of life is unknown. With rapidly changing medical technologies, clinicians have a harder time counseling patients solely on the basis of weighing burdens versus benefits. There may be a lack of consensus amongst treating clinicians regarding the risks and benefits of specific treatments, or patients and families may strongly wish to pursue an intervention despite a clinician’s reservations. In these instances, a “time-limited trial” of a particular intervention with observation for specific clinical outcomes over a pre-specified period of time may be a useful approach. This allows clinicians to maintain a therapeutic relationship with patients and their families and help to diminish conflict. If the intended clinical outcome is not observed, patients and families should be counseled to withdraw the trial intervention. In contrast, the majority of alternative, ineffective treatments are far less accepted. Although belief systems vary among patients and clinicians, the primary issue here is one of informed consent and trying to ensure that patients do not encounter more harm than good in reaching out to such treatments. Furthermore, these discussions present opportunities for clinicians to reframe the conversation around what can be done that will benefit patients and families, such as intensive supportive and comfort-focused care in the case of patients with terminal illness. Mr. K. becomes progressively more debilitated. He decides not to pursue unproven therapies and accepts a comfortfocused approach to care, including a DNR order. He has been spending an increasing percentage of his time in bed when he develops a fever and cough and stops eating and drinking. His family wonders whether he is again suffering pneumonia and asks if he can receive antibiotics. In addition, they question whether a feeding tube should be placed or if intravenous hydration would be helpful. Even when patients have elected to pursue a comfort-focused approach to care, they and their care providers may struggle over the exact limitations of treatment. Antibiotics are particularly interesting because they tend to be among the least refused of medical interventions.57,58 Their use is high even in palliative

42 care units, where they are administered to as many as 30–40% of patients with comfort care plans.59–61 The literature suggests that antibiotics can play a role in symptom relief, yet must be balanced against the burdens of side effects and cost. 59,60 In the case of Mr. K., pneumonia may be his terminal event, with or without the use of antibiotics. He and his family will need to decide whether IV antibiotics are worth a trip to the hospital or even whether it’s worth trying to administer them at home. His symptoms of cough and fever can be managed with antitussives and antipyretics—it is not clear if adding another few days or weeks to his life will meet his goals at this point. Such decisions become highly individualized with no correct answers. Tube feeding has not shown a significant benefit for most patients with terminal illness.62 In contrast, considerable debate exists as to the benefits of artificial hydration. Recent evidence suggests that subcutaneous hydration can alleviate common symptoms of terminal illness with minimal burden.63 Guidelines established by the European Association for Palliative Care recommend a three-step approach.64 Step I includes assessing a variety of clinical factors, Step II involves an assessment of pros and cons to establish a well-defined goal of therapy and end point, and Step III requires periodic reevaluation of the decision. When receiving requests for unproven, limited, or ineffective therapy, physicians should counsel patients openly and not hesitate to give an opinion based upon their knowledge of the intervention and the patient’s values. It is keenly important to acknowledge the patient’s affect and recognize that requests for unproven or ineffective treatments are frequent proxies for patient distress and difficulty coping with impending death. A common pitfall is responding to such distress by offering more therapy rather than engaging the patient’s emotional state. Even in situations where there is a low clinical likelihood of a patient being a candidate for more treatment, patients are often told, “we’ll wait until you’re stronger.” In these situations, clinicians may defer recommending comfort-focused care and access to intensive support services including hospice to avoid engaging in difficult conversations. A more productive technique to use in this situation is the wish statement.65 By letting patients know that “I wish I had a more effective treatment to offer you,” clinicians can both align themselves with patients, while implicitly acknowledging that this goal cannot be met. In these settings, clinicians struggle to promote hope in the patient with advanced disease and to support a positive outlook.1 Incorrectly, they fear that discussing death may distress patients.8,66–69 As a result, doctors frequently convey overly optimistic prognoses or do not give this information at all.70 Fearing the loss of hope, patients frequently cope by expressing denial and may be unwilling to hear what is said.71 Not unexpectedly, patients with more optimistic assessments of their own prognosis are more likely to choose aggressive therapies at the end of life.72,73 Yet, perhaps more importantly, patients who have had no conversation about end-of-life issues at all are most likely to receive aggressive interventions prior to death.74 Physicians should recognize that it is not their job to correct the patient’s hope for an unrealistic outcome.75 Hope is the frame within which patients construct their future.76 It may be a desire for a particular outcome or it may be, more broadly, trust or reliance. The key question is whether the patients’ construction of hope is interfering with appropriate planning and behavior. Clinicians, at their best, can provide an empathic, reflective presence that will help patients to draw strength from their existing resources. Together, the physician and the patient can “hope for

Textbook of Palliative Medicine and Supportive Care the best but prepare for the worst.” 77 Helping the patient and family manage their hope and their resources in a realistic way may leave the family in the best possible shape after their loss.

Responding to intractable terminal suffering Mr. K’S illness progresses, and he is bedbound with fluctuating consciousness. He requires large quantities of opioids for pain and dyspnea. The patient’s daughter is concerned that the medication may hasten his death and resists the hospice nurse’s suggestion to increase it further. Meanwhile, the son feels that his father had completed all he needs to do and is just lingering uncomfortably. He wants to know how much longer his father has and whether there is anything that can be done to stop the waiting. One of the major barriers to aggressive symptom management at the end of life is a clinician’s feelings of inadequacy in responding to suffering. Some clinicians fear that providing intensive symptom management will hasten death. Others struggle with distinguishing between emotional, physical, spiritual, and existential suffering. Clinicians may feel helpless in these situations, leading them to withdraw from patients and their families or experience significant moral distress. Instead, clinicians should “turn towards” their patients’ suffering, opening themselves up to understanding the type and extent of suffering from a place of curiosity and engagement, and ensuring non-abandonment.78 Clinicians should also utilize an interdisciplinary team to ensure patients’ needs are assessed from a whole-person perspective. Despite best efforts, clinicians will encounter patients who experience intractable suffering at the end of life and may be in the position of considering options of last resort to provide relief. Moral clarity on these issues is critically important to ensure that no inappropriate boundaries are overridden and to give reassurance to ethical providers who are working hard to take the best care of patients.79 Many clinicians and family members are unsure where pain control ends and euthanasia begins. In situations such as Mr. K.’s, clinicians generally rely on the principle of double effect to justify their actions. This centuries-old ethical framework allows one to perform beneficial actions with potentially harmful consequences as long as four requirements are met.80 The act itself must not be immoral; it must be undertaken only with the intention of achieving the possible good effect, without intending the possible bad effect even though it may be foreseen; it does not bring about the possible good effect by means of the possible bad effect; and, lastly, it is undertaken for a proportionately grave reason. The principle of double effect has been very useful in medical practice generally and palliative care in particular because it helps many clinicians overcome barriers to prescribing adequate pain relief and it provides a legal defense for opioid prescriptions at the end of life.81 Several problems exist with double effect.82 It can be difficult to distinguish between intended and foreseen consequences, particularly regarding death at the end of life. Conscientious clinicians not sure of their actions may be tormented by the outcome. Furthermore, the principle of double effect prioritizes the absolute prohibition against patient death over patient autonomy. Advocates applaud the principle for exactly this reason. Yet those who wish to allow greater flexibility for ending patient suffering at the end of life find double effect to be constraining. Finally, as

Ethics in the Practice of Palliative Care discussed in the preceding chapter, because the skilled titration of opioids ought not increase the risk of death, some argue that double effect is not really a relevant consideration in these cases.83 Others argue that when someone is known to be dying and the focus of care is a good death, a somewhat shortened time to death is not a bad effect, and double effect doesn’t hold.84 Intractable suffering that does not respond to routine intensive palliation requires consideration of less frequently used treatments. In one practice, termed palliative sedation, patients are deeply sedated to the extent needed to decrease awareness of refractory symptoms.85 This intervention is intended for dying patients, typically with a prognosis of days to weeks, with unbearable symptoms unresponsive to other therapies.86 Ethically, this practice is permissible under the principles of double effect and therapeutic proportionality. These standards are met as the primary intention is to titrate sedating medications to a sufficient decrease in a patient’s awareness to relieve intolerable suffering after all other strategies have been exhausted. In the Netherlands, and perhaps elsewhere, the practice precedes a substantial number of deaths.87 In the United States and most other countries, it still remains fairly rare and is reserved for intractable physical suffering. Use of palliative sedation for refractory existential suffering remains controversial due to persistent ambiguity in the definition, assessment, and treatment of existential suffering.88 Because death is certain if sedation is not withdrawn, some people view this as a form of euthanasia, particularly those who believe in an absolute prohibition of hastening death.89 An important consideration in distinguishing palliative sedation from practices that directly hasten death is the intention behind the practice. Given that sedation is the means of relieving suffering rather than the intent, palliative sedation remains a distinct theoretical entity from other last resort practices at the end of life.90 Whatever the specific ethical justifications, there is a growing consensus in favor of the practice under appropriate circumstances, and it is legal in the United States and many other countries. Concerns remain about potential abuses,91 yet the existence of institutional policies provides some safeguards.83 With regard to hastening death, other practices exist, and a detailed discussion of their history, merits, and risks is beyond the scope of this chapter. Briefly, these would include voluntary cessation of eating and drinking, physician-assisted death, and euthanasia. Prior to delving into the specifics and availability of these last resort options with patients, clinicians should make every effort to explore the reasons underlying a patient’s request for hastened death. Any reversible or treatable factors should be addressed, including ensuring patients and families have access to high-quality palliative care. Any competent patient who is approaching the end of life and confronting overwhelming suffering may choose to voluntarily stop eating and drinking.79 This difficult and potentially unpleasant option takes tremendous conviction.92 Nevertheless, some take advantage of this because it is legally protected under a patient’s right to refuse medical interventions and avoid bodily invasion, and there is a growing ethical consensus in support of the practice. While the lack of requirement for physician involvement removes a significant barrier to patients, clinician supervision is helpful to address any symptoms such as severe thirst or delirium that may arise during later stages of the process.93 In contrast to voluntarily stopping eating and drinking, which has received relatively little attention, physician-assisted death has been at the center of heated debates, including decisions by the US Supreme Court. In the United States and many European

43 nations, there is a majority public support for this practice,94–96 yet considerable controversy exists over its appropriateness.97,98 At the time of this writing, the practice is legal in eight US jurisdictions, Canada, and in at least two European nations, although it is tacitly approved in others. The practice requires a competent patient, which is perceived as a safeguard to abuse, and somewhat distances the agency of physicians, which many prefer. However, physician aid in dying is distinct from voluntarily stopping eating and drinking as a participating clinician is required to have an active role in providing the means for a patient to intentionally hasten his or her death. Ethical arguments supporting physician-assisted death are primarily founded on the basis of patient autonomy (a person’s right to choose how to die) and beneficence (a clinician’s responsibility to relieve intolerable suffering). In contrast, critics argue that physician-assisted death challenges the limits of patient autonomy under the physician’s responsibility to non-maleficence, particularly as the intent of this practice is hastened death. Additional concerns include the potential to disrupt the integrity of the profession as well as the potential for abuse. Euthanasia is the practice whereby someone other than the patient, usually a physician, administers a lethal agent to directly hasten a death. This practice is perceived differently in different countries.99 In the United States, euthanasia is distinguished from physician-assisted suicide and no ethical consensus exists.94 It is illegal everywhere within the United States and likely to be prosecuted. In the Netherlands, Belgium, Canada, and some other countries, the public response to the two practices is fairly similar and more accepting. From a practical perspective, euthanasia does not require a competent patient, which has raised concerns about safeguards to abuses of vulnerable patients.100 As Mr. K lays dying, his daughter may be reassured knowing that aggressive use of opioids is entirely within the accepted standard of care as the intent is focused on controlling his pain and other symptoms. The son’s position is also understandable. It is very difficult to sit at such a vigil and wait for a patient to die. The patient’s son may be reassured that nothing more need to be done to extend his father’s life, such as giving hydration or antibiotics. Clinicians have a responsibility to remain present for patients and families throughout the illness trajectory and be prepared to respond to all forms of suffering encountered at the end of life.101 Regardless of whether or not clinicians practice in a jurisdiction where physician-assisted death is legalized, they will undoubtedly encounter a patient requesting options for hastened death and should be prepared to respond to these requests in an empathic and respectful manner.102 The debate about assisted dying will continue to play out in the press, courts, and legislatures. Yet, in the end, individual patients, families, and health-care providers confront real-life situations that must be resolved within the constraints of individual moral values and the law. All efforts should be focused on the patient’s comfort and helping the family find meaning during these last moments.

Conclusion Ethical challenges lie in the paths of all patients, families, and health-care providers dealing with a life-limiting illness. At different points of an illness, these may range from truth telling to requests for assisted dying. Health-care providers must enter into such issues without assumptions about patient preferences and with an open mind to learn the underlying issues. Careful listening, clear thinking about the ethical issues at stake, and empathic communication will help resolve many such dilemmas.

Textbook of Palliative Medicine and Supportive Care

44 KEY LEARNING POINTS • Truth telling engenders trust and is a central aspect of good palliative care, yet patients vary considerably in their preferences for information. • Advance care planning can serve multiple goals for patients, families, and health-care providers in addition to communicating preferences for future treatment. • Requests for unproven, limited, or ineffective therapies may reflect patient distress and appropriate responses should respond to a patient’s emotional state, not just the underlying question. • Treating suffering at the end of life is an obligation for all clinicians and should be addressed with intensive symptom management and interdisciplinary support, with treatments that hasten death reserved only as options of last resort.

References



1. Butow PN, Dowsett S, Hagerty R, Tattersall MH. Communicating prognosis to patients with metastatic disease: What do they really want to know?. Support Care Cancer 2002;10(2):161–168. 2. Ende J, Kazis L, Ash A, Moskowitz MA. Measuring patients’ desire for autonomy: Decision making and information-seeking preferences among medical patients. J Gen Intern Med 1989;4(1):23–30. 3. Bruera E, Sweeney C, Calder K, Palmer L, Benisch-Tolley S. Patient preferences versus physician perceptions of treatment decisions in cancer care. J Clin Oncol 2001;19(11):2883–2885. 4. Heyland DK, Tranmer J, O’Callaghan CJ, Gafni A. The seriously ill hospitalized patient: Preferred role in end-of-life decision making?. J Crit Care 2003;18(1):3–10. 5. Fallowfìeld Ll, Jenkins VA, Beveridge HA. Truth may hurt but deceit hurts more: Communication in palliative care. Palliat Med 2002;16(4):297–303. 6. Hagerty RG, Butow PN, Ellis PM, et al. Communicating with realism and hope: Incurable cancer patients’ views on the disclosure of prognosis. J Clin Oncol 2005;23(6):1278–1288. 7. Parker SM, Clayton JM, Hancock K, et al. A systematic review of prognostic/end-of-life communication with adults in the advanced stages of a life-limiting illness: Patient/caregiver preferences for the content, style, and timing of information. J Pain Symptom Manage 2007;34(1):81–93. 8. Christakis NA. Death Foretold: Prophecy and Prognosis in Medical Care. Chicago, IL: University of Chicago Press, 2000. 9. Bruera E, Neumann CM, Mazzocato C, Stiefel F, Sala R. Attitudes and beliefs of palliative care physicians regarding communication with terminally ill cancer patients. Palliat Med 2000;14(4):287–298. 10. Peretti-Watel P, Bendiane MK, Obadia Y, et al. Disclosure of prognosis to terminally ill patients: Attitudes and practices among French physicians. J Palliat Med 2005;8(2):280–290. 11. Blackhall LI, Murphy ST, Frank G, Michel V, Azen S. Ethnicity and attitudes toward patient autonomy. JAMA 1995;274(10):820–825. 12. Carrese JA, Rhodes LA. Western bioethics on the Navajo reservation. Benefit or harm?. JAMA 1995;274(10):826–829. 13. Spatz ES, Krumholz HM, Moulton BW. The new era of informed consent: Getting to a reasonable-patient standard through shared decision making. JAMA 2016;315(19):2063–2064. 14. Sudore RL, Lum HD, You JJ, et al. Defining advance care planning for adults: A consensus definition from a multidisciplinary Delphi panel. J Pain Symptom Manage 2017;53(5):821–821. 15. Singer PA, Martin DK, Lavery JV, Thiel EC, Kelner M, Mendelssohn DC. Reconceptualizing advance care planning from the patient’s perspective. Arch Intern Med 1998;158(8):879–884. 16. Appelbaum PS, Grisso T. Assessing patients’ capacities to consent to treatment. N Engl J Med 1988;319(25):1635–1638. 17. Palmer BW, Harmell AL. Assessment of healthcare decision-making capacity. Arch Clin Neuropsychol 2016;31(6):530–540.

18. You JJ, Downar J, Fowler RA, et al. Barriers to goals of care discussions with seriously ill hospitalized patients and their families: A multicenter survey of clinicians. JAMA Intern Med 2015;175(4):549–556. 19. Jonsen, AR, Siegler M, Winslade WJ. Preferences of patients. In: Malley J, Naglieri C, Linskey P, eds. Clinical Ethics: A Practical Approach to Ethical Decisions in Clinical Medicine, 6th edn. New York: McGrawHill Companies, Inc., 2006, pp. 51–108. 20. Hickman SE, Nelson CA, Perrin NA, Moss AH, Hammes BJ, Tolle SW. A comparison of methods to communicate treatment preferences in nursing facilities: Traditional practices versus the physician orders for life-sustaining treatment program. J Am Geriatr Soc 2010;58(7):1241–1248. 21. Lo B, Steinbrook R. Beyond the Cruzan case: The U.S. Supreme Court and medical practice. Ann Intern Med 1991;114(10):895–901. 22. Johnston SC, Pfeifer MP, McNutt R. The discussion about advance directives. Patient and physician opinions regarding when and how it should be conducted. End of life study group. Arch Intern Med 1995;155(10):1025–1030. 23. Towsley GL, Hirschman KB, Madden C. Conversations about end of life: Perspectives of nursing home residents, family, and staff. J Palliat Med 2015;18(5):421–428. 24. Back AL, Arnold RM, Baile WF, et al. Efficacy of communication skills training for giving bad news and discussing transitions to palliative care. Arch Intern Med 2007;167(5):453–460. 25. Fallowfìeld L, Jenkins V, Farewell V, Saul J, Duffy A, Eves R. Efficacy of a cancer research UK communication skills training model for oncologists: A randomised controlled trial. Lancet 2002;359(9307):650–656. 26. van der Steen JT, van Soest-Poortvliet MC, Hallie-Heierman M, et al. Factors associated with initiation of advance care planning in dementia: A systematic review. JAD 2014;40(3):743–757. 27. Hall A, Rowland C, Grande G. How should end-of-life advance care planning discussions be conducted according to patients and informal carers?. A qualitative review of reviews. J Pain Symptom Manage 2019;58(2):311–335. 28. Head BA, Song M-K, Wiencek C, Nevidjon B, Fraser D, Mazanec P. Palliative nursing summit: Nurses leading change and transforming care: The nurse’s role in communication and advance care planning. J Hosp Palliat Nurs 2018;20(1):23–29. 29. Morrison RS, Chichin E, Carter J, Burack O, Lantz M, Meier DE. The effect of a social work intervention to enhance advance care planning documentation in the nursing home. J Am Geriatr Soc 2005;53(2):290–294. 30. Hammes BJ, Rooney BL, Gundrum JD. A comparative, retrospective, observational study of the prevalence, availability, and specificity of advance care plans in a county that implemented an advance care planning microsystem. J Am Geriatr Soc 2010;58(7):1249–1255. 31. Au DH, Udris EM, Engelberg RA, et al. A randomized trial to improve communication about end-of-life care among patients with COPD. Chest 2012;141(3):726–735. 32. Jones CA, Acevedo J, Bull J, Kamal AH. Top 10 tips for using advance care planning codes in palliative medicine and beyond. J Palliat Med 2016;19(12):1249–1253. 33. Detering KM, Hancock AD, Reade MC, Silvester W. The impact of advance care planning on end of life care in elderly patients: Randomised controlled trial. BMJ 2010;340:c1345. 34. Volandes AE, Paasche-Orlow MK, Mitchell SL, et al. Randomized controlled trial of a video decision support tool for cardiopulmonary resuscitation decision making in advanced cancer. J Clin Oncol 2013;31(3):380–386. 35. Bischoff KE, Sudore R, Miao Y, Boscardin WJ, Smith AK. Advance care planning and the quality of end-of-life care in older adults. J Am Geriatr Soc 2013;61(2):209–214. 36. Baker DW, Einstadter D, Husak S, Cebul RD. Changes in the use of do-not-resuscitate orders after implementation of the patient selfdetermination act. J Gen Intern Med 2003;18(5):343–349. 37. Yates JL, Glick HR. The failed patient self-determination act and policy alternatives for the right to die. J Aging Soc Policy 1997;9(4):29–50. 38. Danis M, Southerland LI, Garrett JM, et al. A prospective study of advance directives for life-sustaining care. N Engl J Med 1991;324(13):882–888. 39. Ditto PH, Danks JH, Smucker WD, et al. Advance directives as acts of communication: A randomized controlled trial. Arch Intern Med 2001;161(3):421–430. 40. Hanson L, Tulsky J, Danis M. Can clinical interventions change care at the end of life?. Ann Int Med 1997;126(5):381–388.

Ethics in the Practice of Palliative Care 41. SUPPORT Principal Investigators. A controlled trial to improve care for seriously ill hospitalized patients. The study to understand prognoses and preferences for outcomes and risks of treatments (SUPPORT). JAMA 1995;274(20):1591–1598. 42. Teno J, Lynn J, Wenger N, et al. Advance directives for seriously ill hospitalized patients: Effectiveness with the patient self-determination act and the SUPPORT intervention. SUPPORT Investigators. Study to understand prognoses and preferences for outcomes and risks of treatment. J Am Geriatr Soc 1997;45(4):500–507. 43. Molloy DW, Guyatt GH, Russo R, et al. Systematic implementation of an advance directive program in nursing homes: A randomized controlled trial. JAMA 2000;283(11):1437–1444. 44. Hofmann JC, Wenger NS, Davis RB, et al. Patient preferences for communication with physicians about end-of-life decisions. SUPPORT investigators. Study to understand prognoses and preference for outcomes and risks of treatment. Ann Intern Med 1997;127(1):1–12. 45. Brett AS. Limitations of listing specific medical interventions in advance directives. JAMA 1991;266(6):825–828. 46. Tulsky JA, Fischer GS, Rose MR, Arnold RM. Opening the black box: How do physicians communicate about advance directives?. Ann Intern Med 1998;129(6):441–449. 47. Hopping-Winn J, Mullin J, March L, Caughey M, Stern M, Jarvie J. The progression of end-of-life wishes and concordance with end-of-life care. J Palliat Med 2018;21(4):541–545. 48. Smith TL, Lee JJ, Kantarjian HM, Legha SS, Raber MN. Design and results of phase I cancer clinical trials: Three-year experience at M.D. Anderson Cancer Center. J Clin Oncol 1996;14(1):287–295. 49. Von Hoff DD, Turner J. Response rates, duration of response, and dose response effects in phase I studies of antineoplastics. Invest New Drugs 1991;9(1):115–122. 50. Daugherty C, Ratain MJ, Grochowski E, et al. Perceptions of cancer patients and their physicians involved in phase I trials. J Clin Oncol 1995;13(5):1062–1072. 51. Meropol NJ, Weinfurt KP, Burnett CB, et al. Perceptions of patients and physicians regarding phase I cancer clinical trials: Implications for physician-patient communication. J Clin Oncol 2003;21(13):2589–2596. 52. Hlubocky FJ, Kass NE, Roter D, et al. Investigator disclosure and advanced cancer patient understanding of informed consent and prognosis in phase I clinical trials. J Oncol Pract 2018;14(6):e357–e367. 53. Weinfurt KP, Sulmasy DP, Schulman KA, Meropol NJ. Patient expectations of benefit from phase I clinical trials: Linguistic considerations in diagnosing a therapeutic misconception. Theor Med Bioeth 2003;24(4):329–344. 54. Agrawal M, Emanuel EJ. Ethics of phase 1 oncology studies: Reexamining the arguments and data. JAMA. 2003;290(8):1075–1082. 55. Byock I, Miles SH. Hospice benefits and phase I cancer trials. Ann Intern Med 2003;138(4):335–337. 56. Casarett DJ, Karlawish JH, Henry MI, Hirschman KB. Must patients with advanced cancer choose between a Phase I trial and hospice?. Cancer 2002;95(7):1601–1604. 57. Ahronheim JC, Morrison RS, Baskin SA, Morris J, Meier DE. Treatment of the dying in the acute care hospital: Advanced dementia and metastatic cancer. Arch Intern Med 1996;156(18):2094–2100. 58. Ghusn HF, Teasdale TA, Skelly JR. Limiting treatment in nursing homes: Knowledge and attitudes of nursing home medical directors. J Am Geriatr Soc 1995;43(10):1131–1134. 59. Chen LK, Chou YC, Hsu PS, et al. Antibiotic prescription for fever episodes in hospice patients. Support Care Cancer 2002;10(7):538–541. 60. Clayton J, Fardell B, Hutton-Potts J, Webb D, Chye R. Parenteral antibiotics in a palliative care unit: Prospective analysis of current practice. Palliat Med 2003;17(1):44–48. 61. Pereira J, Watanabe S, Wolch G. A retrospective review of the frequency of infections and patterns of antibiotic utilization on a palliative care unit. J Pain Symptom Manage 1998;16(6):374–381. 62. Teno JM, Gozalo PL, Mitchell SL, et al. Does feeding tube insertion and its timing improve survival?. J Am Geriatr Soc 2012;60(10):1918–1921. 63. Bruera E, Sala R, Rico MA, et al. Effects of parenteral hydration in terminally ill cancer patients: A preliminary study. J Clin Oncol 2005;23(10):2366–2371. 64. Bozzetti F, Amadori D, Bruera E, et al. Guidelines on artificial nutrition versus hydration in terminal cancer patients. European association for palliative care. Nutrition 1996;12(3):163–167. 65. Quill TE, Arnold RM, Platt F. “I wish things were different”: Expressing wishes in response to loss, futility, and unrealistic hopes. Ann Intern Med 2001;135(7):551–555.

45 66. Delvecchio MJ, Good BJ, Schaffer C, Lind SE. American oncology and the discourse on hope. Cult Med Psychiatry 1990;14(1):59–79. 67. Herth K. Fostering hope in terminally-ill people. J Adv Nurs 1990;15(11):1250–1259. 68. Koopmeiners L, Post-White J, Gutknecht S, et al. How healthcare professionals contribute to hope in patients with cancer. Oncol Nurs Forum 1997;24(9):1507–1513. 69. Wenrich MD, Curtis JR, Shannon SE, Carline JD, Ambrozy DM, Ramsey PG. Communicating with dying patients within the spectrum of medical care from terminal diagnosis to death. Arch Intern Med 2001;161(6):868–874. 70. Lamont EB, Christakis NA. Prognostic disclosure to patients with cancer near the end of life. Ann Intern Med 2001;134(12):1096–1105. 71. Kreitler S. Denial in cancer patients. Cancer Invest 1999;17(7):514–534. 72. Murphy DJ, Burrows D, Santilli S, et al. The influence of the probability of survival on patients’ preferences regarding cardiopulmonary resuscitation. N Engl J Med 1994;330(8):545–549. 73. Weeks JC, Cook EF, O’Day SJ, et al. Relationship between cancer patients’ predictions of prognosis and their treatment preferences. JAMA 1998;279(21):1709–1714. 74. Wright AA, Zhang B, Ray A, et al. Associations between end-of-life discussions, patient mental health, medical care near death, and caregiver bereavement adjustment. JAMA 2008;300(14):1665–1673. 75. Tulsky JA. Hope and hubris. J Palliat Med 2002;5(3):339–341. 76. Tulsky JA. Beyond advance directives: Importance of communication skills at the end of life. JAMA 2005;294(3):359–365. 77. Back AL, Arnold RM, Quill TE. Hope for the best, and prepare for the worst. Ann Intern Med 2003;138(5):439–443. 78. Epstein RM, Back AL. A piece of my mind. Responding to suffering. JAMA 2015;314:2. 79. Quill TE, Lo B, Brock DW. Palliative options of last resort: A comparison of voluntarily stopping eating and drinking, terminal sedation, physician-assisted suicide, and voluntary active euthanasia. JAMA 1997;278(23):2099–2104. 80. Sulmasy DP, Pellegrino ED. The rule of double effect: Clearing up the double talk. Arch Intern Med 1999;159(6):545–50. 81. Meisel A, Snyder L, Quill T. American College of Physicians— American Society of Internal Medicine End-of-life Care Consensus Panel. Seven legal barriers to end-of-life care: Myths, realities, and grains of truth. JAMA 2000;284(19):2495–2501. 82. Quill TE, Dresser R, Brock DW. The rule of double effect—A critique of its role in end-of-life decision making. N Engl J Med 1997;337(24):1768–1771. 83. Sykes N, Thorns A. The use of opioids and sedatives at the end of life. Lancet Oncol 2003;4(5):312–318. 84. Allmark P, Cobb M, Liddle BJ, Tod AM. Is the doctrine of double effect irrelevant in end-of-life decision making?. Nurs Philos 2010;11(3):170–177. 85. Kirk TW, Mahon MM, Palliative sedation task force of the national hospice and palliative care organization ethics committee. National Hospice and Palliative Care Organization (NHPCO) position statement and commentary on the use of palliative sedation in imminently dying terminally ill patients. J Pain Sympt Manage 2010;39:914–923. 86. Lo B, Rubenfeld G. Palliative sedation in dying patients: “We turn to it when everything else hasn’t worked” JAMA 2005;294(14):1810–1816. 87. Rietjens JA, van der Heide A, Vrakking AM, Onwuteaka-Philipsen BD, van der Maas PJ, van der Wal G. Physician reports of terminal sedation without hydration or nutrition for patients nearing death in the Netherlands. Ann Intern Med 2004;141(3):178–185. 88. Rodrigues P, Crokaert J, Gastmans C. Palliative sedation for existential suffering: A systematic review of argument-based ethics literature. J Pain Symptom Manage. 2018;55(6):1577–1590. 89. Jansen LA, Sulmasy DP. Sedation, alimentation, hydration, and equivocation: Careful conversation about care at the end of life. Ann Intern Med 2002;136(11):845–849. 90. Have ten H, Welie JVM. Palliative sedation versus euthanasia: An ethical assessment. J Pain Symptom Manage 2014;47(1):123–136. 91. Gillick MR. Terminal sedation: An acceptable exit strategy?. Ann Intern Med 2004;141(3):236–237. 92. Eddy DM. A piece of my mind. A conversation with my mother. JAMA 1994;272(3):179–181. 93. Quill TE, Ganzini L, Truog RD, Pope TM. Voluntarily stopping eating and drinking among patients with serious advanced illness-clinical, ethical, and legal aspects. JAMA Intern Med 2018;178(1):123–127.

46 94. Blendon RJ, Szalay US, Knox RA. Should physicians aid their patients in dying? The public perspective. JAMA 1992;267(19):2658–2662. 95. Emanuel EJ, Fairclough DL, Emanuel LL. Attitudes and desires related to euthanasia and physician-assisted suicide among terminally ill patients and their caregivers. JAMA 2000;284(19):2460–2468. 96. van der Heide A, Deliens L, et al. End-of-life decision-making in six European countries: Descriptive study. Lancet 2003;362(9381): 345–350. 97. Foley KM. Competent care for the dying instead of physician-assisted suicide. N Engl J Med 1997;336(1):54–58. 98. Quill TE, Lee BC, Nunn S. Palliative treatments of last resort: Choosing the least harmful alternative. University of Pennsylvania Center for bioethics assisted suicide consensus panel. Ann Intern Med 2000;132(6):488–493.

Textbook of Palliative Medicine and Supportive Care 99. Willems DL, Daniels ER, van der Wal G, van der Maas PJ, Emanuel EJ. Attitudes and practices concerning the end of life: A comparison between physicians from the United States and from the Netherlands. Arch Intern Med 2000;160(1):63–68. 100. Hendin H, Rutenfrans C, Zylicz Z. Physician-assisted suicide and euthanasia in the Netherlands. Lessons from the Dutch. JAMA 1997;277(21):1720–1722. 101. Amonoo HL, Harris JH, Murphy WS, Abrahm JL, Peteet JR. The physician’s role in responding to existential suffering: What does it mean to comfort always?. J Palliat Care 2019;41(3): 082585971983933–0825859719839335. 102. Spence RA, Blanke CD, Keating TJ, Taylor LP. Responding to patient requests for hastened death: Physician aid in dying and the clinical oncologist. J Oncol Pract 2017;13(10):693–699.

7

UNDERGRADUATE EDUCATION IN PALLIATIVE MEDICINE

Linh My Thi Nguyen

Contents Introduction..........................................................................................................................................................................................................................47 Core competencies..............................................................................................................................................................................................................47 Europe������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������47 United States..............................................................................................................................................................................................................48 Canada�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������48 Colombia....................................................................................................................................................................................................................49 Current status of undergraduate education....................................................................................................................................................................49 Summary and recommendations......................................................................................................................................................................................50 References..............................................................................................................................................................................................................................50

Introduction The integration of palliative care in undergraduate training for health-care professionals was strongly encouraged by a World Health Assembly. As such, clinicians and educators may be called upon to provide competency-based curriculum and instruction in undergraduate settings both in classrooms and at patients’ bedsides. A general fund of knowledge pertaining to core competencies, accreditation standards, and measurable outcomes may help curricular and instructional development in these unique learning environments. National and international investigators and working groups have proposed competencies developed from expert opinion and surveys of health-care professionals and educators. Some recommendations are specific to undergraduate medical education, whereas others apply to all health-care professions working in a setting where palliative care is delivered. This chapter will describe the different conceptual frameworks of competencies, research regarding the current status of palliative care teaching in undergraduate education, and tips for developing palliative care teaching.

Core competencies Because the European recommendations for core competencies include all health-care professionals, this framework is presented first, followed by competencies for medical students in the United States and Canada, and finally competencies for nursing and medical students in Colombia.

Europe

The European Association for Palliative Care (EAPC) has outlined core competencies that health- and social-care professionals should possess who are involved in palliative care in a two-part white paper.1,2 This expert opinion paper is intended for practitioners and educators. The EAPC advocates for a three-tier framework for practitioners in an academic environment. The agreed levels of education reflect the scope and focus of professionals in the delivery of palliative care: (1) palliative care approach, (2) general palliative care, and (3) specialist care (Table 7.1). The first tier,

or the palliative care approach, applies to undergraduate medical students. However, EAPC has emphasized that these proposed competencies are important for all practitioners, irrespective of their specific discipline. The EAPC has identified core constituents that frame the application of palliative care principles and best practices. 3 These core constituents are the background and framework for the ten proposed core competencies. Successful application of the EAPC core competencies requires an understanding of the core constituents of palliative care. The core constituents are autonomy, dignity, relationship between patient and health-care professionals, quality of life, position toward life and death, communication, public education, multiprofessional approach, and grief and bereavement. First, the EAPC suggests key questions that need be asked before competence can be applied: (1) What is the current position of palliative care within the national or hospital system? (2) What is the capacity of the individual or learner to achieve competency in palliative care? (3) What resources are available to enable the individual or learner to learn and practice skills? (4) Are the baseline standards available against which competency can be determined? Next, educators must consider the definitions of competencies. EAPC proposes one clear and meaningful definition of competency which is “a cluster of related knowledge, skills, attitudes that affects a major part of one’s job (a role or responsibility), that correlates with performance on the job, that can be measured against well-accepted standards, and that can be improved via training and development.”4 Finally, the core question of educators should be, “What is my expectation of the learners following this educational program and how well equipped are they now to carry out the duties expected of them?” In that context, educators can now apply the 10 competencies that a practitioner in the field of palliative care must be able to demonstrate (1) apply the core constituents of palliative care in the setting where patients and families are based; (2) enhance physical comfort through the patients’ disease trajectories; (3) meet patient’s psychological needs; (4) meet patients’ social needs; (5) meet patients’ spiritual needs; (6) respond to the needs of family caregivers in relation to short-, medium-, and long-term patient care goals; (7) respond to the challenges of clinical and 47

48 TABLE 7.1 Levels of Education Reflecting the Scope and Focus of Professionals Involved in the Delivery of Palliative Care Palliative care approach • A way to integrate palliative care methods and procedures in settings not specialized in palliative care (e.g., internal medicine, elderly care, etc.) • Should be made available to general practitioners, staff in general hospitals, nursing, and nursing facility staff • May be taught through undergraduate learning (i.e., students undertaking their primary education in any health-care discipline including medicine) or continuing professional development General palliative care • Provided by primary care professionals and specialists treating patients with life-threatening diseases who have good basic palliative care skills and knowledge (e.g., primary care, geriatricians, nurse practitioners, oncologist, geriatricians, and clinical nurse specialists) • Should be made available to professionals who are involved more frequently in palliative care but do not provide palliative care as the main focus of their work • May be taught at undergraduate or postgraduate level or through continuing professional development Specialist palliative care • Provided in services whose main activity is the provision of palliative care (e.g., professionals working solely in the field of palliative care who care for patients with complex and difficult needs and, therefore, require a higher level of education, staff, and resources; specialist palliative care provided by specialized services for patients with complex problems not adequately covered by other treatment options) • Taught at a postgraduate level and reinforced through continuing professional development

ethical decision-making in palliative care; (8) practice comprehensive care coordination and interdisciplinary teamwork across all settings where palliative care is offered; (9) develop interpersonal and professional shills appropriate to palliative care; and (10) practice self-awareness and undergo continuing professional development. The second part of the EAPC white paper describes in more detail the 10 core interdisciplinary competencies in palliative care. Because of the different models in different countries, reflecting different levels of palliative care as a distinct clinical practice, the core competencies proposed by the EAPC should be considered for palliative care practice and education in Europe. Other countries including the United States, Canada, and Colombia have proposed palliative care competencies for medical students.

United States

In 2014, the Association of American Medical Colleges (AAMC) released, “Core Entrustable Professional Activities for Entering Residency” to address concerns that some medical school graduates were not prepared for residency and that there had been no agreement in the undergraduate medical education community about a common core set of behaviors that could/should be expected of all graduates. The drafting panel considered the two prevailing conceptual frameworks in the literature, competencies, and Entrustable Professional Activities (EPAs) and

Textbook of Palliative Medicine and Supportive Care proceeded with EPAs. In the literature, the relationship between competencies and EPAs has been explained: EPAs are considered units of work, while competencies are the abilities of individuals. The disadvantage of competencies is that they may be abstract, whereas the benefits of EPAs are that they are defined as units of professional practice, defined as tasks or responsibilities that trainees are entrusted to perform unsupervised once they have attained specific competence. The drafting panel was charged to delineate those activities that all entering residents should be expected to perform on day 1 of residency without direct supervision, regardless of specialty. In this “Version 1.0,” AAMC has recommended 13 EPAs which describes each activity and the functions of the new interns, expected behaviors, and vignettes for pre-entrustable learners and entrustable learners. Of interest to palliative medical education is EPA 10 which states that new interns will recognize a patient requiring urgent or emergent care and initiate evaluation and management. Furthermore, EPA 10 states that a function of the new intern is to “clarify patient’s goals of care upon recognition of deterioration (e.g., do not resuscitate, do not intubate, comfort care).” In the same year, 2014, other authors published comprehensive palliative care competencies for medical students, in other words, primary palliative care competencies. Schaefer et al. surveyed 71 palliative experts to assess ratings and rankings of proposed competencies and competency domains. 5 The proposed competencies were derived from existing hospice and palliative medicine fellowship competencies and revised to be developmentally appropriate for students. Authors identified 18 competencies, of which 7 were proposed as essential graduation competencies, according to the survey results. The seven essential competencies were (1) describes ethical principles that inform decision-making in serious illness, including the right to forgo or withdraw life-sustaining treatment and the rationale for obtaining a surrogate decision maker; (2) reflects on personal emotional reactions to patients’ dying and deaths; (3) identifies psychosocial distress in patients and families; (4) explores patient and family understanding of illness, concerns, goals, and values that inform the plan of care; (5) defines the philosophy and role of palliative care across the life cycle and differentiates hospice from palliative care; (6) demonstrates patient-centered communication techniques when giving bad news and discussing resuscitation preferences; and (7) assesses pain systematically and distinguishes from nociceptive from neuropathic pain syndromes. In 2016, for undergraduate nursing students, the American Association of Colleges of Nursing endorsed the palliative care competencies published in the document, “CARES: Competencies And Recommendations for Educating undergraduate nursing Students.”6,7 The article outlines 17 competencies new nurses need to have completed by the end of their undergraduate nursing education. Additional recommendations were published, and subsequently, the online curricula was made available.8 The End-of-Life Nursing Education Consortium-Undergraduate Curriculum meets the competencies for primary palliative care at the undergraduate level, is composed of six 1-hour online modules, and requires passing a knowledge assessment at the end of each module.9

Canada

The national undergraduate competencies for palliative and endof-life care were developed through a project called Education Future Physicians in Palliative and End-of-Life Care, subsequently

Undergraduate Education in Palliative Medicine updated through a multi-stage process that included invited stakeholders to comment, and validated by 60 individuals and organizations.10 The goal was to graduate every medical student with the knowledge, skills, and attitudes appropriate to meet patients’ primary palliative care needs. There were several key changes from the original project to the update project which included the shift from “palliative care,” which historically was provided at end of life primarily to patients with cancer, to a “palliative approach to care,” which starts earlier in the course of a life-threatening malignant or non-malignant illness. Competencies, or focused objectives, that address changes in the practice environment to include safe and appropriate use of opioid prescribing, changes in laws around medical assistance in dying, and the growing use of cannabinoids for symptom management. From general to specific, the Canadian framework is composed of key competencies, enabling competencies, specific objectives, and elements of the undergraduate curriculum that may facilitate learning of competencies. The key competencies for graduating medical students are (1) describe a palliative approach to care; (2) address and manage pain and other symptoms; (3) participate in appropriate care for the dying patient and their family; (4) participate in appropriate care for the pediatric patient with palliative care needs and their family; (5) address psychosocial and spiritual needs; (6) address endof-life decision-making and planning using a basic bioethical and legal framework; (7) communicate effectively with patients, families, and other caregivers; (8) collaborate as a member of an interprofessional team; (9) attend to multi-dimensional sources of suffering; and (10) demonstrate self-awareness and self-care in caring for terminally ill patients. The elements of the curriculum that may facilitate palliative care competencies are outlined for each competency. These elements may well help educators with curriculum mapping and help learners with revisiting important topics (e.g., pain physiology and pathophysiology, pharmacology, management of palliative care/oncological emergencies). This outlined curriculum offers suggestions on the timing of specific objectives such as during the pre-clerkship or clerkship years and examples of instructional methods such as small group case-based teaching, standardized patients, and technology-supported methods (e.g., simulations and videos).

Colombia

Pastrana, Wenk, and De Lima, in Colombia, encouraged the distribution and promotion of their consensus-based palliative care competencies for undergraduate medical and nursing schools to universities and academic decision makers.11 Using the International Association for Hospice and Palliative Care (IAHPC) List of Essential Practices (LEP),12 as guidance and the Recommendation of the EAPC for the Development of Undergraduate Curricula in Palliative Medicine,13 36 participants from 16 medical and 6 nursing schools from 18 universities in Colombia were asked to discuss and define palliative care competencies at the undergraduate level. The group identified core competencies in six main categories: (1) definition and principles of palliative care, (2) identification and control of symptoms, (3) end-of-life care, (4) ethical and legal issues, (6) psychosocial and spiritual issues, and (6) teamwork. The main categories were further divided into subcategories and, finally, the competencies. There is significant agreement between the competencies identified by the Colombian participants with the IAHPC LEP. However, the Colombian participants added specific competencies not included in the IAHPC LEP: knowledge of medications

49 such as essential medications for palliative care, medications to be used with caution, opioid rotation, risk factors in opioid abuse, opioid equianalgesia, dilutions, conversions, drug-drug interactions; knowledge of palliative sedation including definitions, recognizing refractory symptoms, administration, operational aspects of palliative sedation, and communication. Conversely, the Colombian participants did not include the IAHPC LEP competencies related to wounds, ulcers, skin rash and skin lesions, dry mouth, mucositis, and cough, fatigue, anorexia, anemia, somnolence, and sweating. Pastrana et al. note that these competencies are much more detailed and specific as opposed to the EAPC core competencies, which are more broad and general. The authors discuss Miller’s pyramid of clinical competence, which consists of four levels: knows, knows how, shows, and does. They note that educational needs vary from learner to learner and in different countries. For instance, for students who engage in clinical practice after graduation, the core competencies should focus mainly on clinical aspects, whereas students who must go through residency, the core competencies can balance palliative care philosophy, humanistic aspects of care, along with basic clinical competencies.

Current status of undergraduate education Fitzpatrick et al. conducted a systematic review in 2017 of palliative care in undergraduate medical education published between 2001 and 2015.14 The review included all original articles about medical schools with palliative care teaching. Excluded from the systematic review were studies regarding graduate medical education, postresidency training, or continuing medical education and nursing and allied health students. The systematic review identified 124 articles. The results of the thematic analysis showed common themes (number of original articles): curricular content (n = 15), curricular development (n = 7); comparison of multiple teaching institutions (n = 14) versus module or curriculum in a single teaching institution (n = 53); hospice learning (n = 16). The articles included different instructional methods: technology or e-learning (n = 2), simulation (n = 4), novel methods (n = 17), and interprofessional teaching (n = 13). Some articles addressed several themes and were counted more than once in these results. The authors observed that there was greater consistency in the content being delivered as part of end-of-life education. Among the most frequently taught topics were attitudes toward death and dying, communication skills, and pain management. Among the less frequently addressed topics were pediatric care and religious and cultural issues. Institutions utilized a broader range of teaching modalities. The authors concluded that significant progress had been made. In 2016, Head et al. reported the overall progress and current direction of palliative medical education published in the English literature between 2005 and 2015. They included 151 articles, summarized palliative medical education efforts outside the United States and notable innovative education efforts, and described the number of learners involved, student time, teaching methodologies, level of evaluation (according to Kirkpatrick’s levels of evaluation), and study outcomes such as learner reported outcomes and increases in knowledge. Head et al. recognized that end-of-life education is mandated by Liaison Committee on Medical Education (LCME) accreditation standards but that palliative care is surprising absent from the LCME accreditation standards. To add to the confusion, content related to palliative care has been added to the United States Medical Licensing

Textbook of Palliative Medicine and Supportive Care

50 TABLE 7.2 Tips for Developing Palliative Care Teaching in Undergraduate Medical Education • Compulsory and integrated across the course • Ensure all students see patients with palliative care needs and those that are dying • Back up teaching with compulsory formative and summative assessments • Secure support from within the university • Ensure all students visit a hospice and/or inpatient palliative care facility • Develop key learning objectives and competencies • Involve palliative care specialists • Join up with interest colleagues in other specialties • Develop variety and innovation in teaching methods • Utilize the hidden curriculum to promote learning • Enable some students to spend more time in palliative care • Encourage interprofessional learning

Exam. Head et al. argue that because the only LCME requirement specifies end-of-life care, the misconception that palliative care and end-of-life care are synonymous will continue. In summary, authors found that medical students value palliative medicine, describe the weaknesses of the current approaches to palliative care educational efforts, and identify barriers to drive initiatives. They also offer specific recommendations for a comprehensive palliative care curriculum focused on competency development that is integrated throughout the four years of medical education.

Summary and recommendations There have been significant advances in undergraduate education in palliative medicine in terms of defining competencies. The EAPC has published core competencies for all health-care professions. Colombians authors have proposed competencies for medical and nursing students, and the United States and Canada have proposed competencies specifically for medical students. Systematic reviews and other reviews have described the current status of undergraduate medical education. However, less is known regarding other disciplines and allied health professionals. Boland, Barclay, and Gibbins have offered practical tips for palliative care teaching for undergraduate medical students, some of which may applied to nursing and other allied health students.15

References













1. Gamondi C, Larkin P, Payne S. Core competencies in palliative care: An EAPC white paper on palliative care education—Part 1. Eur J Palliat Care 2013;20(2):86–91 (Accessed 9 Oct 2019). 2. Gamondi C, Larkin P, Payne S. Core competencies in palliative care: An EAPC white paper on palliative care education—Part 2. Eur J Palliat Care 2013;20(3):140–145 (Accessed 9 Oct 2019). 3. Radbruch L, Payne S. White paper on standards and norms for hospice and palliative care in Europe: Part 1. Eur J Palliat Care 2009;16(6):278–289 (Accessed 12 Oct 2019). 4. Parry SB. The quest for competencies. Training 1996;33(7):48. 5. Schaefer KG, Chittenden EH, Sullivan AM, et al. Raising the bar for the care of seriously ill patients: Results of a national survey to define essential palliative care competencies for medical students and residents. Acad Med 2014;89(7):1024–1031. doi: 10.1097/ ACM.0000000000000271. 6. O’Connor B. CARES: Competencies and recommendations for educating undergraduate nursing students preparing nurses to care for the seriously ill and their families. J Profess Nurs 2016;32(2):78–84. doi: 10.1016/j.profnurs.2016.02.008. 7. O’Connor B. AACN endorses palliative care competencies and recommendations for undergraduate nursing education. J Profess Nurs 2016;32(2):77–77. doi: 10.1016/j.profnurs.2016.02.006. 8. Ferrell B, Malloy P, Mazanec P, Virani R. CARES: AACN’s new competencies and recommendations for educating undergraduate nursing students to improve palliative care. J Profess Nurs 2016;32(5):327–333. doi: 10.1016/j.profnurs.2016.07.002. 9. ELNEC-Undergraduate Curriculum. https://elnec.academy. reliaslearning.com/ELNEC-Undergraduate-Curriculum.aspx. 10. Palliative Care Competencies for Undergraduate Medical Students in Canada. https://www.cspcp.ca/wp-content/uploads/2018/06/PalliativeCare-Competencies-Undergrad-2018-EN.pdf (Accessed 23 Oct 2019). 11. Pastrana T, Wenk R, De Lima L. Consensus-based palliative care competencies for undergraduate nurses and physicians: A demonstrative process with Colombian universities. J Palliat Med 2016;19(1):76–82. doi: 10.1089/jpm.2015.0202. 12. De Lima L, Bennett MI, Murray SA, et al. International association for hospice and palliative care (IAHPC) list of essential practices in palliative care. J Pain Palliat Care Pharmacother 2012;26(2):118–122. doi: 10.3109/15360288.2012.680010. 13. European Association for Palliative Care Task Force on Medical Education. Recommendation of the European Association for Palliative Care for the development of Undergraduate Curricula in Palliative Medicine at European Medical Schools, 2013. 14. Fitzpatrick D, Heah R, Patten S, Ward H. Palliative care in undergraduate medical Education—How far have we come? Am J Hosp Palliat Med 2017;34(8):762–773. doi: 10.1177/1049909116659737. 15. Boland JW, Barclay S, Gibbins J, Boland JW. Twelve tips for developing palliative care teaching in an undergraduate curriculum for medical students. Med Teach 2019:1–7. doi: 10.1080/0142159X.2018.1533243.

8

GRADUATE EDUCATION FOR NONSPECIALISTS

Fiona Rawlinson and Ilora G. Finlay

Contents Introduction..........................................................................................................................................................................................................................51 Domains of learning and learning styles.........................................................................................................................................................................51 Reflective practice................................................................................................................................................................................................................53 Giving feedback to graduate learners..............................................................................................................................................................................53 Role of the educator in a graduate program...................................................................................................................................................................54 Reflective case study (portfolio learning)........................................................................................................................................................................55 Organizing a graduate program........................................................................................................................................................................................55 The graduate student in context........................................................................................................................................................................................56 Planning sessions—A practical approach.......................................................................................................................................................................56 The role of the lecture...................................................................................................................................................................................................56 Flipped classroom..........................................................................................................................................................................................................56 Small group learning.....................................................................................................................................................................................................56 Communication skills.........................................................................................................................................................................................................56 Role-play..........................................................................................................................................................................................................................57 Communication skills case study—The Cardiff 6-point toolkit as a teaching tool.................................................................................................58 Teaching ethics.....................................................................................................................................................................................................................58 Information technology and online learning..................................................................................................................................................................59 Massive open online courses (MOOC’S)..................................................................................................................................................................59 The role of the clinical placement...............................................................................................................................................................................59 Conclusion.............................................................................................................................................................................................................................59 References..............................................................................................................................................................................................................................60

Introduction The global need for palliative care skills continues to increase.1,2 Health-care professionals are likely to be involved in the care of patients with life-threatening illness and who are facing death soon after graduation in their chosen discipline. The World Health Assembly in 2014 Resolution 67.19 urged member states to include palliative care as an integral part of education programs for all health-care professionals according to their role. 3 The proportion of graduates who embark on a career in specialist palliative care is small, yet almost all branches of clinical medicine will involve the management of patients with incurable and potentially life-threatening disease. A white paper from EAPC in 2013 suggests three levels of palliative care delivery that can aid the development of education programs4 (Box 8.1). Furthermore, 10 core constituents of palliative care are identified which need to be addressed in such education programs4 (Box 8.2). An emphasis on developing lifelong learning skills begins in many undergraduate curricula today. Once qualified, the focus shifts more toward those skills and less to a need to pass examinations, although many disciplines—in particular postgraduate medicine—include end-point summative assessments as proof of competence. For the purposes of this chapter, the term “graduate education” refers to training that occurs at any stage following professional registration, and “nonspecialist” refers to training that is not part of a specialty training curriculum in palliative medicine. Graduate education may be delivered on an opportunistic basis

following an encounter with a patient, which develops into a learning opportunity, a set study session or short course, or as part of a delivered curriculum for a higher qualification such as a postgraduate certificate, diploma, or masters. Organizations such as the Quality Assurance Agency in the United Kingdom (UK) define different levels of education depending on the level of critical thinking and innovation employed within that education. An essential feature of all graduate programs for palliative medicine is keeping the patient and their family at the heart of all education initiatives and with an aim that such sessions will result in a positive impact on the palliative care that patients and family receive.

Domains of learning and learning styles A graduate program needs to focus around the four key domains in learning5: 1. Knowledge and understanding 2. Skills and competencies 3. Attitudes and professional behavior 4. Personal and professional development Objective assessment of these competencies is easier in the first two domains (knowledge and understanding, and skills and competencies) than the others, although the importance of attitude and professional behavior should be an underpinning ethos in any graduate program. A curriculum will include information 51

Textbook of Palliative Medicine and Supportive Care

52

BOX 8.1  EUROPEAN ASSOCIATION FOR PALLIATIVE CARE AGREED LEVELS OF PALLIATIVE CARE KNOWLEDGE (FROM REFERENCE [4] WITH PERMISSION) *PALLIATIVE CARE APPROACH A way to integrate palliative care methods and procedures in settings not specialized in palliative care. Should be made available to general practitioners and staff in general hospitals, as well as to nursing services and nursing home staff. May be taught through undergraduate learning or through continuing professional development. *GENERAL PALLIATIVE CARE Provided by primary care professionals and specialists treating patients with life-threatening diseases who have good basic palliative care skills and knowledge. Should be made available to professionals who are involved more frequently in palliative care, such as oncologists or geriatric specliats, but do not provide palliative care as the main focus of their work. Depending on discipline, may be taught at an undergraduate or postgraduate level or through continuing professional development. *SPECIALIST PALLIATIVE CARE Provided in services whose main activity is the provision of palliative care. These services generally care for patients with complex and difficult needs and therefore reuquire a higher level of education, staff, and other resources. Specialist palliative care is provided by specialized services for patients with complex problems not adequately covered by other treatment options. Usually taught at a postgraduate level and reduced through continuing professional development.

deemed to be formal (set by the organizer), informal (developed by the learner in response to the formal curriculum), or “hidden.” The “hidden curriculum” is a side effect of an education session. For example, the values and beliefs conveyed in the classroom and the social environment and its impact should not be underestimated. The way the session is facilitated, the language and attitude of the facilitator toward whichever aspect of care of seriously ill or terminally ill patients is being discussed will influence the quality of learning. Different teaching methods will be better suited to the different domains; a combination of teaching methods may be more effective. A lecture may impart facts and increase “knowledge,” but understanding does not develop until the application to, and facts of, clinical scenarios are explored, understood, and applied. Without understanding, cold “facts” may be applied inappropriately or even dangerously to an individual clinical situation, particularly the one that is complex. Although those embarking on a career in palliative medicine may recognize the need for broad learning methods such as

BOX 8.2  EUROPEAN ASSOCIATION FOR PALLIATIVE CARE CORE CONSTITUENTS OF PALLIATIVE CARE (FROM REFERENCE [4] WITH PERMISSION) • Autonomy • Dignity • Relationship between patient and health-care professionals • Quality of life • Position toward life and death • Communication • Public education • Multi-professional approach • Grief and bereavement

role-play and reflective practice, older learners and those who are used to didactic teaching may struggle initially with reflection or self-directed learning, manifesting their concerns with attitudinal barriers. Before the development of learning can occur, the learner needs to have insight into why their attitude appears inappropriate and negative, understand the fundamental reasons within themselves behind their behavior, and ultimately inherently wish to change. Those who feel there is nothing wrong with their attitude or approach may have not even begun to contemplate the need to change which will make success unlikely.6 Many problems of team working are linked to attitudinal difficulties that may be revealed in course tutorials, small group work, role-play, or in interactions with the course administrative staff when the student’s aggressive or awkward approach is manifest. For all students, sensitive effective feedback is a potent driver to learning. Learning outcomes on a graduate program are driven by the core competencies that have to be attained and, therefore, are assessed by the end of the program. The EAPC core competencies outlined previously provide a comprehensive collection of attributes. A fixed learning agenda, however, will not address sudden needs driven by situations arising from the clinical workplace, and graduate learning is usually driven by a powerful “need to learn.” It is useful to allow graduates to set some of their own learning needs and outcomes as they go through a program and to reflect on what they are learning.7 This is particularly important for the graduate learner who is undertaking palliative care training for application within their own branch of medicine. For example, the learning outcomes of a cardiologist are likely to be different to those of an oncologist, since they care for patients with different diseases, therapeutic options, and disease trajectories. Allowing the student to identify their own learning needs within their clinical context promotes a more meaningful and successful learning process. Such learning outcomes, particularly when defined by the graduate, may not be easily assessed within the context of the graduate course itself. This applies particularly to practical skills, such as draining an ascetic or pleural effusion,

Graduate Education for Nonspecialists although an imaginative curriculum will allow such assessment from the student’s workplace to be fed into the overall assessment on the graduate program. Adults are more likely to learn if they wish to learn and they view the learning to be purposeful. The interaction between learner and the learning material will promote learning, whether in a face-to-face or online environment. Adult learning styles will determine how different graduates learn most effectively on a course.8 The many different facets of adult learning continue to be researched, and a number of self-assessment tools are available for students to explore their own preferred learning style in order to achieve maximum success. However, care is needed in order to avoid this approach simply leading to strategic learning. The effective course organizer will include materials delivered in a variety of styles and use teaching methods aimed to address a diverse collection of learning styles. For example, in palliative care teaching on nausea and vomiting, some learners prefer a diagrammatic approach to the receptors involved, and others prefer to learn from tables or from text.

Reflective practice Reflective practice, described in the early 1930s and championed by Kolb9 and Schon,10 is now a recognized tool for learning and is integrated into most course designs. The reflective practice cycle moves through the stages of having an experience (concrete experience), reflecting on that experience (reflective observation), integrating ideas and facts, learning from the reflections to inform the future (abstract conceptualization), and finally putting those ideas into practice (active experimentation), which, in turn, provides an “experience” and so the cycle or perhaps, more accurately, a spiral of learning starts again. There remains some global disparity—an integrated approach is generally seen within Western cultures, especially the UK, the United States, Canada, and Australasia, but less so in countries where a more traditional lecture-based approach to education remains.11 Awareness of this important distinction is useful in order that an educator can plan and deliver the most appropriate material in the most appropriate way for learners working in a particular culture or region. Reflection involves the learner in thinking about what they are doing, developing insight into their own approaches to a problem, analyzing the way that they tackle the problem, and looking critically at the outcome. It then involves reflecting on that process, paying particular attention to what is being learnt and how practice can be developed. The learner also needs to think about and draw on related knowledge and experiences to be able to criticize, restructure, and apply these principles for further learning. Boud defined reflection as “an important human activity in which people recapture their experience, think about it, mull it over, and evaluate it.”13 Schon calls this type of thinking reflection-on-action. This review of past experiences leads to a critical analysis of what led the learner to change their way of practice; sometimes, reflection during the course of a process (reflection-in-action) involves modifications while dealing with a problem. It is important that reflection is encouraged in a nonthreatening way so that the learner does not become demoralized. Although mistakes or unsatisfactory outcomes often provide the best stimuli for learning, such events need to be handled sensitively and appropriately. Much learning can be effectively undertaken by reflecting on ordinary situations as they arise, thereby building on good practice. This can

53 be particularly important for the learner who lacks confidence. When mistakes have occurred, the learner should be encouraged to reflect on what they would do differently next time, rather than on what they did wrong. In palliative care, clinical situations are often complex, and there can be many different ways of approaching the problem. Emotionally charged situations can leave the clinician feeling inadequate, upset, and sometimes with unrealistic expectations of himself or herself as a practitioner. Supportive nonjudgmental reflection with colleagues can form part of a “debrief” and help develop alternative future strategies for dealing with a similar situation. Greenwood has been particularly critical of Schon’s module because it failed to recognize the importance of reflection-beforeaction.14 In palliative care, such a reflective approach before acting integrates all previous experiences, with acquired knowledge and understanding, to empower the practitioner to behave differently from previously.

Giving feedback to graduate learners “Feedback is given with the intent to improve performance for learning rather than to criticize or to judge.”15 Feedback on learning can be formal or informal and can follow an observed procedure or encounter, be part of an education session, or be in response to a written piece of work—either as an assessment or as part of an online learning or professional development portfolio. Feedback is an essential part of the reflective learning process; giving effective constructive feedback is a core communication skill for educators and should follow some key principles as outlined in Box 8.3. Various frameworks for delivering feedback have developed over the last 30 years in response to the changing culture and ethos of health-care education. Table 8.1 outlines the different attributes. Pendleton’s method of feedback provided an early set of rules by which feedback could be given.17 However, because

BOX 8.3  PRACTICAL PRINCIPLES FOR GIVING EFFECTIVE FEEDBACK (ADAPTED FROM REFERENCES [15,16]) Create the appropriate setting so that feedback is not unexpected. Give feedback as soon after the event as possible. Generally, give feedback on a one-to-one basis, especially if there is a need to highlight poor performance. Focus on observable behavior (or on what is written). Feedback needs to be objective. (If you are giving written feedback, still focus on observable behavior or written facts.) Initially focus on what went well, areas of strength. Explore alternative strategies with the person for the event or the procedure and how they might access support/ resources to enable further development. If necessary, support the learner in creating a plan for further development using clear objectives. Remember giving feedback is a form of interpersonal communication and needs to be considered and planned as such.

Textbook of Palliative Medicine and Supportive Care

54 TABLE 8.1  Attributes of Different Feedback Frameworks

Kurtz et al.18

Calgary—Cambridge (Silverman) “agenda led—outcome based”—SET-GO18

Alexander19

1. Check what the learner wants and whether is ready for feedback 2. Let the learner give comments or background to the material that is being assessed 3. Asking the learner what they felt they did well or were particularly happy with 4. Tutor’s ± peer feedback on what they feel went well 5. Asking the learner what they felt could be improved 6. Tutor ± peer feedback on what they feel could be improved

What is the trainee agenda

Feedback based on

What am I doing well?

7. Develop an action plan for improvement

Suggest alternatives ± trial of alternatives (e.g., role-play in a communication skills scenario) Summarize learning and action plan

Pendleton17

8.  

What was Seen?

What outcome is the learner wanting What else was seen? to achieve? Encourage self-assessment and self-problem solving While group problem solving

What does the learner and others think? Clarify the goals

Descriptive objective feedback on what went well and what might be done differently

Learner ± group discussed and offers alternatives of how to achieve the goals

learners often focus on what did not go well, rather than recognizing strengths to be developed, there is a risk that the framework could become formulaic and thus a barrier to reflection and learning. Silverman, Kurtz, and Draper18 developed an agendaled, outcome-based approach, which has been further worked into a simple framework by Steve Alexander, namely, “What am I doing well? And what do I need to improve?”.19 In all cases, feedback should be expected, descriptive, balanced, objective, nonjudgmental, and timely.

Role of the educator in a graduate program Educators delivering a graduate program need to be aware of adult learning theories and the need to respect learner autonomy, yet still give guidance. All educators need clear guidance about what is expected of them and be familiar with different methods of delivering education that will encourage learners, in addition to styles that should be avoided as they lead to barriers to learning and demoralization. Facilitators need to be aware of the culture and clinical context within which the learners are working. For example, teaching ethics or communication skills in a country where “collective autonomy” is the norm will be different from a more Western approach. Where students are being tutored in groups, confidentiality of the group discussions becomes important and each member of the group must be treated with respect by other group members. Setting “ground rules” for group work and ideally asking the group to discuss and form these rules themselves is an important step. Each member should have time to participate, and care should be taken that no particular member of the group dominates. This is particularly important in small groups of learners from different cultures. A quieter member of a group may notice and listen particularly closely—these attributes can be a useful way to encourage their participation in the group discussion. The most effective teaching occurs in a

What do I need to do to improve?

safe environment where the individual feels supported and good practice is reinforced. However, sometimes, where individuals lack insight, the tutor may need to speak on a one-to-one basis with the student to help that student identify particular problems that they are having. Such difficult conversations should be held outside of the group setting. The role of the hidden curriculum is demonstrated in the choice of faculty which delivers palliative care teaching. Using members of the multidisciplinary team, either giving combined or in separate sessions, gives a strong message to learners about the benefit of the multidisciplinary team in delivering palliative care. Finally, educators themselves need to develop reflective practice on their teaching skills. Bad habits and overfamiliarity with content can mean that attention to learners’ changing needs is missed. Simple peer review of teaching on a regular basis can be an important part of an educators’ portfolio. Attending to professional development that matches, for example, the GMC promoting excellence themes of • • • • •

Learning environment and culture Educational governance and leadership Supporting learners Supporting educators Developing and implementing curricula and assessments

will ensure a comprehensive teaching portfolio of skills.20 For those who wish to formalize teaching, specific training in medical education and validation as a teacher by organizations such as the Higher Education Authority in the UK or the UK Academy of Medical Educators is also worth considering. There is increasing evidence on the effectiveness of different teaching methods—educators need to be up-to-date with education and teaching theory and base their lesson plan and interventions on evidence-based practice where possible.

Graduate Education for Nonspecialists

Reflective case study (portfolio learning) The most powerful stimulus to learn is the need to know, which makes reflective learning, recorded in a portfolio format, a particularly powerful teaching tool for the individual and for a clinical team. Reflection has become an integral part in some national training and professional registration portfolios aided by a formal documentation process. A portfolio allows personalization of the learning experience, particularly when postgraduates come from a wide range of clinical settings and with varying clinical resources. Each student in a group may pursue areas they define as their greatest area of need, with supportive supervision. Although the tutor is usually unable to verify the details of a case described, the learning objectives will be met by a focus on the learning objectives set by the student. The learner can present their learning in a format relevant to the topic, laid out in a way that allows the tutor to follow the learning process. In groups, peer review of such a portfolio can ensure shared learning about the topic and on how to tutor others, particularly when students have come from a tradition of didactic teaching and are unfamiliar with more facilitative styles of teaching that recognize that learning is a dynamic, lifelong process and respects the unique contribution of each person.

Organizing a graduate program When planning graduate education, five distinct phases need to be addressed: • Needs assessment • Precourse planning

BOX 8.4  ELEMENTS OF A SUCCESSFUL REFLECTIVE PORTFOLIO (FROM REFERENCE [21] WITH PERMISSION) • Factual case histories around which the learning usually occurs. • References to diverse sources, e.g., textbook reading, literature search, lay press, conversations with colleagues. • A record of the clinician’s own decision-making processes, including details of decisions made and how the learner arrived at the decision. • Documentation as to how the learner felt at the time and sources of stress or doubts are as useful as the outcome since the personal feelings of the learner will influence how they were able to approach a problem. • Ethical considerations. • Illustrative items such as photographs, drawings, quotations, and poetry may clarify points being made. Care must be taken over anonymization and permission from the patient for such items to be used. • Some form of indexing is important, so the learner and supervisor can follow the learning process and refer to specific items at a later date.

55 • Course delivery • Assessment (especially if the course is part of an Institution Higher award such as PG Certificate or Diploma) • Evaluation after the course to allow modification and confirm that the course has met its own aims and objectives, particularly the impact on the clinical practice A robust system of internal and external quality assurance (QA) underpins all education programs to make sure that agreed standards are being met (or exceeded) and that good practice is shared. This is of the utmost importance for the following reasons: • There are many postgraduate courses available and QA ensures the students have chosen a course that meets appropriate standards. • QA confirms an agreed standard of training has been delivered by the organization. • With several postgraduate courses becoming quotable qualifications, QA is essential to confirm the qualification is of sufficient standard required by medical governing bodies. • It allows for the course to be flexible and develop over time, to reflect the changes in the specialty, market, and teaching resources. Careful pre-course planning is essential; fundamental decisions about the course include its curriculum and format. This may be in response to a needs assessment for that region or country that could use preexisting needs assessment tools22 or be in response to developing health policy and curricula in that region. Planning should not be done by one individual in isolation but rather with the involvement of a committee of potential course tutors and facilitators. In established courses, including a student representative and, depending on the course content and aims, a patient representative will also add diversity and ensure a comprehensive approach. The overall aims and ethos of the course need frequent review in order to reflect changing culture and education and palliative care practices. The curriculum, specific expected learning outcomes, and course delivery should take into account the needs of the learners and the resources available to meet them.23 Graduates have different levels of palliative medicine knowledge and experience. Some may be general practitioners or specialists wishing to expand their palliative medicine skills, while others may be wanting to follow a specialist career in palliative medicine. The number of learners intended on the course and their geographical location will have significant impact on resources and course delivery. Distance learning and web-based courses are more practical for a cohort of learners from a wide geographical distribution, but this will not necessarily be the most effective way to teach communication skills or ethics. Many countries have a core curriculum of learning needs and descriptors of competencies that need to be achieved during the course.24–29 Several courses based upon these competencies have run successfully within the UK. For example, the Cardiff MSc course has trained over 3000 postgraduates at Diploma or Masters level within its 30 years of activity. Although curricula that have been developed by national organizations can serve as “guideposts,” they may not address the specific needs and culture of an individual. 30 Clinicians from a wide variety of clinical, geographical, and cultural backgrounds have highlighted communication skills, multi-professional team working, and psychological

Textbook of Palliative Medicine and Supportive Care

56 aspects of care, which are particularly relevant to their clinical practice.22 These topics lend themselves best to reflective practice and role-play, which need face-to-face small group tutorials rather than distance learning or lecture formats. Clear goals of learning, or learning outcomes, should state explicitly the skills and competencies that the learner is expected to be able to demonstrate. Feedback on any work undertaken is essential, and adult learners should be encouraged at all times to be reflective in the way that they approach a topic. Assessment of learning in a multi-professional holistic patientfocused approach to care requires valid tools to assess reflective practice, portfolio learning, and the medical humanities. Role-play in communication skills training is often met with trepidation, often manifest as resistance, which is overcome by experienced, skilled facilitators/tutors to provide the support and input inevitably required. Any teaching program needs regular evaluation to ensure that it is educationally effective in improving clinical practice, responsive to the changing and individual needs of participants, provides competent teaching in theory and practice, and enables students to make a difference in their clinical practice. 31 Structured feedback should be incorporated throughout the course, which gives opportunities for learners (directly and through student representatives) and tutors to contribute to the course’s evolution through feedback, collated and reviewed annually.

The graduate student in context In selecting graduates for a formal training program, it is important to know what has motivated the student to come forward and wish to learn. Some may have recognized a personal learning need as part of reflective practice and professional development within appraisal, while others may be motivated by their own experience within their own friends or family, or a professional situation where they felt that their practice needed developing. Students may have come from a wide range of clinical situations. While in Western Europe and the United States, libraries, journals, and Internet access abound, in many low- and middleincome countries, there is still limited access to journals in libraries, and Internet access may still be unreliable. It is also important to know about the practice conditions of learners. While it can be useful for learners to be exposed to a wide range of ways of practicing, including some high-tech interventions, for those practicing in developing areas, most of their meaningful understanding and competency development will occur in relation to techniques and actions that they can instigate in their own work environment. Furthermore, there may be differences in access to drugs in common use in other countries, as well as culture-specific spiritual and communication issues that may challenge Western palliative care service models. Using the public health model to underpin education to support developing services in low- and middle-income countries will enhance education and training for sustainable services. 32

Planning sessions—A practical approach Dale’s Pyramid of Learning has been widely cited as a caution against lecture-based education as the single delivery method for education. 33 This view remains contentious because of the

original methodology that developed the model, but the debate is thought-provoking. 34 Using a framework such as Gagne’s nine events of instruction, an effective lesson plan can be devised. 35 Of key importance is setting out the aims and objectives at the start of the session, which can be referred to as the session ends to help consolidate learning. For effective education, it is useful to plan and match activities and interaction to these outcomes and ensure that time allocation is appropriate for each element. Starting and ending the session on time is particularly important for those undertaking sessions within their clinical working environment.

The role of the lecture

Lectures remain effective ways of delivering consistent facts to a large collection of people at the same time, although taking account of Dale’s Pyramid of Learning outlined previously. Interactive tasks can be incorporated within a lecture, such as group work, case discussions, or interactive voting. There is increasing capacity for the lectures to be recorded, either an aide memoir for learners who might want to go back and clarify a point, or using a technique such as “flipped learning,”36 where learners are asked to review a lecture and then participate in group work for further discussion.

Flipped classroom

Increasingly, innovative ways of combining teaching methods are being explored. Flipped classroom refers to a technique where learning materials—reading materials or recorded presentations—are circulated to learners in advance of small group discussions. 36 In the busy clinical environment, it may be a challenge for learners to secure study time in advance of a session in which the material is explored—however, with appropriate pre-session information and guidance, the flipped classroom approach may be useful as a way to catch up on a session which has been missed.

Small group learning

Several core skills and an understanding of group dynamics will increase small group learning. The importance of setting up an effective learning environment has already been discussed. Small group work is not necessarily synonymous with “problem-based learning” (PBL). PBL is a specific teaching technique using small group work to achieve specified outcomes. 37,38

Communication skills The importance of communication skills is widely recognized in palliative care. Communication problems faced by graduates working in oncology are not resolved by time and clinical experience, 39 and there is strong evidence that training courses can significantly improve key communication skills40 to deal with the complex difficulties encountered in palliative care clinical practice. Palliative care consultations are often the most challenging in clinical practice, since they may involve breaking bad news and talking about dying and loss39,41 and be undertaken by clinicians who themselves may be at different points in their own learning or experience of grief and loss. Observing, teaching, and giving feedback on communication skills is challenging in this sensitive environment. Intrusive observation of such sensitive consultations, with recording

Graduate Education for Nonspecialists

57

FIGURE 8.1  Dale’s Pyramid of Learning. (From Reference [33] with permission.) devices or the presence of additional observers, may disrupt the flow of the consultation and hinder the patient’s openness within discussions. Since the palliative care consultation is potentially difficult and may have wide ramifications if badly handled, the trainer must create a safe learning environment where the trainee can feel comfortable making mistakes without repercussions and protect potentially vulnerable patients. It necessarily follows that the use of real patients is not always appropriate.

Role-play

Role-play using either actors or colleagues as patients has long been established as a useful tool for developing communication skills.42 It is best done as a small group of learners with one or more trained facilitators. It is important to keep the groups small enough to ensure that everyone has the opportunity to role-play in the time allocated. People are initially wary of role-play, since, for many, it is unlike any other training they may have encountered. Maintaining a small group with attention to the psychological safety of participants will help them feel more comfortable in the process. Role-play allows people to train for situations they rarely encounter, but when they do, they need to be prepared. The skills for breaking bad news or dealing with anger are best learned prior to encountering these situations in practice. In the real world, one will not get a second opportunity to tackle a difficult consultation from scratch, over and over again. Role-play affords the learner this luxury.

There are several basic principles that should underpin any such learning session: • • • • • • • • •

Clearly established rules of role-play Strict adherence to confidentiality Safe environment Avoidance of role-playing situations that are potentially distressing for learners Option to call “time-out” at any point Opportunity for all learners to participate Nonconfrontational feedback Time for those involved to “come out of role” after a session Review of learning points and debrief at the end of each session

A crucial aspect of role-play is the ability to give feedback as has already been outlined—this feedback is vital to the development. The skills to facilitate such sessions sometimes need to be very sophisticated, so training is strongly recommended before embarking on this teaching style. Most learning of value will occur from the role-play itself and the feedback session. Some graduate programs may choose to develop summative assessments to highlight particular areas that need developing, for example, using trained simulated patients or selected videotaped consultations, although care is needed with patient’s

Textbook of Palliative Medicine and Supportive Care

58

BOX 8.5  A SAMPLE LESSON PLAN Title of the session VENUE DATE Number and background of learners Total TIME for whole session Event within the lesson35

Time allotted within the session Example

Gain attention Inform learners of the objective

Stimulate recall or prior learning Present stimulus material Provide learner guidance Elicit performance (practice) Provide feedback Assess performance Enhance retention

A picture, quotation, case scenario State the aims and objective of the session (this section may be used as an opportunity to ascertain with the learner(s) if there are other objectives that you may or may not have time to cover at the time, and if not, these may inform a future session. The educator needs to be ready to adjust the session however, if there has been a critical incident which would need to take priority as a session. A case discussion, or set tasks, or ask questions to the group Provide some factual material matched to the learning outcomes for the session Questions or group work around the material—use cases or scenarios and real life situations if possible Ask questions based on the factual material and feedback from learners if there have been interactive tasks. Role-play or a practical procedure Respond to queries and use effective feedback principles Ask specific questions around the session—these could be formally assessed using online interactive devices or a formal survey or test The learner needs to be stimulated to remember the session—this could be by case description or further quotations. It is also a useful moment in which to prompt the learner to outline how their practice will change as a result of the session and where their learning needs to go next using the Kolb reflective cycle

confidentiality and legal requirements of data protection over storage and transfer of such information.

Communication skills case study—The Cardiff 6-point toolkit as a teaching tool Recognizing that each patient encounter is unique and that a toolkit of skills is useful for all situations, Cardiff University

BOX 8.6  CARDIFF 6-POINT TOOLKIT FOR COMMUNICATION IN PALLIATIVE CARE (© CARDIFF UNIVERSITY, FROM REFERENCE [43] WITH PERMISSION) 1. Listening/use of silence 2. Reflection 3. Summarizing 4. Question style 5. Comfort 6. Language

developed a 6-point tool kit to help learners focus on aspects of effective communication skills during role-play.43 It allows participants to reflect-in-action on techniques they may use to address specific challenges they face during the consultation. Using the toolkit and encouraging learners to recognize elements of a role-play consultation that demonstrate the separate aspects in any consultation type (e.g., anger, denial, breaking bad news, managing hope, and uncertainty) can be a powerful prompt to reflection. Discussions also focus on other aspects of communication—with families, within teams and with other health-care professionals. The learning outcomes of a communication skills session in palliative medicine can focus beyond the patient and family encounter to encompass team and interprofessional communication.

Teaching ethics Ethical dilemmas abound in care of patients at the end of life. Ethical decision-making is never straightforward, so mastering reflection will help the learner function better within zones of indeterminate practice or as Schon10 describes it as “the swamp.” Ethical decision-making needs a sound understanding of the

Graduate Education for Nonspecialists BOX 8.7  COMMUNICATION SKILLS MODULE LEARNING OUTCOMES (© CARDIFF UNIVERSITY—REPRODUCED WITH PERMISSION) At the end of the module, the students will be able to • Demonstrate nonverbal ways of • Facilitating a patient feeling comfortable and safe • Opening up a communication • Helping a patient disclose their problems • Demonstrate all six elements of the Cardiff 6-point toolkit • The use of open questions • Listening/use of silence • Reflection • Summarizing • Question style—open, closed, and hypothetical • Comfort • Language • Demonstrate the process of checking that a patient has understood information • Apply the process of closure of a consultation • Demonstrate a stepwise approach to breaking bad news • Demonstrate respect of the patient and the patient’s concerns • List potential barriers to communication with patients, patients’ families, and other health-care professional (HCP) colleagues • Suggest ways to overcome barriers to communication • Reflect on their own communication style • Analyze the processes they use in a consultation

59 to learn while practicing clinically in their own environment, learning alongside each other, and sharing ideas and experiences under the supervision of a suitably qualified facilitator. The benefits go far beyond those of administrative convenience; e-mail allows students’ direct access to tutors for guidance and submission of assignments, and web-based chat rooms for students encourage informal sharing of ideas, avoiding the distance learner studying in isolation. As technology has improved and high-speed Internet facilities are more widely available, courses are able to offer greater resources online, including video podcasts on core topics, copies of course lectures, and the opportunity for tutorials through videoconferencing.46,47 Learners tend to prefer face-to-face teaching to videoconferencing, especially for learning about sensitive subjects. However, research suggests that learning outcomes are similar for both modalities.48 With almost all academic journals and major medical texts available online, the ubiquitous personal computer has greatly increased access to “facts,” but not with concomitant teaching for wise decision-making in complex situations. Videoconferencing can link learners across the globe across cultural and political barriers.

Massive open online courses (MOOC’S)

The massive open online courses (MOOC’S) have the potential to deliver palliative care education at no cost to learners on a global scale. In view of the urgent need for palliative care education at all levels, this advance has been recognized as a potential response to this need. They have cost implications in their development— especially as they are “open access,” so do not generate revenue, and the same meticulous attention to detail is needed in their planning as in face-to-face sessions. Although useful to impart some information, they are no substitute for effective analysis and reflection to gain an in-depth understanding of the subject. Some examples of online learning courses are from the International Children’s Palliative Care Network,49 e-cancer programs, and50 e-ELCA in the UK.51

The role of the clinical placement principles of autonomy, beneficence, nonmaleficence, and justice within the patient’s clinical context.44 Gillon has also highlighted the wide issues around each decision, which require the clinician to reflect on the “scope” of application of the decision-making process and its outcomes.45 Although a formal lecture may appear useful to inform on fact and principle, the complex decisionmaking around each case requires ongoing reflection-in-action by both tutor and learner. Being aware of the legal framework of the learner’s country will also help the teaching to be within a practical clinical context.

An attachment to a palliative care team or face-to-face clinical contact with palliative care delivery in any setting will help one to consolidate clinical skills. Although distance learning and blended learning will achieve, when appropriately constructed, many of a curriculum’s competencies, observation and reflection in the clinical workplace will aid in the understanding and application of these skills. Time is the key resource necessary here—both for the student observer and for the supervision and discussion of reflection and feedback. Clear expectations and necessary governance of such placements is crucial.

Information technology and online learning

Conclusion

Information technology has impacted health-care education worldwide, ranging from complete course delivery online to using it to complement learning. Clarity about what the learner should gain from the use of the specific technology is necessary, however. Distance learning postgraduate courses were established to save learners from having to take time away from the workplace and were originally organized as correspondence courses, with learning material packs mailed regularly and completed assignments duly returned. Such courses have moved toward web-based learning, where learners are able to access course material, submit assessments, and access tutor support online. More importantly, it allows professionals from diverse localities and cultures

As palliative care becomes increasingly integrated into medical and surgical specialties, the education opportunities available to graduate health-care professionals need to increase. The nature of palliative medicine with holistic, multi-professional patient-centered care requires new learning techniques alien to the didactic method of training many are accustomed to. Communication skills, bereavement care, ethical decision-making, and spiritual care may be better learned by role-play and reflective practice. Distance-learning courses and using technology facilitate geographically diverse groups of professionals learning together, particularly when combined with face-to-face group work in a blended learning environment. With an inevitable increase in

Textbook of Palliative Medicine and Supportive Care

60 palliative care graduate programs aimed at the nonspecialist, the need for robust QA becomes ever more important. The pursuit of delivering palliative care education to as many nonspecialists as possible should not compromise the importance of all palliative care education being of a high standard such that the training given to nonspecialists can be applied practically to the betterment of our patients.

References











1. Knaul FM, Farmer PE, Krakauer EI, et al. Alleviating the access abyss in palliative care and pain relief – an imperative of universal health coverage: the Lancet Commission report. Lancet 2017; published on line Oct 11. http://dx.doi.org/10.1016/S0140-6736(17)32513–8. 2. Worldwide Palliative Care Alliance 2014. Global Atlas of Palliative Care. Available from: https://www.who.int/nmh/Global_Atlas_of_ Palliative_Care.pdf (Accessed 30 December, 2019). 3. Resolution WHA67.19. Strengthening of palliative care as a component of comprehensive care throughout the life course. In: Sixty-seventh World Health Assembly, Geneva, 19–24 May 2014 http://apps.who. int/gb/ebwha/pdf_files/WHA67/A67_R19-en.pdf (Accessed 17 March, 2018). 4. Gamondi C, Larkin P, Payne S. Core competencies in palliative care: an EAPC White Paper on palliative care education – part 1. EJPC 2013;20(2):86–91. 5. Beard RM, Hartley J. Teaching and Learning in Higher Education. Paul Chapman, London, 1984. 6. Prochaska JO, Velicer WF. The transtheoretical model of health behavior change. Am JHealth Promot 1997;12(1):38–48. 7. Grant J. Learning needs assessment; assessing the need. Br Med J 2002;324:156–159. 8. Knowles M. Self Directed Learning. New York: Association Press, 1988. 9. Kolb DA. Experiential Learning: Experience as the Source of Learning and Development. Englewood Cliffs, NJ: Prentice Hall Inc., 1984. 10. Schon D. Educating the Reflective Practitioner: Towards a New Design for Teaching and Learning in the Professions. San Francisco, CA: Jossey-Bass, 1987. 11. Naidu T, Kumagai AK. Troubling muddy waters: problematising reflective practice in global medical education. Acad Med;91(3):317–321. 12. Kolb DA, Fry R. Towards an applied theory of experiential learning in C Copper (ed) Theories of Group Process London: John Wiley, 1975. 13. Boud D, Keogh R, Walker D. Reflection: Turning Experience into Learning. London, U.K.: Kogan Page, 1985. 14. Greenwood J. The role of reflection in single and double loop learning. J Adv Learn 1998;27;1048–1053. 15. Sargeant J, Mann K, Chapter 7: Feedback in medical education: Skills for improving learner performance. in Cantillon P, Wood D, Yardley D, eds. ABC of Learning and Teaching in Medicine, 3rd ed. UK: John Wiley and Sons 2017 16. Donnelly P, Kirk P. How to Give Feedback in an Educational Setting Part of ‘How to’ Series. Cardiff University, Wales Deanery https://www. cardiff.ac.uk/__data/assets/pdf_file/0006/1159557/How_to_Give_ Feedback_in_an_Educational_Setting.pdf (Accessed May 19, 2019). 17. Pendleton D, Schofield T, et al. The Consultation: An Approach to Learning and Teaching. Oxford, U.K.: Oxford University Press, 1984. 18. Kurtz S, Silverman J, Draper J. Teaching and Learning Communication Skills in Medicine. Oxford, U.K.: Radcliffe Medical Press, 1988. 19. Alexander S. Physicians assessment and Clinical Education Programme (PACE), University of San Diego School of Medicine. Feedback keeps you from crashing: Steve Alexander, Former President of the Medical Board of California: you tube. Relevant clip 6 minutes to 8 minutes. https://youtu.be/EvbR_e_aNkc (Accessed December 30, 2019). 20. General Medical Council. Promoting Excellence: Standards for Medical Education and Training London: GMC, 2015. 21. Finlay IG, Stott NCH, Marsh HM. Portfolio learning in palliative medicine. Eur J Cancer Care 1993;2:41–43. 22. Rawlinson F, Finlay I. Assessing education in palliative medicine: development of a tool based on the Association for Palliative Medicine core curriculum. Palliat Med 2002;16(1):51–55. 23. Ury WA, Arnold RM, Tulsky JA. Palliative care curriculum development: a model for a content and process-based approach. J Palliat Med 2002;5(4):539–548.

24. Association for Palliative Medicine. Palliative Medicine Curriculum. Southampton, U.K.: APM, 2002. 25. Irish Committee on Higher Medical Training. Curriculum for Higher Specialist Training in Palliative Medicine. Dublin, Ireland: RCPI, 1997. 26. Royal Australasian College of Physicians. Requirements for Physician Training (Mango Book). Vocational Training in Palliative Medicine for 2003. Sydney, New South Wales, Australia: RACP, 2002. 27. Hong Kong College of Physicians. Guidelines for Higher Physician Training. Hong Kong, China: HKCP, 2002. 28. LeGrand SB, Walsh D, Nelson KA, Davis MP. A syllabus for fellowship education in palliative medicine. Am J Hosp Palliat Care 2003;20(4):279–289. 29. Gamondi C, Larkin P, Payne S. Core competencies in palliative care: an EAPC White Paper on palliative care education – part 2. EJPC 2013;20(3):140–145. 30. Ury WA, Reznich CB, Weber CM. A needs assessment for a palliative care curriculum. J Pain Symptom Manage 2000;20(6):408–416. 31. Kenny LJ. An evaluation-based model for palliative care education: making a difference to practice. Int J Palliat Nurs 2003;9(5):189–194. 32. Stjernsward J, Foley K, Ferris F. The Public Health Strategy for Palliative Care. JPSM 2004;33(5):466–493. 33. Dale E. Audiovisual Methods in Teaching. Holt, Reinhart and Winston: New York, 1946. 34. Masters K. Edgar Dale’s pyramid of learning in medical education: a literature review. Med Teach 2013;35(11):e1584–e1593. 35. Gagne RM, Briggs LJ, Wager WW. Principles of Instructional Design 4th ed Forth Worth TX, Harcourt brace Jovanovich College, 1992. 36. Prober CG, Heath C. Lecture Halls without lectures – a proposal for medical education N Engl J Med 2012;366:1657–1659. 37. Wood DF. ABC of Learning and Teaching in medicine – problem based learning. BMJ 2003;326:328–330. 38. Davis MH, Harden MH. Problem-based learning: a practical guide. Med Teach 1998;20(2):317–322. 39. Fallowfield L, Jenkins V, Farewell V, Saul J, Duffy A, Eves R. Efficacy of a Cancer Research UK communication skills training model for oncologists: a randomised controlled trial. Lancet 2002;359(9307):650–656. 40. Fellowes D, Wilkinson S, Moore P. Communication skills training for health care professionals working with cancer patients, their families and/or carers. Cochrane Database Syst Rev 2004;(2):CD003751. 41. Mansfield F. Supervised role-play in the teaching of the process of consultation. Med Educ 1991;25:485–490. 42. Finlay IG, Sarangi S. Oral medical discourse, communication skills and terminally ill patients. Encyclopaedia of Language and Linguistics, 2nd edn, New York: Elsevier, 2005. 43. Noble SIR, Pease NJ, Finlay IG. Chapter 57: The United Kingdom general practitioner and palliative care model. In: Kissane DW, Bultz BD, Butow P, Finlay IG, eds. Handbook of Communication in Oncology and Palliative Care, Oxford, U.K.: Oxford University Press, 2010; 659–670. 44. Beauchamp TL, Childress JF. Principles of Biomedical Ethics, 3rd edn. New York: Oxford University Press, 1989. 45. Gillon R. Medical ethics: four principles plus attention to scope. BMJ 1994;309(6948):184–188. 46. Regnard C. Using videoconferencing in palliative care. Palliat Med 2000;14(6):519–528. 47. Lynch J, Weaver L, Hall P, et al. Using telehealth technology to support CME in end- of-life care for community physicians in Ontario. Telemed J E Health 2004;10(1):103–107. 48. van Boxell P, Anderson K, Regnard C. The effectiveness of palliative care education delivered by videoconferencing compared with face-toface delivery. Palliat Med 2003;17(4):344–358. 49. International Children’s Palliative Care Network e-Learning Programmes. Available from: http://www.icpcn.org/icpcns-elearningprogramme/ (Accessed May 19, 2019). 50. Ecancer – e-Learning Courses for Health Care Professionals. Available from: https://ecancer.org/education/course/1-palliative-care-e-learningcourse-for-healthcare-professionals-in-africa.php (Accessed May 19, 2019). 51. e-Learning to Enhance Education and Training for End of Life Care e-ELCA. Available from: https://www.e-lfh.org.uk/programmes/endof-life-care/ (accessed December 30, 2019).

9

CHALLENGES OF RESEARCH IN PALLIATIVE AND SUPPORTIVE MEDICINE

Irene J. Higginson

Contents Introduction..........................................................................................................................................................................................................................61 The value of planning, protocol, feasibility, and pilot studies.....................................................................................................................................61 Scientific challenges.............................................................................................................................................................................................................62 Setting the aims and objectives and/or hypothesis or research question...........................................................................................................62 Study design....................................................................................................................................................................................................................62 Selection and recruitment............................................................................................................................................................................................63 Measurement, interviews, and data collection........................................................................................................................................................64 Missing data and attrition............................................................................................................................................................................................65 Clinical, organizational, and practical challenges.........................................................................................................................................................66 Animal models: issues in translating findings to people..............................................................................................................................................66 Ethical issues and dealing with Institutional Review Boards......................................................................................................................................66 Involving users in research: consumer collaboration...................................................................................................................................................67 Reporting the results...........................................................................................................................................................................................................67 Conclusions...........................................................................................................................................................................................................................67 References..............................................................................................................................................................................................................................68

Introduction All research, whatever the field, faces scientific, practical, and ethical challenges. Palliative and supportive medicine are no exception.1,2 The challenges in palliative and supportive care are often greater than those of other fields of medical research, because of the nature and complexity of the problems faced by patients and their families, the services they receive, and the settings of care and way that patients’ conditions can change dramatically in a short period of time. This is particularly so for palliative medicine and research among patients who are at the end of life. There is often a web of challenges that the investigator has to face. As much as possible, problems should be anticipated and prepared for in advance to minimize their impact. But not every difficulty can be anticipated; sometimes problems must be dealt with as they arise. Often, it requires great courage, skill, and hard work to overcome the setbacks that occur during the course of a study and to minimize the effect these have on the quality of the results. Many of the challenges described here apply equally to clinical audits, quality assurance, and total quality management projects. 3 An audit where the design is not appropriate, or a quality assurance review that collects information from a very biased sample of people, suffers from the same weaknesses and limitations as a research study with these problems.4 The wealth of studies already conducted in palliative care and the evidence base to date demonstrate that successful research and audit are possible. 5,6

The value of planning, protocol, feasibility, and pilot studies The protocol should lay out what is planned in the study, step by step. Increasingly study proposals for grants, and some study protocols, include a list or register of the possible problems, how

likely they are and anticipated actions should they arise. The protocol should specify exactly what will be done and consider decision points, for example, if there is falling recruitment, that are triggered. Careful piloting of the methods and testing the feasibility studies can test and determine possible solutions and may uncover further challenges that need to be planned for. Pilot and feasibility studies nowadays are an expected early step in research studies, after a good literature review and appropriate patient and public involvement. Their standing is such that in 2015 a new online journal called “Pilot and Feasibility Studies” was launched to provide a dedicated place for publication of this important developmental, allowing all to learn from these activities, as well as a forum for discussion of methodological issues.7 Although the terms are often used imprecisely, there is nowadays a recognized distinction between feasibility and pilot studies. Feasibility studies are usually described as “pieces of research done before a main study in order to answer the question Can this study be done? They are used to estimate important parameters that are needed to design the main study.” A pilot study is usually considered “a smaller version of the main study used to test whether the components of the main study can all work together. It is focused on the processes of the main study, for example, to ensure that recruitment, randomization, treatment, and followup assessments all run smoothly.” 7,8 The objectives of feasibility and pilot studies should be different from those of the future definitive study and should stipulate the issues of uncertainty to be addressed in preparation for the future large-scale study. Moreover, pilot and feasibility studies are not designed (or powered) to address the effectiveness of an intervention and should not become mini-randomized controlled trials that mirrored the main trial, except on smaller numbers of participants, often in one center as that is easier. Instead, they are 61

Textbook of Palliative Medicine and Supportive Care

62 commonly used to assess one or more of the seven main objectives in planning a study: 1. to test the integrity of the study protocol for the future trial (which gives a valid reason for randomization), 2. to gain initial estimates for sample size calculation, 3. to test data collection forms or questionnaires, 4. to test randomization procedure(s), 5. to estimate rates of recruitment and consent, 6. to determine the acceptability of the intervention, and 7. to select the most appropriate primary outcome measure(s).9 There are recommended guidelines for reporting pilot and feasibility studies, including an extension to the CONSORT statement for randomized trials, and guidance in non-randomized studies.10–12 An example of the use of feasibility studies can be seen in a recent feasibility study for a randomized trial of a repurposed pharmaceutical treatment. This was able to determine the rates of recruitment and consent, meet prior feasibility criteria for continuing to a main trail, estimate blinding levels, test the primary outcome, and obtain data to enable a more accurate sample size calculation.13 The “Scientific challenges” section considers the main steps in research, the challenges, and possible ways to overcome them.

Scientific challenges Setting the aims and objectives and/ or hypothesis or research question

All research is driven by a question or idea that the investigator wants to answer or better understand. Focusing one’s ideas on what is to be explored and what can be investigated in a study is an important step, requiring knowledge of clinical concerns, literature review, and self-discipline. It is better to decide to answer a question or explore an issue that can be achieved realistically within the resources and timescale available than to attempt to answer a whole multitude of questions that are very broad and cannot be adequately covered within the study. Time spent refining the aims and objectives and then considering if these can be answered by the right study design is a fundamental step in any study. In a study following a grounded theory method (in qualitative research), the process varies from that above, but guidance is available.14 That said, it is important that the research question or aim builds on existing work and takes it further, rather than simply repeating earlier small studies. One of many challenges within palliative care research is that there are many small studies that describe levels of need and problems, often repeatedly, without these being taken further to develop and test solutions to those problems.15 This may be partly as a result of a lack of funding and capacity in the field, as sustainable funding and capacity are needed to ensure that research builds from one investigation to the next.16 A further challenge is that many new interventions and services are complex, and even more simple interventions are offered to patients and/or their families with complex needs or circumstances. The new MORECare (Methods Of Researching palliative and End of Life Care) statement on the evaluation of interventions in palliative and end of life care proposes that a theoretical framework is developed to help both develop interventions and understand how it may be affecting outcomes.17 This is an important step: a theoretical model will help to understand the

potential benefits and harms of any intervention or new service or treatment, and also what components are key to its success.

Study design

Choosing the most appropriate design for a study’s aims and objectives is then one of the most important decisions that any researcher can make.18 Always the aims and research questions should lead the design. For example, there is no point attempting to test the efficacy of a new drug treatment by conducting a survey of patient’s views of the drug. While such a survey might give interesting information about acceptability, side effects, actual use, and patient views, it will not give information about efficacy (i.e., whether the drug works better than the current best practice, in controlled conditions). Chapter 23 outlines the different research designs and options for the researcher. Certain study designs are problematic in palliative care, and perhaps the most often discussed is the randomized controlled trial. These have experienced such severe problems that the trial failed.19 Nowadays, trials, especially crossover trials, for drug treatments in palliative care are more often used,20,21 although there can be difficulties with recruitment, attrition, and measurement (see below). However, trials of nondrug interventions often face additional difficulties in maintaining a difference between intervention and control, and because they are difficult to blind can have problems of contamination and disappointment (if patients feel they are not receiving a service they wish to receive).22–24 There is a growing body of literature showing that although a well-conducted randomized controlled trial is the gold standard method in evaluative research, alternative quasi-experimental and observational methods can yield valuable results if their biases can be accounted for or controlled.17,18,25,26. Successful randomized trials have been conducted, for example, communication skills training,27 breathlessness support services,29,30 community palliative care teams, 31,32 or early palliative care different disease groups. 33–36 A broader range of trial methods have been developed, including cluster randomized trials, 37–39 fast-track trials, and wait list controlled trials (both of which need careful timing and are often possible only among patients with longer life expectancy)40–47 and N of 1 trials.48–50 Careful reading of the designs of others, including those researching outside of palliative care, and their successes and failings, can often provide useful guides. 51 In addition, once a design is chosen, there are now many statements that help guide their conduct and reporting. The EQUATOR network (Enhancing the QUAlity and Transparency Of health Research, found at https://www.equatornetwork.org/) is an international initiative that seeks to improve the reliability and value of published health research literature by promoting transparent and accurate reporting and wider use of robust reporting guidelines. It contains reporting guides now for almost every study design used. Examples include the CONSORT statement for randomized trials52–55 and the STROBE statement for observational studies.56–60 But there are many more, including reporting guides for qualitative studies, published protocols, systematic reviews, prognostic studies, case reports, quality improvement studies, and economic evaluations. I often find these reporting guides useful when planning a study and even writing a grant application, as they serve as a useful reminder of the key aspects to plan. Increasingly mixed-method study designs (combining quantitative and qualitative methods) are being used in health services and clinical research. These methods have much to offer palliative care.17,61,62 The quantitative approaches can count numbers of

Challenges of Research in Palliative and Supportive Medicine

63

TABLE 9.1  Priority Sequencing Model Offering Four Ways of Combining Qualitative and Quantitative Data in Mixed Method Studies Depending on Priority and Sequencing Smaller component is preliminary

Smaller component is follow-up

Source:

Quantitative Component Priority

Qualitative Component Priority

1. Qualitative preliminary qual—QUANT Purposes: smaller qualitative study helps guide the data collection in a principally quantitative study Example: initial qualitative interview study helps plan methods for recruitment in a larger survey or trial 3. Qualitative follow-up QUANT—qual Purposes: Smaller qualitative study helps evaluate and interpret the results from a principally quantitative study Example: qualitative interviews after completion of survey or trial to aid understanding of the results

2. Quantitative preliminary quant—QUAL Purposes: Smaller quantitative study helps guide the data collection process in a principally qualitative study Example: survey of hospices and palliative care services helps the selection of hospices for in-depth case study 4. Quantitative follow-up QUAL—quant Purposes: Smaller quantitative study helps evaluate and interpret results from a principally qualitative study Example: survey of hospital palliative care teams informs generalizability of results of qualitative study in one team.

Adapted and updated from Morgan DL.70

affected patients and provide external validity, whereas the qualitative methods can help one to understand the more intangible aspects of symptoms, feelings, or treatment effects and provide internal validity.63–69 A key in the mixed-method study is to plan in advance the way in which the methods will be combined. In the priority sequencing model, four ways of combining methods are described (see Table 9.1).70 However, methods can also be combined simultaneously, using a nested or imbedded design, perhaps examining some aspects of the data in more depth. This combination should also be described in the analysis plan. The MORECare statement gives specific suggestions as to how the mixed methods may be combined and reported.17

Selection and recruitment

Many studies in palliative care, whatever the design, can have problems with patient selection and recruitment. Selection (or sampling) bias occurs when the group of patients selected for or included in the study is different from the total population of interest. For example, we might wish to study the management of pain in patients toward the end of life, but the way that we are able to recruit patients means that we exclude patients in the last week of life—because they could not participate in interviews, or for some other reason. There are many reasons why selection or sampling bias may occur, some of the common types and their effects are shown in Table 9.2. Chapter XX considers the patient population in greater depth and the issues and problems of recruitment, including among disadvantaged groups. Further recruiting patients who are often quite ill, or caregivers who are distressed and/or bereaved can be difficult.71 Many research studies assessing the efficacy of drug treatments have automatically excluded elderly people (even those over 65 years), and those with multiple pathologies, because of the difficulties of recruiting individuals who are ill. In palliative care, excluding people in these categories would remove almost the entire sample, leading to considerable selection bias (see Table 9.2). However, recruiting ill or frail people into research studies requires skill, time, and energy. It involves winning the hearts of professionals who may refer patients to the study, and interviewing patients and families in a way that makes them feel prepared to take part and continue to be involved. Jordhoy et al. have written useful guidance on methods of improving recruitment,1,72 including ensuring staff awareness,

regular updates, feedback, etc. (see Chapter 26 for useful tips, and Chapter 22 for more information on selecting the patient population). In palliative care, interviewers must be sensitive and flexible when attempting to recruit patients. There may need to be three or four visits to patients to secure one interview (because patients are ill, factors change, and patients may prefer the interviewer to come back at a different time). In one study at King’s College London, among patients with advanced cancer, in one instance, more than 10 contacts were required to secure a complete interview, despite the patient are wishing to be involved in the study.73 The MORECare statement gives suggestions as to how the recruitment can be optimized.17 A recent qualitative study investigated motivations for recruitment and retention in a trial of a pharmaceutical treatment in palliative care—motivations, especially for retention in the study included lack of burdensome questionnaires, which were deemed as relevant; continuity of relationship with the interviewer or research nurse; a personcentered approach to individuals in the study; and an easy to take medication.74 Despite the difficulties of recruitment in palliative care, many patients in palliative and supportive care do wish to be involved in research and to tell their story, particularly if they feel it may help others in their situation in the future. Equally families, both contemporaneously and during bereavement, may also wish to be involved. A recent systematic review found evidence in many countries and investigations that patients and families often welcome the opportunity to be involved. Including some open questions in any questionnaires, to allow the participant to “tell their story” or make comments as they wish is recommended.75,76 Also recommended is working with patients and families using the services and with clinicians to plan recruitment.17 A common challenge in palliative care is establishing suitable criteria for recruitment to the study. If prognosis is used, then past experiences suggest that patients may be referred too late for the study. In one instance, when patients with a prognosis of less than 1 year were to be referred to the study, one in four patients had died before the interviewer could recruit them.22 The criterion of the clinician “not being surprised if the patient had died within 1 year” has been suggested as likely to be more successful.77 Validation work has suggested that this is a feasible and effective tool in cancer and some other conditions,78–80 although

Textbook of Palliative Medicine and Supportive Care

64

TABLE 9.2  Common Biases (i.e., Systematic Rather Than Random Errors) That Can Be Encountered in Palliative Care Research Type of Bias

Definition

Sampling bias —Selection bias

The inclusion of subjects that distort the nature of those that would have been chosen by chance. The selection of subjects that distort the nature of those that would have been chosen by chance, for example, selection by nurses or doctors or patients suitable for interview. There are many ways this can occur, but the selection of any sample is likely to result in sample bias, especially in palliative care where patients may become too ill to contact, or may not be in contact with particular services from which patients are selected (e.g., clinic, hospital, primary care doctor), or may be excluded because staff feel they are too ill for interview. The biasing of the sample due to the nature of those who do not respond being different to those who do respond. For example, relatives who are most distressed may (or may not) respond to a questionnaire. The biasing of the sample due to subjects being lost to follow-up because they choose not to be involved in the study, or become too ill for interview, move away, or die. Some attrition bias is inevitable in palliative care. The biasing of the responses due to some subjects not responding to some questions. For example, if the most distressed patients do not answer questions about depression, there is in effect a nonresponse by some of the samples to some of the questions. The collection of data or measurements that distort the nature of the data collected from its true state. The biasing of data collected because of inaccurate or varied recall, perhaps for some events more than others, or because of varied time (e.g., 1 year vs. 6 weeks) or events. The use of measurement tools that introduces bias because they are not valid or reliable in certain situations or among certain cultures. The use of measurement tools that introduce bias because respondents choose particular digits in their answers, for example, a scale of 1–100; most people tend to use numbers that end in 0 (10, 20, etc.). The systematic error introduced by an expectation or belief on the part of the observer or researcher (this can be quite unconscious and is most common when researchers are not blinded to situations, although it can occur even then). The systematic error introduced by an expectation or belief on the part of the research subject (this can be quite unconscious and is most common when subjects are not blinded to situations, although it can occur even then). The change in behavior made by people (e.g., staff or patients) when they know they are being studied. The effect was first noticed in the Hawthorne plant of Western Electric. Production increased not as a consequence of actual changes in working conditions introduced by the plant’s management but because management demonstrated interest in such improvements. The reporting and publication of research findings in a way that distorts the dissemination of findings toward more positive or negative findings. The publication or nonpublication of research findings, depending on the nature and direction of the results. In general, positive studies are more often published than negative ones. The publication of research findings in a particular language, depending on the nature and direction of the results. Research findings in some languages, particularly those in English, are more accessible. The reporting of research findings, depending on how the results accord with the aspirations of the funding body. Further, there may be a considerable hidden bias in the nature of research supported, whereby certain investigations are not funded. The selective reporting of some outcomes but not others, depending on the nature and direction of the research findings. For example, positive findings are reported, but a lot of negatives ones are not. The delayed (or rapid) publication of research findings, depending on the nature and direction of the results. The publication of findings, depending on whether the authors were based in developed or in developing countries.

—Nonresponse bias —Attrition/dropout bias —Missing data bias

Measurement bias —Recall bias —Poor measurement tools, validity/reliability —Digit preference bias —Observer/researcher’s bias

—Subject bias

—Hawthorne effect

Reporting bias —Publication bias —Language bias —Funding bias

—Selective outcome reporting bias —Time-lag reporting bias —Developed-country bias Note:

Main categories of bias are shown in bold; subcategories/causes of this type of bias are shown in the table. Note that there are over 100 different types of biases that are known, but three main categories, sampling, measurement, and reporting, include most types.

it may not be acceptable in some cultures and there is variability in how different disciplines use it.81 Prognostication is very difficult but a range of estimated survival is more likely to be correct than any absolute assessment.82 Further work is improving our prognostic assessments, by providing information on other relevant factors.83 Other recruitment criteria, such as the nature of problems or functional assessment, or a combination of these, may also be needed1,84 (see Chapters 22 and 26). Careful piloting or preliminary qualitative work testing different approaches may shed light on the most effective strategies and methods for

recruiting the research subjects, and the information and updates needed for staff and subjects.

Measurement, interviews, and data collection

A constant challenge in palliative care research is to find measures that detect relevant changes and yet are suitable among very ill populations. This creates a tension between attempting to capture individual detail—by using long standardized measures or conducting qualitative interviews—and having short interviews—with short measures and/or short qualitative

Challenges of Research in Palliative and Supportive Medicine interviews. In the end, the researcher must balance the amount of information that can realistically, reliably, and validly be collected with the ideal needed. Often the plan of analysis is helpful here, as well as referring back to the aim, objectives, and/ or hypothesis of the research. The analysis plan helps to clarify how the data will be used, and this in turn clarifies what needs to be collected. There are now many hundreds of quality of life instruments and a range of palliative outcome scales, which have been developed or validated specifically for palliative care. Chapter 24 provides more details of individual scales and outcome measurement. In addition, there are several books on quality of life assessment and reviews of the measures.85–91 The European Community supported project PRISMA-assessed potential outcome measures and measurement tools used in research and clinical practice.92–94 It identified not only common tools but also a problem of many different tools being used, with a lack of consistency.93,95 Therefore, there is now every opportunity for researchers and clinicians to use validated and tested scales. Only if a thorough systematic review reveals that no fully or partially suitable scale is available, should a new scale be developed. The MORECare statement makes recommendations of the key features required of outcome measures in research studies, their timing, and whether proxy or patient is used.17,96 Less frequently qualitative researchers publish their topic guides that are generally developed for specific lines of enquiry. Such publication is useful, for conducted open qualitative interviews is a highly skilled activity. Listening to the tapes of, or reading or typing the transcripts of highly skilled qualitative interviews is very instructive. In general, interviews should be kept as short as possible, and in some instances, the researcher should order the questions or scales so as to collect the more important information first. Missing data for some questions among some patients will be inevitable, and researchers should minimize this for the primary outcomes of their study. When patients become very tired there or do not wish to continue interview, the data collection should be terminated, because collection will become unreliable if patients cannot concentrate. It may be necessary to return to complete the interview if the person is willing. Deciding the primary outcome of the study is vital. Many journals and funders will require a single primary outcome— which is the basis of the sample size calculation, and the primary analysis, especially in randomized trials, and will place great weight on the significance or not of those results. Thus, the choice of the primary outcome is critical, as it must be responsive to change that is expected by the intervention. Many outcome measures as not as well validated as expected or exist in multiple formats. For example, exploration of the widely used numerical rating scale to assess breathlessness suggests that this was not a unidimensional measure and highlighted multiple wording in questions. In fact, the scale does represent qualitative comments from patients, and so probably is appropriate in many circumstances, but care is needed regarding these previously assumed properties.97 A recent debate has also emerged regarding the overreliance of statements of statistical significance, and especially a single P value of 90%) was reported in a recent study carried out by O’Mahony et al. after evaluating data regarding 592 consecutive patients seen by their palliative care consult team during a 16-month period.52 Additionally, timely referral to palliative care consult teams has been shown to dramatically reduce the amount of time patients spend in the hospital, leading to a decrease in overall health-care charges. In a recent retrospective study, Macmillan et al. looked at early palliative care consults in patients with various chronic medical conditions, including cancer, at a university-affiliated community-based urban acute care hospital.53 They found a significant difference in the median length of stay for patients referred to palliative care consultation services within 24 hours of being admitted to the hospital versus patients not referred (4.2 days versus 9.7 days, P < .001). Consequently, the total cost of hospital charges significantly decreased from $95,300 (patients not referred) to $38,600 (patients referred within 24 hours). These results further support the early referral of patients to palliative care, along with displaying the importance of palliative care consult teams in acute care facilities.

Palliative care units

A PCU, more recently called an APCU, is designated for terminally ill patients who require intensive involvement of a specialist IDT able to manage their complex problems. von Gunten defined it as an academic medical center where specialist knowledge for the most complex cases is practiced, researched, and taught.54 Given the complexity of the physical, psychosocial, and spiritual nature of the PCU patient population, the ideal location for such a unit is in an acute care hospital that offers a full range of diagnostic and interventional procedures, along with support services including specialty and subspecialty consultations. The PCU staffing includes palliative care specialists, nurse practitioners, registered nurses, research nurses, licensed practical nurses, nursing attendants, a chaplain, a social worker, a physical therapist, an occupational therapist, a pharmacist, a clinical dietician, a palliative care counselor, a clerk, and volunteers. The optimal unit size for staffing efficiency is 16–24 beds and the minimum size is 10–12 beds.55 Fournier discusses this setting in depth in Chapter 26. One example of a PCU is the Edmonton Regional Palliative Care Program (ERPCP) PCU in Canada.56 The ERPCP is a publicly funded program that provides a comprehensive range of palliative care services, including home care and specialist consultation in the community, long-term care, hospices, ambulatory care, and acute care settings. Its PCU is located in an acute care teaching hospital, and it has 14 beds. Amenities include a patient smoking room, a family lounge, a kitchenette, a quiet room, and a conference room. Family members may stay overnight if they wish, and pets are allowed. Referrals are screened after a direct patient assessment by the palliative care consultants. Such patients are referred for acute symptom control, emotional and family distress, difficult discharge planning, and rehabilitation. As discussed in Chapter 26, the PCU is intended to be a shortterm place of care until symptoms have stabilized sufficiently to allow discharge of the patient to another palliative care setting; the expected length of stay is less than 2 weeks. The goal of admission and its temporary nature should be discussed with the patients and their families. Most patients are asked to agree electively to a do-not-resuscitate status prior to admission. Discussing do-not-resuscitate status is a valuable opportunity to clarify the

131 patient’s and family’s understanding of the illness, prognosis, and goals of care.57 The tools used daily for assessment are ESAS,44 CAGE questionnaire,45 MMSQ,46 Edmonton Staging System (ESS) for cancer pain, 58 Edmonton Labeled Visual Information System59, Edmonton Functional Assessment Tool60 (EFAT), palliative performance score61 (PPS), and constipation score.62 A family conference coordinated by the social worker and attended by the team, the patient, family members, and friends whom the patient wishes to involve is often advisable to clarify goals and establish plans of care and further discharge to a more appropriate palliative care setting that will satisfy their needs. Patients have the option not to be present at the family conference. For those patients who are discharged home, clear and timely communication with community health-care providers (e.g., primary care physician, home care manager, and pharmacist) is critical. Transfer to a hospice may pose a difficult transition for the patients and their families because of their need to adjust to a new environment and staff and most importantly because they may view hospice as a lower level of care and feel a sense of abandonment.63 These concerns may be alleviated by explaining to them that the fact that the patient does not require treatment in a PCU is a positive outcome and that the option of coming back is possible if the symptoms exacerbate and the patient decides so. The PCU provides an excellent environment for research in which all the IDT’s medical members are expected to participate. Since patients are under direct care of the medical team, the process of screening and recruiting them for studies becomes easier. The PCU of the ERPCP receives undergraduate and postgraduate medical trainees from the University of Alberta on a regular basis. Clinical teaching is enhanced by journal club,64 held three mornings a week, during which time-relevant articles to palliative care are presented and discussed. Other educational activities include tests taken before and after the residents’ PCU rotation,61 seminars, weekly grand rounds, and presentations from other specialists sharing their expertise as applied directly or indirectly to palliative care. In order to determine the optimal setting of palliative care delivery, Casarett et al.64 conducted a nationwide telephone survey with one family member of each of the 5901 patients who died in one of the 77 Veterans Administration medical centers that offered palliative care consultation services and dedicated PCUs between July 1, 2008, and December 31, 2009. The survey consisted of one global rating item and nine core rating items describing the patient’s care in the last month of life. Families of patients who received care in PCUs were more likely to report excellent care than the ones who received a palliative care consultation (adjusted proportions: 63 vs. 53%; OR (Odds Ratio), 1.52; 95% CI (Confidence Interval), 1.25–1.85; P < .001). The authors found that care received in PCUs offered more improvements in care through communication, providing physical, emotional, and spiritual support than those achieved with the palliative care consultations during the last month of life. Another example is the APCU at MD Anderson, which was established in 2003 and has since demonstrated an increase in overall hospital mortality rate, financial feasibility, and successful reduction of distressing symptoms in advanced cancer patients.65 Another APCU was established in 2007 at the Montefiore Medical Center, for the treatment of all patients with palliative care needs.66 Typical characteristics of these APCUs include a private room that can accommodate the patient and a companion, a conference room for family and staff meetings, and the presence of an IDT. Studies show that both APCUs provide cost-effective

132 palliative interventions for patients with advanced cancer (MD Anderson) or chronic illnesses (Montefiore Medical Center).65,66

Inpatient hospices

Hospice is a model designed to provide care at the end of life. The goal of hospice is to palliate the suffering at the end of life by addressing the emotional, social, physical, and spiritual needs of the patient and their family. Inpatient hospice care is the highest level of care within a hospice program. It is designed to control physical suffering and support family and patients when such care is not manageable at home. The majority of inpatient hospices are staffed by at least one full-time physician trained in palliative medicine, nurses, physiotherapists, occupational therapists, social workers, and chaplains and offer bereavement support services. In addition to providing inpatient end-stage care, patients are admitted for symptom control, rehabilitation, and sometimes respite care. Statistically, five independent factors were found to predict inpatient hospice care: pain in the last year of life, constipation, breast cancer, being under 85 years of age, and being dependent on others for help with the activities of daily living between 1 and 6 months before death. 67 Hinton demonstrated a higher rate of admission from patients receiving PHC over those that were living alone or with unfit relatives and those with breast cancer. 68 One study of data relating to cancer deaths showed that patients accessing palliative care services were significantly younger and had longer survival times from diagnosis. 69 An analysis of place of death of cancer patients demonstrated an increased likelihood of dying in a hospice if they lived close by.70 In the United States, cancer diagnosis accounted for 30% of hospice admissions during 2017 while non-cancer diseases accounted for 70%: end-stage heart disease and dementia were the most two common terminal illnesses.71 While routine home care was the most common level of hospice care, accounting for approximately 98% of all hospice days in 2017, inpatient hospice care only accounted for approximately 1.5% of days.72 One reason for this is that compared to home hospice care, inpatient hospice care is not cost-effective, which creates a huge barrier for the use of such services.

Textbook of Palliative Medicine and Supportive Care care residents to enroll in hospice within 30 days (21/107 [20%] vs. 1/98 [1%]; P < .001 [Fisher exact test]) and to enroll in hospice during the follow-up period (27/207 [25%] vs. 6/98 [6%]; P < .001). Intervention residents had fewer acute care admissions (mean: 0.28 vs. 0.49; P = .04 [Wilcoxon rank sum test]) and spent fewer days in an acute care setting (mean: 1.2 vs. 3.0; P = .03 [Wilcoxon rank sum test]). Families of intervention residents rated the resident’s care more highly than did families of usual care residents (mean on a scale of 1–5: 4.1 vs. 2.5; P = .04 [Wilcoxon rank sum test]). In conclusion, by increasing early access to hospice care in an NH setting by a simple and prompt communication intervention, pain will be better controlled, inappropriate medications as well as physical restraint use and acute hospital’s admissions will decrease, and families’ satisfaction of end-of-life care will increase.74

Integration of care Figure 17.2 summarizes the different components of palliative care delivery. Home is considered the center of palliative care delivery since most patients and their families prefer to stay at home as long as possible,23 and during all the early stages of the illness, patients receive all their care while residing at home. From home, a patient can be moved to an acute care hospital (e.g., patient develops hematemesis), to a PCU (e.g., control of severe symptoms or psychosocial distress), or even to an inpatient hospice unit in case the RC becomes ill or needs a respite. Of note, patients can also be transferred from one setting to another within this model based on their as well as their family needs (e.g., after controlling an acute exacerbation of a right arm pain in a PCU, a patient can be moved to an inpatient hospice unit while awaiting his caregiver to recover from a severe flu; the same or a different patient can be transferred from an inpatient hospice unit to an acute care hospital after a hip fracture secondary to a fall from his bed; again, the same or a different patient can be transferred from a surgery floor to a PCU if he/she develops a delirium that the surgeon cannot manage appropriately). In any of these settings, the discharge plan would be directed,

Consult teams in nursing homes

More than 25% of Americans die in an NH.73 Considerable evidence indicates that NH residents do not receive optimal endof-life care,74,75 their pain is undertreated,76 and they are often transferred to an acute care setting to receive aggressive rather than palliative treatment in the last weeks of life.77,78 Therefore, families express dissatisfaction with the end-of-life care that their loved ones receive in NHs.79 Hospice care may improve the quality of end-of-life care for NH residents, but it is underutilized by this population, in part because physicians are not aware of their patients’ preferences.74 Casarett et al. carried out a randomized controlled trial of 205 NH residents and their surrogate decision makers in 3 US NHs to determine whether it is possible to increase hospice utilization and improve the quality of end-of-life care by identifying residents whose goals and preferences are consistent with hospice care.74 A structured interview identified NH residents whose goals for care, treatment preferences, and palliative care needs made them appropriate for hospice care. Of the 205 NH residents, 107 were randomly assigned to receive the intervention, and 98 received usual care. Intervention residents were more likely than usual

FIGURE 17.2  Home as the center of palliative care delivery.

Models of Palliative Care Delivery if practical and desirable, toward returning the patient home to spend his last days surrounded by his loved ones. During the past several decades, terminally ill patients were increasingly dying in acute care settings.80–82 With the recent changes in healthcare, there is greater emphasis on providing care at home and supporting families to enable more home deaths.82,83 Since home death may not be simple, practical, or desirable in every family situation,82–85 there is a need for an objective way to assess the viability of a home death in each family situation. Home death is not universal and has its limitations. Decreased support, symptom distress, and inability of the PHC and caregivers to meet patients’ needs make peaceful death at home impossible. Also, patients and caregivers can change their minds about their desire for a home death as their circumstances change.17,86 In these cases, the patient has to be moved to a higher skilled setting. Indeed, the most important aspects of this model are the different arrows connecting the different settings of care. The flow of the patient needs to be seamless, and this is facilitated by using compatible assessment tools, similar treatment and counseling protocols, and frequent communication among the different teams, using videoconferencing, regular teaching rounds, or bus rounds. However, the different settings do not need to have a unified ownership or administrative structure to be able to meet the goal of seamless patient and family care. Inpatient care can be delivered, in decreasing order of patient and family distress, at the PCU, by consult teams in acute care hospitals, or in hospices. In a review of admission data for all patients discharged from the ERPCP from November 1, 1997 to October 31, 1998, patients with high symptom distress, positive screening for alcoholism, and poor prognostic indicators of cancer pain (ESS66 > 0/5) were referred to the PCU, while those with a lower level of distress, negative screening for alcoholism, and better prognostic indicators (ESS = 0) were treated in acute care hospitals, hospices, and the community.4 The availability of a palliative care consult team allows patients access to palliative care at an early stage of their illness, when they are still receiving active treatment and are still candidates for cardiopulmonary resuscitation.50 It has reduced significantly hospital charges52 as well as length of stay, 50,52 interunit transfers, 52 and admissions for social reasons.50 Integration of palliative care requires action at different levels of palliative care delivery and education: (1) educating patients, families, and referring physicians on the benefits of palliative care and simultaneous care; (2) increasing the availability of outpatient palliative care clinics to enhance earlier referral to palliative care; (3) increasing the availability of PCUs to improve symptom control and emotional suffering at the end of life; (4) encouraging physicians to participate regularly in family conferences and palliative care educational rounds, and similarly encouraging palliative care specialists to attend physician boards to increase earlier referral to palliative care; (5) enhancing the education of medical fellows in core competencies related to palliative care to prompt more timely referrals to palliative care; and (6) dedicating more resources toward research in the models of palliative care integration and clinical outcomes. The availability and degree of integration of palliative care at US cancer centers vary widely between NCI and non-NCI designated cancer centers despite the significant increase in the number of palliative care programs in the past decade. Hui et al.27 conducted a survey of 71 NCI and 71 non-NCI designated cancer centers between June and October 2009. NCI-designated cancer centers were significantly more likely to have a palliative care program

133 (98 vs. 78%; P = .002), at least one palliative care physician (92 vs. 74%; P = .04), an inpatient palliative care consultation team (92 vs. 56%; P < .001), and an outpatient palliative care clinic (59 vs. 22%; P < .001). Few centers had dedicated palliative care beds (23%) or an institution-operated hospice (37%). The median (interquartile range) reported durations from referral to death were 7 (4–16), 7 (5–10), and 90 (30–120) days for inpatient consultation teams, inpatient units, and outpatient clinics, respectively. Executives were supportive of stronger integration and increasing palliative care resources. A more recent survey showed that while there had been an increase in the number of outpatient palliative care clinics between 2009 and 2018 (59 vs. 95%; OR 13.1, 95% CI 2.6– 66.8; P = .0004), there was no significant growth in PCUs (26 vs. 40%), inpatient palliative care consultation team (92 vs. 90%), or institute-run hospice (31 vs. 18%).87 Possible reasons for the slow growth of PCUs include issues with staffing, space, and funding. In the outpatient setting, the interdisciplinary outpatient clinic allows a better integration of care between a cancer center and community-based physicians and nurses. It also allows patients access to multiple disciplines that are not available outside tertiary centers. 33 The two main issues in deciding the setting of care are the level of distress and available support. The patient’s distress may be physical, psychosocial, or spiritual and can be measured with the ESAS,44 the Memorial Delirium Assessment Scale (MDAS), the McGill Quality of Life Questionnaire88 (MQOL), the EFAT,60 the PPS,61 the constipation score,62 and others. The level of support can be determined by the structure and function of the family, financial status, medical insurance, and overall physical condition of the home. If there is worsening of the physical and the psychosocial distress, the patient has to be transferred to an acute care hospital where he/she will have access to many disciplines (e.g., consult teams or PCU). Once the distress is controlled, the patient can be moved to the community or home if they have good social and financial support. Otherwise, a transfer to an inpatient hospice unit would be more appropriate. If the distress could not be alleviated or the support could not be provided, the patient would not be able to return home and might die in an acute care hospital or in the inpatient hospice unit (Figure 17.3). The MDAS is a widely used and validated screening tool for delirium in cancer patients. In a pilot study conducted by Fadul et al.,89 31 palliative care health professionals obtained the correct diagnosis of delirium in 90–100% of the time on three simulated patients’ scenarios after they received a training session on the MDAS. The authors concluded that MDAS provided an accurate test to diagnose delirium once palliative care health professionals were trained on how to use it. Further research in the palliative care clinical setting is needed to further confirm these results. MDAS has replaced MMSQ and is being used by our palliative care providers as a tool to diagnose delirium. In summary, palliative care services should match the needs of patients and families. These services can be provided in an inpatient or outpatient setting. Inpatient care can be delivered in PCUs, acute care hospitals, and the inpatient hospice units. Outpatient care can be delivered at home, in NHs, or in outpatient clinics. No single palliative care program needs to have all of these components. These settings can be owned by one institution or can have different owners to integrate palliative care delivery. Most importantly, every palliative care patient should be able to have access to any of these settings in a seamless way appropriate to their needs.

Textbook of Palliative Medicine and Supportive Care

134





FIGURE 17.3  Matching palliative care services to the patient and family needs. To reach a seamless network for the delivery of care, palliative care programs should have resources: agreement between different settings, bus rounds, common assessment tools, common treatment guidelines, and regular communication (audiovisual: patient care and education).

Conclusion In more than 30 years since the inception of the modern hospice movement, a number of clinical programs have emerged. These programs have demonstrated their value in a number of specific patient populations. One of the greater challenges has been to make it possible for patients in different regimens of the world to access the system that is most appropriate to their needs (i.e., home care as compared to inpatient hospice or inpatient acute care facility). In addition, a setting that is appropriate for a patient at a certain time, that is, a patient’s comfort at home with home care, may be inappropriate when there is complete family burnout or severe aggravation of symptom distress. One of the greatest challenges is to have seamless care so that patients at any given time are able to receive palliative care in the setting that is most appropriate to their needs. There has been significant progress in recognizing that the different settings described in this chapter are complementary rather than competitive. There is still considerable need for research on the best way to integrate these different programs into a seamless network.

References

1. Hui D, Hannon BL, Zimmermann C, et al. Improving patient and caregiver outcomes in oncology: team-based, timely, and targeted palliative care. CA Cancer J Clin 2018;68:356–376.





2. Hui D, Bruera E. Integrating palliative care into the trajectory of cancer care. Nat Rev Clin Oncol 2016;13:159–171. 3. Neuenschwander H, Bruera E, Cavalli F. Matching the clinical function and symptom status with the expectations of patients with advanced cancer, their families, and health care workers. Support Care Cancer 1997;5(3):252–256. 4. Bruera E, Neumann C, Brenneis C, et al. Frequency of symptom distress and poor prognostic indicators in palliative cancer patients admitted to a tertiary palliative care unit, hospices, and acute care hospitals. J Palliat Care 2000;16(3):16–21. 5. McMillan SC, Small BJ. Symptom distress and quality of life in patients with cancer newly admitted to hospice home care. Oncol Nurs Forum 2002;29(10):1421–1428. 6. Farber SJ, Egnew TR, Herman-Bertsch JL, et al. Issues in end-oflife care: patient, caregiver, and clinician perceptions. J Palliat Med 2003;6(1):19–31. 7. Tringali CA. The needs of family members of cancer patients. Oncol Nurs Forum 1986;13(4):65–70. 8. Given BA, Given CW, Kozachik S. Family support in advanced cancer. CA: Cancer J Clin 2001;51:213–231. 9. Doyle D, Hanks G, Cherny N, et al., eds. Oxford Textbook of Palliative Medicine. 3rd edn., New York: Oxford University Press, 2004, pp. 1033–1084. 10. Hall P, Weaver L. Interdisciplinary education and teamwork: a long and winding road. Med Educ 2001;35:867–875. 11. Stepans MB, Thompson CL, Buchanan ML. The role of the nurse on a transdisciplinary early intervention assessment team. Public Health Nurs 2002;19:238–245. 12. Pesamaa L, Ebeling H, Kuusimaki ML, et al. Videoconferencing in child and adolescent telepsychiatry: a systematic review of the literature. J Telemed Telecare 2004;10(4):187–192. 13. Kuulasma A, Wahlberg KE, Kuusimaki ML. Videoconferencing in family therapy: a review. J Telemed Telecare 2004;10(3):125–9. 14. Solloway M, LaFrance S, Bakitas M, et al. A chart review of seven hundred eighty-two deaths in hospitals, nursing homes, and hospice/home care. J Palliat Med 2005;8(4):789–796. 15. Wilkinson J. Ethical issues in palliative care. In: Doyle D, Hanks GWC, MacDonald C, eds, Oxford Textbook of Palliative Medicine. New York: Oxford Medical Publications, 1993. 16. von Gunten CF, Martinez J. A program of hospice and palliative care in a private, nonprofit U.S. Teaching Hospital. J Palliat Med 1998;1(3):256–276. 17. Cantwell P, Turco S, Brenneis C, et al. Predictors of home death in palliative care cancer patients. J Palliat Care 2000;16(1):23–28. 18. Neale, B. Informal care & community care. In Clark, D, ed, The Future for Palliative Care: Issues of Policy and Practice. Buckingham, U.K.: Open University Press;1993: 52–67. 19. Claxton-Oldfield S, Jefferies J, Fawcet C, et al. Palliative care volunteers: why do they do it? J Palliat Care 2004;20(2):78–84. 20. Tyrera F, Exley C. Receiving care at home at end of life: characteristics of patients receiving hospice at home care. Fam Pract 2005;22(6):644–646. 21. Randall F, Downie RS. Palliative Care Ethics, a Companion for All Specialties. New York: Oxford Medical Publications. 1999. ISBN 0-19-263068-7. 22. Van Eys J. The ethics of palliative care. J Palliat Care 1991;7(3):27–32. 23. Lattimer, EJ. Ethical decision-making in the care of the dying and its application to clinical practice. J Pain Symptom Manage 1991;6:329–336. 24. Fleming DA. The burden of caregiving at the end-of-life. Mo Med 2003;100(1):82–86. 25. Delgado-Guay MO, Rodriguez-Nunez A, De la Cruz V, et al. Advanced cancer patients’ reported wishes at the end of life: a randomized controlled trial. Support Care Cancer 2016;24:4273–4281. 26. De La Cruz M, Noguera A, San Miguel-Arregui MT, et al. Delirium, agitation, and symptom distress within the final seven days of life among cancer patients receiving hospice care. Palliative and Supportive Care 2015;13:211–216. 27. Hui D, Elsayem A, De la Cruz M, et al. Availability and Integration of palliative care at U.S. cancer centers. JAMA 2010;303(11):1054–1061. 28. Davis MP, Strasser F, Cherny N. How well is palliative care integrated into cancer care? A MASCC, ESMO and EAPC project. Support Care Cancer 2015;23(9):2677–2685. 29. Davis MP, Strasser F, Cherny N, et al. MASCC/ESMO/EAPC survey of palliative programs. Support Care Cancer 2015;23(7):1951–1968.

Models of Palliative Care Delivery 30. Hui D, Cherny N, Latino N, et al. The ‘critical mass’ survey of palliative care programme at ESMO designated centres of integrated oncology and palliative care. Ann Oncol 2017;28(9):2057–2066. 31. Hui D, Kim SH, Roquemore J, et al. Impact of timing and setting of palliative care referral on quality of end-of-life care in cancer patients. Cancer 2014;120(11):1743–1749. 32. Strasser F, Sweeney C, Willey J, et al. Impact of a half-day multidisciplinary symptom control and palliative care outpatient clinic in a comprehensive cancer center on recommendations, symptom intensity, and patient satisfaction: A retrospective descriptive study. J Pain Symptom Manage 2004;27(6):481–491. 33. Bruera E, Michaud M, Vigano A, et al. Multidisciplinary symptom control clinic in a cancer center: A retrospective study. Support Care Cancer 2001;9(3):162–168. 34. Walsh D, Donnelly S, Rybicki L. The symptoms of advanced cancer: Relationship to age, gender, and performance status in 1,000 patients. Support Care Cancer 2000;8:175–179. 35. Vainio A, Auvinen A. Prevalence of symptoms among patients with advanced cancer: An international collaborative study. Symptom Prevalence Group. J Pain Symptom Manage 1996;12:3–10. 36. Bruera E. Symptom control in patients with cancer. J Psychosoc Oncol 1990;8:47–73. 37. Hui D. Palliative cancer care in the outpatient setting: Which model works best? Curr Treat Options Oncol 2019;20:17. 38. Bakitas M, Lyons KD, Hegel MT, et al. Effects of a palliative care intervention on clinical outcomes in patients with advanced cancer: the project ENABLE II randomized controlled trial. JAMA 2009;302(7):741–749. 39. Bakitas M, Tosteson T, Li Z, et al. Early versus delayed Initiation of Concurrent palliative oncology care: patient outcomes in the ENABLE III randomized controlled trial. J Clin Oncol 2015;33(13):1438–1445. 40. El Osta B, Palmer JL, Paraskevopoulos T, et al. Interval between first palliative care consult and death in patients diagnosed with advanced cancer at a comprehensive cancer center. J Palliat Med 2008;11(1):51–57. 41. Fadul N, Elsayem A, Palmer JL, et al. Supportive versus palliative care: what’s in a name?: a survey of medical oncologists and midlevel providers at a comprehensive cancer center. Cancer 2009;115(9):2013–2021. 42. Dalal S, Palla S, Hui D, et al. Association between a name change from palliative to supportive care and the timing of patient referrals at a comprehensive cancer center. Oncologist 2011;16(1):105–111. 43. Dalal S, Bruera S, Hui D, et al. Use of palliative care services in a tertiary cancer center. Oncologist 2016;21:110-118. 44. Bruera E, Kuehn N, Miller MJ, et al. The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care 1991;7:6–9. 45. Ewing J. Detecting alcoholism: the CAGE questionnaire. JAMA 1984;252:1905–1907. 46. Folstein MF, Folstein S, McHugh PR. “Minimental state”: a practical method for grading the cognitive state of patients for the clinician. J Psych Res 1975;12:189–198. 47. Bruera E, Pituskin E, Calder K, et al. The addition of an audiocassette recording of a consultation to written recommendations for patients with advanced cancer: a randomized, controlled trial. Cancer 1999;86(11):2420–2425. 48. Yennurajalingam S, Kang JH, Hui D, et al. Clinical response to an outpatient palliative care consultation in patients with advanced cancer and cancer pain. J Pain Symptom Manage 2012;44(3):340–350. 49. Kang JH, Kwon JH, Hui D, et al. Changes in symptom intensity among cancer patients receiving outpatient palliative care. J Pain Symptom Manage 2013;46(5):652–660. 50. Jenkins CA, Schulz M, Hanson J, et al. Demographic, symptom, and medication profiles of cancer patients seen by a palliative care consult team in a tertiary referral hospital. J Pain Symptom Manage 2000;19(3):174–184. 51. Fins JJ, Miller FG. A proposal to restructure hospital care for dying patients. N Engl J Med 1996;334:1740–1742. 52. O’Mahony S, Blank AE, Zallman L, et al. The benefits of a hospitalbased inpatient palliative care consultation service: preliminary outcome data. J Palliat Med 2005;8(5):1033–1039. 53. Macmillan PJ, Chalfin B, Fard AS, et al. Earlier palliative care referrals associated with reduced length of stay and hospital charges. J Palliat Med 2019; DOI: 10.1089/jpm.2019.0029 54. von Gunten CF. Secondary and tertiary palliative care in U.S. hospitals. JAMA 2002;287:875–881.

135 55. von Gunten CF, Ferris FD, Portenoy R, et al., eds, CAPC Manual: Everything You Wanted to Know About Developing a Palliative Care Program but Were Afraid to Ask. 2001. Available at: http://www.capcmssm.org. 56. Brenneis C, Bruera E. Models for the delivery of palliative care: the Canadian model. In: Bruera E, Portenoy RK, eds, Topics in Palliative Care, Volume 5. New York: Oxford University Press; 2001, pp. 3–23. 57. von Gunten CF. Discussing do-not-resuscitate status. J Clin Oncol 2001;19:1576–1581. 58. Bruera E, Schoeller T, Wenk R, et al. A prospective multicenter assessment of the Edmonton Staging System for cancer pain. J Pain Symptom Manage 1995;10:348–355. 59. Walker P, Nordell C, Neumann CM, et al. Impact of the Edmonton Labeled Visual Information System on physician recall of metastatic cancer patient histories: a randomized controlled trial. J Pain Symptom Manage 2001;21:4–11. 60. Kaasa T, Loomis J, Gillis K et al. The Edmonton Functional Assessment Tool: preliminary development and evaluation for use in palliative care. J Pain Symptom Manage 1997;13:10–19. 61. Oneschuk D, Fainsinger R, Hanson J, et al. Assessment and knowledge in palliative care in second year family medicine residents. J Pain Symptom Manage 1998;14:265–273. 62. Bruera E, Suarez-Almazor M, Velasco A, et al. The assessment of constipation in terminal cancer patients admitted to a palliative care unit: a retrospective review. J Pain Symptom Manage 1994;9:515–519. 63. Maccabee J. The effect of transfer from a palliative care unit to nursing homes—are patients’ and relatives’ needs met? Palliat Med 1994;8:211–214. 64. Casarett D, Johnson M, Smith D, et al. The optimal delivery of palliative care: A national comparison of the outcomes of consultation teams vs inpatient units. Ach Intern Med 2011;171(7):649–655. 65. Elsayem A, Calderon BB, Camarines EM, et al. A month in an acute palliative care unit: clinical interventions and financial outcomes. Am J Hosp Palliat Med 2011;28(8):550–555. 66. Eti S, O’Mahony S, McHugh M, et al. Outcomes of the acute palliative care unit in an Academic Medical Center. Am J Hosp Palliat Med 2014;31(4):380–384. 67. Addington-Hall J, Altmann D, McCarthy M. Which terminally ill cancer patients receive hospice in-patient care? Soc Sci Med 1998;46:1011–1016. 68. Hinton J. Which patients with terminal cancer are admitted from home care? Palliat Med 1994;8:197–210. 69. Gray JD, Forster DP. Factors associated with the utilization of specialist palliative care services: A population based study. J Public Health Med 1997;19:464–469. 70. Gatrell AC, Harman J, Francis BJ, et al. Place of death: analysis of cancer deaths in part of North West England. J Public Health Med 2003;25:53–58. 71. National Hospice and Palliative Care Organization. Hospice Facts and Figures 2018. www.nhpco.org Accessed July 29, 2019. 72. Report to the Congress Medicare Payment Policy. March 2019. www. medpac.gov Accessed July 29, 2019. Page 344 73. Teno J. The Brown Atlas of Dying in the United States: 1989–2001. Available at: http://www.chcr.brown.edu/dying/brownsodinfo.htm (Accessed November 23, 2004). 74. Casarett D, Karlawish J, Morales K, et al. Improving the use of hospice services in nursing homes: a randomized controlled trial. JAMA 2005;294(2):211–217. 75. Rice KN, Coleman EA, Fish R, et al. Factors influencing models of end-of-life care in nursing homes: results of a survey of nursing home administrators. J Palliat Med 2004;7(5):668–675. 76. Bernabei R, Gambassi G, Lapane K, et al. Management of pain in elderly patients with cancer. JAMA 1998;279:1877–1882. 77. Levy CR, Fish R, Kramer AM. Site of death in the hospital versus nursing home of Medicare skilled nursing facility residents admitted under Medicare’s Part A Benefit. J Am Geriatr Soc 2004;52:1247–1254. 78. Miller SC, Gozalo P, Mor V. Hospice enrollment and hospitalization of dying nursing home patients. Am J Med 2001;111:38–44. 79. Teno J, Clarridge B, Casey V, et al. Family perspectives on end-of-life care at the last place of care. JAMA 2004;291:88–93. 80. Thorpe G. Enabling more dying people to remain at home. J Palliat Care 2000;16(1):23–28. 81. Mount BM, Ajemian I. The palliative care service integration in a general hospital. In: Ajemian I, Mount BM, eds, The R.V.H. Manual on Palliative/Hospice Care, New York: Arno Press, 1980, pp. 269–280.

136 82. Stajduhar KI, Davies B. Death at home: challenges for families and directions for the future. J Palliat Care 1998;14(3):8–14. 83. McWhinney IR, Bass MJ, Orr V. Factors associated with location of death (home or hospital) of patients referred to a palliative care team. CMAJ 1995;152(3):361–367. 84. Stephany TM. Place of death: home or hospital. Home Healthc Nurse 1992;10(3):62–62. 85. Dudgeon DJ, Kristjanson L. Home versus hospital death: assessment of preferences and clinical challenges. CMAJ 1995;152(3):337–340. 86. Hinton J. Can home care maintain an acceptable quality of life for patients with terminal cancer and their relatives? Palliat Med 1994;8(3):183–196.

Textbook of Palliative Medicine and Supportive Care 87. Hui D, De La Rosa A, Chen J, et al. Growth of palliative care (PC) in United States cancer centers: a national survey. J Clin Onc 2019; 37:11601–11601. 88. Cohen SR, Mount BM, Bruera E, et al. Validity of the McGill quality of life questionnaire in the palliative care setting: a multi-centre Canadian study demonstrating the importance of the existential domain. Palliat Med 1997;11:3–23. 89. Fadul N, Kaur G, Zhang T, et al. Evaluation of the Memorial Delirium Assessment Scale (MDAS) for the screening of delirium by means of simulated cases by palliative care health professionals. Support Care Cancer 2007;15(11):1271–1276.

18

HOME PALLIATIVE CARE

Heather Grant and Dana Lustbader

Contents Introduction........................................................................................................................................................................................................................137 Identifying the seriously ill population..........................................................................................................................................................................137 Scope of service..................................................................................................................................................................................................................138 Models of home palliative care........................................................................................................................................................................................138 Metrics and measurement...............................................................................................................................................................................................139 Barriers.................................................................................................................................................................................................................................140 Conclusion...........................................................................................................................................................................................................................140 References............................................................................................................................................................................................................................140

Introduction Home palliative care programs have experienced rapid growth, largely driven by the failure of a complex and poorly coordinated health-care system to adequately meet the needs of people with serious or complex chronic conditions. These individuals often find themselves in the emergency department or hospitalized for medical conditions that could be more safely managed at home.1 Unfortunately, frail medically complex patients are often instructed to go to the emergency department as medical practices are poorly equipped to manage these patients, especially during off hours or weekends. Functional limitations and inadequate social support make it challenging for vulnerable patients to prioritize or even get to their physician’s office for care.2 These patients are too sick to benefit from telephonic only case-management programs that deliver monthly outbound calls but fail to provide in-home support or 24/7 availability with bidirectional calling. 3 While seriously ill, these patients are not terminally ill or willing to forgo disease-directed therapies and are, therefore, not eligible for hospice care, which also requires a prognosis of 6 months or less to live.4 In an effort to fill the health-care void between single organ disease management and hospice, home palliative programs have emerged. 5 They have formed through a variety of organization types, including large hospital health systems,6 home health agencies, hospice providers, accountable care organizations (ACOs), and venture funded start-ups.7 The primary goal of these home-based programs is to provide comprehensive patient and family centered medical care where people live: in the home, assisted living, or long-term care facility. Innovative new valuebased payment models are evolving to better support the growing demand. This chapter explores enrollment triggers, models, quality metrics, and challenges in the delivery of home palliative care services.

Identifying the seriously ill population There are more patients who could benefit from home palliative care than there are available resources. Therefore, the specific population to be served should be identified based on the needs of the overall population and various stakeholders involved (e.g.,

payers, provider groups, and community resources). Factors used to identify a seriously ill population include specific advanced diseases, number of chronic comorbidities, being mostly homebound, frailty, and health-care utilization patterns. Using claims data, one study evaluated a fee for service Medicare population and found that for the 4% of beneficiaries who had a serious illness, at least one activity of daily living impairment and at least one hospitalization in the prior 6 months, the average annual health-care cost per beneficiary was $34k and the average 1-year mortality rate was 30%.8 Others have found the seriously ill population to have an average health-care cost of over $60k per year. This high-cost, high-need population can be identified through predictive modeling for home palliative care services. Triggers for enrollment can include evidence of recent care fragmentation (e.g., hospital admission or emergency department visit in the prior 6 months) plus at least one of the following serious illnesses: 1. Advanced cancer (e.g., poor prognosis, metastatic, or hematologic) 2. Heart failure (e.g., requiring home oxygen or ejection fraction 80 years 9. End stage renal disease (ESRD) 10. Multimorbidity with 5+ chronic conditions Predictive models often use payer claims data that includes serious illness International Classification of Diseases (ICD-10) diagnosis codes, utilization of hospital, emergency department and SNFs, pharmacy, and demographic data including zip codes, which correlate with social determinants of health-related risk. When combined with markers of frailty such as the ordering of a wheelchair, commode, or hospital bed, the evaluation of 137

Textbook of Palliative Medicine and Supportive Care

138 functional status from an in-person visit and predictive models can be useful to identify a seriously ill population likely to benefit from home palliative care. The limitations to using algorithms for identifying an eligible population include payer claims lag, poor correlation between ICD-10 codes and disease burden, difficulty capturing frailty, and the inability to identify those lacking social support. The surprise question may also be used to identify high risk patients: Would you be surprised if this patient died within a year? If the answer is no, they may be eligible and benefit from home palliative care services. While this question performs well in ESRD9,10 and cancer populations,11 it fell short in a primary care setting.12 Prognosis alone may not account for symptom burden, functional decline or the need for other psychosocial support services in the home. It is difficult to identify a cohort of people that reliably die in the future, especially early in the disease trajectory. Less than 10% of those who end up dying within a given year have an annual mortality prediction of greater than 50%.13 Most people with a serious illness and high health-care spending are not in their final year of life.14 Some home palliative care programs rely on direct referrals from physicians, nurse case managers, or other providers. Often these referrals are clinically appropriate but can occur late, sometimes days or weeks before death when the patient is better served by a direct referral to a hospice program for terminal care. When this occurs, many non-hospice home palliative care programs make a direct referral to a local hospice provider to avoid a delayed hospice transition during the dying process. Cost is another potential trigger for identification of high-need patients since over half of all health-care spending for a Medicare population is concentrated in the sickest 5% of the population.15 Importantly, not all high-cost patients remain high cost over time. In one study of Medicare beneficiaries, only 28% identified as high cost, remained high cost over a 3-year period. On average, persistently high-cost patients spent $64,434 compared to $4,538 for never high-cost patients.16 Factors that correlate with highcost persistency in a Medicare population include age 20%.143,144 Especially in the United States, the consumption of opioid analgesics has increased dramatically since 1990, making up one-third of global annual opioid consumption despite having only 5% of the global population. This dramatic rise has been associated by an increase in the number of opioidrelated deaths as an illegal market of heroin and fentanyl as well as diversion of opioid analgesics have blossomed up.147 This socalled opioid epidemic may not be ensconced within US borders as many other western countries have been moving in the same direction.146 Although opioids are the cornerstone of cancer pain management, both in palliative and supportive care, more systematic empirical knowledge is needed concerning addiction in “chronic” cancer patients. That includes identification of risk factors for opioid addiction as well as development of efficient opioid tapering off programs. Regarding opioid addiction, the µ-opioid receptor gene encodes the receptor targets for some endogenous opioids and studies about µ-opioid receptor polymorphisms have contributed substantially to knowledge of genetic influences on opioid addiction. Monoaminergic system genes and other genes of the endogenous opioid system, particularly genes encoding the dopamine, serotonin, and norepinephrine transporters, and dopamine β-hydroxylase, have also been studied.148 Clarke et al. analyzed the role of rs1076560 in opioid dependence by genotyping 1,325 opioid addicts. The single nucleotide polymorphism (SNP), 1076560 of the DRD2, was associated with increased risk for drug dependence when combined opioid-addicted ancestral samples were examined.149 There exist numerous positive studies for many candidate genes associated with all reward deficiency syndromes behaviors, especially involving alcoholism,150 and it is possible that opioids are also associated. Particularly, pharmacogenomic identification of candidate genes may result in future pharmacogenomic personalized solutions, and improved clinical outcomes in terms of analgesic response, optimal side effect profiles and avoidance of addiction.

Immune system

Long-term opioid use has been suspected to be associated with increased risk of infections151 and development and progression

228 of cancer diseases, respectively.152 The observations of potential immune suppression have mainly been based on an animal- and in vitro studies153,154 as well as short-term opioid use in humans.155,156 Studies have indicated that opioids may modulate and suppress both the innate and adaptive immune system by involving the immune cells directly and the neuroendocrine system indirectly. Regarding the immune cells the composition and function of T lymphocytes (T cells), B lymphocytes (B cells) and natural killer cells (NK cells) seem to be influenced.130,158 Further, a reduced number of the different cell types has been shown, which may be mediated by modulation of the toll-like receptors (TLRs).159 The TLRs play a central role in the innate immune system by detecting microbes and activating the immune cell response.160 Studies have shown that opioids are TLR4 agonists,161,162 which can produce immune signals involving a neuroinflammatory reaction, which in turn may reduce analgesic effects.161 The µ-receptor is also expressed on peripheral cells such as lymphocytes, which may explain the suppression of NK cell activity during morphine administration.162 Further, other studies have shown that morphine can suppress cytokine production by interacting with the surface receptors.163 A recent systematic review found indication that long-term opioid treatment alters the immune system in chronic noncancer pain patients. These alterations involved reduction of NK cells and IL-1β production.164 In addition, different opioids seem to act differently on the immune system, as exemplified through methadone, which may be less suppressive than morphine.91,92 Clinical data regarding the effects of opioids on cancer development and progression are limited. A study in breast cancer patients found a polymorphism in the gene encoding MOR, which confers decreased response to opioids, and was correlated with longer breast cancer-specific survival,165 whereas high MOR receptor expression has been associated with shorter survival in prostate cancer.166 Most clinical studies have mainly focused on the effects of perioperative opioid use and a few studies have focused on the long-term effects of opioids on cancer development in chronic noncancer pain conditions and progression of disease in patients with cancer. The outcomes of these studies are inconclusive.167–173 Finally, an enhanced sensitivity to viral and bacterial infections has been demonstrated in drug abusers.93 However, for the time being due to lack of sound clinical research, there is little if any clinical evidence that opioids potential effect on the immune system should influence the traditional clinical practice on pain management in cancer care.

Reproductive system

Among patients treated with opioids intrathecally, Abs et al.94 found decreased libido or impotence in almost all the men and significantly lowered serum testosterone levels. Decreased libido was present in about 70% of women receiving opioids, and all premenopausal females developed amenorrhea or an irregular menstrual cycle. Serum luteinizing hormone, estradiol, and progesterone levels were significantly lower in the opioidtreated group than among the controls. Finch et al.95 and Roberts et al.96 have also found decreased libido and testosterone levels in men, and it can be concluded that opioids administered intrathecally may induce hypogonadotropic hypogonadism, which is of clinical importance for the majority of men and in premenopausal women. A study in men on methadone or

Textbook of Palliative Medicine and Supportive Care buprenorphine maintenance treatment (MMT, BMT) investigated the prevalence and etiology of hypogonadism. Men on MMT had high prevalence of hypogonadotrophic hypogonadism, whereas the extent of hormonal changes associated with buprenorphine needs to be explored further in larger studies.97 The decline in production of sex hormones can cause a negative effect on patients’ sex life since a low level of testosterone, in both genders, negatively influences sexual desire and fertility.174 Other studies have indicated that a differential effect of gender on bone mineral density might be explained in part by differences in gonadal function during long-term opioid therapy. A study of individuals in MMT indicated that low levels of testosterone are associated with accelerated bone loss particularly in men,98 but hypogonadism has also been reported in women during treatment with oral opioids.99 In summary, these findings may suggest that individuals receiving long-term methadone, and maybe other opioids, are at increased risk of osteoporosis and physicians should consider evaluating the skeletal health of such individuals, including the estimation of absolute fracture risk. Controlled longitudinal studies of bone mineral density and bone turnover are indicated to define the timing and pace of the bone loss. Furthermore, future studies of hypogonadism in opioid-treated individuals should examine the potential benefits of dose reduction, choice of opioid medication, and sex hormone replacement therapy.175 Finally, there is increasing evidence that opioid treatment may cause varying degrees of hypopituitarism, which may involve cognitive deficiencies, fatigue, decreased libido, depression, and insomnia.176,177 Although some of these effects are well-known as opioid-induced effects, the indirect contribution from hypopituitarism has not yet been established.

Summary This chapter discussed the history and recent evidence regarding opioid receptors along with clinical observations of individual responses and incomplete cross-tolerance to different opioids. The up-to-date pharmacology of the most commonly used strong opioids—morphine, methadone, oxycodone/oxymorphone, fentanyl, and buprenorphine—has been reviewed. Important clinical issues associated with long-term administration of these drugs are highlighted.

KEY LEARNING POINTS • Variability regarding opioid efficacy, side effects, and cross-tolerance in different patients suggest μ-receptors subtypes and opioid interaction with other molecular targets. • Pharmacogenetic knowledge of opioid effects is still limited. • Morphine may still be the first drug of choice; however, selection of opioids should be based on clinical assessment and the respective pharmacokinetics/dynamics of each opioid analgesic. • New routes of fentanyl and buprenorphine administration have been developed, but titration difficulties and clinical relevance are still discussed.

Opioid Analgesics

229

• Long-term opioid treatment has other consequences than the “classic” side effects. In palliative medicine, physical dependence, tolerance, OIH, and addiction should also be considered as these may be related to poor treatment outcomes. • New research concerning the potential influence of long-term administration of opioids on the immune and reproductive systems is needed.

References





















1. Portoghese PS. Stereochemical factors and receptor interactions associated with narcotic analgesics. J Pharm Sci 1966;55:865–887. 2. Mollereau C, Parmentier M, Mailleux P, et al. ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization. FEBS Lett 1994;341:33–38. 3. Dale O, Moksnes K, Kaasa S. European palliative care research collaborative pain guidelines: opioid switching to improve analgesia or reduce side effects. a systematic review. Palliat Med 2011;25:494–503. 4. Klepstad P, Fladvad T, Skorpen F, et al. Influence from genetic variability on opioid use for cancer pain: a European genetic association study of 2294 cancer pain patients. Pain 2011;152:1139–1145. 5. Stein C, Pfluger M, Yassouridis A, et al. No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia. J Clin Invest 1996;98:793–799. 6. World Health Organization. Cancer Pain Relief and Palliative Care. Geneva, Switzerland: World Health Organization, 1996. 7. Caraceni A, Hanks G, Kaasa S, et al. Use of opioid analgesics in the treatment of cancer pain: Evidence-based recommendations from the EAPC. Lancet Oncol 2012;13:58–68. 8. Brunk SF, Delle M. Morphine metabolism in man. Clin Pharmacol Ther 1974;16:51–57. 9. Poulain P, Hoskin PJ, Hanks GW, et al. Relative bioavailability of controlled release morphine tablets (MST Continus) in cancer patients. Br J Anaesth 1988;61:569–574. 10. Christrup LL, Sjogren P, Jensen N-H, et al. Steady-state kinetics and dynamics of morphine in cancer patients. Is sedation related to the absorption rate of morphine? J Pain Symptom Manage 1999;18:164–173. 11. Olsen GD. Morphine binding to human plasma proteins. Clin Pharmacol Ther 1975;17:31–35. 12. Owen JA, Sitar DS, Berger L, et al. Age-related morphine kinetics. Clin Pharmacol Ther 1983;34:364–368. 13. Säwe J, Kager L, Svensson J-O, Rane A. Oral morphine in cancer patients: In vivo kinetics and in vitro hepatic glucuronidation. Br J Clin Pharmacol 1985;19:495–501. 14. Osborne R, Joel S, Trew D, Slevin M. Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide. Clin Pharmacol Ther 1990;47:12–19. 15. Crotty B, Watson KJR, Desmond PV, et al. Hepatic extraction of morphine is impaired in cirrhosis. Eur J Clin Pharmacol 1989;36:501–506. 16. Wahlström A, Pacifici GM, Lindstrom B, Hammar L, Rane A. Human liver morphine UDP-glucuronyl transferase enantioselectivity and inhibition by opioid congeners and oxazepam. Br J Pharmacol 1988;94:864–870.

17. King CD, Rios GR, Assouline JA, Tephly TR. Expression of UDPglucuronosyltransferases (UGTs) 2B7 and 1A6 in the human brain and identification of 5-hydroxytryptamine as a substrate. Arch Biochem Biophys 1999;365:156–162. 18. Coffman BL, Rios GR, King CD, Tephly TR. Human UGT2B7 catalyzes morphine glucuronidation. Drug Met Disp 1997;25:1–4. 19. Stone AN, Mackenzie PI, Galetin A, Houston JB, Miners JO. Isoform selectivity and kinetics of morphine 3-and 6-glucuronidation by human udp-glucuronosyltransferases: evidence for atypical glucuronidation kinetics by UGT2B7. Drug Metab Dispos 2003;31:1086–1089. 20. Andersen G, Sjogren P, Hansen SH, et al. Pharmacological consequences of long-term morphine treatment in patients with cancer and chronic non-malignant pain. Eur J Pain 2004;8:263–271. 21. Innocenti F, Liu W, Fackenthal D, et al. Single nucleotide polymorphism discovery and functional assessment of variation in the UDP-glucuronosyltransferase 2B7 gene. Pharmacogenet Genomics 2008;18:683–697. 22. Di YM, Chan E, Wei MQ, Liu JP, Zhou SF. Prediction of deleterious non-synonymous single-nucleotide polymorphisms of human uridine diphosphate glucuronosyltransferase genes. AAPS J 2009;11:469–480. 23. Holthe M, Klepstad P, Zahlsen K, et al. Morphine glucuronide-tomorphine plasma ratios are unaffected by the UGT2B7 H268Y and UGT1A1⋆28 polymorphisms in cancer patients on chronic morphine therapy. Eur J Clin Pharmacol 2002;58:353–356. 24. Osborne R, Joel S, Grebenik K, et al. The pharmacokinetics of morphine and morphine glucuronides in kidney failure. Clin Pharmacol Ther 1993;54:158–167. 25. Klepstad P, Dale O, Kaasa S, et al. Influences on serum concentrations of morphine, M6G and M3G during routine clinical drug monitoring: a prospective survey in 300 adult cancer patients. Acta Anaesthesiol Scand 2003;47:725–731. 26. Hasselström J, Berg U, Löfgren A, Säwe J. Long lasting respiratory depression induced by morphine-6-glucuronide? Br J Clin Pharmac 1989;27:515–518. 27. Bodd E, Jacobsen D, Lund E, et al. Morphine-6-glucuronide might mediate the prolonged opioid effect of morphine in acute renal failure. Human Exp Toxicol 1990;9:317–321. 28. King S, Forbes K, Hanks GW, Ferro CJ, Chambers EJ. A systematic review of the use of opioid medication for those with moderate to severe cancer pain and renal impairment: a European Palliative Care Research Collaborative opioid guidelines project. Palliat Med 2011;25:525–552. 29. Van Dongen RTM, Crul BJP, Koopman-Kimenai PM, Vree TB. Morphine and morphine-glucuronide concentrations in plasma and CSF during long-term administration of oral morphine. Br J Clin Pharmacol 1994;38:271–273. 30. Goucke CR, Hackett LP, Ilett KF. Concentrations of morphine, morphine-6-glucuronide and morphine-3-glucuronide in serum and cerebrospinal fluid following morphine administration to patients with morphine-resistant pain. Pain 1994;56:145–149. 31. Wu D, Kang YS, Bickel U, Pardrige WM. Blood-Brain Barrier permeability to morphine-6-glucuronide is markedly reduced compared with morphine. Drug Met Disp 1997;25:768–771. 32. Stain-Texier F, Boschi G, Sandouk P, Scherrmann JM. Elevated concentrations of morphine 6-beta-D-glucuronide in brain extracellular fluid despite low blood-brain barrier permeability. Br J Pharmacol 1999;128:917–924. 33. Frances B, Gout R, Monsarrat B, Cros J, Zajac J-M. Further evidence that morphine-6b-glucuronide is a more potent opioid agonist than morphine. J Pharmacol Exp Ther 1992;262:25–31. 34. Osborne R, Thomsen P, Joel S, et al. The analgesic effect of morphine6-glucuronide. Br J Clin Pharmacol 1992;34:130–138.

230 35. Dennis GC, Soni D, Dehkordi O, et al. Analgesic responses to intrathecal morphine in relation to CSF concentrations of morphine-3b-glucuronide and morphine-6, beta-glucuronide. Life Sci 1999;64:1725–1736. 36. Klepstad P, Kaasa S, Borchgrevink PC. Start of oral morphine to cancer patients: effective serum morphine concentrations and contribution from morphine-6-glucuronide to the analgesia produced by morphine. Eur J Clin Pharmacol 2000;55:713–719. 37. Quigley C, Joel S, Patel N, et al. Plasma concentrations of morphine, morphine-6-glucuronide and their relationship with analgesia and side effects in patients with cancer-related pain. Palliat Med 2003;17:185–190. 38. Klepstad P, Borchgrevink PC, Dale O, et al. Routine drug monitoring of serum concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide do not predict clinical observations in cancer patients. Palliat Med 2003;17:679–687. 39. Smith MT, Watt JA, Cramond T. Morphine-3-glucuronide: a potent antagonist of morphine analgesia. Life Sci 1990;47:579–585. 40. Gong Q-L, Hedner J, Bjorkman R, Hedner T. Morphine-3-glucuronide may functionally antagonize morphine-6-glucuronide induced antinociception and ventilatory depression in the rat. Pain 1992;48:249–255. 41. Hewett K, Dickenson AH, McQuay HJ. Lack of effect of morphine3-glucuronide on the spinal antinociceptive actions of morphine in the rat: an electrophysiological study. Pain 1993;53:59–63. 42. Quellet DM, Pollack GM. Effect of prior morphine-3-glucuronide exposure on morphine disposition and antinociception. Biochem Pharmacol 1997;53:1451–1457. 43. Smith MT. Neuroexcitatory effects of morphine and hydro-morphine: evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol 2000;27:524–528. 44. Rozan JP, Kahn CH, Warfield CA. Epidural and intravenous opioidinduced neuroexcitation. Anesthesiology 1995;83:860–863. 45. SjØgren P, Jonsson T, Jensen NH, Drenck NE, Jensen TS. Hyperalgesia and myoclonus in terminal cancer patients treated with continuous intravenous morphine. Pain 1993;55:93–97. 46. Bruera E, Pereira J. Acute neuropsychiatric findings in a patient receiving fentanyl for cancer pain. Pain 1997;69:199–201. 47. Penson TP, Joel SP, Clark S, et al. Limited phase 1 study of morphine3-glucuronide. J Pharm Sci 2001;90:1810–1816. 48. Symonds P. Methadone and the elderly. Br Med J 1977;1:512. 49. Hunt G, Bruera E. Respiratory depression in a patient receiving oral methadone for cancer pain. J Pain Symptom Manage 1995;10:636–648. 50. Bruera E, Fainsinger R, Moore M, et al. Local toxicity with subcutaneous methadone. Experience of two centers. Pain 1991;45:141–143. 51. Fainsinger R, Schoeller T, Bruera E. Methadone in the management of cancer pain: a review. Pain 1993;52:137–147. 52. Nilsson MI, Meresaar U, Anggard E. Clinical pharmacokinetics of methadone. Acta Anaesthesiol Scand 1982;74(Suppl):S66–S69. 53. Gourlay GK, Cherry DA, Cousins MJ. A comparative study of the efficacy and pharmacokinetics of oral methadone and morphine in the treatment of severe pain in patients with cancer. Pain 1986;25:297–312. 54. Säwe J. High-dose morphine and methadone in cancer patients. Clinical pharmacokinetic considerations of oral treatment. Clin Pharmacokinet 1986;11:87–106. 55. Dole VP, Kreek MJ. Methadone plasma levels: sustained by a reservoir of drug in tissue. Proc Natl Acad Sci USA 1973;70:10. 56. Inturrisi CE, Colbum WA, Kaiko RF, et al. Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain. Clin Pharmacol Ther 1987;41:392–401. 57. Kristensen K, Christensen CB, Christrup L. The mu1, mu 2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci 1995;56:45–50.

BK-TandF-BRUERA_9780367642037-200160-Chp25.indd 230

Textbook of Palliative Medicine and Supportive Care 58. Kristensen K, Blemmer T, Angelo HR, et al. Stereoselective pharmacokinetics of methadone in chronic pain patients. Ther Drug Monitor 1996;18:221–227. 59. Plummer JL, Gourlay GK, Cherry DA, Cousins MJ. Estimation of methadone clearance: application in management of cancer pain. Pain 1988;33:313–322. 60. Ripamonti C, Zecca E, Bruera E. An update on the clinical use of methadone for cancer pain. Pain 1997;70:109–115. 61. Bruera E, Sweeney C. Methadone use in cancer patients with pain: a review. J Palliat Med 2002;5:127–138. 62. Quigley C. Opioid switching to improve pain relief and drug tolerability. Cochrane Database Syst Rev 2004;3:CD004847. 63. Kalso E, Vainio A. Morphine and oxycodone hydrochloride in the management of cancer pain. Clin Pharmacol Ther 1990;47:639–646. 64. Leow KP, Smith MT, Williams B, et al. Single-dose and steady-state pharmacokinetics and pharmacodynamics of oxycodone in patients with cancer. Clin Pharmacol Ther 1992;52:487–495. 65. Sloan P, Slatkin N, Ahdieh H. Effectiveness and safety of oral extendedrelease oxymorphone for the treatment of cancer pain: a pilot study. Support Care Cancer 2005;13:57–65. 66. Poyhia R, Seppala R, Olkkola KT, Kalso E. The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects. Br J Clin Pharmacol 1992;33:617–621. 67. Sinatra RS, Hyde NH, Harrison DM. Oxymorphone revisited. Semin Anesth 1988;7:208–215. 68. Matsumoto AK. Oral extended-release oxymorphone: a new choice for chronic pain relief. Expert Opin Pharmacother 2007;8:1515–1527. 69. Heiskanen T, Kalso E. Controlled-release oxycodone and morphine in cancer related pain. Pain 1997;73:37–45. 70. Zhukovsky DS, Walsh D, Doona M. The relative potency between high dose oral oxycodone and morphine: a case illustration. J Pain Symptom Manage 1999;18:53–55. 71. Kaiko RF, Benziger DP, Fitzmartin RD, et al. Pharmacokineticpharmacodynamic relationship of controlled-release oxycodone. Clin Pharmacol Ther 1996;59:52–61. 72. Villiger JW, Ray LJ, Taylor KM. Characteristics of fentanyl binding to the opiate receptor. Neuropharmacology 1983;22:447–452. 73. Varvel JR, Sharfer SL, Hwang SS, et al. Absorption characteristics of transdermally administered fentanyl. Anesthesiology 1989;70:928–934. 74. Jeal W, Benfield P. Transdermal fentanyl. Drugs 1997;53:109–138. 75. Paix A, Cloeman A, Lees J, et al. Subcutaneous fentanyl and sufentanil infusion substitution for morphine intolerance in cancer pain management. Pain 1995;63:263–269. 76. Miser AW, Narang PK, Dothage JA, et al. Transdermal fentanyl for pain control in patients with cancer. Pain 1989;37:15–21. 77. Sorge J, Sittl R. Transdermal buprenorphine in the treatment of chronic pain: Results of a phase III, multicenter, randomized, doubleblind, placebo-controlled study. Clin Ther 2004;26:1808–1820. 78. Sittl R, Griessinger N, Likar R. Analgesic efficacy and tolerability of transdermal buprenorphine in patients with inadequately controlled chronic pain related to cancer and other disorders: a multicenter, randomized, double-blind, placebo-controlled trial. Clin Ther 2003;25:150–168. 79. Pergolizzi J, Aloisi AM, Dahan A et al. Current knowledge of buprenorphine and its unique pharmacological profile. Pain Pract 2010;10:428–450. 80. Kress HG. Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine. Eur J Pain 2009;13:219–230. 81. Way WL. Basic mechanisms in narcotic tolerance and physical dependence. Ann N Y AcadSci 1978;311:61–68. 82. Jaffe J. Opiates: clinical aspects. In: Lowinson JH, Ruiz P, Millman RG, eds. Substance Abuse: A Comprehensive Textbook. Baltimore, MD: Williams and Wilkens, 1992, pp. 186–194.

24/06/21 11:46 AM

Opioid Analgesics 83. Savage SR. Addiction in the treatment of pain: Significance, recognition and treatment. J Pain Symptom Manage 1993;8:265–278. 84. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med 2003;349:1943–1953. 85. Finn AK, Whistler JL. Endocytosis of the mu opioid receptor reduces tolerance and a cellular hallmark of opiate withdrawal. Neuron 2001;32:829–839. 86. Raith K, Hochhaus G. Drugs used in the treatment of opioid tolerance and physical dependence: a review. Int J Clin Pharmacol Ther 2004;42:191–203. 87. Blackburn D, Somerville E, Squire J. Methadone: an alternative conversion regime. Eur J Pall Care 2002;9:93–96. 88. Axelrod DJ, Reville B. Using methadone to treat opioid-induced hyperalgesia and refractory pain. J Opioid Manage 2007;3:113–114. 89. Koppert W, Sitti R, Scheuber K, Alsheimer M, Schmelz M, Schuttler J. Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by s-ketamine and clonidine in humans. Anesthesiology 2003;99:152–159. 90. Forero M, Chan PSL, Restrepo-Garces CE. Successful reversal of hyperalgesia/myoclonus complex with low-dose ketamine infusion. Pain Pract 2012;12:154–158. 91. Sacerdote P, Manfredi B, Mantegazza P, Panerai AE. Antinociceptive and immunosuppressive effects of opiate drugs: a structure related study. Br J Pharmacol 1997;121:834–840. 92. De Waal EJ, Van Der Laan JW, Van Loveren H. Effects of prolonged exposure to morphine and methadone on in vivo parameters of immune function in rats. Toxicology 1998;129:201–210. 93. Roy S, Ninkovic J, Banerjee S, et al. Opioid drug abuse and modulation of immune function: consequences in the susceptibility to opportunistic infections. J Neuroimmune Pharmacol 2011;6:442–465. 94. Abs R, Verhelst J, Maeyaert J et al. Endocrine consequences of longterm intrathecal administration of opioids. J Clin Endocrinol Metab 2000;85:2215–2222. 95. Finch PM, Roberts LJ, Price L et al. Hypogonadism in patients treated with intrathecal morphine. Clin J Pain 2000;16:251–254. 96. Roberts LJ, Finch PM, Bhagat CI, Price LM. Sex hormone suppression by intrathecal opioids: A prospective study. Clin J Pain 2002;18:144–148. 97. Hallinan R, Byrne A, Agho K, McMahon CG, Tynan P, Attia J. Hypogonadism in men receiving methadone and buprenorphine maintenance treatment. Int J Androl 2009;32:131–139. 98. Grey A, Rix-Trott K, Horne A, Gamble G, Bolland M, Reid IR. Decreased bone density in men on methadone maintenance therapy. Addiction 2011;106:349–354. 99. Daniell HW. Opioid endocrinopathy in women consuming prescribed sustained-action opioids for control of nonmalignant pain. J Pain 2008;9:28–36. 100. Law PY, Reggio PH, Loh HH. Opioid receptors: toward separation of analgesic from undesirable effects. Trends Biochem Sci 2013;38(6):275–282. 101. Pasternak GW. Multiple opiate receptors: deja vu all over again. Neuropharmacology 2004;47(S1):312–323. 102. Xu J, Faskowitz AJ, Rossi GC, et al. Stabilization of morphine tolerance with long-term dosing: association with selective upregulation of mu-opioid receptor splice variant mRNAs. Proc Natl Acad Sci U S A 2015;112(1):279–284. 103. Olson KM, Duron DI, Womer D, Fell R, Streicher JM. Comprehensive molecular pharmacology screening reveals potential new receptor interactions for clinically relevant opioids. PLOS ONE 2019;14(6):e0217371. 104. Stein C. Opioid receptors. Annu Rev Med 2016;67:433–451. 105. World Health Organization. WHO guidelines for the pharmacological and radiotherapeutic management of cancer pain in adults and adolescents. Geneva: World Health Organization; 2018. Licence: CC BY-NC-SA 3.0 IGO.

BK-TandF-BRUERA_9780367642037-200160-Chp25.indd 231

231 106. Fallon M, Giusti R, Aielli F, et al. On behalf of the ESMO Guidelines Committee. Ann Oncol 2018;29(Suppl 4):iv166–iv191. 107. Roeckel LA, Utard V, Reiss D, et al. Morphine-induced hyperalgesia involves mu opioid receptors and the metabolite morphine-3-glucuronide. Sci Rep 2017;7(1):10406. 108. Sande TA, Laird BJ, Fallon MT. The use of opioids in cancer patients with renal impairment: a systematic review. Support Care Cancer 2017;25(2):661–675. 109. De Gregori S, Minella CE, De Gregori M, et al. Clinical pharmacokinetics of morphine and its metabolites during morphine dose titration for chronic cancer pain. Ther Drug Monit 2014;36(3):335–344. 110. Klimas R, Mikus G. Morphine-6-glucuronide is responsible for the analgesic effect after morphine administration: a quantitative review of morphine, morphine-6-glucuronide, and morphine-3-glucuronide. Br J Anaesth 2014;113(6):935–944. 111. Wiffen PJ, Wee B, Moore RA. Oral morphine for cancer pain. Cochrane Database Syst Rev 2016;4:CD003868. 112. Yu Z, Wen L, Shen X, et al. Effects of the OPRM1 A118G Polymorphism (rs1799971) on opioid analgesia in cancer pain: A systematic review and meta-analysis. Clin J Pain 2019;35(1):77–86. 113. Nicholson AB, Watson GR, Derry S, et al. Methadone for cancer pain. Cochrane Database Syst Rev 2017;2:CD003971. 114. McLean S, Twomey F. Methods of rotation from another strong opioid to methadone for the management of cancer pain: a systematic review of the available evidence. J Pain Symptom Manage 2015;50(2):248–259. 115. Behzadi M, Joukar S, Beikb A. Opioids and cardiac arrhythmia: a literature review. Med Princ Pract 2018;27(5):401–414. 116. Mercadante S, Bruera E. Methadone as a first-line opioid in cancer pain management: a systematic review. J Pain Symptom Manage 2018;55(3):998–1003. 117. US Food and Drug Administration. FDA requests removal of Opana ER for risks related to abuse. FDA News release, 2017. Available at: https://www. fda.gov/news-events/press-announcements/fda-requests-removalopana-er-risks-related-abuse. 118. Kinnunen M, Piirainen P, Kokki H, et al. Updated clinical pharmacokinetics and pharmacodynamics of oxycodone. Clin Pharmacokinet 2019;58(6):705–725. 119. Smith HS. Clinical pharmacology of oxymorphone. Pain Med 2019;10(S1):3–10. 120. Adams MP, Ahdieh H. Pharmacokinetics and dose-proportionality of oxymorphone extended release and its metabolites: results of a randomized crossover study. Pharmacotherapy 2004;24(4):468–476. 121. Soleimanpour H, Safari S, Shahsavari Nia K, et al. Opioid drugs in patients with liver disease: a systematic review. Hepat Mon 2016;16(4):e32636. 122. Treillet E, Laurent S, Hadjiat Y. Practical management of opioid rotation and equianalgesia. J Pain Res 2018;11:2587–2601. 123. Schmidt-Hansen M, Bennett MI, Arnold S, et al. Oxycodone for cancer-related pain. Cochrane Database Syst Rev 2017;8:CD003870. 124. Schug SA, Ting S. Fentanyl formulations in the management of pain: an update. Drugs 2017;77(7):747–763. 125. Schmidt-Hansen M, Bromham N, Taubert M, et al. Buprenorphine for treating cancer pain. Cochrane Database Syst Rev 2015;(3) :CD009596. 126. Mercadante S, Bruera E. Opioid switching in cancer pain: from the beginning to nowadays. Crit Rev Oncol Hematol 2016;99:241–248. 127. Rennick A, Atkinson T, Cimino NM, et al. Variability in opioid equivalence calculations. Pain Med 2016;17(5):892–898. 128. McNicol E. Opioid side effects and their treatment in patients with chronic cancer and noncancer pain. J. Pain Pall. Care Pharmacother 2008;22(4):270–281. 129. Williams JT, Ingram SL, Henderson G, et al. Regulation of μ-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev 2013;65(1): 223–254.

24/06/21 11:46 AM

Textbook of Palliative Medicine and Supportive Care

232 130. Ferrini F, Trang T, Mattioli TA, et al. Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl- homeostasis. Nat Neurosci 2013;16(2): 183–192. 131. Roeckel LA, Le Coz GM, Gavériaux-Ruff C, et al. Opioid-induced hyperalgesia: cellular and molecular mechanisms. Neuroscience 2016;338:160–182. 132. Evans CJ, Cahill CM. Neurobiology of opioid dependence in creating addiction vulnerability. F1000Res. 2016;5. pii: F1000 Faculty Rev-1748. 133. Sevarino KA, Saxon AJ, Hermann R. Opioid withdrawal in adults: clinical manifestations, course, assessment and diagnosis. UpToDate. 2019. Available at: https://www.uptodate.com/contents/opioid-withdrawalin-adults-clinical-manifestations-course-assessment-and-diagnosis/ print (Accessed December 12, 2019). 134. Cai Y, Kong H, Pan YB, et al. Procyanidins alleviates morphine tolerance by inhibiting activation of NLRP3 inflammasome in microglia. J Neuroinflammation 2016;13(1):53. 135. Higgins C, Smith BH, Matthews K. Evidence of opioid-induced hyperalgesia in clinical populations after chronic opioid exposure: a systematic review and meta-analysis. Br J Anaesth 2019;122(6):e114–e126. 136. Colvin L, Fallon MT. Opioid-induced hyperalgesia: a clinical challenge. Br J Anaesth 2010;104:125e7 137. King T, Ossipov MH, Vanderah TW, et al. Is paradoxical pain induced by sustained opioid exposure an underlying mechanism of opioid antinociceptive tolerance? Neurosignals 2005;14(4): 194–205. 138. Ossipov MH, Lai J, King T, Vanderah TW, et al. Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure. Biopolymers 2005;80(2-3):319–324. 139. Mao J. Opioid-induced abnormal pain sensitivity. Curr Pain Headache Rep 2006;10(1): 67–70. 140. Ballantyne JC, Sullivan MD. Discovery of endogenous opioid systems: what it has meant for the clinician’s understanding of pain and its treatment. Pain 2017;158(12):2290–2300. 141. Højsted J, Sjøgren P. Addiction to opioids in chronic pain patients: a literature review. Eur J Pain 2007;11(5):490–518. 142. Yennurajalingam S, Edwards T, Arthur JA, et al. Predicting the risk for aberrant opioid use behavior in patients receiving outpatient supportive care consultation at a comprehensive cancer center. Cancer 2018;124(19):3942–3949. 143. Okie S. A flood of opioids, a rising tide of deaths. N Engl J Med 2010;363(21):1981–1985. 144. Bohnert ASB, Valenstein M, Bair MJ, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA 2011;305(13):1315–1321. 145. Paulozzi LJ, Kilbourne EM, Shah NG, et al. A history of being prescribed controlled substances and risk of drug overdose death. Pain Med 2012;13(1):87–95. 146. Häuser W, Petzke, Radbruch, et al. The opioid epidemic and the longterm opioid therapy for chronic noncancer pain revisited: a transatlantic perspective. Pain Manag 2016;6(3):249–263. 147. Chen Q, Larochelle MR, Weaver DT, et al. Prevention of prescription opioid misuse and projected overdose deaths in the United States. JAMA Netw Open 2019;2(2):e187621. 148. McClung E, Nestler V, Zachariou V. Regulation of gene expression by chronic morphine and morphine withdrawal in the locus coeruleus and ventral tegmental area. J Neurosci 2005;25(25): 6005–6015. 149. Clarke T, Weiss A, Ferarro T, et al. The dopamine receptor D2 (DRD2) SNP rs1076560 is associated with opioid addiction. Ann Hum Genet 2014;78(1):33–39. 150. Yan J, Aliev F, Webb B, et al. Using genetic information from candidate gene and genome-wide association studies in risk prediction for alcohol dependence. Addict Biol 2014;19(4):708–721.



151. Al-Hashimi M, Scott SWM, Thompson JP, et al. Opioids and immune modulation: more questions than answers. Br J Anaesth 2013;111(1):80–88. 152. Sjøgren P, Kaasa S. The role of opioids in cancer progression: emerging experimental and clinical implications. Ann Oncol 2016;27(11):1978–80. 153. Cornwell WD, Lewis MG, Fan X, et al. Effect of chronic morphine administration on circulating T cell population dynamics in rhesus macaques. J Neuroimmunol 2013;265(1-2):43–50. 154. Dutta R, Krishnan A, Meng J, et al. Morphine modulation of tolllike receptors in microglial cells potentiates neuropathogenesis in a HIV-1 model of coinfection with pneumococcal pneumoniae. J Neurosci 2012;32(29):9917–9930. 155. Sacerdote P, Bianchi M, Gaspani L, et al. The effects of tramadol and morphine on immune responses and pain after surgery in cancer patients. Anesth Analg 2000;90(6):1411–1414. 156. Velásquez JF, Ramírez MF, Ai DI, et al. Impaired immune function in patients undergoing surgery for bone cancer. Anticancer Res 2015;35(10):5461–5466. 157. Katz N, Mazer NA. The impact of opioids on the endocrine system. Clin J. Pain 2009;25(2):170–175. 158. Suzuki S, Miyagi T, Chuang TK, et al. Morphine upregulates mu opioid receptors of human and monkey lymphocytes. Biochem Biophys Res Commun 2000;279(2):621–628. 159. Meng J, Yu H, Ma J, et al. Morphine induces bacterial translocation in mice by compromising intestinal barrier function in a TLRdependent manner. PLOS ONE 2013;8(1):e54040. 160. Nicotra L, Loram LC, Watkins LR, et al. Toll-like receptors in chronic pain. Exp Neurol 2012;234(2):316–329. 161. Hutchinson MR, Bland ST, Johnson KW, et al Opioid-induced glial activation: mechanisms of activation and implications for opioid analgesia, dependence, and reward. Sci World J 2007;7:98–111. 162. Chuang LF, Killam KF, Chuang RY. Induction and activation of mitogen-activated protein kinases of human lymphocytes as one of the signaling pathways of the immunomodulatory effects of morphine sulfate. J Biol Chem 1997;272(43):26815–26817. 163. Vallejo R, de Leon-Casasola O, Benyamin R. Opioid therapy and immunosuppression: a review. Am J Ther 2004;11(5):354–365. 164. Diasso PDK, Birke H, Nielsen SD, et al. The effects of long-term opioid treatment on the immune system in chronic non-cancer pain patients: A systematic review. Eur J Pain 2019 November 9. Doi: 10.1002/ejp.1506. 165. Bortsov AV, Millikan RC, Belfer I, et al. Mu-opioid receptor gene A118G polymorphism predicts survival in patients with breast cancer. Anesthesiology 2012;116(4): 896–902. 166. Zylla D, Gourley BL, Vang D, et al. Opioid requirement, opioid receptor expression, and clinical outcomes in patients with advanced prostate cancer. Cancer 2013;119(23): 4103–4110. 167. Myles PS, Peyton P, Silbert B, et al. Perioperative epidural analgesia for major abdominal surgery for cancer and recurrence-free survival: randomised trial. BMJ 2011;342: d1491. 168. Exadaktylos AK, Buggy DJ, Moriarty DC, et al. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology 2006;105(4):660–664. 169. Biki B, Mascha E, Moriarty DC, et al. Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: a retrospective analysis. Anesthesiology 2008;109(2):180–187. 170. Maher DP, Wong W, White PF, et al. Association of increased postoperative opioid administration with non-small-cell lung cancer recurrence: a retrospective analysis. Br J Anaesth 2014;113(Suppl 1): i88–94. 171. Smith TJ, Staats PS, Deer T, et al. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain:

Opioid Analgesics

172.

173.

174.

impact on pain, drug-related toxicity, and survival. J Clin Oncol 2002;20(1):4040–4049. Ekholm O, Kurita GP, Højsted J, et al. Chronic pain, opioid prescriptions, and mortality in Denmark: a population-based cohort study. Pain 2014;155(12): 2486–2490. Cronin-Fenton DP, Heide-Jørgensen U, Ahern TP, et al. Opioids and breast cancer recurrence: a Danish population-based cohort study. Cancer 2015;121(19):3507–3514. Gudin JA, Laitman A, Nalamachu S. Opioid related endocrinopathy. Pain Med 2015;16(Suppl 1):S9–15.

233 175. Huang G, Travison T, Maggio M, et al. Effects of testosterone replacement on metabolic and inflammatory markers in men with opioid-induced androgen deficiency. Clin Endocrinol (Oxf). 2016;85(2):232–238. 176. Vuong C, Van Uum SHM, O’Dell LE, et al. The effects of opioids and opioid analogs on animal and human endocrine systems. Endocr Rev 2010;31(1):98–132. 177. Elliott JA, Opper SE, Agarwal S, et al. Non-analgesic effects of opioids: opioids and the endocrine system. Curr Pharm Des 2012;18(37):6070–6078.

26

ASSESSMENT AND MANAGEMENT OF OPIOID SIDE EFFECTS

Shalini Dalal

Contents Introduction....................................................................................................................................................................................................................... 235 Opioid-mediated gastrointestinal side effects............................................................................................................................................................. 235 Constipation................................................................................................................................................................................................................. 236 Assessment and management of constipation...................................................................................................................................................... 236 Nausea................................................................................................................................................................................................................................. 238 Assessment and management of opioid-induced nausea................................................................................................................................... 238 Sedation.............................................................................................................................................................................................................................. 238 Driving and opioids.....................................................................................................................................................................................................239 Opioid-induced neurotoxicity.........................................................................................................................................................................................239 Cognitive impairment and delirium.........................................................................................................................................................................239 Hallucinations...............................................................................................................................................................................................................239 Myoclonus and seizures..............................................................................................................................................................................................239 Hyperalgesia and allodynia....................................................................................................................................................................................... 240 Mechanism of opioid-induced neurotoxicity........................................................................................................................................................ 240 Assessment of OIN..................................................................................................................................................................................................... 240 Management of OIN....................................................................................................................................................................................................241 Respiratory depression......................................................................................................................................................................................................241 Opioid-induced bladder dysfunction............................................................................................................................................................................ 242 Pruritus and allergic reactions........................................................................................................................................................................................ 242 Opioid-induced endocrine and immune effects......................................................................................................................................................... 242 Opioid effects on immune function........................................................................................................................................................................ 243 Physiological and psychological responses to opioid use................................................................................................................................... 243 References........................................................................................................................................................................................................................... 244

Introduction Opioids are the cornerstone of pain management in the palliative care setting. Successful pain management with opioids requires that adequate analgesia be achieved without excessive side effects. Approximately 10–30% of patients treated with opioids do not have a successful outcome due to either excessive side effects and inadequate pain relief or a combination of both.1 All opioids have the potential for side effects (Table 26.1), which may compel some patients to decrease or discontinue opioids. The most common include constipation, nausea, and sedation, while doselimiting side effects typically involve the central nervous system (CNS) and include cognitive impairment, delirium, and myoclonus. In recent years with the increased long-term use of opioids such as in the chronic nonmalignant pain situation, effects of prolonged use on the endocrine, particularly on sex hormones, and the immune system are being increasingly recognized and researched. The clinical importance of these effects for palliative care patients is not yet clear. The concept of individualizing analgesic therapy to the patient’s pain syndrome with close monitoring of treatment outcomes (pain relief, side effects of treatments) and changing clinical circumstances is fundamental to achieving success with pain management. Depending on these assessments, opioids are titrated or switched to another to maintain a favorable balance between efficacy and side effects.1 Further, some opioids may be better suited

than others among vulnerable patients, such as the elderly or terminal cancer patients, who may already have or be at increased risk for impaired renal and hepatic functions. Assessment of hydration status and renal functions plays an important role when using opioids in palliative care patients. Greater compliance is likely if clinicians educate patients/family of anticipated side effects and discuss plans for management. Side effects may be limited by using appropriate opioid doses, coadministration of adjuvant analgesics if indicated, and use of medications to prevent/manage expected side effects.

Opioid-mediated gastrointestinal side effects The etiology of opioid-induced gastrointestinal (GI) effects is multifactorial and predominantly mediated by three opioid receptors, mu-, delta-, and kappa-, which are widely distributed in the myenteric and submucosal neurons throughout the GI tract.2–4 Opioids modify GI function by interacting with these opioid receptors, thereby reducing neuronal excitability and neurotransmitter (acetylcholine) release, with an overall inhibitory effect on motility and secretion.2–6 Major physiological effects include inhibition of gastric emptying and increased gastric acid secretion; delayed colonic transit, increased colonic tone/segmentation, increased colonic absorption, and decreased secretion; increased pyloric and anorectal tone; and increased gall bladder contraction with decreased secretion, and spasm of 235

236 TABLE 26.1  Opioid Side Effects Gastrointestinal • Nausea • Constipation Central nervous system • Sedation • Opioid-induced neurotoxicity • Severe sedation • Delirium • Hallucinations • Myoclonus and seizures • Hyperalgesia and allodynia Cutaneous • Pruritis • Sweating Respiratory/cardiac • Respiratory depression • Non-cardiogenic pulmonary edema Autonomic • Dry mouth • Urinary retention Endocrine • Hypogonadism • Hypopituitarism Immune

sphincter of Oddi. 3,4 The inhibitory effect on colonic secretions also appears to involve complex mechanisms involving 5-HT2 receptors, α2-adrenoreceptors, and noradrenaline release.7 These effects may result in a myriad of GI symptoms that include early satiety, nausea and emesis, abdominal bloating and cramping, and constipation (passage of hard stool, infrequent stool, straining during bowel movement, and incomplete evacuation). In addition, opioid-induced gallbladder effects may result in biliary pain and delayed digestion. This constellation of opioid-induced GI symptoms is referred to as opioid-induced bowel dysfunction, 3 of which constipation is the most frequently reported and distressing symptom in patients taking opioids.8

Textbook of Palliative Medicine and Supportive Care uremia, hypercalcemia), neurological lesions, prolonged immobility, dehydration, or other medications (such as anticholinergics, antacids, or antidepressants). The etiology of constipation in the palliative care setting is discussed in detail in Chapter 59.

Assessment and management of constipation

Assessment should include a history of the frequency and difficulty of defecation and consideration of other possible contributors. Physical examination should include palpation of the abdomen, and a rectal examination may be needed. Occasionally, an abdominal X-ray may be required if the history is unclear.11,12 Constipation-specific instruments that assess the impact and severity of the condition include the Patient Assessment of Constipation Quality of Life (PAC-QOL) and the Patient Assessment of Constipation Symptoms (PAC-SYM) questionnaires. The PAC-QOL and PAC-SYM instruments have been shown to be reliable, valid, and responsive measures of constipation and opioid-induced constipation, respectively,13,14 and predominantly used in research setting. All patients receiving opioids should be counseled about opioid-induced constipation and have an individualized bowel regimen plan in place. This may include a combination of measures, as illustrated in Table 26.2. Therapeutic interventions include the administration of oral laxatives, suppositories, rectal enemas, peripherally restricted opioid receptor antagonists, and manual disimpaction. Oral laxatives include bulk agents, osmotic agents, contact cathartics, lubricants, and prokinetic agents. Lower doses of opioids, or weaker opioids such as codeine, are just as likely to cause constipation, and clinicians should, therefore, base laxative prescribing and titration on bowel function rather than opioid type and dose.15 There is no single correct approach to laxative prescribing in palliative care. Although there are various recommendations in the literature on initiating patients on a bowel regimen, the most important point to remember is that regimens should be individualized and titrated to response. One approach to constipation prevention and management is presented in Table 26.3. While there are no studies revealing the superiority of one approach over the other, the most common treatment, the palliative care setting, is the use of a bowel stimulant such as senna, with or without a stool softener. Additionally, milk of magnesium oral concentrate, polyethylene glycol, or lactulose

Constipation

Constipation is the most common side effect of opioid use9 and should be anticipated, monitored, and treated throughout the duration of opioid therapy. In the noncancer setting, approximately 40% of chronic opioid users for pain management develop constipation.8 This frequency is higher in patients with advanced illness such as cancer, where more than 90% of patients on opioids develop constipation.9,10 Often dismissed as a trivial side effect, constipation can adversely impact patient’s quality of life and make patients avoid or reduce the opioid dose, resulting in decreased analgesic benefits. Untreated and severe constipation can lead to partial or complete bowel obstruction with attendant issues of severe morbidity. Unlike many of the other opioid side effects such as nausea and sedation that may occur on opioid initiation, constipation usually does not improve over time, and the majority of patients will require therapy. Frequently, several other factors predisposing to constipation coexist in palliative care patients, such as autonomic failure, metabolic disorders (such as

TABLE 26.2  Prevention and Management of Opioid-Induced Constipation Nonspecific measures • Maintaining adequate hydration • Maintaining ambulatory status • Diet rich in fruit and vegetables, fiber • Availability of privacy during defecation • Opioid sparing regimens Therapeutic measures • Laxatives: e.g., sennosides, bisacodyl, poly • Rectal suppositories, enemas • Prokinetic agents: e.g., metoclopramide • Peripherally restricted opioid receptor antagonists: e.g., methylnaltrexone (parenteral administration) • Manual disimpaction

Assessment and Management of Opioid Side Effects

237

TABLE 26.3  Suggested Approach for the Prevention and Management of Opioid-Induced Constipation and Nausea Side Effect

Prevention

Constipation

Unless there are existing alterations in bowel patterns such as bowel obstruction or diarrhea, all patients receiving opioids should be started on laxative bowel regimen and receive education for bowel management. 2. Stimulant laxative ± stool softener: e.g.: senna 8.6 plus docusate 50 mg 4. Ensure adequate fluids, dietary fiber and exercise if feasible. 5. Prune juice following by warm beverage may be considered.

Nausea and vomiting

Titrate opioid dose slowly and steadily. Make antiemetics available with opioid prescription. Metoclopramide 10 mg PO For patients at high risk of nausea, consider around the clock regimen for 5 days and then change to PRN.

Management 1. Assess potential cause that can cause constipation (such as recent opioid dose increase, use of other constipating medications, new bowel obstruction) 2. Increase senna and/or docusate tablets and add 1 or both of the following: a. Milk of Magnesia oral concentrate: 10 mL PO every 2–4 times daily b. Polyethylene glycol: 17 g in 8 ou beverage once daily c. Lactulose 15–30 cc every 4–6 hours 3. If no response to above, do digital rectal examination (DRE) to rule out low impaction. Continue above steps AND • If impacted: disimpact manually if stool is soft. If not, soften with mineral oil fleets enema before disimpaction. Follow up with milk of molasses enemas until clear with no formed stools. • Consider use of rescue analgesics before disimpaction. • If not impacted on rectal examination, patient may still have higher level impaction, and if history is appropriate consider abdominal imaging and/or administer milk of molasses enema along with magnesium citrate 8 oz PO. Please note: DRE, manual disimpaction, and enemas may be contraindicated in several circumstances such as the presence of colitis, neutropenia, thrombocytopenia, or coagulopathy. Investigate other causes of nausea (e.g., constipation, bowel obstruction, chemotherapy, or other medications) and treat per guideline.

Initiate around the clock antiemetic regimen. Example Metoclopramide 5–10 mg PO, IV, or subcutaneously around the clock every 4–6 hours. Add or increase non-opioid or adjuvant medications for additional pain relief so that opioid dose can be reduced. If analgesia is satisfactory, reduce opioid dose by 25%. Consider opioid rotation if nausea remains refractory

may be initiated and titrated until a large bowel movement occurs. Bisacodyl suppository, a milk-and-molasses enema, or a fleet enema may be required. Bulk-forming laxatives should be avoided in patients unable to maintain adequate fluid intake. Nondrug approaches, such as increasing fluid intake and increasing physical activity, should be implemented if feasible but are seldom sufficient by itself. Occasionally, it may be required to switch opioids. There is preliminary evidence to suggest that transdermal fentanyl may be less constipating than morphine and oxymorphone.16,17 In a retrospective study of laxative use, laxative doses needed were significantly lower with methadone than with equianalgesic doses of morphine or hydromorphone.18 Tapentadol, a mu-opioid receptor agonist that also inhibits norepinephrine reuptake has been shown to have a more favorable GI side effect profile than oxycodone in several studies.19–21 Two peripherally restricted opioid receptor antagonists, methylnaltrexone and alvimopan, do not cross the blood–brain barrier at therapeutic doses and selectively counteract opioid-inducing constipating effects without reversal of analgesia. Methylnaltrexone, a quaternary ammonium derivative of naltrexone, has been investigated in several clinical studies, including two phase III studies

of patients with advanced illness.22–25 In the study by Thomas et al.,24 133 patients with terminal illness (cancer or other end-stage disease) on opioids for 2 or more weeks with opioid-induced constipation despite the use of laxatives for 3 or more days received methylnaltrexone (at 0.15 mg/kg) or placebo subcutaneously (s.c.) every other day for 2 weeks. Methylnaltrexone was found to be superior (P < .0001) to placebo on the primary outcomes of laxation (defecation) within 4 hours after the first dose (48 vs 16%), and laxation within 4 hours after two or more of the first four doses (52 vs 9%). For those who responded to methylnaltrexone, the median time to laxation was 30 minutes. Methylnaltrexone was well tolerated, with transient abdominal cramping and flatulence being the most common adverse events. Methylnaltrexone for s.c. use has been approved by regulatory agencies in the United States, Canada, and the European Union for the management of opioid-induced constipation in patients with late-stage, advanced illness who are receiving chronic opioid therapy.26 The usual dosing schedule is one dose every other day, as needed, but no more frequently than one dose in a 24-hour period. The recommended dose of methylnaltrexone is 8 mg for patients weighing 38–62 kg or 12 mg for patients weighing 62–114 kg. Patients whose weight falls outside of these ranges should be dosed at 0.15 mg/kg.

Textbook of Palliative Medicine and Supportive Care

238 Alvimopan is an orally administered peripherally restricted mu-opioid receptor antagonist approved for short-term use in hospitalized patients for the management of postoperative ileus in patients undergoing bowel resection. It is not approved for the management of opioid-induced constipation. While several studies in chronic noncancer pain patients have suggested benefit, 27,28 a recent double-blind, placebo-controlled trial conducted over 12 weeks in 485 patients with noncancer pain found no statistically significant difference in the proportion of patients with spontaneous bowel movements (primary outcome) between the three groups: alvimopan 0.5 mg once daily (63%), alvimopan 0.5 mg twice daily (63%), or placebo (56%, P > .05). 29 Naloxone, a peripherally acting opioid antagonist with low systemic bioavailability (1

70%

Intranasal Intranasal fentanyl spray—INFS Fentanyl pectin nasal spray—FPNS

5

>1

90%

10

>1

65%

Formulation

Note:

Bioavailability (approximate)

Notes

Overall bioavailability: 50% (25% from rapid oromucosal absorption + 25% from slower gastrointestinal absorption, after swallowing remaining dose) 65%

Consumed slowly over 15 minutes by rubbing compressed sweetened lozenge (which is attached to a plastic applicator) across the oral, particularly buccal, mucosa Enhanced buccal delivery of fentanyl: Drug delivery system utilizes effervescence to cause pH shifts Small bioerodible polymer film with the fentanyl-containing layer, which adheres to patient’s cheek, separated from saliva by an outer layer Tablet rapidly breaks down with a bioadhesive component enabling carrier particles to adhere to the sublingual mucosa Aqueous solution; multidose device nasal spray Aqueous nasal spray that forms a gel on contact with nasal mucosa—this attenuates the peak plasma concentration

Earliest statistically significant onset from fentanyl products and placebo studies. Clinically meaningful onset usually takes longer. For further details, see individual product monographs.

Other routes

The use of nebulized fentanyl has been reported in a small case series,70 but more evidence is needed to support its use in clinical practice.

Other drugs used for breakthrough pain

Intermittent subcutaneous midazolam has been used for the temporary sedation of patients with pathological hip fractures and severe BTP.71 Subanesthetic ketamine, in a subcutaneous bolus dose of 20–40 mg, may be used before predictable movementrelated BTP, such as difficult dressing changes or repositioning of a patient with a fractured long bone. It may be combined with a bolus injection of midazolam.72 The sublingual and intranasal routes of ketamine have also been utilized in the management of BTP, as has nitrous oxide.73–75

Nonpharmacological approaches

Psychosocial interventions are a fundamental component of a multimodal approach to the management of cancer pain.76 Patients frequently use nonpharmacological strategies to relieve BTP, including repositioning, rest and sleep, movement and exercise, heat or cold, rubbing and massage, relaxation, visualization, and distraction.12,19,25 Transcutaneous electrical nerve stimulation has been utilized.77 Referral to physiotherapy and occupational therapy is beneficial for patients with movementrelated BTP. Orthotic devices, bracing, or aids may be necessary, in addition to lifestyle modification. Acupuncture may

have a potential adjunctive role in the management of BTP, but more research is needed.78

Interventional approaches

For patients with resistant BTP, anesthetic or neurosurgical intervention may be required. Techniques used include peripheral nerve or neurolytic blocks, spinal (intrathecal or epidural) analgesia, and percutaneous or open cordotomy.79,80

Future directions For cancer-related BTP, an internationally agreed upon definition and simple classification system is still needed for consistency in characterization. BTP has been identified as a key variable to be included in a future standardized classification system for cancer pain. 81 Standardization of the BTP phenomenon will help further high-quality research and evidence-based clinical practice. A validated screening tool and practical BTP assessment instrument should be used in daily clinical practice to characterize and measure pain intensity over short periods of time, in addition to detailing the impact on patients. Double-blind RCTs comparing different transmucosal products are warranted. Future studies should investigate the appropriate dosing and titration techniques for “rescue” analgesia and examine the most appropriate management of different BTP mechanisms.

Breakthrough (Episodic) Pain in Cancer Patients KEY LEARNING POINTS • BTP is common and challenges the WHO “ladder” for pain management. • Current terminology and definitions are confusing. • BTP is typically characterized by both rapid onset and brief duration. • Thorough assessment of both breakthrough and baseline pains is vital. • ATC analgesia for baseline pain must first be optimized. • The parenteral and transmucosal routes are efficacious for “rescue” analgesia, for medications with appropriate pharmacodynamic properties. • BTP management should be individualized and requires both pharmacological and nonpharmacological therapeutic strategies, as well as a comprehensive multidisciplinary and interprofessional approach.

Conclusion Breakthrough (episodic) pain is a common heterogeneous phenomenon in cancer patients which is often undertreated. Comprehensive patient assessment and optimization of the control of baseline cancer pain are essential. The choice of medication for BTP episodes needs to be appropriate for the postulated BTP mechanism and characteristics of the individual’s BTP (frequency, speed of onset, duration, etc.) and also guided by patient preference and medication availability. Nonpharmacological strategies are a fundamental component of management, as are the provisions of support and education to the patient. More research is needed in order to inform multidisciplinary clinical guidelines to improve the management of BTP in cancer patients.

References







1. Bruera E, MacMillan K, Hanson J, MacDonald RN. The Edmonton staging system for cancer pain: preliminary report. Pain 1989;37:203–209. 2. Nekolaichuk CL, Fainsinger RL, Lawlor PG. A validation study of a pain classification system for advanced cancer patients using content experts: The Edmonton Classification System for Cancer Pain. Palliat Med 2005;19:466–476. 3. Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain 1990;41:273–281. 4. Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteristics and impact in patients with cancer pain. Pain 1999;81:129–134. 5. Davies AN, Dickman A, Reid C, et al. The management of cancerrelated breakthrough pain: recommendations of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland. Eur J Pain 2009;13:331–338. 6. Hagen NA, Stiles C, Nekolaichuk C, et al. The Alberta Breakthrough Pain Assessment Tool for cancer patients: a validation study using a Delphi process and patient think-aloud interviews. J Pain Symptom Manage 2008;35:136–152. 7. Haugen DF, Hjermstad MJ, Hagen N, et al. Assessment and classification of cancer breakthrough pain: a systematic literature review. Pain 2010;149:476–482. 8. Caraceni A, Weinstein SM. Classification of cancer pain syndromes. Oncology 2001;15:1627–1640. 9. Portenoy RK. Treatment of temporal variations in chronic cancer pain. Semin Oncol 1997;24:S16-7–16-12. 10. McQuay HJ, Jadad AR. Incident pain. Cancer Surveys 1994;21:17–24.

329 11. Banning A, Sjogren P, Henriksen H. Treatment outcome in a multidisciplinary cancer pain clinic. Pain 1991;47:129–134. 12. Petzke F, Radbruch L, Zech D, et al. Temporal presentation of chronic cancer pain: transitory pains on admission to a multidisciplinary pain clinic. J Pain Symptom Manage 1999;17:391–401. 13. Caraceni A, Portenoy RK. An international survey of cancer pain characteristics and syndromes. IASP Task Force on Cancer Pain. International Association for the Study of Pain. Pain 1999;82:263–274. 14. Mercadante S, Radbruch L, Caraceni A, et al. Episodic (breakthrough) pain: consensus conference of an expert working group of the European Association for Palliative Care. Cancer 2002;94:832–839. 15. Ashby MA, Fleming BG, Brooksbank M, et al. Description of a mechanistic approach to pain management in advanced cancer. Preliminary report. Pain 1992;51:153–161. 16. Bruera E, Fainsinger R, MacEachern T, Hanson J. The use of methylphenidate in patients with incident cancer pain receiving regular opiates. A preliminary report. Pain 1992;50:75–77. 17. Fine PG, Busch MA. Characterization of breakthrough pain by hospice patients and their caregivers. J Pain Symptom Manage 1998;16:179–183. 18. Zeppetella G, O’Doherty CA, Collins S. Prevalence and characteristics of breakthrough pain in cancer patients admitted to a hospice. J Pain Symptom Manage 2000;20:87–92. 19. Swanwick M, Haworth M, Lennard RF. The prevalence of episodic pain in cancer: a survey of hospice patients on admission. Palliat Med 2001;15:9–18. 20. Gómez-Batiste X, Madrid F, Moreno F, et al. Breakthrough cancer pain: prevalence and characteristics in patients in Catalonia, Spain. J Pain Symptom Manage 2002;24:45–52. 21. Hwang SS, Chang VT, Kasimis B. Cancer breakthrough pain characteristics and responses to treatment at a VA medical center. Pain 2003;101:55–64. 22. Greco MT, Corli O, Montanari M, et al. Epidemiology and pattern of care of breakthrough cancer pain in a longitudinal sample of cancer patients: results from the Cancer Pain Outcome Research Study Group. Clin J Pain 2011;27:9–18. 23. Caraceni A, Martini C, Zecca E, et al. Breakthrough pain characteristics and syndromes in patients with cancer pain. An international survey. Palliat Med 2004;18:177–183. 24. Zeppetella G. Opioids for cancer breakthrough pain: a pilot study reporting patient assessment of time to meaningful pain relief. J Pain Symptom Manage 2008;35:563–567. 25. Davies A, Zeppetella G, Andersen S, et al. Multi-centre European study of breakthrough cancer pain: pain characteristics and patient perceptions of current and potential management strategies. Eur J Pain 2011;15:756–763. 26. Mercadante S, Maddaloni S, Roccella S, Salvaggio L. Predictive factors in advanced cancer pain treated only by analgesics. Pain 1992;50:151–155. 27. Fainsinger RL, Nekolaichuk C, Lawlor P, et al. An international multicentre validation study of a pain classification system for cancer patients. Eur J Cancer 2010;46:2896–2904. 28. Webber K, Davies AN, Cowie MR. Breakthrough pain: a qualitative study involving patients with advanced cancer. Support Care Cancer 2011;19:2041–2046. 29. Fortner BV, Okon TA, Portenoy RK. A survey of pain-related hospitalizations, emergency department visits, and physician office visits reported by cancer patients with and without history of breakthrough pain. J Pain 2002;3:38–44. 30. Breivik H, Cherny N, Collett B, et al. Cancer-related pain: a pan-European survey of prevalence, treatment, and patient attitudes. Ann Oncol 2009;20:1420–1433. 31. Rustøen T, Geerling JI, Pappa T, et al. A European survey of oncology nurse breakthrough cancer pain practices. Eur J Oncol Nurs 2013;17:95–100. 32. Soden K, Ali S, Alloway L, et al. How do nurses assess and manage breakthrough pain in specialist palliative care inpatient units? A multicentre study. Palliat Med 2010;24:294–298. 33. Sze WM, Shelley M, Held I, Mason M. Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy. Cochrane Database Syst Rev 2002;(1):CD004721. doi:10.1002/14651858. CD004721. 34. Roqué i Figuls M, Martinez-Zapata MJ, Scott-Brown M, Alonso-Coello P. Radioisotopes for metastatic bone pain. Cochrane Database Syst Rev 2011;(7):CD003347. doi:10.1002/14651858. CD003347.pub2.

Textbook of Palliative Medicine and Supportive Care

330 35. Wong RKS, Wiffen PJ. Bisphosphonates for the relief of pain secondary to bone metastases. Cochrane Database Syst Rev 2002;(2):CD002068. doi:10.1002/14651858.CD002068. 36. Body JJ. Bisphosphonates for malignancy-related bone disease: current status, future developments. Support Care Cancer 2006;14:408–418. 37. Cheung G, Chow E, Holden L, et al. Percutaneous vertebroplasty in patients with intractable pain from osteoporotic or metastatic fractures: a prospective study using quality-of-life assessment. Can Assoc Radiol J 2006;57:13–21. 38. Jackson K, Ashby M, Martin P, et al. “Burst “ketamine for refractory cancer pain: an open-label audit of 39 patients. J Pain Symptom Manage 2001;22:834–842. 39. Caraceni A, Hanks G, Kaasa S, et al. Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol 2012;13:e58–e68. 40. Davies AN, Vriens J, Kennett A, McTaggart M. An observational study of oncology patients’ utilization of breakthrough pain medication. J Pain Symptom Manage 2008;35:406–411. 41. Hanks GW, Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 2001;84:587–593. 42. Coluzzi PH, Schwartzberg L, Conroy JD, et al. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain 2001;91:123–130. 43. Freye E, Levy JV, Braun D. Effervescent morphine results in faster relief of breakthrough pain in patients compared to immediate release morphine sulfate tablet. Pain Pract 2007;7:324–331. 44. Collins SL, Faura CC, Moore RA, McQuay HJ. Peak plasma concentrations after oral morphine: a systematic review. J Pain Symptom Manage 1998;16:388–402. 45. Levy MH. Pharmacologic treatment of cancer pain. N Engl J Med 1996;335:1124–1132. 46. Enting RH, Mucchiano C, Oldenmenger WH, et al. The “pain pen” for breakthrough cancer pain: a promising treatment. J Pain Symptom Manage 2005;29:213–217. 47. Mercadante S, Villari P, Ferrera P, et al. Safety and effectiveness of intravenous morphine for episodic (breakthrough) pain using a fixed ratio with the oral daily morphine dose. J Pain Symptom Manage 2004;27:352–359. 48. Zeppetella G. Opioids for the management of breakthrough cancer pain in adults: a systematic review undertaken as part of an EPCRC opioid guidelines project. Palliat Med 2011;25:516–524. 49. Swanson G, Smith J, Bulich R, et al. Patient-controlled analgesia for chronic cancer pain in the ambulatory setting: a report of 117 patients. J Clin Oncol 1989;7:1903–1908. 50. Dale O, Hjortkjaer R, Kharasch ED. Nasal administration of opioids for pain management in adults. Acta Anaesthesiol Scand 2002;46:759–770. 51. Zhang H, Zhang J, Streisand JB. Oral mucosal drug delivery: clinical pharmacokinetics and therapeutic applications. Clin Pharmacokinet 2002;41:661–680. 52. Grassin-Delyle S, Buenestado A, Naline E, et al. Intranasal drug delivery: an efficient and non-invasive route for systemic administration: Focus on opioids. Pharmacol Ther 2012;134:366–379. 53. Twycross R, Prommer EE, Mihalyo M, Wilcock A. Fentanyl (transmucosal). J Pain Symptom Manage 2012;44:131–149. 54. Hagen NA, Fisher K, Stiles C. Sublingual methadone for the management of cancer-related breakthrough pain: a pilot study. J Palliat Med 2007;10:331–337. 55. Coluzzi PH. Sublingual morphine: efficacy reviewed. J Pain Symptom Manage 1998;16:184–192. 56. Zeppetella G. Sublingual fentanyl citrate for cancer-related breakthrough pain: a pilot study. Palliat Med 2001;15:323–328. 57. Gardner-Nix J. Oral transmucosal fentanyl and sufentanil for incident pain. J Pain Symptom Manage 2001;22:627–630. 58. Duncan A. The use of fentanyl and alfentanil sprays for episodic pain. Palliat Med 2002;16:550. 59. Zeppetella G. An assessment of the safety, efficacy, and acceptability of intranasal fentanyl citrate in the management of cancer-related breakthrough pain: a pilot study. J Pain Symptom Manage 2000;20:253–258. 60. Good P, Jackson K, Brumley D, Ashby M. Intranasal sufentanil for cancer-associated breakthrough pain. Palliat Med 2009;23:54–58. 61. Pavis H, Wilcock A, Edgecombe J, et al. Pilot study of nasal morphinechitosan for the relief of breakthrough pain in patients with cancer. J Pain Symptom Manage 2002;24:598–602.

62. Smith H. A comprehensive review of rapid-onset opioids for break through pain. CNS Drugs 2012;26:509–535. 63. Farrar JT, Cleary J, Rauck R, et al. Oral transmucosal fentanyl citrate: randomized, double-blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients. J Natl Cancer Inst 1998;15:611–616. 64. Portenoy RK, Payne R, Coluzzi P, et al. Oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough pain in cancer patients: A controlled dose titration study. Pain 1999;79:303–312. 65. Hagen NA, Fisher K, Victorino C, Farrar JT. A titration strategy is needed to manage breakthrough cancer pain effectively: observations from data pooled from three clinical trials. J Palliat Med 2007;10:47–55. 66. Mercadante S, Porzio G, Aielli F, et al. The use of fentanyl buccal tablets for breakthrough pain by using doses proportional to opioid basal regimen in a home care setting. Support Care Cancer 2013:21(8):2335–2339. 67. Mercadante S, Adile C, Masedu F, et al. Factors influencing the use of opioids for breakthrough cancer pain: a secondary analysis of the IOPS-MS study. Eur J Pain 2019;23(4):719–726. 68. Passik SD, Messina J, Golsorkhi A, Xie F. Aberrant drug-related behavior observed during clinical studies involving patients taking chronic opioid therapy for persistent pain and fentanyl buccal tablet for breakthrough pain. J Pain Symptom Manage 2011;41:116–125. 69. Rollman JE, Heyward J, Olson L, et al. Assessment of the FDA Risk Evaluation and Mitigation Strategy for transmucosal immediaterelease fentanyl products. JAMA 2019;321(7):676–685. 70. Zeppetella G. Nebulized and intranasal fentanyl in the management of cancer-related breakthrough pain. Palliat Med 2000;14:57–58. 71. del Rosario MA, Martín AS, Ortega JJ, Feria M. Temporary sedation with midazolam for control of severe incident pain. J Pain Symptom Manage 2001;21:439–442. 72. Kotlińska-Lemieszek A, Luczak J. Subanesthetic ketamine: An essential adjuvant for intractable cancer pain. J Pain Symptom Manage 2004;28:100–102. 73. Mercadante S, Arcuri E, Ferrera P, et al. Alternative treatments of breakthrough pain in patients receiving spinal analgesics for cancer pain. J Pain Symptom Manage 2005;30:485–491. 74. Carr DB, Goudas LC, Denman WT, et al. Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study. Pain 2004;108:17–27. 75. Parlow JL, Milne B, Tod DA, et al. Self-administered nitrous oxide for the management of incident pain in terminally ill patients: a blinded case series. Palliat Med 2005;19:3–8. 76. Sheinfeld Gorin S, Krebs P, Badr H, et al. Meta-analysis of psychosocial interventions to reduce pain in patients with cancer. J Clin Oncol 2012;30:539–547. 77. Bennett MI, Johnson MI, Brown SR, et al. Feasibility study of transcutaneous electrical nerve stimulation (TENS) for cancer bone pain. J Pain 2010;11:351–359. 78. Paley CA, Johnson MI, Bennett MI. Acupuncture: a treatment for breakthrough pain in cancer? BMJ Support Palliat Care 2011;1:335–338. 79. Brogan SE, Winter NB. Patient-controlled intrathecal analgesia for the management of breakthrough cancer pain: a retrospective review and commentary. Pain Med 2011;12:1758–1768. 80. Bhaskar AK. Interventional management of cancer pain. Curr Opin Support Palliat Care 2012;6:1–9. 81. Knudsen AK, Brunelli C, Kaasa S, et al. Which variables are associated with pain intensity and treatment response in advanced cancer patients? Implications for a future classification system for cancer pain. Eur J Pain 2011;15:320–327. 82. Zeppetella G. Breakthrough pain in cancer patients. Clin Oncol 2011;23:393–398. 83. Rauck R, Reynolds L, Geach J, et al. Efficacy and safety of fentanyl sublingual spray for the treatment of breakthrough cancer pain: a randomized, double-blind, placebo-controlled study. Curr Med Res Opin 2012;28:859–870.

BTP chapter: NEW References for 2019 edition

A. Løhre ET, Klepstad P, Bennett MI, et al. From “breakthrough” to “episodic” cancer pain? A European Association for Palliative Care Research Network Expert Delphi survey toward a common

Breakthrough (Episodic) Pain in Cancer Patients



terminology and classification of transient cancer pain exacerbations. J. Pain Symptom Manage 2016;51(6):1013–1019. B. Deandrea S, Corli O, Consonni D, et al. Prevalence of breakthrough cancer pain: a systematic review and a pooled analysis of published literature. J Pain Symptom Manage 2014;47(1):57–76. C. Davies A, Buchanan A, Zeppetella G, et al. Breakthrough cancer pain: an observational study of 1000 European oncology patients. J Pain Symptom Manage 2013;46(5):619–628. D. Sperlinga R, Campagna S, Berruti A, et al. Alberta Breakthrough Pain Assessment Tool: a validation multicentre study in cancer patients with breakthrough pain. Eur J Pain 2015;19(7):881–888. E. Webber K, Davies AN, Zeppetella G, et al. Development and validation of the breakthrough pain assessment tool (BAT) in cancer patients. J Pain Symptom Manage 2014;48(4):619–631.

331

F. Azhar A, Kim YJ, Haider A, et al. Response to oral immediate-release opioids for breakthrough pain in patients with advanced cancer with adequately controlled background pain. Oncologist 2019;24(1):125–131. G. Fallon M, Giusti R, Aielli F, et al. Management of cancer pain in adult patients: ESMO Clinical Practice Guidelines. Ann Oncol 2018;29(Suppl 4):iv166–iv191. H. Alarcón MDL, Estévez FV, Cabezón-Gutiérrez L, et al. Expert consensus on the management of breakthrough cancer pain in older patients. A Delphi study. J Geriatr Oncol 2019;10(4):643–652. I. Mercadante S. Treating breakthrough pain in oncology. Expert Rev Anticancer Ther 2018;18(5):445–449.

35

SOMATIC SYMPTOMS, SYMPTOM CLUSTERS, AND SYMPTOM BURDEN

David V. Nelson and Diane M. Novy

Contents Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������333 Symptom burden���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������333 Diagnosing somatic symptoms��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������334 Theories of pain perception��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������334 Treatment recommendations�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������335 Summary�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������335 References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������335

Introduction Somatic symptoms such as pain, fatigue, nausea, headache, dizziness, and insomnia are common complaints among people seen in palliative care settings.1–3 Although symptoms such as these are often described as “somatic” in nature, care must be taken to avoid any of the pejorative connotations often associated with the term somatization, which imply a strong potential psychogenic etiology that undermines the validity of patients’ reports.4 Rather, it is common for patients in medical settings, including pain centers and palliative care settings to endorse somatic symptoms as well as some emotional, cognitive, and behavioral symptoms. Among palliative care patients, in particular, these clusters of symptoms may be part of the complex burden related to aspects of illness, side effects of medical treatment, or psychological suffering.

Symptom burden Patients receiving palliative care typically have a high symptom burden, with a median of 14 symptoms occurring simultaneously.5,6 Fatigue is one of the most commonly reported symptoms in palliative care patients.7 In a palliative care setting, fatigue was reported by 84% of cancer patients and in up to 99% of patients following radio- or chemotherapy.7 Many factors potentially influence fatigue in cancer patients, including aspects of the disease, the cancer treatment, and a psychological component of suffering.8 Similarly, large percentages of non-cancer patients (e.g., HIV, multiple sclerosis, chronic obstructive pulmonary disease, heart failure) also report fatigue.1,7,9 This highlights the problems with classifying symptoms such as fatigue as “somatic” in medical populations, where patients often have complex symptom profiles and a high symptom burden. Empirical evidence supports a relation among symptoms such as pain, fatigue, nausea, sleep disturbance, and negative mood states such as depression and anxiety in many medical settings.10,11 Symptoms often occur in clusters that may interact and that may share overlapping mechanisms and treatment approaches.12 In palliative care settings, depression and anxiety have consistently been found to relate to greater reporting of medical symptoms.13,14 For example, research has found that about one in four patients with advanced cancer receiving palliative

care experienced depression; and depression symptoms were associated with greater symptoms of fatigue and pain.15 Among patients with chronic cancer pain, anxiety and depression have been shown to be higher than among those who are not being treated for cancer-related pain.16,17 In other research on cancer patients with and without pain, hostility, anxiety, and depression were found to be more common among those who were experiencing pain. Moreover, among patients with advanced cancer, negative mood states were found to be associated with greater fatigue, drowsiness, and pain and lower quality of life.13 The relation between pain and negative mood states has also been demonstrated in patients with chronic non-cancer pain. For example, patients with chronic non-cancer pain had T-score means approximately one standard deviation above the community norms for anxiety and depression.18 Strong positive relations were also found between somatic symptoms and negative mood states among patients with non-cancer pain.16,17 Consistently, in literature reviews of studies examining symptom reporting among patients with chronic pain, greater depression and somatic symptoms were found in chronic pain patients, compared to patients without pain.19,20 Patients with chronic medical illness and comorbid depression have been found to report a significantly higher number of somatic symptoms than those with a chronic medical illness but no depression, even when controlling for the severity of the medical illness.21 Thus, the relation between negative mood and physical symptoms is supported by research findings with a wide variety of patients across various treatment settings. The commonly observed associations between mood, pain, and other somatic symptoms highlight the difficulty, if not futility, in attempting to separate these symptoms into “real” body symptoms and psychological symptoms. Moreover, this research highlights the problematic nature of the “somatic” label, as symptoms such as headache, nausea, and fatigue have multiple and complex causes and may not fit a traditional definition of somatization, especially in palliative care populations. Indeed, studies of somatization per se often operationalize somatization simply as a count of somatic symptoms endorsed, with the presumption that somatic symptoms reflect the expression or communication of emotional distress or other psychological factors.22,23 This presumption ignores the bidirectional influences of somatic and psychosocial processes and the possibility of shared underlying mechanisms in symptom clusters.12 333

Textbook of Palliative Medicine and Supportive Care

334

Diagnosing somatic symptoms Past editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM) specified diagnostic criteria for somatization (somatoform) disorders as being largely focused on medically unexplained or accounted for symptoms. The distinction between medically explained and unexplained symptoms can be problematic, and physicians have acknowledged that many patientreported somatic symptoms cannot easily be classified as either medically explainable or unexplainable.16,17 Prevalence rates for medically unexplained symptoms in pain populations vary widely, with estimates ranging from 0 to 80%.16,17,24,25 Not only are there problems with grounding a diagnosis on limited reliability and high variability, but also such a perspective reinforces mind– body dualism that is not useful. Furthermore, somatization disorders were associated with a pejorative characterization. Currently, the DSM-526 has shifted away from giving a mental disorder diagnosis solely because a medical cause cannot be demonstrated. In the DSM-5, there is a new category of disorders called somatic symptom and related disorders, and somatization is not included as a possible diagnosis. The major diagnosis in this category is somatic symptom disorder. This diagnosis is made on the basis of physical symptoms and signs (e.g., pain, fatigue, nausea, headache, dizziness, insomnia), emotional suffering (mostly anxiety and worry), troubling cognition (thoughts about the seriousness of possible causes of somatic symptom), and abnormal behaviors (possible repeated bodily checking and seeking medical assistance and reassurance). There is a recognition that genetic and biological vulnerability, early traumatic experiences, learning, and cultural and social norms contribute to the disorders in this category. Individual differences in symptom presentation are likely the result of the interactive factors of a complex biopsychosocial context. There are five other diagnoses in the DSM-5 somatic symptom category that appreciate a conceptualization of physical and psychological symptoms as interacting processes. The first of these is illness anxiety disorder that focuses on the preoccupation with and anxiety about having an illness or somatic symptom. In the disorder of psychological factors affecting other medical conditions, the diagnostic criteria include psychological or behavioral factors that adversely affect the development, exacerbation, or treatment of a medical condition. Factitious disorder is quite different in that there is falsification of physical or psychological symptoms in the absence of obvious external rewards. Two diagnoses, other specified somatic symptom and related disorder and unspecified somatic symptom and related disorder, are used when full criteria of the more defined diagnoses are not met. There are two diagnoses in the DSM-5 somatic symptom category in which medically unexplained symptoms remain a key feature. These include conversion disorder (having one or more symptoms of altered voluntary motor or sensory function incompatible with neurological or medical conditions) and pseudocyesis. In both of those diagnoses, it is possible to demonstrate that the symptoms are not consistent with medical pathophysiology.27,28

Theories of pain perception All patients experience illness, pain, and other somatic symptoms differently. The overall suffering and discomfort experienced by each patient will depend on multiple factors. These include aspects of the disease and treatment, how the patient interprets and experiences illness, pain, other somatic symptoms, and

social support available to them, as well as their level of psychological distress, depression, and anxiety, and ability to cope with previous life difficulties. Thus, multiple and complex factors are involved in the experience of pain and other somatic symptoms. Regarding pain, theories of pain provide some insight into the potential mechanisms involved in pain perception. One such theory proposes that a sensitizing effect on physiological events in some patients may heighten bodily awareness and increase pain.29 The support for this theory can be found in research on patients with chronic pain conditions such as fibromyalgia which has found that these patients have increased responsiveness and sensitivity to various sensory stimulation, including pain, auditory tones, and tactile stimuli. 30 A similar perspective presents a neurobiological model of pain in which a patient’s tendency to focus on bodily symptoms activates pain facilitation neurons. 31 The activation of these neurons is believed to sharpen the perception of the painful stimulus. Consistent with this theory, some people attend to and focus on pain and pain-related stimuli to a greater degree, a practice that has been found to be related to greater pain reporting. 32 A third perspective draws from cognitive–behavioral theories of pain. 33 Cognitive–behavioral perspectives propose that pain can be examined on three dimensions: (1) an affective dimension that describes pain-related affect (depression, anxiety, and anger), (2) a behavioral dimension that includes maladaptive behaviors related to pain (inactivity, avoiding others), and (3) a cognitive dimension that includes maladaptive beliefs and thoughts about pain (e.g., belief that one cannot function when in pain). These various dimensions all influence a person’s overall experience of pain. Moreover, this model supports bidirectional relations between dimensions. As an illustration, negative mood can lead to changes in pain behaviors, such as inactivity, thus leading to deconditioning in some patients and increasing the body’s vulnerability to illness and injury. 34 Negative mood state may also affect the interpretation of physical changes, such that the body’s cues and signals (e.g., heart palpitations, shortness of breath) are inaccurately interpreted as more enduring symptoms or conditions. 35 Additionally, pain can also influence mood states. For example, the way in which a person interprets their chronic pain condition (e.g., the degree to which they believe the pain will interfere in their life) can influence the later development of depression symptoms. 36 Other so-called somatic symptoms reflect the complex interactions of physiology and emotional, cognitive, and behavioral processes. The phenomena associated with breathlessness provide another example of the multifactorial nature of such symptoms.5 Chronic or refractory breathlessness is commonly associated with various advanced diseases (e.g., advanced cancer, COPD) and is periodically complicated by episodes of severe worsening. While incompletely understood, it appears that impaired respiratory mechanics interact with neural networks involving emotional and sensory perception of breathlessness, as well as neurological circuits involved in threat perception and fear conditioning and other potential environmental, psychiatric, mood, and personality contributions. 37 Lastly, cultural, social, and institutional factors that emphasize physical symptoms rather than psychological factors may also contribute to a heightened focus on physical symptoms. 38 Research has found that some patients with chronic pain report certain experiences, such as affective distress, as pain. 38 Additionally, qualitative examination of patient’s and provider’s beliefs suggests that cultural factors can influence how physicians

Somatic Symptoms, Symptom Clusters, and Symptom Burden respond to patients’ problems, the relationship between healthcare providers and patients, and how patients respond to illness, including the reporting of pain and psychological symptoms. 38 Many of these principles also apply more broadly to more complex symptom clusters, although there are controversies and other competing models guiding current research is this area.12

KEY LEARNING POINTS • Due to its often pejorative connotations, somatization is not a useful diagnosis and it does not adequately reflect the complexity of multiple contributing factors inherent in so-called somatic symptoms. • The distinction between medically explained and unexplained symptoms is not required for most diagnoses in the DSM-5. • Unexplained symptoms do not necessarily indicate a psychiatric diagnosis. • Chronic pain patients and large percentages of other patients with chronic illnesses consistently report more symptoms, including fatigue and sleep difficulties. • Negative mood is associated with greater pain and physical complaints among patients with both chronic non-cancer and cancer pain. • Multidisciplinary approaches to symptom management are more effective than other forms of treatment for chronic pain and complex symptom clusters.

Treatment recommendations The discussion presented in this chapter highlights the multifaceted and interrelated nature of pain and other physical and psychological complaints. It is important to recognize that in palliative care, symptoms such as pain, nausea, and fatigue will likely reflect aspects of the chronic medical condition or its treatment. Additionally, each patient will experience pain and other bothersome somatic symptoms differently. The overall suffering and discomfort experienced by each patient will depend on multiple factors such as how the patient interprets and experiences illness, pain, and other somatic symptoms; the social support available to them; and their level of psychological distress, depression, and anxiety. Given the high co-occurrence of psychological symptoms with physical complaints and research findings presenting evidence for the interactive nature of these symptoms, the use of a multidisciplinary treatment approach is recommended. In the treatment of pain, multidisciplinary teams often include professionals from pain medicine, palliative care, psychology, social work, and nursing. Treatment models in which these disciplines are integrated fully into the treatment team for pain or more complex symptom clusters are ideal, but utilizing these services on a consulting basis may be necessary in some settings due to financial, geographic, or institutional constraints. Multidisciplinary approaches to pain management have consistently been found to be more effective than other forms of treatment for chronic pain.39 Additionally, research demonstrates that incorporating routine screening for psychological distress in cancer pain patients leads to improved detection of psychological symptoms and more appropriate referrals to specialized services.16,40 Current recommendations for assessment and treatment of broader symptom clusters also focus on multidisciplinary approaches.41,42 A multidisciplinary approach to management may help one to address potential difficulties that can occur when treating some patients presenting with somatic complaints—when appropriate, involve other services, including psychology and social work, in the patient’s treatment. We also recommend using caution in assigning a somatoform disorder or other psychiatric diagnoses, as these labels may invalidate patients’ physical symptoms or unfairly alter the perception of the patient held by other

BOX 35.1  MANAGEMENT GUIDELINES FOR SOMATIC SYMPTOMS • Utilize a multidisciplinary team approach. • Rule out and/or treat diagnosable medical disease. • Assess for psychological distress. • Consider the cultural and social context. • Build a collaborative relationship with the patient. • Provide a caring physician attitude. • Make appropriate referrals to specialized services.

335

providers. Moreover, as demonstrated in this article, diagnosis of somatization disorders is unreliable and can be complicated in patients with chronic medical conditions. Symptom management guidelines, based in part on suggestions presented by Barsky and Borus43 and Purcell,44 are presented in Box 35.1.

Summary In summary, somatic symptoms such as pain, fatigue, nausea, headache, dizziness, and insomnia are common complaints among people with medical conditions, and they often occur in clusters. Among palliative care patients, these symptoms may be related to aspects of the illness, side effects of medical treatment, or psychological suffering. The new category of somatic symptom disorder and related disorders of the DSM-5 reflects an appreciation for the close relation between psychological and physical symptoms and the inherent difficulty with past editions that classified symptoms as “medically unexplained.” This current appreciation is especially appropriate for palliative care patients who commonly have a complex symptom profile and high symptom burden. Negative mood is associated with greater pain and greater symptom reporting among patients with both chronic non-cancer and cancer pain. Theories of pain perception offer insights into the relation between mood, somatic symptoms, and pain, which suggest that these symptoms are interactive, rather than distinct, independent symptoms. This conceptualization of pain and related symptoms clusters supports a multidisciplinary treatment approach where psychological treatment and other specialized services are integrated at all stages of care.

References

1. Solano J, Gomes B, Higginson I. A comparison of symptom prevalence in far advance cancer, AIDS, heart disease, chronic obstructive pulmonary disease, and renal disease. J Pain Symptom Manage 2006;31(1):58–69.

336











2. Teunissen S, Wesker W, Kruitwagen C, de Haes H, Voest E, de Graef A. Symptom prevalence in patients with incurable cancer: a systematic review. J Pain Symptom Manage 2007;34(1):94–104. 3. Wilkie D, Ezenwa M. Pain and symptom management in palliative care and at end of life. Nursing Outlook 2012;60(6):357–364. 4. Creed F, Henningsen P, Fink P, eds. Medically Unexplained Symptoms, Somatisation and Bodily Distress: Developing Better Clinical Services New York, NY: Cambridge University Press, 2011. 5. Bausewein C, Booth S, Gysels M, Kühnbach R, Haberland B, Higginson IJ. Understanding breathlessness: cross-sectional comparison of symptom burden and palliative care needs in chronic obstructive pulmonary disease and cancer. J Palliat Med 2010;13(9):1109–1118. 6. Cleeland C. Symptom burden: multiple symptoms and their impact as patient-reported outcomes. J Natl Cancer Inst Monogr 2007;37:16–21. 7. Radbruch L, Strasser F, Elsner F, Goncalves J, Loge J, Kaasa S, Research Steering Committee of the European Association for Palliative Care (EAPC). Fatigue in palliative care patients-an EAPC approach. Palliat Med 2008;22(1):13–32. 8. Strasser F, Walker P, Bruera E. When both pain and suffering hurt. J Palliat Care 2005;21(2):69–79. 9. Moens K, Higginson IJ, Harding R, EURO IMPACT. Are there differences in the prevalence of palliative care-related problems in people living with advanced cancer and eight non-cancer conditions? A systematic review. J Pain Symptom Manage 2014;48(4):660–677. 10. Cooley M, Siefert M. Assessment of multiple co-occurring cancer symptoms in the clinical setting. Semin Oncol Nurs 2016;32(4):361–372. 11. Kroenke K, Zhong X, Theobald D, Wu J, Tu W, Carpenter J. Somatic symptoms in patients with cancer experiencing pain or depression: prevalence, disability, and health care use. Arch Intern Med 2010;170(18):1686–1694. 12. Barsevick A. Defining the symptom cluster: how far have we come? Semin Oncol Nurs 2016;32(4):334–350. 13. Delgado-Guay M, Parson H, Li Z, Palmer J, Bruera E. Symptom distress in advanced cancer patients with anxiety and depression in the palliative care setting. Support Care Cancer 2009;17(5):573–579. 14. Rayner L, Lee W, Price A, et al. The clinical epidemiology of depression in palliative care and the predictive value of somatic symptoms: cross-sectional survey with four-week follow-up. Palliat Med 2011;25(3):229–241. 15. Lloyd-Williams M, Dennis M, Taylor F. A prospective study to determine the association between physical symptoms and depression in patients with advance cancer. Palliat Med 2004;18(6):558–563. 16. Berry M, Palmer J, Bruera E, Novy D. Predictors of unexplained somatic symptoms in cancer and noncancer pain. Paper presented at: American Psychological Association Annual Meeting July 2004. 17. Novy D, Berry M, Palmer J, Mensing C, Wiley J, Bruera E. Somatic symptoms in patients with chronic noncancer and cancer pain. J Pain Symptom Manage 2005;29(6):603–612. 18. Zimmerman L, Story K, Gaston-Johansson F, Rowles J. Psychological variables and cancer pain. Cancer Nurs 1996;19(1):44–53. 19. Campbell L, Clauw D, Keefe F. Persistent pain and depression: a biopsychosocial approach. Biol Psychiatry 2003;54(3):399–409. 20. Fishbain D, Lewis J, Gao J, Cole B, Steele Rosomoff R. Is chronic pain associated with somatization/hypochondriasis? An evidence-based structured review. Pain Practice 2009;9(6):449–467. 21. Katon W, Ciechanowski P. Impact of major depression on chronic medical illness. J Psychosom Res 2002;53(4):859–863.

Textbook of Palliative Medicine and Supportive Care 22. Cohen M, Willaims L, Knight P, Snider J, Hanzik K, Fisch M. Symptom masquerade: understanding the meaning of symptoms. Support Cancer Care 2004;12(3):184–190. 23. Derogatis L. Brief Symptom Inventory 18. National Computer Systems, Inc. Minneapolis, MN 2000. 24. Kroenke D, Spitzer R, Williams J, et al. Physical symptoms in primary care: predicators of psychiatric disorders and functional impairment. Arch Family Med 1994;3(9):774–779. 25. Sikorski J, Stampfer H, Cole R, Wheatley A. Psychological aspects of chronic low back pain. Austr N Zeal J Surg 1996;66(5):294–297. 26. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5 ed. Washington, DC: American Psychiatric Association, 2013. 27. Campos S, Link D. Pseudocyesis. J Nurse Pract 2016;12(6):390–394. 28. Kaufman D, Geyer H, Milstein M. Kaufman’s Clinical Neurology for Psychiatrists. 8th ed. Elsevier; 2017. 29. Barsky A, Goodson D, Lane R, Cleary P. The amplification of somatic symptoms. Psychosom Med 1988;50(5):510–519. 30. Clauw D. Fibromyalgia: a clinical review. J Am Med Assoc 2014:311(15):1547–1555. 31. Geisser M, Gaskin M, Robinson M, Greene A. The relationship of depression and somatic focus to experimental and clinical pain in chronic pain patients. Psychol Health 1993;8(6):405–415. 32. Van Damme S, Legrain V, Vogt J, Crombez G. Keeping pain in mind: a motivational account of attention to pain. Neurosci Biobehav Rev 2010;34(2):204–213. 33. Novy D, Nelson D, Francis D, Turk D. Perspectives of chronic pain: an evaluative comparison of restrictive and comprehensive models. Psychol Bull 1995;218(2):238–247. 34. Grombez G, Eccleston C, Van Damme S, Vlaeyen J, Karoly P. Fearavoidance model of chronic pain: the next generation. Clin J Pain 2012;28(6):475–483. 35. Mechanic D. The experience and reporting of common physical complaints. J Health Soc Behav 1980;21(2):146–155. 36. Rudy T, Kerns R, Turk D. Chronic pain and depression: toward a cognitive-behavioral mediation model. Pain 1988;35(2):129–140. 37. Lovell N, Wilcock A, Bajwah S, et al. Mirtazapine for chronic breathlessness? A review of mechanistic insights and therapeutic potential. Expert Rev Respir Med 2019;(13(2):173–180. 38. Bates M, Rankin-Hill L, Sanchez-Ayendez M. The effects of the cultural context of health care on treatment of and response to chronic pain and illness. Soc Sci Med 1997;45(9):1433–1447. 39. Loeser J. Multidisciplinary pain management. In: Merskey H, Loeser J, Dubner R, eds. The Paths of Pain 1975-2005. Seattle, WA: IASP Press, 2005:1433–1447. 40. Ford S, Fallowfield L, Lewis S. Can oncologists detect distress in their out-patients and how satisfied are they with their performance during bad news consultations. Br J Cancer 1994;70(4):767–770. 41. Kwekkeboom K. Cancer symptom cluster management. Semin Oncol Nurs 2016;32(4):373–382. 42. Xiao W, Chow K, So W, Leung D, Chan C. The effectiveness of psychoeducational intervention on managing symptom clusters in patients with cancer: a systematic review of randomized controlled trials. Cancer Nurs 2016;39(4):279–291. 43. Barsky A, Borus J. Functional somatic syndromes. Ann Intern Med 1999;130(11):910–921. 44. Purcell T. The somatic patient. Emerg Med Clin N Am 1991;9(1):137–159.

36

PAIN IN PATIENTS WITH ALCOHOL AND DRUG DEPENDENCE

Leah Couture, Malisa Dang, and Danielle Noreika

Contents Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������337 Definitions, diagnosis and prevalence of alcohol and drug dependence and substance use disorder�������������������������������������������������������������337 Screening for substance use disorder in palliative care patients�����������������������������������������������������������������������������������������������������������������������������338 Non-opioid management of pain in palliative patients with SUD��������������������������������������������������������������������������������������������������������������������������339 Opioid management of pain in palliative patients with SUD����������������������������������������������������������������������������������������������������������������������������������339 Substance abuse disorder for patients in the last 6 months of life��������������������������������������������������������������������������������������������������������������������������340 Interdisciplinary team support in palliative patients with SUD������������������������������������������������������������������������������������������������������������������������������341 Naloxone�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������341 Conclusion��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������341 References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������341

Introduction Substance use disorder (SUD) is a significant public health concern. In the United States in 2017 SUD affected approximately 19.7 million people aged 12 or older.1 This included 14.5 million people who had an alcohol use disorder, 7.5 million people who had an illicit drug use disorder, and an estimated 2.1 million people who had an opioid use disorder.1 Worldwide the World Health Organization estimates there were 27 million people living with SUD in 2016 and approximately 450,000 dying as a result of drug use in 2015.2 SUD not only impacts the individual, contributing greatly to disease burden, but also involves substantial social and economic costs.1 Even with the challenges of the opioid crisis, opioids still serve as a mainstay of pain management for palliative and cancer patients. Many of these patients experience pain, and the use of opioids and other controlled substances may be necessary for optimal symptom management.2 Substance abuse disorder can affect all dimensions of palliative care (Chapter 5);3 therefore, appropriate identification is important to allow the consideration of support and management options.

Definitions, diagnosis and prevalence of alcohol and drug dependence and substance use disorder As with much of medicine, the definition of substance abuse disorder is evolving. In the update from the DSM IV to the DSM 5, the definitions of substance abuse and substance dependence were merged into a new term of SUD, which was then clarified into severity depending on the number of criteria met.4,5 The revisions for the DSM-5 were formulated by a multidisciplinary team of experts whose overall aim was overcoming problems identified in the DSM-IV to provide an improved approach to SUD.5 Modifications to the DSM-IV included dropping legal problems as a criterion, adding “cravings or strong desire or urge to use substance” as a criterion, and changing the diagnostic threshold to ≥2 criteria within a 12-month period. Furthermore, severity was

represented as a range from mild (2–3 criteria), moderate (4–5 criteria), and severe (≥6) (Table 36.1).5,6 Prevalence of SUD in populations of patients cared for by palliative care and hospice teams are less well established. A recent large retrospective review of National Veteran Health Administration data showed that of 482,688 patients with cancer, 6.64% had a diagnosed comorbid substance abuse disorder.7 Data on alcohol and substance abuse in the palliative care population remains scarce due to limited application of urine drug screening or implementation of existing screening tools for misuse8; however, some studies suggest that this problem may be at least as common in the palliative population.9,10 In a study of terminally ill cancer patients admitted to a palliative care unit, 27% of those able to be assessed were found to meet the criteria for alcohol abuse using the Cut Down, Annoyed, Guilty, Eye-Opener (CAGE) questionnaire as a screening tool.11 Notably approximately one-third of patients found to have an alcohol use disorder had not been diagnosed previously. Other studies have also suggested that alcoholism is not only prevalent but frequently undocumented and underdiagnosed in patients with advanced cancer.12,13 For palliative care providers who manage patients who have transitioned to cancer survivorship, there may be additional challenges in creating a long-term pain management plan in the setting of comorbid SUD.14 While most providers are able to recognize the outward manifestations of substance use, such as the impairment in behavioral control, cravings, and decreased recognition of problems TABLE 36.1  DSM-IV and DSM-5 Criteria for Substance Use Disorders (from Reference [5] with Permission) 1

2 3 4

One or more abuse criteria within a 12-month period and no dependence diagnosis; applicable to all substances except nicotine, for which DSM-IV abuse criteria were not given Three or more dependence criteria within a 12-month period Two or more substance use disorder criteria within a 12-month period Withdrawal not included for cannabis, inhalant, and hallucinogen disorders in DSM-IV. Cannabis withdrawal added in DSM-5

337

Textbook of Palliative Medicine and Supportive Care

338

FIGURE 36.1  Model of interacting circuits in which disruptions contribute to compulsive-like behaviors underlying drug addiction. The overall neurocircuitry domains correspond to three functional domains: binge/intoxication (reward and incentive salience: basal ganglia), withdrawal/negative affect (negative emotional states and stress: extended amygdala and habenula), and preoccupation/anticipation (craving, impulsivity, and executive function: PFC, insula, and allocortex). Arrows depict major circuit connections between domains, and numbers refer to neurochemical and neurocircuit-specific pathways known to support brain changes that contribute to the allostatic state of addiction. PFC, prefrontal cortex; ACC, anterior cingulate cortex; OFC, orbitofrontal cortex; NAc– VTA, nucleus accumbens–ventral tegmental area. (From Reference [15], with permission.) in behaviors and relationships, many providers are less familiar with the physiologic changes that occur during the development of SUD. There is growing research regarding the neurobiological changes that occur during addiction affecting neurotransmission within the reward structures of the brain, including the nucleus accumbens, anterior cingulate cortex, amygdala, and basal ganglia.15 Understanding these changes can help providers reframe the behaviors that manifest at least partially from this physiological state (Figure 36.1).

Screening for substance use disorder in palliative care patients Based on the 2016 CDC Guidelines for Prescribing Opioids for Chronic Pain, providers should ask all patients about prior alcohol and substance use.16 While there is an entire paragraph at the beginning of these guidelines exempting palliative care and

hospice patients, given that patients with a prior history of SUD and alcohol abuse are at increased risk for opioid misuse as well as death from opioid use, it would be clinically appropriate to identify these patients. The actual use of screening tools in palliative care is unfortunately low, perhaps in part due to a lack of guidelines for opioid prescribing among people with SUD or alcohol abuse. In a survey of palliative care fellowship directors, 67.6% stated that their program did not have a written policy regarding the use of a screening tool for substance abuse.8 Of those that did have a policy, only 18.9% stated it was required on all patients.8 Multiple screening tools have been validated to identify patients at increased risk for opioid misuse: the CAGE questionnaire (as well as the updated version that includes “drugs,” CAGE-AID), the Opioid Risk Tool (ORT), and the Screener and Opioid Assessment for Patients with Pain—Revised (SOAPP-R).17 Although small studies have evaluated the prevalence of positive screening in palliative care populations,10 none of these tools have

Pain in Patients with Alcohol and Drug Dependence

339

Population of Patients with Cancer

Aberrant Behavior Diversion Misuse Addiction

Chemical coping

Abuse

FIGURE 36.2  Spectrum of aberrant opioid-related behavior. (From Reference [17] with permission.) been specifically designed for patients with life limiting illness. Identification of patients at risk for opioid misuse allows providers to have an informed discussion with patients about their specific potential benefits and risks of opioid therapy (Figure 36.2).

Non-opioid management of pain in palliative patients with SUD Although palliative and hospice patients often have pain that would benefit from opioid management, treatment strategies should be multimodal as often as possible and not focus solely on opioids. In some areas of this field, there is a paucity of data to guide evidence-based practice and guidelines on specific groups of patients (for example, cancer patients) or chronic pain are extrapolated for use. This is especially true for non-pharmacologic measures where there may be low cost and little risk of harm. One recent study analyzed the types of non-pharmacologic therapy and frequency of use in patients with chronic musculoskeletal pain. They included clinician-directed forms of therapy (physical therapy, transcutaneous electrical nerve stimulation, massage, etc.) as well as self-directed (yoga, pool exercises, herbal medicines, etc.). The majority of patients (71%) had used at least one non-pharmacologic measure over the preceding 6 months, and individual activities were rated as being helpful by more than half of all users (range 51–79%).18 Technology may offer more opportunities over time for nonpharmacologic management of substance abuse and symptoms including pain in palliative care patients. Currently, publications are few; for instance, a 2019 meta-analysis of virtual reality in cancer-related symptom management only returned six papers for review.19 In a more recent small prospective study for cancer patients, the use of virtual reality to allow patients to “travel” to a comforting place was associated with significant improvements in multiple symptoms including pain.20 For more upstream palliative patients with substance misuse disorders, avatars have been utilized to increase access to treatment.21 Adjunctive medications are commonly utilized in chronic pain disorders but integration in pain management for palliative care or hospice patients may be challenging due to comorbid conditions, risks of polypharmacy, or timeline to efficacy. There is a lack of evidence to guide practitioners who are trying to incorporate adjunctive medications in palliative pain management. For instance, a recent review of nonsteroidal anti-inflammatory medications found that study duration and discordance in outcome

measures limited the ability to identify the areas of efficacy.22 A randomized, double blind, placebo-controlled trial of additive duloxetine for 70 patients with cancer-related neuropathy who were nonresponsive to opioid-pregabalin combination therapy suggested that there may have been some meaningful pain improvement but concluded that further studies are needed.23 Depending upon the prognosis of the patient, the time to efficacy may be a potential barrier for making this a treatment strategy. Although gabapentin and pregabalin are sometimes used in the palliative care setting, data to support their use is mixed and side effect profiles are notable.24

Opioid management of pain in palliative patients with SUD When considering the use of opioids to manage pain in palliative care patients with SUD, it is important to consider the unique aspects of this population and the goals of treatment. As the focus of palliative care is to reduce suffering in life-limiting illness, it may be appropriate to very cautiously continue the management with opioids even in the setting of active substance abuse, whereas in other patient populations, this may be an indication to stop opioids.25 When it is deemed on full assessment appropriate and necessary to continue opioids, other action providers may take to try to minimize harms, in particular reducing the risk of overdose, adverse effects, and aberrant behaviors (such as misuse and diversion).26 Similar to patients being started on opioid therapy for chronic pain management, palliative care patients should complete a comprehensive pain and symptom history as the foundation of creating the management plan (see Table 36.2).26 In addition to a comprehensive pain assessment, it may be beneficial to assess for substance abuse using a standardized assessment tool as previously described. While the identification of active substance abuse and high-risk behaviors may place patients at risk for opioid misuse, it should not automatically preclude them from starting opioid treatment. Instead, it may help identify patients who may need more support and monitoring to allow for safe and successful treatment. If possible, patients with active SUDs may be referred to an addiction specialist to help comanage their pain and SUD.26 The concept of pain agreements is familiar to most providers caring for chronic pain patients; however, the use of these agreements in palliative care is not well studied. When personalized to

340 TABLE 36.2  Evaluation and Documentation Considerations for Palliative Patients on Opioid Medications 1. Comprehensive pain history 2. Past medical history including psychiatric or substance use diagnosis and treatment 3. Family history to include substance use disorders 4. Extensive social history 5. Risk assessment screening tool for all patients (CAGE, SOAPP-R, ORT, etc.) 6. Review of records in state prescription drug-monitoring program 7. Full physical exam 8. (If applicable) review of outside records of pain management 9. (If applicable) review of urine drug screen results 10. Review of laboratory or imaging data related to pain diagnosis 11. Consideration of non-pharmacological and adjunctive-management options 12. Documentation of risk assessment and corresponding treatment plan based on risk assessment 13. (When available/indicated) interdisciplinary team support and access to addiction specialists and resources 14. (If applicable) consideration for and education on naloxone 15. Informed consent for opioid therapy (to include benefits, risks, shared goals, and safety parameters); this process many include a written agreement with the patient

a specific patient and setting it can be a helpful tool in the establishment of informed consent, development of expectations for both the patient and provider; setting of functional goals and discussion of safe opioid use practices.27 Urine drug screening is another modality that is utilized often in chronic pain patients but is with no specific recommendations in palliative care populations. This can be beneficial in patient care, but it should be applied in a structured and supportive manner with a clear understanding of result interpretation.28 General consensus for patients with a history of SUD or high risk indicators is to begin with short prescriptions to allow for close monitoring.29 State prescription monitoring plans provide helpful information on controlled substances that have been dispensed to patients and should be accessed routinely over the course of care. 30 For patients being followed for pain management with a history of SUD, it is important to ask about their substance use at follow up visits as it may change over the course of their disease and with changes in their pain management. If patients either admit to substance use or inappropriate use of their medications (or if discovered through a UDS), it is important to obtain further information as all substance use is not equal.29 For example, a patient with cannabis on a UDS but otherwise appropriate behavior versus a patient with multiple non-prescribed opioids are not at the same risk for overdose or other serious consequences. This consistent weighing of benefits and burdens rather than the strict discontinuance of opioid therapy may be a critical difference when using opioid therapy in a palliative population versus patients with chronic pain. 30 Finally, after risk assessment, the above choice of opioid may be a consideration for patients with an active substance abuse disorder and palliative pain-management needs. There are no guidelines which direct initial opioid choices in patients with SUD in palliative or hospice patients and care plans must be individualized. Although methadone has been cited in multiple resources

Textbook of Palliative Medicine and Supportive Care as beneficial in refractory cancer pain management, 31–33 a recent white paper has recommended that active illicit drug use or misuse be considered a contraindication to using methadone. 34 Buprenorphine and buprenorphine/naloxone use has increased with the opioid crisis over the past several years. A review in 2015 on the effectiveness of buprenorphine for cancer pain recommended consideration as a fourth line agent in specified situations. 35 Finally, abuse deterrent formations may be considered a way of decreasing the potential for nonoral abuse. 36

Substance abuse disorder for patients in the last 6 months of life One distinct population of patients in palliative care that requires specific focus is patients approaching death or in the last 6 months of life, and in the community. Palliative care patients may range anywhere along the spectrum of a life limiting illness. In the United States, hospice patients are, according to the current Medicare benefit definitions, terminally ill with an expected prognosis of less than 6 months, if the illness runs usual course. In other countries, these distinctions are not used, but commonly, patients receiving palliative care and hospice care are in advanced stages of illness. When patients are at home, which is common for many palliative care and hospice services, including US hospices, there is an additional concern of staff safety when caring for the patient with a potential substance abuse disorder. Despite estimates of SUD incidence in US hospice upward 25% and the recognition that these patients may have additional psychosocial support needs. 37,38 There are no guidelines for screening nor are many organizations caring for patients with advanced disease routinely performing standardized risk assessments. In a recent nationwide study of US hospices, although 68% were assessing for potential substance abuse disorders, most were not using validated risk assessment tools. 39 Additionally, even when aberrancy has been noted, there is little to guide practitioners in publications and state or national guidelines or regulations. Although a potentially helpful resource, there is little practical availability of substance abuse providers to follow these patients. 38 As is the case in palliative care extrapolations from SUD, in other pain, the patients have been applied to managing end-oflife care in the home setting with a known history of aberrant behaviors. Communication is paramount and should include family caregivers who are present in the home. Interdisciplinary team members can support this process to create a multimodal pain-management plan with partners’ hospice staff, patients, and families to regulate medications for safety. Inpatient care can be utilized when needed to monitor medications and dose titrations as well as create transition plans to other locations of care. 38 Education is also essential and should include the entire interdisciplinary team. Despite the increase in awareness around substance abuse disorders, there are gaps in training around this topic for interdisciplinary team members.8,38 As these patients can be in challenging circumstances, education and training is critical to provide practitioners with a toolkit to assess for risk mitigation in their patients. Consideration of the safe disposal of opioid medications should also be an area of focus from a public health perspective. There are resources available on the Internet to guide patients and families in their local region for safe disposal of unused medications as well as many pharmacies that will take back unused medications.

Pain in Patients with Alcohol and Drug Dependence

Interdisciplinary team support in palliative patients with SUD Palliative care patients with concurrent pain management needs and substance abuse disorders may be the most challenging to manage in daily practice. Unfortunately, as referenced earlier in this chapter, education on this topic remains underutilized in fellowship training.8 This lack of preparation for management strategies in a challenging patient population may increase distress for not only the provider but also the patient and family who are also struggling with these comorbid conditions. In addition to the lack of guidelines to shape practice for managing pain in the setting of substance abuse in palliative care, there is also little evidence on provider support strategies for managing these patients outside of trying to increase education. Dedicated substance abuse resources are limited in many regions and may not be accessible for hospice and palliative patients. 38 One novel study by Arthur et al. that investigated ways of providing support to both patients and the treating palliative care team in the case of aberrant opioid behaviors was reported in the Oncologist.40 The “CHAT” (Compassionate High Alert Team) was created to follow a pilot group of clinic patients who met the criteria for one or more of eight aberrant behaviors during their assessment. The team consisted of a palliative care physician and two or more of the following members: a palliative care nurse, psychologist or counselor, pharmacist, social worker, and patient advocate plus potentially a representative from risk or security depending on the scenario. The team met to debrief before and after the patient encounter and conducted the meeting in a supportive and nonjudgmental manner. Outcomes noted were decrease in the number of aberrant behaviors per month via chart abstraction as well as a decrease in median morphine equivalent daily dose. It was hypothesized that the expertise of multiple providers to address the complex issues in these patients would be “likely to prevent burnout in any individual provider who tries to address the issue alone.”40

Naloxone Over time, naloxone accessibility in the community has increased as one of the ways of mitigating the risks of the current opioid crisis. In addition to training programs, for first responders in most states in the United States to be able to use naloxone between 2010 and 2014, there was a three-fold increase in the number of laypersons with naloxone kits (52,032–152,283).41 Most states now have laws to expand naloxone access to laypersons, and depending on the type of law, this may reduce the risk of fatal overdose. In a 2019 study in JAMA Internal Medicine, Abouk et al. reviewed the type of policy in each state (whether the pharmacist had direct authority to prescribe) as well as fatal and nonfatal overdoses. States with laws that allowed pharmacists to directly prescribe had a significant reduction in fatal overdose compared to states with indirect authority.42 Although these studies have documented the effects of community naloxone availability globally to this point, there is little data to guide efforts in palliative populations. One publication addressed palliative provider confidence in multiple measures with prescribing naloxone and managing addiction being the lowest among all variables, but this paper focused on chronic pain in cancer survivors and not those with life limiting diseases.43 Most of the existing resources and laws in the United States also exempt cancer, palliative, and

341 end of life/hospice care patients (SAMSHA, CDC, etc.).44 If naloxone is incorporated into care, education on how to use the specific product is essential and must be undertaken by the prescribing provider or pharmacist with the patient and family.45 Many states offer educational brochures that can be shared with patients and families; for example, Virginia has created the REVIVE program to use as a resource to guide these conversations (see further http://www.dbhds.virginia.gov/library/substance%20abuse%20 services/revive%20pharmacy%20dispensing%20brochure%20 v10.pdf).46

Conclusion Palliative care patients often have complex physical, psychosocial, and spiritual needs. When palliative or hospice situations also involve substance misuse, they become some of the more challenging circumstances for teams to manage. Although as described before, considering risk assessment strategies, multimodal therapy, resources in settings of care, and reversal agents are all tools to apply to these situations—the most powerful is that of the interdisciplinary team. A highly functioning interdisciplinary team with different backgrounds and strengths—utilizing all of the strategies above—can help patients and families to overcome the challenges that a comorbid substance misuse disorder brings to serious illness care.

References



1. Substance Abuse and Mental Health Services Administration. Key Substance Use and Mental Health Indicators in the United States: Results from the 2017 National Survey on Drug Use and Health (HHS Publication No. SMA 18-5068, NSDUH Series H-53). Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration, 2018. Retrieved from: https://www.samhsa.gov/data/. 2. WHO. WHO Information Sheet on Opioid Overdose. Available from: https://www.who.int/substance_abuse/information-sheet/en/ (Accessed November 1, 2019). 3. WHO. WHO Definition of Palliative Care. Available from: http://www. who.int/cancer/palliative/definition/en/.2010 (Accessed October 30, 2019). 4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington: American Psychiatric Association, 2013. 5. Hasin DS, O’Brien CP, Auriacombe M, et al. DSM-5 criteria for substance use disorders: recommendations and rationale. Am J Psychiatry 2013;170(8):834–851. 6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR, (4th ed., Text Revision). Washington, DC: American Psychiatric Association, 2000. 7. Ho P, Rosenheck R. Substance use disorder among current cancer patients: rates and correlates nationally in the Department of Veterans Affairs. Psychosomatics 2018; May–Jun;59(3):267–276. 8. Tan PD, Barclay JS, Blackhall LJ. Do palliative care clinics screen for substance abuse and diversion? Results of a national survey. J Palliat Med 2015;18(9):752–757. 9. Sager ZS, Buss MK, Hill KP, Driver JA, Skarf LM. Managing opioid use disorder in the setting of a terminal disease: opportunities and challenges. J Palliat Med 2019;23(2):296-299. Jul. doi:10.1089/jpm.2019.0101. 10. Barclay JS, Owens JE, Blackhall LJ. Screening for substance abuse risk in cancer patients using the Opioid Risk Tool and urine drug screen. Support Care Cancer 2014; Jul;22(7):1883–1888. 11. Bruera E, Moyano J, Seifert L, Fainsinger RL, Hanson J, SuarezAlmazor M. The frequency of alcoholism among patients with pain due to terminal cancer. J Pain Symptom Manage 1995;10(8):599–603. 12. Dev R, Parsons HA, Palla S, Palmer JL, Del Fabbro E, Bruera E. Undocumented alcoholism and its correlation with tobacco and illegal drug use in advanced cancer patients. Cancer 2011;117(19):4551–4556.

342 13. Parsons HA, Delgado-Guay MO, El Osta B, et al. Alcoholism screening in patients with advanced cancer: impact on symptom burden and opioid use. J Palliat Med 2008;11(7):964–968. 14. Chwistek M, Ewerth N. Opioids and chronic pain in cancer survivors: evolving practice for palliative care clinics. J Palliat Med 2016; Mar;19(3):254. 15. Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry 2016; Aug;3(8):760–773. 16. CDC. CDC Guideline for Prescribing Opioids for Chronic Pain-United States, 2016 Morbidity and Mortality Weekly Report, 2016. Available from: http://www.cdc.gov/mmwr/cme/conted.html (Accessed June 17, 2019). 17. Arthur J, Hui D. Safe opioid use: management of opioid related adverse effects and aberrant behaviors. Hematol Oncol Clin North Am 2018; Jun;32(3):387–403. 18. Lozier C, Nugen S, Smith N, et al. Correlates of use and perceived effectiveness of non-pharmacologic strategies for chronic pain among patients prescribed long term opioid therapy. J Gen Intern Med 2018; May;33(Suppl 1):46–53. 19. Zeng Y, Zhang JE, Cheng ASK, Cheng H, Wefel JS. Meta-analysis of the efficacy of virtual reality based interventions in cancer-related symptom management. Integr Cancer Ther 2019; Jan–Dec;18. doi:10.1177/ 1534735419871108. 20. Niki K, Okamoto Y, Maeda I, et al. A novel palliative care approach using virtual reality for improving various symptoms of terminal cancer patients: a preliminary prospective multicenter study. J Palliat Med 2019; Jun;22(6):702–707. 21. Gordon MS, Carswell SB, Schadegg M, et al. Avatar assisted therapy: a proof of concept pilot study of novel technology-based intervention to treat substance abuse disorders. Am J Drug Alcohol Abuse 2017; Sept;43(5):518–524. 22. Magee DJ, Jhanji S, Poulogiannis G, Farguhar-Smith P, Brown MRD. Nonsteroidal anti-inflammatory drugs and pain in cancer patients: a systematic review and reappraisal of the evidence. Br J Anaesth 2019; Aug;123(2):e412–e423. 23. Matsuoka H, Iwase S, Miyaji T, et al. Additive duloxetine for cancerrelated neuropathic pain nonresponsive or intolerant to opioidpregabalin therapy: a randomized controlled trial (JORTC-PAL08). J Pain Symptom Manage 2019; Oct;58(4):645–653. 24. Clark K, Quinn SJ, Doogue M, Sanderson C, Lovell M, Currow DC. Routine prescribing of gabapentin or pregabalin in supportive and palliative care: what are the comparative performances of the medications in a palliative care population. Support Care Cancer 2015; Sept;23(9):2517–2520. 25. Krashin D, Murinova N, Ballantyne J. Management of pain with comorbid substance abuse. Curr Psychiatry Rep 2012; Oct;14(5):462–468. 26. Kennedy AJ, Arnold RM, Childers JW. Opioids for chronic pain in patients with history of substance use disorders, part 1: Assessment and initiation #311. J Palliat Med 2016; Aug;19(8):888–889. 27. Tobin DG, Forte KK, Mcgee SJ. Breaking the pain contract: a better controlled-substance agreement for patients on chronic opioid therapy. Cleve Clin J Med 2016;83(11):827–835. 28. Arthur JA, Haider A, Edwards T, et al. Aberrant opioid use and urine drug testing in outpatient palliative care. J Palliat Med 2016; Jul;19(7):778–782. 29. Kennedy AJ, Arnold RM, Childers JW. Opioids for chronic pain in patients with history of substance use disorders, part 2: Management and monitoring #312. J Palliat Med 2016; Aug;19(8):890–891.

Textbook of Palliative Medicine and Supportive Care 30. Paice JA. Risk assessment and monitoring of patients with cancer receiving opioid therapy. Oncologist 2019; Oct;24(10):1294–1298. 31. Khoo SY, Aziz FA, Nambbiar P. Opioid rotation to methadone for refractory cancer pain: a case series. J Pain Palliat Care Pharmacother 2019; Sep–Dec;33(3–4):125–130. 32. Okayama S, Matsuda Y, Yoshikawa Y. A comparative study of opioid switching to methadone for cancer pain control in successful and unsuccessful cases. J Palliat Med 2019; Jul;22(7):844–847. 33. Porta-Sales J, Garzon-Rodriguez C, Villavicencio-Chavez C, LlorensTorrome S, Gonzalez-Barboteo J. Efficacy and safety of methadone as a second line opioid for cancer pain in an outpatient clinic: a prospective open label study. Oncologist 2016; Aug;21(8):981–987. 34. McPherson ML, Walker KA, Davis MP, et al. Safe and appropriate use of methadone in hospice and palliative care: expert consensus white paper. J Pain Symptom Manage 2019; Mar;57(3):635–645. 35. Schmidt-Hansen M, Bromham N, Taubert M, Arnold S, Hilgart JS. Buprenorphine for treating cancer pain. Cochrane Database Syst Rev 2015; Mar 31;2015(3):CD009596. 36. Kata V, Novitch M, Jones MR, Anyama BO, Helander EM, Kaye AD. Opioid addiction, diversion, and abuse in chronic and cancer pain. Curr Opin Support Palliat Care 2018; Jun;12(2):124–130. 37. Groninger H, Knapik M. Twelve-step programs and spiritual support at the end of life. Am J Hosp Palliat Care 2019; Sep;36(9):807–811. 38. Gabbard J, Jordan A, Mitchell J, Corbett M, White P, Childers J. Dying on hospice in the midst of an opioid crisis: what should we do now? Am J Hosp and Palliat Med 2019;36(4):273–281. 39. Sacco P, Cagle JG, Moreland ML, Camlin EAS. Screening and assessment of substance abuse in hospice care; examining content from a national sample of psychosocial assessments. J Palliat Med 2017;20(8):850–856. 40. Arthur J, Edwards T, Reddy S, et al. Outcomes of a specialized interdisciplinary approach for patients with cancer with aberrant opioid related behavior. Oncologist. 2018; Feb;23(2):263–270. 41. NIDA. Medications to Treat Opioid Use Disorder. National Institute on Drug Abuse, 8 Jun 2018. Available from: https://www.drugabuse. gov/publications/research-reports/medications-to-treat-opioid-usedisorder (Accessed June 22, 2019). 42. Abouk R, Liccardo Pacula R, Powell D. Association between state laws facilitating pharmacy distribution of naloxone and risk of fatal overdose. JAMA Int Med 2019;179(6):805–811. 43. Merlin JS, Patel K, Thompson N, et al. Managing chronic pain in cancer survivors prescribed long term opioid therapy: a national survey of ambulatory palliative care providers. J Pain Symptom Manage 2019; Jan;57(1):20–27. 44. SAMHSA. Opioid Overdose Prevention Toolkit. Substance Abuse and Mental Health Services Administration, 2018 (Accessed June 22, 2019). 45. DiScala S, Fudin J, Coulson E, Lodl E, Kral L, Herndon C. Society of Pain and Palliative Care Pharmacists (SPPCP) position statement on the proposed change of naloxone to over-the-counter (OTC) status. J Pain Palliat Care Pharmacother 2019;33(1–2):1–5. 46. Virginia Department of Behavioral Health and Developmental Services, REVIVE! Opioid Overdose and Naloxone Education for Virginia. Available from: http://www.dbhds.virginia.gov/library/substance%20abuse%20services/revive%20pharmacy%20dispensing%20 brochure%20v10.pdf (Accessed October 28, 2019).

37

CACHEXIA–ANOREXIA SYNDROME

Paul Zelensky, Mallika Dammalapati, and Egidio Del Fabbro

Contents Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������344 Diagnostic criteria and definitions��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������344 Malnutrition�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������344 Cachexia������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������344 Sarcopenia��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������344 Prognostication�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������345 Poor appetite and nutritional impact symptoms (NIS)���������������������������������������������������������������������������������������������������������������������������������������345 Weight loss�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������345 Body composition�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������345 Laboratory biomarkers�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������345 Inflammation����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������345 Testosterone�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������345 Mechanisms of cachexia��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������346 Cachexia and starvation���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������346 Inflammation����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������346 Peripheral effects���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������346 Central effects��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������346 Other mechanisms causing muscle and fat atrophy��������������������������������������������������������������������������������������������������������������������������������������������347 Endocrine dysfunction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������347 Metabolic dysfunction, including increased resting energy expenditure��������������������������������������������������������������������������������������������������347 Nutritional impact symptoms�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������347 Assessment�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������347 Nutrition risk screening and identification������������������������������������������������������������������������������������������������������������������������������������������������������������347 Health-related quality of life�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������348 Weight and body composition���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������348 Body mass index (BMI)����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������348 Anthropometrics���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������348 Bioelectrical impedance analysis (BIA)������������������������������������������������������������������������������������������������������������������������������������������������������������349 Imaging��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������349 Physical performance�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������349 Management����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������349 Non-pharmacological intervention�������������������������������������������������������������������������������������������������������������������������������������������������������������������������349 Nutritional supplementation������������������������������������������������������������������������������������������������������������������������������������������������������������������������������349 Psychosocial intervention������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������350 Exercise and physical therapy�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������350 Pharmacological management���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������350 Nutrition impact symptoms (NIS)���������������������������������������������������������������������������������������������������������������������������������������������������������������������350 Metoclopramide����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������351 Mirtazapine������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������351 Corticosteroids������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������351 Cannabinoids���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������351 Thalidomide������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������351 Beta blockade���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������351 Nonsteroidal anti-inflammatory drugs (NSAIDs)������������������������������������������������������������������������������������������������������������������������������������������351 Androgens���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������352 Ghrelin and ghrelin agonists�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������352 Combination therapy��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������352 Conclusion��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������352 References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������352

343

Textbook of Palliative Medicine and Supportive Care

344

Introduction Cachexia–anorexia syndrome (CAS) is a multifactorial syndrome characterized by involuntary loss of skeletal muscle and fat, reduced quality of life, and decreased survival. CAS occurs in a variety of seemingly disparate illnesses, including cancer, acquired immune deficiency syndrome (AIDS), heart failure (HF),1 human immunodeficiency virus (HIV), tuberculosis, malaria, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD),2 kidney failure, 3 and liver failure. Comorbidities such as diabetes may contribute to muscle abnormalities in patients with cancer,4 and in older patients, 5 age-related muscle loss6 and decreased physical activity exacerbate CAS. Although epidemiological studies are scarce, the estimated prevalence of cachexia in Europe, the United States, and Japan is as high as 1% or 12 million people,7 with mortality rates ranging from 15 to 80% depending on the type of chronic illness. In developing countries, cachexia is likely to be a more frequent cause of death in patients with chronic illness.

Diagnostic criteria and definitions The conditions of malnutrition, cachexia, frailty, and sarcopenia overlap may occur in the same individual (8%)8 and are especially common among older patients. They share features such as weight loss and/or changes in body composition (BC), and all are associated with adverse clinical outcomes. A survey from four European countries found nutrition-related disorders and their distinguishing features were suboptimally recognized in clinical practice.9

Malnutrition

Malnutrition is often used as an overarching term that encompasses nutrition-related disorders such as starvation, cachexia, and sarcopenia. Recently, a consensus-based set of criteria for malnutrition, independent of the clinical setting or etiology,10 recommended the diagnosis of malnutrition be based on either a low body mass index (BMI) (10% indefinite of time or >5% over 3 months) together with either reduced BMI (age-specific) or a low fat-free mass index (FFMI) using sex-specific cutoffs.

Cachexia

Defining cachexia is challenging since several mechanisms, including poor appetite, inflammation, and metabolic dysregulation, may contribute variably to decreased muscle and fat in any individual patient. Furthermore, the patient’s clinical presentation may span a wide spectrum of weight loss, BMI, symptoms, and physical performance. The most commonly applied definitions in research and daily practice include the cancer-specific definition by Fearon11 and a definition by Evans12 that is applicable to all disease states. Importantly, variation in diagnostic criteria for cachexia will of course alter its clinical prevalence.13 Fearon’s definition for cancer cachexia is largely weight based and emphasizes direct measures of muscularity, requiring >5% weight loss within the last 6 months or >2% weight loss in patients with a BMI 8000 European and Canadian patients revealed a greater percentage weight loss in lower BMI patients who were associated with shorter survival. Based on these findings, a grading system combining baseline BMI and weight loss was able to distinguish survival when applied to a variety of specific cancers, stages, ages, and performance statuses. 32 A single weight loss percentage cutoff is no longer appropriate as a diagnostic criterion since patients have varying degrees of risk based on their initial BMI.

Body composition

While a higher BMI and energy reserves are a survival advantage in cancer, there is also an increasing body of evidence showing high BMI and excess adiposity may be detrimental when present in patients with low muscle mass (sarcopenia/myopenia). The reasons for the poorer survival are unclear; however, it may be that patients with low muscle mass are deconditioned due to aging

345 and/or a sedentary lifestyle, or perhaps high fat mass inflates drug doses in body surface area–based treatments, causing an increased rate of dose-limiting toxicity. SO is independently associated with higher mortality and complications in medical and surgical cancer treatment across multiple tumor types. 33 Low muscle mass identified on imaging in nonobese patients is associated with decreased survival in both early-34–36 and latestage cancer. More recently, the combination of sarcopenia and systemic inflammation decreased progression-free survival and overall survival in patients treated with immunotherapy in phase I clinical trials. 37 A systematic review of pre-therapeutic sarcopenia found associations with surgery and chemotherapy complications; diminished overall survival during chemotherapy; decreased relapse-free survival after surgery for extrahepatic biliary cancer, hematopoietic stem cell transplantation, and hepatectomy; and decreased progression-free survival after chemotherapy for hepatocellular carcinoma and metastatic breast cancer. 38 In ambulatory patients with clinically stable chronic HF, muscle loss appears to have a more pronounced effect on clinical outcomes such as physical performance and quality of life than weight loss alone. 39 Similarly, in stable COPD patients, sarcopenia is associated with more severe dyspnea40 and decreased exercise tolerance.41 Sarcopenia in COPD patients is also linked with abnormalities such as the loss of oxidative muscle fibers, suggesting impaired muscle quality.42

Laboratory biomarkers Inflammation

Inflammation is thought to be the dominant driver of cachexia, and a meta-analysis of CT imaging studies and inflammation showed a consistent association between low skeletal muscle mass and a systemic inflammatory response.43 The Glasgow prognostic score (GPS) is a simple, systemic inflammation-based approach (using CRP and albumin levels) with prognostic value independent of tumor stage, performance status, and treatment, in a variety of solid tumors.44 The GPS is also useful for prognostication in non-cancer conditions such as pulmonary fibrosis45 and HF.46 Despite the importance of inflammation as a driver of cachexia and its role in prognostication, small, preliminary studies incorporating anorexia scores, CRP, and weight loss have thus far failed to distinguish between the stages of cancer cachexia based on survival.16,17

Testosterone

Testosterone may be a useful prognostic indicator in patients with cancer cachexia; however, the literature is limited to preliminary, retrospective studies with small sample sizes. An association between low testosterone and decreased survival has been reported in male patients with cancer cachexia.47 Low testosterone correlated inversely with CRP levels, dyspnea, and insomnia in males with >5% weight loss in the preceding 6 months. In other conditions such as cardiac cachexia, the evidence is more limited. Some studies show that decreased testosterone is associated with myocardial damage, lower exercise capacity, and higher mortality in men with HF48; however, this is inconsistent. More research is needed to develop a more robust prognostic model that combines the various cachexia domains with biomarkers such as lymphocyte count, albumin, or CRP levels. As cachexia is common to a variety of diseases, prognostic models should be tailored to specific diseases, even though

Textbook of Palliative Medicine and Supportive Care

346 some indicators such as inflammation may be applied to most (but not all) patients.

Mechanisms of cachexia CAS is characterized by a complex interplay of various mechanisms, leading to loss of muscle and fat as well as poor appetite. Based on our current knowledge, the aberrant pro-inflammatory response may be the dominant mechanism that drives systemic effects on muscle, fat, and appetite regulation. Additional mechanisms contributing to the syndrome include endocrine dysfunction, increased resting energy expenditure (REE), and diminished caloric intake due to nutritional impact symptoms (NIS). It is important to note that the various mechanisms for CAS should not be regarded in isolation, as they appear to be interrelated.

Cachexia and starvation

Cachexia can be distinguished from starvation by a number of features, including hormonal abnormalities such as elevated insulin and ghrelin levels, increased REE in some patients, and continued weight loss despite caloric supplementation. There are some key differences between cachexia and starvation (see Table 37.1), although, for individuals with involuntary weight loss, a combination of the two conditions may be present simultaneously, e.g., a patient with esophageal cancer and dysphagia.

Inflammation

The inflammatory response may be the major factor contributing to changes in metabolism, protein synthesis, and endocrine homeostasis in CAS. Immune cells and tumors produce small proteins called cytokines that act as messengers, with cell signaling effects on the nervous system, peripheral fat, and muscle.49 In spite of robust preclinical evidence, there are inconsistent findings in the literature concerning cytokine serum levels and clinical outcomes. Some studies show an association between elevated serum cytokines and cancer cachexia, particularly IL-1β50 and IL-6, 51 while others have shown no correlation between cytokine levels and cachexia52 or weight loss.53 A review of small, early phase clinical trials showed that anti-IL-6 monoclonal antibody treatment in patients with multiple myeloma, renal cell carcinoma, and B-cell lymphoproliferative disorders decreased CRP levels and the incidence of cachexia.54 The reasons for these discrepancies are unclear; plasma levels do not necessarily reflect true tissue concentrations, and cytokines may act locally in a paracrine rather than endocrine fashion. A preliminary study TABLE 37.1  Starvation versus Cachexia Starvation Caloric Intake REE Body fat Lean body mass Acute phase reactants Insulin Legend: ↔ Unchanged ↓ Reduce ↓↓ Markedly reduced ↓↑ Increased or reduced ↑ Increased

↓↓ ↓ ↓↓ ↓ ↔ ↓

Cachexia ↓ ↓↑ or ↔ ↓ ↓ ↑ or ↔ ↑

in non-small cell lung cancer55 found decreased muscle function in pre-cachectic patients but identified muscle wasting only once a transition occurred from systemic to local inflammation and activation of the ubiquitin–proteasome system (UPS)mediated proteolysis pathway. Other studies have also indicated that elevated levels of pro-inflammatory cytokines are only a late manifestation of disease and that biomarkers such as circulating monocyte chemoattractant protein-1 (MCP-1) may be more relevant56 earlier in the disease process.

Peripheral effects

Interleukin (IL)-6, tumor necrosis factor (TNF), and interferon (IFN-γ) are thought to have an important role in skeletal muscle wasting and decreased muscle synthesis. One pathway for muscle wasting is through downregulation of myosin heavy chain (MyHC), a myofibrillar protein that supports skeletal muscle structure. In myogenic cell culture, TNF and IFN-γ reduce myoblast determination protein (MyoD), a nuclear transcription factor regulating MyHC; and in vivo, INF and TNF selectively reduced MyHC as compared to other myofibrillar proteins, such as actin or troponin.57 Another pathway for muscle wasting modulated by cytokines is the ligase-dependent ubiquitin–proteasome pathway. Several studies suggest that IL-6 produces skeletal muscle breakdown by modulating this specific proteolytic pathway.58 There may be cross talk between muscle and fat so that maintenance of adipose tissue homeostasis also prevents wasting of muscle, even in a pro-inflammatory state. Cachectic tumor mouse models with high levels of circulating cytokines maintained normal levels of adipose and gastrocnemius muscle59 with genetic ablation of adipose triglyceride lipase. Other important effects by cytokines on adipose tissue have emerged in recent years. White adipose tissue (WAT) lipolysis and white-to-brown transdifferentiation of WAT, resulting in thermogenic gene expression (WAT browning) and ultimately adipose atrophy, have been identified in renal and cancer cachexia.60 Animal models reveal that inflammation mediated by IL-6 might promote cancer cachexia by regulating WAT lipolysis in early-stage cachexia and browning in late-stage cachexia.61

Central effects

Systemic pro-inflammatory cytokines affect appetite regulation and endocrine homeostasis by stimulating the expression of cytokines in the hypothalamus, which can then act through second messengers.62 Hypothalamic appetite regulation consists of two major opposing peripheral hormones: leptin and ghrelin. Leptin, from adipocytes, is anorexigenic, while ghrelin, predominantly from the stomach, is orexigenic. Cytokines mimic the anorexigenic signals of leptin and suppress orexigenic signals from neuropeptides such as ghrelin and agouti-related peptide (AgRP). Cytokines also stimulate pathways in the hypothalamus to release anorexigenic peptides, such as α-melanocyte-stimulating hormone (α-MSH), which inhibits feeding and increases energy expenditure.63 Central effects mediated by cytokines through the hypothalamic–pituitary–adrenal (HPA) axis also produce effects peripherally; for example, IL-1β causes significant muscle atrophy64 when administered centrally in animal models. Since an intact HPA axis appears to be necessary for muscle wasting, it is possible glucocorticoids may combine with local cytokines to promote muscle atrophy. In addition, cytokines decrease oral intake by generating symptoms such as early satiety (via IL-1) and depression (IL-6).65

Cachexia–Anorexia Syndrome Other mechanisms causing muscle and fat atrophy

Inflammation, cytokines, tumor factors, and hormones play a role in altered catabolism and anabolism leading to muscle and fat atrophy in cachexia. In progressive cancer cachexia, body fat is lost more rapidly than lean tissue.66 However, both muscle and fat loss occur by either decreased synthesis, increased degradation, or both. As noted previously, there is also evidence of “cross talk” between muscle and fat through various pathways, including via parathyroid hormone–related protein and myostatin.67 Myostatin,68 an extracellular cytokine, is a negative regulator of muscle growth and is upregulated across various diseases implicated with cachectic muscle wasting.69 For muscles specifically, in addition to the UPS, there are proteolytic pathways that are lysosomal, calcium dependent, and caspase dependent.70 Lipolysis in cachexia is associated with increased expression of zinc-α2glycoprotein (ZAG), an adipokine and catabolic marker71,72 found in COPD,73 renal, and cancer cachexia patients. Additionally, medications, alcohol,74 and vitamin D75 have been implicated in the “browning” and atrophy of fat, while corticosteroids76 can induce subacute and chronic muscle loss.

Endocrine dysfunction

Changes in the response to hormones or altered hormone levels can contribute to the muscle/fat wasting and poor appetite seen in CAS. The role of anabolic hormones, such as ghrelin, insulin, and androgens, as well as catabolic hormones, such as epinephrine, norepinephrine, and cortisol, is important to consider in the development of CAS. Ghrelin is secreted predominantly by the stomach during fasting, resulting in increased appetite, gastrointestinal motility, and reduced inflammation. Ghrelin may also activate ghrelin receptors in the terminals of the vagus nerve and trigger neuronal signaling to the nucleus of the solitary tract (NTS) in the brain stem and indirectly the hypothalamus.77 In addition to stimulating appetite, ghrelin acts on multiple other mechanisms that cause muscle atrophy, including downregulating inflammation, p38/C/ EBP-β/myostatin, and activating Akt, myogenin, and myoD. Ghrelin’s release is inhibited by food-associated stimuli; unexpectedly, levels are elevated in patients with cancer cachexia, 56 suggesting they may be ghrelin “resistant.” Insulin resistance may contribute to the muscle wasting seen in cancer cachexia, as insulin has the dominant hormonal control over muscle proteolysis. Specifically, insulin’s signaling pathway activates molecules that overlap with the ubiquitin–proteasome pathway so that resistance to insulin results in increased proteolysis78 while insulin sensitivity decreases proteolysis. Adrenal hormones are associated with weight loss and decreased survival in patients with congestive HF (CHF). Cachectic patients showed increased levels of epinephrine, norepinephrine, and cortisol as compared to control or non-cachectic patients.79 One of the pathways by which catecholamines may produce wasting includes the activation of uncoupling protein 1 (UCP1) and increased thermogenesis within brown adipose tissue.80

Metabolic dysfunction, including increased resting energy expenditure

Metabolic abnormalities in cachexia include mitochondrial dysfunction81 leading to altered amino acid metabolism and an increased rate of whole-body glycolysis driven by the tumor glucose demand and increased gluconeogenesis due to lactate production.

347 The use of lactate as a substrate is extremely energy inefficient, requiring six ATP to produce one molecule of glucose. Reasons are unclear as to why tumor cells favor this relatively inefficient process or “Warburg effect” even in the presence of adequate oxygen. More recent research into the metabolism of tumor cells suggests there is substantial metabolic heterogeneity within a tumor, allowing cancer and stromal cells to couple and transfer metabolites between them to support maximal cellular growth.82 Other elements of metabolic dysfunction have also been identified; for example, during the development of peritoneal metastases, hypoxia-inducible factor-1α (HIF-1α) plays a key role in activating both aerobic and anaerobic glycolysis, increasing the uptake of glucose, lipid, and glutamine into cancer cells. HIF-1α also stimulates the utilization of glutamine and fatty acids as alternative energy substrates.83 Increased utilization of energy by tumors may also be quite substantial84 (estimated at between 100 and 1400 kcal/day) and, along with fat “browning,” could contribute to the increased REE seen in some, but not all, patients.

Nutritional impact symptoms

Symptoms can exacerbate the cachectic state by decreasing nutritional intake. NIS include nausea, vomiting, constipation, diarrhea, early satiety, severe pain, dyspnea, anxiety or depression, stomatitis, dysgeusia, xerostomia, and dysphagia. Some NIS (e.g., depression) may be precipitated by the same endocrine dysfunction (low testosterone) and pro-inflammatory cytokine response (increased IL-6) that produce CAS. Other NIS are caused by the disease itself or by its treatment (e.g., mucositis because of chemotherapy). A retrospective database review evaluated the impact of 17 symptoms on 635 patients with head and neck cancer referred to a cancer center. 30 Participants were only on oral intake and using no enteral tube feeding or parenteral nutrition. Individual symptoms significantly associated with reduced food intake included loss of appetite, difficulty chewing, dry mouth, thick saliva, and pain. Importantly, aggregate symptom burden was found to be an independent predictor of reduced intake, weight loss, and survival (Figure 37.1).

Assessment Nutrition risk screening and identification

There is no consensus regarding the use of a particular screening tool for cachexia. The Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF) is often used in the oncology setting and is a valid screening tool in chemotherapy outpatients. 85 The PG-SGA SF provides additional prognostic value in evaluating patients with cancer, can be completed by patients in less than 5 minutes, and includes information about the severity and rate of weight loss, food intake, nutritional symptoms, and functional status. In addition to identifying patients at risk, self-completion of the PG-SGA SF by patients increases self-awareness regarding malnutrition risk after completing the PG-SGA SF. Among 1001 patients with gastric cancer, a comparison of four commonly used tools, including the Malnutrition Universal Screening Tool, the Nutritional Risk Screening 2002, the Malnutrition Screening Tool (MST), and the Short Nutritional Assessment Questionnaire (SNAQ), found the MST had the greatest ability to detect cancer cachexia. However, in a study of 725 patients, abnormal BC (sarcopenia or myosteatosis) identified on CT imaging was misclassified as “low risk” by the MUST and

348

Textbook of Palliative Medicine and Supportive Care

FIGURE 37.1  Multiple factors contributing to cachexia. MST in more than 50% of patients. The Nutritional Risk Index proved to be the most useful in capturing “hidden malnutrition” among ambulatory oncology patients.86 Tools may need to be tailored to a specific disease or setting; in patients with cirrhosis, the six-question Liver Disease Undernutrition Screening Tool was only one of two tools shown to be accurate for detecting malnutrition in cirrhotic patients, 87 and in hospitalized older people, the Simplified Nutritional Appetite Questionnaire (SNAQ) identified patients at higher risk of poor outcomes.88 A single tool for evaluating cachexia, sarcopenia, and malnutrition would be ideal for clinical practice. Unfortunately, a systematic review of 38 studies using 22 validated tools found no single tool that contained all accepted components for all three conditions.89

Health-related quality of life

The most frequently used questionnaire to assess health-related quality of life (HRQoL) in cachexia is the anorexia/cachexia subscale (A/CS) of the functional assessment of anorexia/cachexia therapy (FAACT). Recently, shortened versions for FAACT and FACT fatigue subscale have been published specifically for NSCLC,90 and higher cutoff values have been proposed (≤37 for the FAACT–A/CS and ≤70 for the visual analog scale for appetite, with 100 being a good appetite) in an attempt to improve the positive predictive value and capture more cachectic patients.91 Although the HRQoL instruments are traditionally confined to the research setting, it is possible that shortened versions may be feasible for daily clinical practice.

A relatively new European cancer cachexia questionnaire has been developed (EORTC QLQ-CAX24), which provides a more comprehensive assessment and includes 24 items, 5 multi-item scales (food aversion, eating and weight-loss worry, eating difficulties, loss of control, and physical decline) and 4 single items.92

Weight and body composition Body mass index (BMI)

BMI (BMI = body weight divided by height in kg/m2) is not useful in evaluating BC but does provide important information regarding energy reserves and, in combination with percentage weight loss, has been incorporated into a grading system for predicting prognosis. Other measures are necessary to evaluate BC and vary with regard to accuracy, cost, and patient comfort.

Anthropometrics

Anthropometrics to quantify skeletal muscle mass are noninvasive but require training and are difficult to measure accurately in obese and very old patients. A simple regional measure can be used in clinical practice to monitor the impact of therapy on arm muscle area,93 e.g., (Mid-arm circumference [MAC] in centimeters) − π × tricipital skinfold thickness [in millimeters])2/(4 × π) minus a correction factor of 10 for men and 6.5 for women. Another very simple test, requiring no equipment and found to be effective in screening for muscle atrophy in chronic liver disease, is the “finger-circle test’” that compares the size of the circle

Cachexia–Anorexia Syndrome

349

made with the bilateral thumb and index fingers of the patient with that of the calf of their leg.94

volume and change in response to an exercise intervention for chronic kidney disease patients.105

Bioelectrical impedance analysis (BIA)

Physical performance

BIA is noninvasive, portable, inexpensive, and uses a constant, low-level alternating current to measure impedance, consisting of resistance (water and electrolytes in fluids and tissues) and the reactance component in tissues (cells and tissue interfaces). The phase angle, a direct derivative of the reactance and resistance measurements, has correlated with outcome and health status in diverse cancer populations and even with healthy controls.95 Low sensitivity to detect subjects with reduced muscle mass is a limitation of BIA96; however, a systematic review concluded that BIA was a viable alternative to more expensive imaging modalities. The best use of BIA is for evaluation of individuals over time and monitoring a change in phase angle as the disease progresses.97

Imaging

Imaging is useful for assessment of BC and diagnosing sarcopenia. Skeletal muscle mass and composition have correlated with outcomes of muscle function, strength, and physical performance. Depending on resources, assessment goals, and patient comfort, imaging may entail DEXA, CT and magnetic resonance imaging (MRI), or ultrasound (US).

DEXA

DEXA has been the gold standard for research and clinical practice, providing information on lean soft tissue and fat at relatively low radiation levels and modest cost. DEXA also provides useful information regarding bone mineral content so that the composite musculoskeletal system (i.e., muscle plus bone) can be evaluated. This is especially important in older persons where the combination of osteopenia/osteoporosis and sarcopenia (osteosarcopenia) may be a marker for frailer individuals at higher risk of institutionalization, falls, and fractures.98

CT and MRI

CT scanning has the advantage of producing high-quality images that also provide measures of tissue composition and quality.99 Disadvantages of CT scans include radiation exposure and higher cost; however, CT scans may be regarded as a very useful “opportunistic tool”100 since oncology patients often have CT scans done as part of their routine care. BC analysis of muscle and different adipose tissue depots at the third lumbar vertebra cross-sectional area correlates with whole BC. Although a radiologist is not required for evaluation of BC, the CT images and the software for analysis, as well as trained personnel are required for accurate evaluation.104 In addition to BC assessment, CT or MRI is able to identify reduced muscle attenuation, an indicator of intermuscular adipose tissue or poor “quality” skeletal muscle. Muscle attenuation or myosteatosis has correlated with survival101 in oncology patients and recurrence-free survival after resection of pancreatic cancer.102 Myosteatosis also is also associated with reduced aerobic physical fitness in patients undergoing hepatobiliary and pancreatic surgery.103

Ultrasound

US is inexpensive, can be done repeatedly in the clinic or bedside, avoids radiation exposure,104 and is a reliable indicator of change in muscle size, based on preliminary studies. Analysis of rectus femoris by US was shown to be a reliable index of total quadriceps

There is no consensus regarding the use of specific tests for measuring physical performance in cachexia; however, assessments that are relatively brief and associated with cachexia-relevant outcomes include the short physical performance battery (SPPB), handgrip strength, stair climb,106 and 6MW test.

Short physical performance battery

The SPPB assesses lower extremity physical performance and requires between 6 and 10 minutes to complete. A meta-analysis found the SPPB score 80% of patients were mildly frail with an SPPB score of 30 days. In patients with rapidly progressive disease, evidence of advanced carcinomatosis with moderate-to-severe ascites, multiple levels of obstruction on cross-sectional imaging, a poor performance status, or a very short life expectancy of less than 30 days are best served by medical palliation of symptoms or the insertion of a drainage percutaneous endoscopic gastrostomy (PEG). The recently described endoscopic ultrasound-guided gastrojejunostomy (EUS-GJ) offers a potential improvement to endoscopic stenting with greater durability and longevity. This technique uses an echoendoscope to visualize, through the stomach wall, the surrounding organs, to locate the proximal jejunum, puncture into the jejunal lumen, and advance a covered self-expanding lumen apposing stent, with flanges to anchor the gastric and jejunal wall to prevent migration of the stent into the jejunum.68–70 This quickly creates a stent-assisted stoma between the stomach and jejunum. Initial case series and prospective registries have demonstrated a technical success rate of 92% and clinical success rate of 85% for relief of obstruction. This technique may be another minimally invasive alternative for managing patients with malignant gastric and duodenal obstruction.

Malignant small-bowel obstruction

Most gastroscopes are unable to reach beyond the ligament of Treitz, and colonoscopes are unable to reach very far retrograde into the terminal ileum. The recent development of long enteroscopes that can be advanced far into the small intestine through an overtube with pleating of the small bowel has permitted some investigators to report anecdotal success in stenting areas of the small intestine not previously accessible to standard endoscopes. With time and increasing experience, the ability to treat midjejunal and ileal points of malignant obstruction may become more available.70–73 The selection of patients appropriate for such interventions will, however, remain challenging.

Malignant colorectal obstruction

Malignant large-bowel obstruction can be managed by sigmoidoscopy, colonoscopy, or transanal wire-guided approaches under fluoroscopy alone. Published series have shown technical success rates for insertion of metallic stents ranging from 80 to 100%, with clinical improvement in symptoms reported in more than 75% of patients.48,74,75 Many patients treated with stents have a durable relief of symptoms until death from progression of disease, but as has been seen with the use of stents in other parts of the body, restenosis does occur, usually caused by tumor ingrowth through the interstices of the stent or stent migration. This can usually be managed with insertion of another stent, endoscopic dilation, or laser ablation.74–77

Malignant Bowel Obstruction Two analyses of pooled data from the multiple reported case series have been published.78,79 Both report clinical success rates of 88 and 91%, defined as resolution of obstructive symptoms following the insertion of stents. The limitations to success are a very proximal location of obstruction in the proximal colon and the ability to traverse a tortuous or tightly obstructing tumor with the endoscope or a guide wire. A greater success with stenting primary colorectal cancer has been noted, with lesser success for obstruction caused by extrinsic compression from metastatic or locally invasive pelvic tumors.77,80,81 Limited data on cost effectiveness of colorectal stenting are available in published reports, with some calculations suggesting a potential reduction in the estimated cost of palliation for such patients of approximately 50% compared to surgery.78 This is predominantly attributed to a reduced hospital stay with stenting. A recent multicenter study was completed demonstrating similar results with a newer generation of nitinol SEMS, called the Wallflex.82 This study, like most others, demonstrates the ease of use, high technical and short-term clinical efficacy, and low overall and serious complication rate. As in stenting in other parts of the GI tract, these procedures have acceptable published safety rates, with bleeding and perforation occurring in less than 5% of cases.78,79,83 One limitation of stent use in malignant colorectal obstruction is the location of obstruction involving the lower rectum. Although not widely published, stent placement for tumors that obstruct the mid or lower rectum may result in relief of obstruction but an insufficient remaining rectal reservoir, resulting in the development of intractable tenesmus and incontinence which severely impairs QOL.84 It is best to recognize such patients as inappropriate for treatment with a stent and consider performing surgical diversion or other palliative approaches. The proper evaluation of the efficacy of palliative treatments requires a careful assessment of the effect of each treatment on symptoms and the QOL and less attention on survival. In one prospective, nonrandomized study evaluating the effect of endoscopic stenting and surgical diversion in palliating malignant colorectal obstruction, symptoms improved significantly after either treatment but were more durable after stenting than after surgery. Although there was a trend, neither stenting nor surgery had a significant effect on overall QOL.82 This and other studies demonstrate how difficult it is to actually quantify the benefits of therapeutic interventions in the dying patient.

Drainage percutaneous endoscopic gastrostomy in bowel obstruction

Some patients with significant intraperitoneal disease not amenable to other options experience intractable nausea and vomiting which are relieved by the insertion of NGT. Long-term use of this tube is, however, associated with severe nasopharyngeal discomfort, pain with swallowing, speaking, and coughing, or may be cosmetically unacceptable and confine the patient at home. In such patients, gastric venting with PEG tube placement has become a widely acceptable alternative for palliating nausea and vomiting.27,84,85 Endoscopic or radiographically guided placement of drainage PEG tubes is a rapid and safe method of achieving symptomatic relief without the risks of a traditional surgical procedure even in the presence of ascites, adhesions, or tumor infiltration of the stomach. 84–87 However, for most patients with MBO from advanced peritoneal carcinomatosis, drainage PEG tubes only help to reduce some of the symptoms associated with MBO and often require additional efforts at controlling symptoms.

387

Pharmacological management of symptoms The pharmacological management of bowel obstruction due to advanced cancer focuses on the treatment of nausea, vomiting, pain, and other symptoms without the use of an NGT. If a central venous catheter has been previously inserted, this can be used to administer drugs for symptom control. Continuous subcutaneous infusion of drugs using a portable syringe driver allows the parenteral administration of different drug combinations, produces minimal discomfort for the patient, and is easy to use in a home setting. Drug therapy comprising analgesics, antisecretory drugs, and antiemetics, without using an NGT, was first described by Baines et al.88 Several authors have confirmed the efficacy of this approach. 3–7 In most MBO patients, oral administration is not suitable and most drugs can be administered via parenteral continuous infusion. To relieve continuous abdominal pain, opioid analgesics via continuous subcutaneous or intravenous infusion are necessary in most patients. The drugs and dosage has to be titrated and frequently reassessed for each patient until pain relief is achieved. Anticholinergics may be administered in association to opioids to control colicky pain7 (Figure 41.3). Vomiting can be managed using two different pharmacological approaches and reduced to an acceptable level for the patient (e.g., 1–2 times/day): (1) drugs such as anticholinergics (scopolamine butylbromide [SB], glycopyrrolate) and/or octreotide, which reduce GI secretions, and (2) antiemetics acting on the central nervous system, alone or in association with drugs to reduce GI secretions (Figure 41.3). For example, olanzapine at the dose of 4.9 mg ± 1.2 mg for 23 ± 16 days significantly decreased the average nausea score in 90% of patients and the vomiting frequency (p < 0.001) in incomplete bowel obstruction unresponsive to chlorpromazine, corticosteroids, domperidone, haloperidol, metoclopramide, or prochlorperazione.89 Another strategy to reduce gastric secretions is the use of histamine-2 receptor antagonists and proton-pump inhibitors (PPIs). A meta-analysis based on seven randomized controlled trials (RCTs) showed both drugs reduced gastric secretions and ranitidine was the most potent.90 Based on this report, we cannot make final conclusions, but these findings represent another tool available in the management of this condition and something that needs further investigation. Several authors recommend the use of corticosteroids for the symptoms due to bowel obstruction because it can reduce peritumoral inflammatory edema, thus improving intestinal motility. No robust trials have been carried out and administration routes and dosing of these drugs have not been standardized as yet. A systematic review showed a tendency but not significant reduction in symptoms in the steroids group compared to the placebo. In terms of mortality, there are no differences between both groups. The role of corticosteroids in treating bowel obstruction is still controversial.91 However, the coadministration of octreotide, corticosteroids, and metoclopramide produced a prompt resolution of GI symptoms and recovery of bowel movements within 5 days.92 SB is a frequently used drug for both vomiting and colicky pain by some palliative care centers.88,93–95 This drug differs from both atropine and scopolamine hydrobromide in having a low lipid solubility. It does not penetrate the blood–brain barrier as much as these other drugs and, consequently, may produce fewer side effects, such as somnolence and hallucinations, when administered in combination with opioids. The anticholinergic activity

388

Textbook of Palliative Medicine and Supportive Care

FIGURE 41.3  Symptomatic pharmacological approach.

of SB decreases the tonus and peristalsis in smooth muscle and decreases the secretions in the GI tract. The antiemetic, antisecretory, as well the analgesic role of SB administered subcutaneously by a syringe driver has been well documented. Dry mouth is reported to be the most significant side effect, but the patients tolerated it by sucking ice cubes and drinking small sips of water. Anticholinergic agents such as scopolamine hydrobromide or butylbromide and glycopyrrolate reduce colicky pain and the volume of intestinal secretions. Glycopyrrolate, which is used as an antisecretory drug in the United States, is more potent than scopolamine hydrobromide and may be effective in some patients who fail to respond to scopolamine.96 It has little central nervous system penetration and is unlikely to cause the delirium that has been associated with tertiary amine anticholinergics. Octreotide, a synthetic analog of somatostatin that has a more potent biological activity and a longer half-life, has been shown to inhibit the release and activity of GI hormones, modulate GI function by reducing gastric acid secretion, slow intestinal motility, decrease bile flow, increase mucous production, and reduce splanchnic blood flow. It reduces GI contents and increases absorption of water and electrolytes at intracellular level via cAMP and calcium regulation. Submucosal somatostatin-containing neurons, activated by octreotide, inhibit excitatory nerves, mainly by an inhibition of acetylcholine output. Octreotide has been shown to have a potent anti-VIP effect resulting in the inhibition of intestinal secretions.97–99 Also in the in vitro experiments on rabbit ileum, somatostatin was able to stimulate water and NaCl absorption, inhibit HCO3 secretion, and inhibit water secretion in the jejunum.13,100 As a result, muscle relaxation can occur, ameliorating the spastic activity responsible for colicky pain. The drug may therefore break the vicious circle represented by secretion, distension, and contractile hyperactivity.

Experimental studies suggest that the principal mechanism of fluid secretion in bowel obstruction depends on VIP-induced inflammatory events.13,97,101 Another inhibitory mechanism of hormonal release occurs through the activation of a G protein, which, on stimulating the potassium channels, determines the hyperpolarization of the cell, with the consequent blockage of the flux of calcium to the cell.102 Octreotide may be administered by subcutaneous bolus or continuous subcutaneous or intravenous infusion. Its half-life is about 1.5 hours after intravenous or subcutaneous administration and its kinetics are linear. The recommended starting dose is 0.3 mg/day subcutaneously. The dose can be titrated upward until symptom control is achieved in general 0.6–0.9 mg/day. Octreotide is an expensive drug, and its cost–benefit ratio should be carefully considered, especially for prolonged treatment. However, the cost of the drug should be interpreted in the widest possible sense, that is, if the use of a drug results in a more rapid improvement of GI symptoms that potentially limits the bed stay or the admission to an inpatient unit in addition to a better QOL of the patient.103

Efficacy of octreotide in patients with GI symptoms due to inoperable malignant bowel obstruction

Many studies, although uncontrolled, strongly support the use of octreotide in reducing GI secretions, nausea, and vomiting in patients with MBO. 3,5,7,12,104–121 In many cases, the NGT can be removed. Reported effective doses range from 100 to 600 mcg/ day either as a continuous infusion or as intermittent subcutaneous boluses. Octreotide has been coadministered with numerous other agents including morphine, haloperidol, and SB. All the authors were able to show the efficacy on emesis in cancer patients with intractable continual vomiting due to small-/ large-bowel obstruction that was unresponsive to conventional therapy (prochlorperazine, metoclopramide, cyclizine, and

Malignant Bowel Obstruction

389

dexamethasone). Octreotide was administered subcutaneously in association (or not) with opioid analgesics and with antiemetics. Symptom control was maintained until death. No adverse effects were attributable to the drugs. The NGT was removed in most patients. In the four prospective studies published in 2000–2018,118–121 different antiemetics were used as single agent or in association.118 Frequently antiemetics are used in association with corticosteroids and so it may be the combination rather than the single drug which was effective. Octreotide was successfully used for treating nausea and vomiting in patients with different primary cancers. 3,5,7,12,104–121 In the presence of marked and diffuse bowel distension, the administration of octreotide may reduce GI secretions and thus allow an appropriate site for PEG placement to be obtained.112 These studies, although uncontrolled, support the use of octreotide in the management of GI symptoms due to inoperable MBO. Reported effective doses range from 0.1 to 0.6 mg/ day either as a continuous parenteral infusion or as intermittent subcutaneous or intravenous boluses. Octreotide, administered in association, respectively, with morphine or hyoscine butylbromide (HB) or haloperidol (0.5—1.2 mg/mL), does not show visual precipitation when mixed in the syringe.7 Recognizing that octreotide is an expensive therapy and considering the fact that the goal of the treatment is the improvement in the QOL of the patient and based on the strong evidence available in the literature that supports a real benefit with the use of this medication,

the authors of this chapter consider that octreotide should be part of the treatment once the patient is diagnosed despite the cost. Randomized clinical trials carried out in patients with MBO are summarized in Table 41.4.122–125 From 2009 to 2018, four randomized trials (three double-blind) were published.122–125 Results related to octreotide are fairly consistent across studies (see Table 41.4 for details). In trials where corticosteroids were not used,119–121,123 there was an important improvement of nausea and vomiting with improvements in secondary outcomes as opposed to trials that included corticosteroids and antiemetics.122,124

Comparative studies between octreotide and scopolamine butylbromide

Three randomized trials have compared octreotide with SB.126–128 In all of these trials, octreotide was superior in the control of symptoms compared to SB. Two randomized prospective studies were carried out to compare the antisecretory effects of octreotide (0.3 mg/day) and SB (60 mg/day) administered by continuous subcutaneous infusion for 3 days in 17 patients with inoperable bowel obstruction having an NGT126 and in 15 patients without NGT.127 In both studies, 50% of the patients were cared for at home and the other half were hospitalized in surgical wards. In both studies, the hospitalized patients received significantly more parenteral hydration (2000 vs. 500 mL daily) with respect to the patients cared for at home.

TABLE 41.4  Summary of Randomized Controlled Trials122–125 Standard Therapy Drugs Under Study Co-administered Currow DC122

Infusion in 24 hours Ocreotide 600 µg (OCT) or placebo (P) Comparative trial

Peng X123 SC infusion in 24 hours of OCT 300 µg or scopolamine butylbromide (SB) 60 mg comparative trial

Infusion in 24 hours: Ranitidine 200 mg Dexamethasone 8 mg Hydration 10/20 mL/Kg As needed therapies - Hyoscine butylbromide (HB) PRN for colic - Opioids for pain - Haloperidol for nausea Not possible: The use of steroids, antiemetics, anticholinergics, H2 blockers, omeprazole 3.5 L of fluids used Pain treated according WHO guidelines

Type of n. PT Population Study with Cancer Duration 87 patients Double blind, (45 on OCT): placebo - No cancer controlled treatments randomized - Inoperable 3 days (clinical assessment of 2 medical practitioners)

96 patients with RCT advanced 3 days ovarian cancer and NGT (48 on OCT): - No cancer treatments - Inoperable (assessment of surgeon)

Outcomes and Tools

Results

Primary - Pts reported days free of vomiting at 72 hours Secondary - Vomiting episodes - Patient-rated global impression of change (-3% + 3) - Survival - Nausea (NGT-CTCAE) - Pain (BPI) - Australian KPS Primary - Antisecretive effect between OCT and SB Parameters measured daily: - Number of vomiting episodes - Nausea, dry mouth drowsiness, continuous and colicky pain By a Likert scale (0 = no, 1 = slight, 2 = moderate, 3 = severe) - ECOG - Quantity of GI secretions through the NGT

- No difference in number of days free from vomiting: 1.87 vs. 1.69 (OCT vs. controls) - Significant decrease in vomiting episodes with OCT (IRR = 0.4, 95% CI: 0.19–0.86, p = 0.019) - No difference in patient perceived global improvement and survival - No difference in nausea or pain - OCT was associated with increased need for HB (OR = 2) - OCT significantly reduced secretions > SB(p < 0.05) - SB reduced secretions at (T3) - OCT reduced vomiting significantly more than SB day 1–3 (p < 0.05) - Reduction of vomiting with SB occurred at day 3 - OCT reduced nausea at day 2, 3, 7 more than SB (p < 0.05) - No change in colicky pain, dry mouth or drowsiness - Continuous pain was significantly lower with OCT as compared with SB at day 2 and 3 (p < 0.05) (Continued)

Textbook of Palliative Medicine and Supportive Care

390

TABLE 41.4  Summary of Randomized Controlled Trials122–125 (Continued) Standard Therapy Drugs Under Study Co-administered Laval G124 On days 1,29,57 30 mg IM OCT LAR + On days 1 to 6 600 µg OCT IR, SC or IV and IV bolus methylprednisolone (3 to 4 mg/kg/day)

Mariani et al.125

30 mg lanreotide microparticles vs. placebo Patients previously treated with IV corticosteroids and proton-pump inhibitors

Possible therapies Parenteral hydration/ nutrition, antiemetics, antispasmodics, proton-pump inhibitors, H2 anatagonists, analgesics, and NGT

Type of n. PT Population Study with Cancer Duration The study started in 2005 and finished in 2008 102 patients planned and 64 enrolled (32 OCT and 32 P) All the patients had peritoneal carcinomatosis - Inoperable (assessment of surgeon) 80 patients with peritoneal carcinomatosis (37 P) 67 pts (84%) completed the study - Inoperable (assessment of surgeon)

Randomized phase II pilot study Double blind Placebo group noncomparison 14 days

Outcomes and Tools

Results

Primary Imbalance with lower KPS in ITT at day 14 octreotide arm - Response = < 2 vomiting • 28 withdrew between episode days 10–13, baseline to day 14 - No NGT between day • ITT analysis 10–13 • Response: 12 octreotide, 9 - No anticholinergic until placebo, (p > 0.05) day 14, withdrawal prior to • Median survival: 31.5 days day 14 octreotide, 44 days placebo Secondary QoL by ESAS

Double blind Primary More patients on lanreotide than parallelProportion of patients placebo were responders but not group phase responding on day 7 (1 or statistically significant for the 10 days less episodes of vomiting/ primary analysis (ITT ) day or no vomiting population and statistically recurrence after NGT significant for the supportive PP removal for ≥ 3 analysis (p < 0.05) and ITT consecutive days analysis on the basis of Secondary investigators’ assessments Frequency of vomiting/ (p < 0.05) NGT secretions, nausea, Well-being significantly greater abdominal pain, wellwith lanreotide on days 3, 6, and 7 being, safety No difference for secondary end-points

Abbreviations: SC, subcutaneously; NGT, nasogastric tube; RCT, randomized clinical trial, IM, intramuscular; LAR, long-acting release; IR, immediate release.

In the study of Ripamonti et al.,126 octreotide was shown to significantly reduce the amount of GI secretions already at T2 (p = 0.016) and T3 (p = 0.020). The NGT could be removed in all 10 home care patients and in 3 hospitalized patients without changing the dosage of the drug. In three patients, it was possible to remove the NGT when the octreotide was added to SB (one patient) or when the SB dose was doubled and parenteral hydration was reduced (one patient). Also in these patients, octreotide showed a trend toward better efficacy than SB. It can be hypothesized that in the hospitalized patients, the major difficulty in removing the NGT was associated with the higher amount of parenteral hydration. In the second study,127 octreotide treatment induced a significantly rapid reduction in the number of daily episodes of vomiting and intensity of nausea when compared to SB-treated patients, examined at the different time intervals. In the third RCT, Mystakidou et al.128 evaluated the efficacy of octreotide in the management of nausea, vomiting, and abdominal pain, secondary to MBO in inoperable cancer patients. Sixtyeight terminally ill patients were enrolled, and the patients were randomly assigned to two equal groups. One group received SB 60–80 mg/day and chlorpromazine 15–25 mg/day, and the comparative group received octreotide 0.6–0.8 mg/day and chlorpromazine 15–25 mg/day. The drugs were administered via continuous subcutaneous infusion. Patients on octreotide presented significant less intensity of nausea and quantity of vomiting episodes. The survival time ranged from 7 to 61 days.128

The association of the two drugs (octreotide and SB) may reduce GI secretions and vomiting whenever one drug alone is ineffective.117,126 Recently 2016 updated MASCC/ESMO consensus recommendations on the management of nausea and vomiting in advanced cancer was published.129 Octreotide is the recommended drug in MBO, it has to be dosed around the clock and given alongside an antiemetic (with the committee recommended haloperidol). If octreotide plus antiemetic is ineffective, the use of anticholinergic antisecretory agents (e.g., SB and glycopyrronium bromide) and/or corticosteroids is recommended as either adjunct or alternative interventions. The use of cyclizine or 5-HT3 receptor antagonists is ill defined in this setting. Metoclopramide is relatively contraindicated in partial bowel obstruction and absolutely contraindicated in complete bowel obstruction.

Conclusions Bowel obstruction should be carefully evaluated by experienced physicians, considering individual and prognostic factors, as well as life expectancy. Different options may be chosen depending on the goals of intervention, and the modalities of occurrence of bowel obstruction, as well as the patient’s conditions. Involvement of patient and family members in this therapeutic decision-making is mandatory, based on clear information about the clinical status and the possible evolution of the clinical course. Further controlled studies on large

Malignant Bowel Obstruction numbers of patients are needed, looking at the problems from the epidemiological and prognostic point of view. Comparative trials performed at different stages of bowel obstruction could make an important contribution to defining the best treatments in potentially reversible conditions as well as established MBO.

391

KEY LEARNING POINTS



• MBO is the most distressing outcome in patients with abdominal and pelvic cancer in the advanced and terminal stage of disease. • Surgery should not routinely be undertaken in patients with poor prognostic criteria such as intra-abdominal carcinomatosis, poor performance status, and massive ascites. • Medical measures such as analgesics, antisecretory drugs, and antiemetics administered alone or in combination should be used to relieve symptoms. • Endoscopic management of MBO should always be considered. • An NGT should be used only as a temporary measure, and a venting gastrostomy should be considered if drugs fail in reducing vomiting to an acceptable level. • Total parenteral nutrition (TPN) should be considered only for patients who may die sue to starvation rather than from tumor spread. • Parenteral hydration is sometimes indicated to correct nausea, and regular mouth care is the treatment of choice for dry mouth. • A collaborative approach by surgeons and physicians can offer patients an individualized and appropriate symptom management plan.



References





1. Anthony T, Baron T, Mercadante S, et al. Report of the clinical protocol committee: development of randomized trials for malignant bowel obstruction. J Pain Symptom Manage 2007;34:S49–S59. 2. Krouse RS. The international conference on malignant bowel obstruction: a meeting of the minds to advance palliative care research. J Pain Symptom Manage 2007;34:S1–S6. 3. Baines M. The Pathophysiology and Management of Malignant Intestinal Obstruction. In: Doyle D, Hanks GWC, and MacDonald N, eds. Oxford Testbook of Palliative Medicine, 2nd edn. New York: Oxford University Press, 1998, p. 526. 4. Ripamonti C. Malignant Bowel Obstruction. In: Ripamonti C, Bruera E, eds. Gastrointestinal Symptoms in Advanced Cancer Patients. New York: Oxford University Press, 2002, vol. 12, p. 235. 5. Ripamonti C, Mercadante S. Pathophysiology and Management of Malignant Bowel Obstruction. In: Doyle D, Hanks G, et al., eds., Oxford Textbook of Palliative Medicine, 3rd edn. New York: Oxford University Press, 2004. vol. 8, pp. 496–506. 6. Krebs HB, Goplerud DR. Mechanical intestinal obstruction inpatients with gynecologic disease: a review of 368 patients. Am J Obstet Gynecol 1987;157:577–579. 7. Ripamonti C, Twycross R, Baines M, et al. Clinical-practice recommendations for the management of bowel obstruction in patients with end-stage cancer. Support Care Cancer 2001;19:23–34. 8. Feuer DJ, Broadley KE, Shepherd JH, Barton DPJ. Systematic review of surgery in malignant bowel obstruction in advanced gynecological and gastrointestinal cancer. Gynecol Oncol 1999;75:313–322.









9. Tunca JC, Buchler DA, Mack EA, Ruzicka FF, Crowley JJ, Carr WF. The management of ovarian-cancer-caused bowel obstruction. Gynecol Oncol 1981;12:186–192. 10. Krebs HB Goplerud DR. Surgical management of bowel obstruction in advanced ovarian carcinoma. Obstet Gynecol 1983;61:327–330. 11. Correa R, Ripamonti CI, Dodge JE, Easson AM. Malignant bowel obstruction. In: Davis M, et al. eds. Supportive Oncology. Philadelphia, PA: Elsevier/ Saunders, 2011; vol.30, pp. 326–341. 12. Riley J, Fallon MT. Octreotide in terminal malignant obstruction of the gastrointestinal tract. Eur J Palliat Care 1994;1:23–28. 13. Ripamonti C, Panzeri C, Groff L, et al. The role of somatostatin and octreotide in bowel obstruction: Pre-clinical and clinical results. Tumori 2001;87:1–9. 14. Furukawa A, Yamasaki M, Takahashi M, et al. CT diagnosis of small bowel obstruction: scanning technique, interpretation and role in the diagnosis. Semin Ultrasound CT MR 2003;24(5):336–352. 15. Suri S, Gupta S, Sudhakar PJ, Venkataramu NK, Sood B, Wig JD. Comparative evaluation of plain films, ultrasound and CT in the diagnosis of intestinal obstruction. Acta Radiol 1999;40(4):422–428. 16. Angelelli G, Moschetta M, Binetti F, Cosmo T, Stabile Ianora AA. Prognostic value of MDCT in malignant large-bowel obstructions. Radiol Med 2010;115(5):747–757. 17. Angelelli G, Moschetta M, Sabato L, Morella M, Scardapane A, Stabile Ianora AA. Value of “protruding lips” sign in malignant bowel obstructions. Eur J Radiol 2011;80(3):681–685. 18. Krouse RS. Malignant bowel obstruction. J Surg Oncol 2019;120(1):74–77. 19. Ferguson HJ, et al. Management of intestinal obstruction in advanced malignancy. Ann Med Surg (Lond) 2015;4(3):264–270. 20. Wancata LM, et al. Outcomes after surgery for benign and malignant small bowel obstruction. J Gastrointest Surg 2017;21(2):363–371. 21. Cousins SE, et al. Surgery for the resolution of symptoms in malignant bowel obstruction in advanced gynaecological and gastrointestinal cancer. Cochrane Database Syst Rev 2016;(1):Cd002764. 22. Lee YC, et al. Malignant bowel obstruction in advanced gynecologic cancers: an updated review from a multidisciplinary perspective. Obstet Gynecol Int 2018;2018:1867238. 23. Tuca A, et al. Malignant bowel obstruction in advanced cancer patients: epidemiology, management, and factors influencing spontaneous resolution. Cancer Manage Res 2012;4:159–169. 24. Furnes B, et al. Challenges and outcome of surgery for bowel obstruction in women with gynaecologic cancer. Int J Surg 2016;27:158–164. 25. Dean E, et al. Malignant bowel obstruction in advanced ovarian cancer. Future Oncol 2017;13(6):513–521. 26. Deutsch GB, et al. Intellectual equipoise and challenges: accruing patients with advanced cancer to a trial randomizing to surgical or nonsurgical management (SWOG S1316). Am J Hosp Palliat Care 2020;37(1):12–18. 27. Dittrich A, et al. Benefits and risks of a percutaneous endoscopic gastrostomy (PEG) for decompression in patients with malignant gastrointestinal obstruction. Support Care Cancer 2017;25(9):2849–2856. 28. Helyer LK, Law CH, Butler M, Last LD, Smith AJ, Wright FC. Surgery as a bridge to palliative chemotherapy in patients with malignant bowel obstruction from colorectal cancer. Ann Surg Oncol 2007;14(4):1264–1271. 29. Wright FC, Chakraborty A, Helyer L, Moravan V, Selby D. Predictors of survival in patients with non-curative stage IV cancer and malignant bowel obstruction. J Surg Oncol 2010;101(5):425–429. 30. Imai K, Yasuda H, Koda K, et al. An analysis of palliative surgery for the patients with malignant bowel obstruction. Gan To Kagaku Ryoho 2010;37(Suppl 2):264–267. 31. Hancock K, Clayton JM, Parker SM, et al. Truth-telling in discussing prognosis in advanced life-limiting illnesses: a systematic review. Palliat Med 2007;21(6):507–517. 32. Hofmann B, Haheim LL, Soreide JA. Ethics of palliative surgery in patients with cancer. Br J Surg 2005;92(7):802–809. 33. Lilley, EJ, et al. Using a palliative care framework for seriously ill surgical patients: the example of malignant bowel obstruction. JAMA Surg 2016;151(8):695–696. 34. Lilley EJ, et al. Palliative care in surgery: defining the research priorities. Ann Surg 2018;267(1):66–72. 35. Dalal KM, Gollub MJ, Miner TJ, et al. Management of patients with malignant bowel obstruction and stage IV colorectal cancer. J Palliat Med 2011;14(7):822–828. 36. Chakraborty A, Selby D, Gardiner K, Myers J, Moravan V, Wright F. Malignant bowel obstruction: natural history of a heterogeneous

392











patient population followed prospectively over two years. J Pain Symptom Manage 2011;41(2):412–420. 37. Santangelo ML, et al. Bowel obstruction and peritoneal carcinomatosis in the elderly. A systematic review. Aging Clin Exp Res 2017;29(Suppl 1):73–78. 38. Maeda Y, et al. A laparoscopic approach is associated with a decreased incidence of SSI in patients undergoing palliative surgery for malignant bowel obstruction. Int J Surg 2017;42:90–94. 39. Abelson JS, et al. Long-term postprocedural outcomes of palliative emergency stenting vs. stoma in malignant large-bowel obstruction. JAMA Surg 2017;152(5):429–435. 40. Daniele A, et al. Palliative care in patients with ovarian cancer and bowel obstruction. Support Care Cancer 2015;23(11):3157–3163. 41. Braga M, Ljungqvist O, Soeters P, Fearon K, Weimann A, Bozzetti F. ESPEN guidelines on parenteral nutrition: surgery. Clin Nutr 2009;28(4):378–386. 42. MacDonald N, Easson AM, Mazurak VC, Dunn GP, Baracos VE. Understanding and managing cancer cachexia. J Am Coll Surg 2003;197(1):143–161. 43. Bozzetti F, Arends J, Lundholm K, Micklewright A, Zurcher G, Muscaritoli M. ESPEN guidelines on parenteral nutrition: nonsurgical oncology. Clin Nutr 2009;28(4):445–454. 44. Varker KA, Ansel A, Aukerman G, Carson WE, III. Review of complementary and alternative medicine and selected nutraceuticals: background for a pilot study on nutrigenomic intervention in patients with advanced cancer. Altern Ther Health Med 2012;18(2):26–34. 45. Paccagnella A, Morassutti I, Rosti G. Nutritional intervention for improving treatment tolerance in cancer patients. Curr Opin Oncol 2011;23(4):322–330. 46. Rabinovitch R, Grant B, Berkey BA, et al. Impact of nutrition support on treatment outcome in patients with locally advanced head and neck squamous cell cancer treated with definitive radiotherapy: a secondary analysis of RTOG trial 90–03. Head Neck 2006;28(4):287–296. 47. Rueda JR, Sola I, Pascual A, Subirana CM. Non-invasive interventions for improving well-being and quality of life in patients with lung cancer. Cochrane Database Syst Rev 2011;2011(9):CD004282. 48. Mainar A, De Gregorio MA, Tejero E, et al. Acute colorectal obstruction: treatment with self-expandable metallic stents before scheduled surgery: results of a multicenter study. Radiology 1999;210:65–69. 49. Lowe AS, Beckett CG, Jowett S, et al. Self-expandable metal stent placement for the palliation of malignant gastroduodenal obstruction: experience in a large, single, UK centre. Clin Radiol 2007;62:738–744. 50. Telford JJ, Carr-Locke DL, Baron TH, et al. Palliation of patients with malignant gastric outlet obstruction with the enteral wall stent: outcomes from a multicenter study. Gastrointest Endosc 2004;60:916–920. 51. Dormann A, Meisner S, Verin N, et al. Self-expanding metal stents for gastroduodenal malignancies: systematic review of their clinical effectiveness. Endoscopy 2004;36:543–550. 52. Nassif T, Prat F, Meduri B, et al. Endoscopic palliation of malignant gastric outlet obstruction using self-expandable metallic stents: Results of a multicenter study. Endoscopy 2003;35:483–489. 53. Costamagna G, Tringali A, Spicak J, et al. Treatment of malignant gastroduodenal obstruction with a nitinol self-expanding metal stent: an international prospective multicentre registry. Dig Liv Dis 2012;44(1):37–43. 54. Arya N, Bair D, Arya P, Pham J. Community experience of colonic stenting in patients with acute large bowel obstructions. Can J Surg 2011;54(4):283–285. 55. Piesman M, Kozarek RA, Brandbur JJ, et al. Improved oral intake after palliative duodenal stenting for malignant obstruction: a prospective multicenter clinical trial. Am J Gastro 2009;104:2403–2411. 56. Espinel J, Sanz O, Vivas S, et al. Malignant gastrointestinal obstruction: Endoscopic stenting versus surgical palliation. Surg Endosc 2006;20:1083–1087. 57. Lillemoe KD, Cameron JL, Hardacre JM, et al. Is prophylactic gastrojejunostomy indicated for unresectable periampullary cancer? A prospective randomized trial. Ann Surg 1999;230:322–328. Discussion 328–330. 58. Jeurnink SM, Steyerberg EW, Hof GV, et al. Gastrojejunostomy versus stent placement in patients with malignant gastric outlet obstruction: a comparison in 95 patients. J Surg Oncol 2007;96:389–396. 59. Mendelsohn RB, Gerdes H, Markowitz AJ, et al. Carcinomatosis is not a contraindication to enteral stenting in selected patients with malignant gastric outlet obstruction. Gastrointest Endosc 2011 June;73(6):1135–1140.

Textbook of Palliative Medicine and Supportive Care 60. Kim JH, Son HY, Shin JH, et al. Metallic stent placement in the palliative treatment of malignant gastroduodenal obstructions: prospective evaluation of results and factors influencing outcome in 213 patients. Gastrointest Endosc 2007;66:256–264. 61. Holt AP, Patel M, Ahmed MM. Palliation of patients with malignant gastroduodenal obstruction with self-expanding metallic stents: the treatment of choice? Gastrointest Endosc 2004;60:1010–1017. 62. Jang JK, Song HY, Kim JH, et al. Tumor overgrowth after expandable metallic stent placement: Experience in 583 patients with malignant gastroduodenal obstruction. Am J Roentgenol 2011 June;196(6):W831–W836. 63. Dafnis G. Repeated coaxial colonic stenting in the palliative management of benign colonic obstruction. Eur J Gastroenterol Hepatol 2007 January;19(1):83–86. 64. Wong YT, Brams DM, Munson L, et al. Gastric outlet obstruction secondary to pancreatic cancer: surgical vs endoscopic palliation. Surg Endosc 2002;16:310–312. 65. Phillips MS, Gosain S, Bonatti H, et al. Enteral stents for malignancy: A report of 46 consecutive cases over 10 years, with critical review of complications. J Gastrointest Surg 2008 November;12(11):20452050. 66. Mehta S, Hindmarsh A, Cheong E, et al. Prospective randomized trial of laparoscopic gastrojejunostomy versus duodenal stenting for malignant gastric outflow obstruction. Surg Endosc 2006;20:239–242. 67. Schmidt C, Gerdes H, Hawkins W, et al. A prospective observational study examining quality of life in patients with malignant gastric outlet obstruction. Am J Surg 2009;198:92–99. 68. Tyberg A, et al., Endoscopic ultrasound-guided gastrojejunostomy with a lumen-apposing metal stent: a multicenter, international experience Endosc Int Open. 2016 March;4(3):E276–E281. 69. Khashab MA, et al., EUS-guided gastroenterostomy: the first U.S. clinical experience (with video). Gastrointest Endosc 2015 Nov;82(5):932–938. 70. Itoi T, et al., Prospective evaluation of endoscopic ultrasonographyguided double-balloon-occluded gastrojejunostomy bypass (EPASS) for malignant gastric outlet obstruction Gut 2016 February;65(2):193–195. 71. Lennon AM, Chandrasekhara V, Shin EJ, et al. Spiral-enteroscopyassisted enteral stent placement for palliation of malignant smallbowel obstruction. GIE 2010;71(2):422–425. 72. Ross AS, Semrad C, Waxman I, et al. Enteral stent placement by double balloon enteroscopy for palliation of malignant small bowel obstruction. GIE 2006;65(5):835–837. 73. Lee H, Park JC, Shin SK, et al. Preliminary study of enteroscopyguided, self-expandable metal stent placement for malignant small bowel obstruction. J Gastroenterol Hepatol 2012;27(7):1181–1186. 74. Camunez F, Echenagusia A, Simo G, et al. Malignant colorectal obstruction treated by means of self-expanding metallic stents: effectiveness before surgery and in palliation. Radiology 2000;216: 492–497. 75. Law WL, Chu KW, Ho JW, et al. Self-expanding metallic stent in the treatment of colonic obstruction caused by advanced malignancies. Dis Colon Rectum 2000;43:1522–1527. 76. Nash CL, Markowitz AJ, Schattner M, et al. Colorectal stents for the management of malignant large bowel obstruction. Gastrointest Endo 2002;55:AB216. 77. Pothuri B, Guiguis A, Gerdes H, et al. The use of colorectal stents for palliation of large bowel obstruction due to recurrent gynecologic cancer. Gynecol Oncol 2004;95:513–517. 78. Khot UP, Wenk Lang A, Murali K, et al. Systematic review of the efficacy and safety of colorectal stents. Br J Surg 2002;89:1096–1102. 79. Sebastian S, Johnston S, Geoghegan T, et al. Pooled analysis of the efficacy and safety of self-expanding metal stenting in malignant colorectal obstruction. Am J Gastro 2004;99:2051–2057. 80. Caceres A, Zhou Q, lasonos A, et al. Colorectal stents for palliation of large-bowel obstructions in recurrent gynecologic cancer: an updated series. Gynecol Oncol March 2008;108(3):482–485. 81. Nagula S, Ishil N, Nash C, et al. Quality of life and symptom control after stent placement or surgical palliation of malignant colorectal obstruction. J Am Coll Surg 2010;210:45–53. 82. Meisner S, Gonzalez-Huix F, Vandervoort JG, et al. Self-expandable metal stents for relieving malignant colorectal obstruction: short-term safety and efficacy within 30 days of stent procedure in 447 patients. Gastro Endo 2011;74(4):876–884. 83. Dohmoto M, Hunerbein M, Schlag PM. Application of rectal stents for palliation of obstructing rectosigmoid cancer. Surg Endosc 1997;11:758–761.

Malignant Bowel Obstruction 84. Campagnutta E, Cannizzaro R, Gallo A, et al. Palliative treatment of upper intestinal obstruction by gynecological malignancy: the usefulness of percutaneous endoscopic gastrostomy. Gynecol Oncol 1996;62:103–105. 85. Pothuri B, Montemarano M, Gerardi M, et al. Percutaneous endoscopic gastrostomy tube placement in patients with malignant bowel obstruction due to ovarian carcinoma. Gynecol Oncol 2005;96:330–334. 86. Vashi PG, Dahlk S, Vashi RP, et al. Percutaneous endoscopic gastrostomy tube occlusion in malignant peritoneal carcinomatosisinduced bowel obstruction. Eur J Gastroenterol Hepatol November 2011;23(11):1069–1073. 87. Piccinni G, Angrisano A, Testini M, et al. Venting direct percutaneous jejunostomy (DPEJ) for drainage of malignant bowel obstruction in patients operated on for gastric cancer. Support Care Cancer 2005;13:535–539. 88. Baines M, Oliver DJ, Carter RL. Medical management of intestinal obstruction in patients with advanced malignant disease: a clinical and pathological study. Lancet 1985;2:990–993. 89. Kaneishi K, Kawabata M, Morita T. Olanzapine for the relief of nausea in patients with advanced cancer and incomplete bowel obstruction. J Pain Symptom Manage 2012;44(4):604–607. 90. Clark K, Lam L, Currow D. Reducing gastric secretions: a role for histamine 2 antagonists or proton pump inhibitors in malignant bowel obstruction? Support Care Cancer 2009;17(12):1463–1468. 91. Feuer DJ, Broadley KE; members of the systematic review steering committee. Systematic review and meta-analysis of corticosteroids for the resolution of malignant bowel obstruction in advanced gynaecological and gastrointestinal cancers. Ann Oncol 1999;10:1035–1041. 92. Porzio G, Aielli F, Verna L, et al. Can malignant bowel obstruction in advanced cancer patients be treated at home? Support Care Cancer 2011;19:431–433. 93. Ventafridda V, Ripamonti C, Caraceni A, et al. The management of inoperable gastrointestinal obstruction in terminal cancer patients. Tumori 1990;76:389–393. 94. Fainsinger RL, Spachynski K, Hanson J, et al. Symptom control in terminally ill patients with malignant bowel obstruction. J Pain Symptom Manage 1994;9:12–18. 95. De Conno F, Caraceni A, Zecca E, et al. Continuous subcutaneous infusion of hyoscine butylbromide reduces secretions in patients with gastrointestinal obstruction. J Pain Sympt Manage 1991;6:484–486. 96. Davis MP, Furste A. Glycopyrrolate: a useful drug in the palliation of mechanical bowel obstruction. J Pain Symptom Manage 1999;18:153–154. 97. Basson MD, Fielding LP, Bilchik AJ, et al. Does vasoactive intestinal polypeptide mediate the pathophysiology of bowel obstruction? Am J Surg 1989;157:109–115. 98. Nellgard P, Bojo L, Cassuto J. Importance of vasoactive intestinal peptide and somatostatin for fluid losses in small-bowel obstruction. Scan J Gastroenterol 1995;30:464–469. 99. Neville R, Fielding P, Cambria RP, Modlin I. Vascular responsiveness in obstructed gut. Dis Col Rect 1991;34:229–235. 100. Dharmsathaphorn K, Binder HJ, Dobbins WJ. Somatostatin stimulates sodium and chloride absorption in the rabbit ileum. Gastroenterology 1980;78:1559–1565. 101. Nellgard P, Cassuto J. Inflammation as a major cause of fluid losses in small-bowel obstruction. Scand J Gastroenterol 1993;28:1035–1041. 102. Yatani A, Birnbaumer L, Brown AM. Direct coupling of the somatostatin receptor to potassium channels by a G protein. Metabolism 1990;39(9 Suppl):91–95. 103. Ripamonti C, Mercadante S. How to use octreotide for malignant bowel obstruction. J Support Oncol 2004;2(4):357–364. 104. Yamaner S, Bugra D, Muslumanoglu M, Bulut T, Cubukcu O, Ademoglu E. Effects of octreotide on healing of intestinal anastomosis following small bowel obstruction in rats. Dis Colon Rectum 1995;38(3):308–312. 105. Mercadante S, Avola G, Maddaloni S, Salamone G, Aragona F, Rodolico V. Octreotide prevents the pathological alterations of bowel obstruction in cancer patients. Support Care Cancer 1996;4:393–394. 106. Sun X, Li X, Li H. Management of intestinal obstruction in advanced ovarian cancer: an analysis of 57 cases. Chung Hua Chung Liu Tsa Chih 1995;17:39–42. 107. Khoo D, Riley J, Waxman J. Control of emesis in bowel obstruction in terminally ill patients. Lancet 1992;339:375–376. 108. Mercadante S, Maddaloni S. Octreotide in the management of inoperable gastrointestinal obstruction in terminal cancer patients. J Pain Symptom Manage 1992;7(8):496–498.

393 109. Mercadante S, Spoldi E, Caraceni A, Maddaloni S, Simonetti MT. Octreotide in relieving gastrointestinal symptoms due to bowel obstruction. Palliat Med 1993;7:295–299. 110. Mangili G, Franchi M, Mariani A, et al. Octreotide in the management of bowel obstruction in terminal ovarian cancer. Gynecol Oncol 1996;61:345–348. 111. Steadman K, Franks A. A woman with malignant bowel obstruction who did not want to die with tubes. Lancet 1996;347:944. 112. Sartori S, Trevisani L, Nielsen I, Tassinari D, Righini E. Identification of a safe site for percutaneous endoscopic gastrostomy placement in patients with marked bowel distension: May octreotide have a role? Endoscopy 1994;26:710–711. 113. Mercadante S, Kargar J, Nicolosi G. Octreotide may prevent definitive intestinal obstruction. J Pain Symptom Manage 1997;13:352–355. 114. Fainsinger RL, MacEachern T, Miller MJ, et al. The use of hypodermoclysis for rehydration in terminally ill cancer patients. J Pain Sympt Manage 1994;9:298–302. 115. Shima Y, Ohtsu A, Shirao K Sasaki Y. Clinical efficacy and safety of octreotide (SMS201–995) in terminally ill Japanese cancer patients with malignant bowel obstruction. Jpn J Clin Oncol 2008;38:354–359. 116. Hisanaga T, Shinjo T, Morita T, et al. Multicenter prospective study on efficacy and safety of octreotide for inoperable malignant bowel obstruction. Jpn J Clin Oncol 2010;40:739–745. 117. Mercadante S. Scopolamine butylbromide plus octreotide in unresponsive bowel obstruction. J Pain Symptom Manage 1998;16(5):278–280. 118. Tuca A, Roca R, Sala C, Porta J, Serrano G, Gonzalez-Barboteo J. Efficacy of granisetron in the antiemetic control of nonsurgical intestinal obstruction in advanced cancer: a phase II clinical trial. J Pain Symptom Manage 2009;37(2):259–270. 119. Hisanaga T, Shinjo T, Morita T, Nakajima N, Ikenaga M, Tanimizu M, et al. Multicenter prospective study on efficacy and safety of octreotide for inoperable malignant bowel obstruction. JPN J Clin Onc 2010;40(8):739–745. 120. Watari H, Hosaka M, Wakui Y, Nomura E, Hareyama H, Tanuma F, et al. A prospective study on the efficacy of octreotide in the management of malignant bowel obstruction in gynecologic cancer. Int J Gynecol Cancer 2012;22(4):692–696. 121. Kubota H, Taguchi K, Kobayashi D, Naruyama H, Hirose M, Fukuta K, et al. Clinical impact of palliative treatment using octreotide for inoperable malignant bowel obstruction caused by advanced urological cancer. Asian Pacific J. Cancer Pres 2013;14:7107–7110 122. Currow D, Quinn S, Agar M, Fazekas B, Hardy J, et al. Double-blind, placebo controlled, randomized trial of octreotide in malignant bowel obstruction. J Pain Symptom Manage 2015;49(5):814–820. 123. Peng X, Wang P, Li S, Zhang G, Hu S. Randomized clinical trial comparing octreotide and copolamine butylbromide in symptom control of patients with inoperable bowel obstruction due to advanced ovarian cancer. World J Surg Oncol 2015;13:50. 124. Laval G, Rousselot H, Toussaint-Martel S, Mayer F, Terrebonne E, Francois E, et al. SALTO: a randomized, multicenter study assessing octreotide LAR in inoperable bowel obstruction, Bull Cancer 2012;99(2):E1–E9. 125. Mariani P, Blumberg J, Landau A, Lebrun-Jezekova D, Botton E, Beatrix O, et al. Symptomatic treatment with lanreotide microparticles in inoperable bowel obstruction resulting from peritoneal carcinomatosis: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol 2012;30:4337–4343. 126. Ripamonti C, Mercadante S, Groff L, Zecca E, De Conno F, Casuccio A. Role of octreotide, scopolamine butylbromide and hydration in symptom control of patients with inoperable bowel obstruction having a nasogastric tube. A prospective, randomized clinical trial. J Pain Symptom Manage 2000;19(1):23–34. 127. Mercadante S, Ripamonti C, Casuccio A, Zecca E, Groff L. Comparison of octreotide and hyoscine butylbromide in controlling gastrointestinal symptoms due to malignant inoperable bowel obstruction. Support Care Cancer 2000;8:188–191. 128. Mystakidou K, Tsilika E, Kalaidopoulou O, Chondros K, Georgaki S, Papadimitriou L. Comparison of octreotide administration vs conservative treatment in the management of inoperable bowel obstruction in patients with far advanced cancer: A randomized, double- blind, controlled clinical trial. Anticancer Res 2002;22:1187–1192. 129. Walsh D, Davis M, Ripamonti C, Bruera E, Davies A, Molassiotis A. 2016 Updated MASCC/ESMO consensus recommendations: Management of nausea and vomiting in advanced cancer. Support Care Cancer 2017;25:333–340.

42

ENDOSCOPIC TREATMENT OF DIGESTIVE SYMPTOMS

Pasquale Spinelli

Contents Introduction........................................................................................................................................................................................................................395 Palliative treatments..........................................................................................................................................................................................................395 Surgery.......................................................................................................................................................................................................................... 396 Radiotherapy................................................................................................................................................................................................................ 396 Chemotherapy............................................................................................................................................................................................................. 396 Endoscopy and gastrointestinal symptoms................................................................................................................................................................. 396 Dysphagia, regurgitation, salivation, odynophagia, bleeding, and vomiting.................................................................................................. 396 Palliative endoscopic options for dysphagia.................................................................................................................................................................397 Nasogastric tube...........................................................................................................................................................................................................397 Dilation...........................................................................................................................................................................................................................397 Laser treatment.............................................................................................................................................................................................................397 Photodynamic therapy................................................................................................................................................................................................397 Endoscopic intratumoral injection of alcohol or chemotherapeutic drugs.....................................................................................................397 Cryotherapy...................................................................................................................................................................................................................397 Other treatments (electrocoagulation, argon plasma, and adrenalin injection).............................................................................................397 Prostheses......................................................................................................................................................................................................................397 Percutaneous gastrostomy/jejunostomy.................................................................................................................................................................398 Malignant jaundice............................................................................................................................................................................................................398 Constipation..................................................................................................................................................................................................................398 Palliative endoscopic options for constipation and colon and rectum obstructions.....................................................................................398 Surgery...........................................................................................................................................................................................................................398 Endoscopic options......................................................................................................................................................................................................398 Conclusions.........................................................................................................................................................................................................................398 References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������399

Introduction The number of patients surviving a long time after the diagnosis of a non-curable digestive cancer is continuously increasing. Most of these patients need to be supported by further treatments aiming to improve the quality of life.1 It is extremely important to identify the borders between curable and non-curable cancers through accurate staging procedures. In patients not curable or not responding to therapy, the palliation of symptoms is essential, involving a multidisciplinary team.2 Mistakes in this evaluation can result in giving anticancer treatments to patients with non-curable diseases and, on the other hand, deprive a curable patient of proper and effective treatments. This is the source of cases of over- or undertreatments. Before deciding to propose a palliative treatment, the oncologist should consider the following points: • Give the correct information about the curative potentials of surgery, radiotherapy, chemotherapy, or monotherapy, immunotherapy, and possible therapeutic combinations and any other kind of certified treatments. • Evaluate the risk factors relevant to the circumstances of a particular patient.

• Consider the side effects of a treatment and weigh up the pros and cons, especially the likely quality and duration of the remaining life of the patient. • Weigh up the likely impact of the therapeutic procedures with regard to the expected benefits. With the availability of a variety of old and new prognostic tools in the form of clinical, pathological, and molecular tests, the possibility of identifying the correct stage of a cancer with extreme precision and predicting the response to an anticancer treatment are becoming possible.

Palliative treatments Cancer of the alimentary tract growing inside the digestive tube and bleeding from ulcerations causes obstructive symptoms, associated hemorrhage, and consequent anemia. Treatment opportunities are quite different in intrathoracic (esophageal) and intra-abdominal tumors3,4 Palliative care should not be limited to the patients with preterminal disease, but greatly expanded, starting with the control of symptoms as soon as the disease is staged and classified as incurable.

395

396 Surgery

The classical option to overcome both obstruction and bleeding in the digestive tube is resective surgery with end-to-end anastomosis. When this is not possible or advisable due to the local conditions of the lesion or the general conditions of the patient, the other surgical possibility is a bypass operation.5 Surgery is generally the first option to be considered. From the surgeon’s standpoint, therapy is considered palliative when removal of all known tumor sites is not possible. So, the success of the therapy is determined by restoring the lumen and reducing bleeding by removing a tumor mass. The operation must be performed through laparoscopic access, achieving the double goal of minimum trauma and quick recovery.6 The appropriate use of surgery in these settings can improve the quality of life.

Radiotherapy

This is mainly used for esophageal cancer and cancers of the rectum. External radiotherapy and endoscopic brachytherapy4 are used to reduce the tumor mass. They can be used in combination with chemotherapy in selected cases of large cancers to make the tumor become surgically resectable. Under specific circumstances, external radiotherapy can be combined with endoscopic treatments, thus combining endoluminal with the extraluminal benefits of mass reduction. In some cancers causing local symptoms, the irradiation of mediastinal tissue surrounding the esophagus and reduction of the size of the tumor may also result in partial control of pain. The effect of brachytherapy is ephemeral and generally lasts no more than 5–12 weeks. Esophagitis is a frequent complication of both external radiotherapy and brachytherapy and must be treated by appropriate medical support.

Chemotherapy

Perioperative, adjuvant or neoadjuvant chemotherapy with multiagent regimens, also in association with radiotherapy, is used to treat cancers located in the esophagus as well as in stomach, liver, pancreas, colon, and rectum. The treatments aim to reduce the size of neoplastic masses and to restore the transit.7 Furthermore, in patients who have locally advanced, unresectable disease and in patients in whom tumors are resected with palliative intent, the duration of survival can be increased with palliative chemotherapy and irradiation. The therapy is based on cisplatin, 5-fluoruracil, or taxanes plus radiotherapy.

Endoscopy and gastrointestinal symptoms7 Esophagogastrointestinal symptoms may be produced by digestive or by extradigestive tumors. The gastrointestinal tract has cavities that function as “containers” or as “canals” (stomach, esophagus, intestine, biliary, and pancreatic tract). Tumors reduce the space available and impair the functions of containing (the stomach) and transit (the esophagus and intestine); moreover, tumors infiltrating and ulcerating the walls of these cavities cause hemorrhage, obstruction, perforation, and fistula formation. The most important symptoms of digestive tumors are dysphagia, odynophagia, salivation, vomiting, jaundice, pain, constipation, and hemorrhage. All these symptoms can be treated by endoscopic modalities. There are different ways to achieve relief from symptoms. The physician must be able to discuss with the patient the different symptom relief methods available so that the patient can choose the one that fits better with the preferred lifestyle. For example,

Textbook of Palliative Medicine and Supportive Care esophageal stenosis can be relieved by a nasogastric tube, by a laser or other thermal treatment, by a gastrostomy, by stent insertion or palliative radio-chemotherapy. Patients must be informed about these options so that they can decide which one is the most suitable for their way of life.

Dysphagia, regurgitation, salivation, odynophagia, bleeding, and vomiting

Malignant dysphagia can be related to the presence of primary or secondary esophageal tumors, or it can be consequent to esophagitis after a surgical treatment or a radiotherapy or chemotherapy. Dysphagia can be defined as an abnormal swallowing, characterized by difficulty in transferring solid or liquid food or saliva from the mouth to the stomach; various degrees of dysphagia are used to evaluate the response to the treatment. Beyond the most common causes, in oncological patients, dysphagia may occur due to the following: • Neurological reasons, for example, cricopharyngeal dysphagia because of recurrent nerve palsy due to perineural and neural infiltration by tumor tissue; neurological dysphagia may also occur due to vagal or sympathetic tumoral infiltration, with the involvement of the skull base or due to brain metastases. • Mucositis related to candidosis, bacterial infection, herpes, radiotherapy, chemotherapy, gastric or biliary reflux. • Asthenia/cachexia. A patient becomes dysphagic when the diameter of the esophageal lumen is less than 14 mm, but an uncertain feeling of trouble in swallowing is generally complained some weeks or months before the diagnosis of esophageal cancer. Esophagoscopy is indicated when a patient complains of dysphagia; it allows to locate a tumor, to measure its length, to appreciate the circular extent and the size of the residual esophageal lumen, and to obtain histological samples. Echoendoscopy is extremely useful for determining the level of infiltration across the esophageal wall, the involvement of neighboring anatomical structures and the eventual presence of metastatic lymph nodes. Infiltration of the wall interrupts the progression of peristaltic movements and stops the progression of food; this interruption causes a variety of symptoms, depending on whether it is partial or total. Partial obstruction can stop solid food but allow passage of liquids; total obstruction causes liquids to collect above the site of the obstruction and the upper esophageal sphincter.7 Long-standing stenoses can cause incompetence—permanent or episodic—of the upper esophageal sphincter and the regurgitation of undigested material together with inhalation leading to cough and sometimes pneumonia. Total esophageal obstruction stops the passage of saliva to the stomach and causes the onset of another invalidating symptom, the salivation. The patient complaining of salivation is obliged to spit or dribble continuously and walks around with a bag full of handkerchiefs, deprived of a social life. Dysphagia can be associated with odynophagia, generally caused by inflammation of the esophageal wall or by candidiasis or herpes virus; odynophagia too may cause salivation. Salivation and regurgitation often cause coughing as patients attempt to swallow. After insertion of a stent into a stenotic esophagus, cough on swallowing disappears because, after the opening of the esophageal transit, there is no more esophagotracheal regurgitation. Endoscopic treatment can be beneficial for bleeding and vomiting from gastric or extra-gastric (e.g., pancreatic) tumors infiltrate

Endoscopic Treatment of Digestive Symptoms the gastric wall.16 Malignant ulcerations bleed and produce anemic conditions, speeding up the progression toward cachexia. To stop bleeding, endoscopic laser photocoagulation, electrocoagulation, cryotherapy, and injection of sclerosing drugs and/ or adrenalin can be used for cytoreductive as well as hemostatic purposes. The duration of the effect of these treatments is limited and the rebleeding is a rule. Vomiting is produced by gastric or intestinal obstruction. Duodenal obstructions can be treated by performing a translaparoscopic bypass between the gastric body and the first jejunal loop, although expandable prostheses are also used to bypass stenosing lesions. Duodenum and gastric antrum can be obstructed by primary or metastatic tumors. Malignant lymph nodes, pancreatic, and ampullary cancers are the most frequent causes of duodenal obstruction. Together with biliary tumors, these conditions are responsible for biliary obstruction and cause malignant jaundice.

Palliative endoscopic options for dysphagia Nasogastric tube

Treatment of dysphagia and its sequels is based on crossing the obstacle that prevents the passage of food: This can be achieved by a nasogastric tube, by restoring the esophageal lumen by dilation, laser treatment, photodynamic therapy, endoscopic injection of chemotherapeutic drugs or alcohol, endoluminal brachytherapy, argon plasma coagulation, cryotherapy, prostheses insertion, and finally, performing a gastrostomy or jejunostomy. All these different options have specific indication.8–10 The purpose of inserting a nasogastric tube is feeding liquid food. The indication is restricted to cases in which the stenotic obstacle cannot be dilated more than 4–8 mm; this mainly happens when there is postoperative or postradiotherapy fibrotic stenosis that makes forced dilation dangerous as there is a possibility of perforation. There are several different disadvantages of the nasogastric tube: Esthetic: the patient is obliged to live with the tube coming out of the nose. Functional: the external surface of the tube adheres strictly to the inner surface of the stenotic tract, and this prevents saliva from being swallowed, leading to salivation. Sensuous: with food introduced through the tube, the patient is unable to enjoy its taste, one of the few pleasant sensations remaining at this stage of the life. Patients complain of these disadvantages also after the creation of a gastrostomy or jejunostomy.

Dilation

Dilation can be performed using pneumatic balloon dilators, metallic olives, and plastic bougies: All can slide along a previously introduced guidewire and enlarge the esophageal lumen up to 20 mm. or more.9 The drawback of the dilation is that the stenosis will recur in 1–3 weeks, and dilations must be frequently repeated.

Laser treatment

This aims to reopen the esophageal lumen through the thermal coagulation–destruction of the cancer tissue: power laser radiation increases the local temperature of the irradiated tissues and causes the tissue water to evaporate.10 The neodymium:yttrium aluminum garnet (Nd:YAG) laser is the most frequently used due to the depth of the penetration of its radiation (1064 nm) into the cancer tissue. The treatment is precise and safe in appropriate hands, and the esophageal lumen can be fully restored so as

397 to obtain a satisfactory eating function; the mean duration of the patency of the lumen is estimated to be 4–8 weeks. Laser treatments were more popular before the end of last century. Most centers abandoned laser techniques in favor of stents, easier to be inserted, safer, and maintaining a more durable palliation.

Photodynamic therapy

Photodynamic therapy (PDT) uses intravenously injected photosensitizing drugs from the group of porphyrins that are selectively fixed by the tumor tissue. The photosensitizer, activated by light, produces singlet oxygen that is toxic for biological tissues and causes a necrotic effect;11 unlike the procedures discussed earlier, which are immediately effective, the necrotic effect of PDT needs 4–8 days to become apparent, and the relief from obstruction lasts for 5–10 weeks.12,13 Moreover, patients submitted to PDT have to avoid direct sunlight for 4–6 weeks because of skin photosensitization.

Endoscopic intratumoral injection of alcohol or chemotherapeutic drugs

These forms of locally induced necrosis are technically simple, not expensive14 and do not need special and sophisticated technologies. Related to tumor bulk 10–20 ml of pure ethanol are injected under endoscopic visual control into the tumor tissue.15 Among the various chemotherapeutic drugs, mitomycin and 5-fluoruracil are the most frequently used to be injected into the tumor and provide intensive and durable necrotic phenomena, especially if the injection is combined with laser therapy.

Cryotherapy

Cryotherapy is based on the sudden reduction of local temperature in the tumor mass. The reduction of temperature is obtained using special probes introduced through an endoscope and put in contact with the tumor. The effect of the sudden reduction in temperature is that the bleeding stops and tumor necrosis is produced, so as to temporarily reopen the esophageal transit.15,16

Other treatments (electrocoagulation, argon plasma, and adrenalin injection)

These kinds of treatments combine the effect of destroying tumor tissue with stop bleeding. The techniques are based on the effect of a beam of heat (e.g., laser, electrocoagulation) on a bleeding surface. In the case of argon-plasma a jet of argon gas switched to form argon plasma is directed to the tumor surface under endoscopic control to coagulate the bleeding source. Transedoscopic adrenalin injection is also used for immediate stop of a bleeding artery. Sometimes cryotherapy also can be used.

Prostheses

Introducing a stent after reopening a stenotic tract prevents an early recurrence of the obstruction. Inserting an expandable stent is no more traumatic than performing a normal flexible esophagoscopy. New 3D printing technique may allow manufacturing personalized stents. Drug-eluting stents open a new horizon for these patients, giving anticancer drugs directly to the tumor simultaneously with the reopening of the obstructed lumen. Gemcitabine, docetaxel, or paclitaxel in bilayer films, progressively releasing the drugs into the tumor tissue, have been used. The best results are obtained when the prosthesis does not interfere with the mechanism of a sphincter (the pharyngoesophageal or the cardiac sphincter). When the cardiac sphincter is infiltrated by the tumor and the prosthesis keeps it open, the

Textbook of Palliative Medicine and Supportive Care

398 natural antireflux mechanism is impaired and the gastric content flows back into the esophagus. The acid gastric secretion can be responsible for supra-prosthetic esophagitis and this condition causes dysphagia even though the esophagus is patent. However, in patients submitted to gastrectomy, the reflux through the prosthesis may give rise to an alkaline esophagitis.16 The evolution of the cancer through the esophageal wall can develop a fistula, connecting the esophageal lumen with the skin of the neck, the trachea, a bronchus, the mediastinum, or the pleural space. Prostheses are equally used in these patients to bypass the fistula, allowing passage of the oral intake.18 In case of esophagotracheal or esophagobronchial fistula a stent can be inserted into the respiratory tract avoiding aspiration pneumonia, a frequent cause of death. Generally, plastic stents introduced with a rigid tracheo-bronchoscope under general anesthesia give the solution. Expandable stents can also be used in patients with inoperable cancers stenosing the gastric antrum, causing vomiting, with immediate recovery of gastric transit accompanied by stopping of vomiting.

Percutaneous gastrostomy/jejunostomy

Percutaneous endoscopic gastrostomy (PEG)19 is proposed only when it is impossible to carry out one of the previously described procedures. It consists of the insertion of a feeding/venting tube into the stomach, through the abdominal wall under direct endoscopic control. Such a tube can be advanced to reach the jejunum, thus becoming a jejunostomy and it can also be used for decompressing an obstructed intestine.

Malignant jaundice Biliary obstruction caused by biliary, pancreatic, metastatic cancer or by lymphomas, obstructing the common bile duct or the hepatic ducts, causes jaundice. Transpapillary biliary cannulation (ERCP) and the insertion of a stent is the most used procedure of drainage; in cases of failure, the drainage can be performed under endoscopic ultrasonographic (EUS) guidance and punction/cannulation of the biliary duct.22,23 EUS-guided drainage can be considered as an alternative in cases of failure of ERCP.21 Palliative treatments alternatives to the endoscopic ones (surgical and percutaneous) have higher costs and complications and lower success rate. They are indicated in case of failure of the endoscopic procedures. Expandable stents have a low occlusion and complication rate, are easy to place with low trauma and immediate effect; stools become well-stained in the 24–48 h after the procedure, the urine loses progressively its intensive brown color, and itchiness disappears.

Constipation

Constipation is a very frequent symptom; more than 50% of advanced cancer patients need to be treated for the infrequent passage of hard stools. The cause should be clarified. When caused by anticancer chemotherapeutic drugs (mainly vincristine), opioids, metabolic problems such as hypokalemia, or global electrolyte imbalances; it is mostly of the type of a dynamic ileus and is frequently accompanied by generalized abdominal pain. Intestinal obstruction by endoluminal masses or by extraintestinal compressions is more frequently accompanied by colicky pain.

Palliative endoscopic options for constipation and colon and rectum obstructions

In oncological patients with longstanding constipation resistant to common treatments, endoscopy helps in treating the bowel

distension. Colonoscopy with large channel endoscopes allows aspiration of gas, washing fecal materials and to perform the first palliative treatment by dilation, laser, or stenting in rectum and colon.23–25 Obstruction can also occur due to metastatic involvement of the mesenteric lymph nodes or diffuse peritoneal nodular metastases, for example, in papillary carcinomas, mainly ovarian and pancreatic.

Surgery6

Persistence of bowel obstruction has a strong influence on prognostic outcome. Bypass operations and diverting stomas alleviate symptoms due to obstruction but do not interfere with symptoms related to the presence of the tumor, such as bleeding and pain. It must be managed as soon as possible.

Endoscopic options

Patients to be submitted to endoscopic palliation are those with very advanced and non-removable cancers. They generally appear in bad general conditions with weight loss, sometimes cachexia and surgical operations carry a high mortality, about 10%, and a survival rate of around 5% at 5 years.26 In the case of stenosing lesion infiltrating the bowel wall, a trans-stenotic guidewire has to be introduced under endoscopic guidance and a dilator slid on it; once dilation has been achieved, the fecal transit can been reestablished, the emergency problem overcome, and the bowel cleaned. If the patient is inoperable, inserting a stent will keep open the intestinal lumen and maintain the bowel functions with a durable effect in more than 80% of treated patients. If surgery can be performed, the stent will be a bridge to surgery. We started inserting stents in primary rectal tumors and in recurrences in rectal anastomoses with a success rate of more than 90%. In most of our cases, patency of the stent lasts until death. There are different endoscopic possibilities of treatment, related to the kind of the obstructing lesion and in particular to its shape and to the tumor bulk, growing into the lumen or infiltrating the bowel wall. Once the fecal transit has been reestablished, the emergency problem overcome, and the bowel cleaned, if the tumor is operable, the lesion can be resected or a bypass operation performed through a laparoscopic procedure, which is planned for the following days; if the patient is inoperable because of high-risk conditions or because the lesion is not removable, the endoscopic alternative is the only feasible option. To keep open the intestinal lumen and maintain the bowel functions, an expandable prosthesis must be inserted in these cases to obtain a durable effect. Insertion of a prosthesis with a correct technique and indication allows the patency of the large bowel to be maintained in more than 80% of treated patients. When inserting stents in primary rectal tumors and in recurrences in colorectal anastomoses, we reported a success rate of more than 90%.26 In most of our cases, patency of the stent lasts until death.

Conclusions The features of endoscopic palliation are: 1. Achievement of an immediate result in the control of symptoms and the restoration of a normal function, whereas other options of palliation, such as radiotherapy and chemotherapy, can have important side effects and need longer times to become effective; 2. Absence of contraindications; and 3. The possible combination of endoscopic treatments with any other form of treatment.

Endoscopic Treatment of Digestive Symptoms Palliative treatments, in each case, should be tailored to the individual patient, and to the patient’s capability to undergo the treatments, consisting of a decrease or disappearance of symptoms and of improvement of performance status. Endoscopic palliative treatments aim to obtain the best possible quality of life with immediate and durable benefits with negligible trauma, side effects, and incidence of complications related to the proposed advantages.27 Although the primary purpose of a palliative procedure is not to increase survival, the treatment of severe symptoms (nutritional, respiratory or metabolic) very often results in an effective extension of the survival. Consequently, palliation becomes, in many cases, not just the simple treatment of symptoms, but offers the patient a wide range of therapeutic opportunities during the entire course of the disease.

References

1. Ikeda M. Significant host and tumor-related factors for predicting prognosis in patients with esophageal carcinoma. Ann Surg 2003;238:197–202. 2. Moroney MR, Lefkowits C. Evidence for integration of palliative care into surgical oncology practice and education. J Surg Oncol 2019;120:17–22. 3. Halpern AL, McCarter MD. Palliative management of gastric and esophageal cancer. Surg Clin N Am 2019;99:555–569. 4. Taggar AS, Pitter KL, Cohen GN, et al. Endoluminal high-dose-rate brachytherapy for locally recurrent or persistent esophageal cancer. Brachytherapy 2018;17: 621–627. 5. Freeman RA, Ascioti AJ, Mahidhara RJ. Palliative therapy for patients with unresectable esophageal carcinoma. Surg Clin North Am 2012;92:1337–1351. 6. Cloyd JM. Minimally invasive surgery for palliation. Surg Oncol Clin N Am 2019;28:79–88. 7. Baines MJ. Symptom control in advanced gastrointestinal cancer. Eur J Gastroenterol Hepatol 2000;12:375–379. 8. Shah MB, Schnoll-Sussman F. Novel use of cryotherapy to control bleeding in advanced esophageal cancer. Endoscopy 2010;42:E46. 9. Spinelli P, Dal Fante M, Mancini A. Endoscopic palliation of malignancies of the upper gastrointestinal tract using Nd:YaG laser: Results and survival in 308 treated patients. Lasers Surg Med 1991;11:550–555. 10. Spinelli P, Cerrai FG, Meroni E. Pharingo-esophageal prostheses in malignancies of the cervical esophagus. Endoscopy 1991;23:213–214.

399 11. Lightdale CJ. Role of photodynamic therapy in the management of advanced esophageal cancer. Gastrointest Endosc Clin North Am 2000;10:397–408. 12. Lightdale CJ, Heier SK, Marcon NE, et al. Photodynamic therapy with porfimer sodium versus thermal ablation therapy with Nd:YaG laser for palliation of esophageal cancer: a multicenter randomized trial. Gastrointest Endosc 1995;42:507–512. 13. Shishkova N, Kuznetsova O, Berezov T. Photodynamic therapy in gastroenterology. J Gastrointest Cancer 2013;44:251–259. 14. Ramakrishnaiah VP, Ramkumar J, Pai D. Intratumoural injection of absolute alcohol in carcinoma of gastroesophageal junction for palliation of dysphagia. Ecancermedicalscience 2014;8:395. 15. Goetz M, Malek NP, Kanz L, Hetzel J. Cryorecanalization for in-stent recanalization in the esophagus. Gastroenterology 2014;146:1168–1170. 16. Lal P, Thota PN. Cryotherapy in the management of premalignant and malignant conditions of the esophagus. World J Gastroenterol 2018;24:4862–4869. 17. Pais-Cunha I, Castro R, Libânio D, et al. Endoscopic stenting for palliation of intra-abdominal gastrointestinal malignant obstruction: predictive factors for clinical success. Eur J Gastroenterol Hepatol 2018;30:1033–1040. 18. Markos P, Markos S, Ivekovic H, Bilic B, Rustemovic N. Self-expandable metal stent for dysphagia caused by mediastinal masses in patients with lung cancer. Arab J Gastroenterol 2019;20:28–31. 19. Russel TR, Brotman M, Norris F. Percutaneous gastrostomy: a new simplified and cost-effective technique. Am J Surg 1984;148:132–137. 20. Classen M, Koch H, Demling L. Diagnostische Bedeutung des endoscopischen Kontrastdarstellung des Pankreas-gang-systems. Leber Magen Darm 1972;2:79–81. 21. Costamagna G. Therapeutic biliary endoscopy. Endoscopy 2000;32:209. 22. Aadam AA, Liu K. Endoscopic palliation of biliary obstruction. J Surg Oncol 2019;120:57–64. 23. Logiudice FP, Bernardo WM, Galetti F, et al Endoscopic ultrasounrguided vs endoscopic retrograde cholangiopancreatography biliary drainage for obstructed distal malignant biliary strictures: A systrematic review and metanalysis. World J Gastrointest Endosc 2019;11:281–291. 24. Krouse RS. Malignant bowel obstruction. J Surg Oncol 2019;120:74–77. 25. Moon S, Yang S, Na K. An acetylated polysaccharide-PTFE membrane-covered stent for the delivery of gemcitabine for treatment of gastrointestinal cancer and related stenosis. Biomaterials 2011;32:3603–3610. 26. Spinelli P, Mancini A. Use of self-expanding metal stents for palliation of rectosigmoid cancer. Gastrointest Endosc 2001;53:203–206. 27. Spinelli P, Mancini A, Dal Fante M. Endoscopic treatment of gastrointestinal tumors: indications and results of laser photocoagulation and photodynamic therapy. Semin Surg Oncol 1995;11:307–318.

43

MECHANISM, ASSESSMENT, AND MANAGEMENT OF FATIGUE

Sean Hutchinson, Sriram Yennurajalingam

Contents Introduction....................................................................................................................................................................................................................... 402 Definition of fatigue.................................................................................................................................................................................................... 402 Frequency..................................................................................................................................................................................................................... 402 Mechanism of fatigue................................................................................................................................................................................................. 403 Tumors, host-derived factors, and cytokines........................................................................................................................................................ 403 Muscle abnormalities................................................................................................................................................................................................. 403 Mitochondrial enzymes............................................................................................................................................................................................. 403 Deconditioning............................................................................................................................................................................................................ 403 Central nervous system abnormalities.................................................................................................................................................................... 403 Relationship between fatigue and cachexia........................................................................................................................................................... 404 Infection........................................................................................................................................................................................................................ 404 Anemia.......................................................................................................................................................................................................................... 404 Autonomic dysfunction............................................................................................................................................................................................. 404 Psychological issues.................................................................................................................................................................................................... 404 Metabolic and endocrine disorders......................................................................................................................................................................... 404 Paraneoplastic neurological syndromes................................................................................................................................................................. 404 Other cancer-related symptoms............................................................................................................................................................................... 404 Side effects of cancer treatment............................................................................................................................................................................... 405 Genetics and cancer-related fatigue........................................................................................................................................................................ 405 Assessment of fatigue................................................................................................................................................................................................. 405 Assessment of fatigue in clinical practice............................................................................................................................................................... 405 Management of fatigue.............................................................................................................................................................................................. 407 Cancer............................................................................................................................................................................................................................ 408 Therapies and medications........................................................................................................................................................................................ 408 Chemotherapy and radiotherapy....................................................................................................................................................................... 408 Biological therapy.................................................................................................................................................................................................. 408 Opioids.................................................................................................................................................................................................................... 409 Cytokine modulation.................................................................................................................................................................................................. 409 Treatment of cachexia................................................................................................................................................................................................ 409 Management of autonomic failure.......................................................................................................................................................................... 409 Neurological disorders................................................................................................................................................................................................410 Treating anemia............................................................................................................................................................................................................410 Pain..................................................................................................................................................................................................................................410 Other comorbidities..........................................................................................................................................................................................................410 Infection.........................................................................................................................................................................................................................410 Psychogenic disorders.................................................................................................................................................................................................411 Insomnia........................................................................................................................................................................................................................411 Metabolic and endocrine abnormalities..................................................................................................................................................................411 Hypogonadism..............................................................................................................................................................................................................411 Chronic hypoxia...........................................................................................................................................................................................................411 Symptomatic management of fatigue............................................................................................................................................................................411 Pharmacological management..................................................................................................................................................................................411 Established agents..............................................................................................................................................................................................................412 Corticosteroids.............................................................................................................................................................................................................412 Progestational steroids................................................................................................................................................................................................412 Psychostimulants..........................................................................................................................................................................................................412 Testosterone..................................................................................................................................................................................................................413 Emerging pharmacological agents......................................................................................................................................................................413 Nonpharmacological management..........................................................................................................................................................................413

401

Textbook of Palliative Medicine and Supportive Care

402

Physical activity or exercise..................................................................................................................................................................................413 Acupuncture............................................................................................................................................................................................................414 Cognitive behavorial therapy...............................................................................................................................................................................414 Neurofeedback........................................................................................................................................................................................................414 Light therapy...........................................................................................................................................................................................................414 Nutritional supplements.......................................................................................................................................................................................414 Education.................................................................................................................................................................................................................415 Counseling...............................................................................................................................................................................................................415 Conclusion...........................................................................................................................................................................................................................416 References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������416

Introduction Fatigue is a subjective sensation of weakness, lack of energy, or becoming easily tired.1–5 It is one of the most common and chronic symptoms experienced by advanced cancer patients.6 Fatigue is debilitating and profoundly impacts the quality of life (QOL) of the patients and their families.7 With the availability of effective treatments for pain and nausea, screening and treatment of fatigue has become a major focus of symptom management in advanced cancer.6

Definition of fatigue Cancer-related fatigue (CRF) is defined as a “distressing persistent, subjective sense of physical, emotional and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning”3(NCCN guidelines 2010). In contrast to muscle fatigue, clinical fatigue is a multidimensional phenomenon and includes three major components: (1) generalized weakness, resulting in inability to initiate certain activities; (2) easy fatigability and reduced capacity to maintain performance; and (3) mental fatigue resulting in impaired concentration, loss of memory, and emotional lability. Despite the distinction to three major dimensions (physical, affective, and cognitive), it is unresolved whether these dimensions are stable and reproduced in more general settings.8 Due to the limitation in distinction and reproducibility of various dimensions, there is also an emerging thought among fatigue researchers about more of having a “case

FIGURE 43.1  Contributors to fatigue.

definition” for CRF that may best capture and describe what constitutes clinically significant fatigue in subgroups of patients with advanced cancer.2

Frequency Fatigue is reported as prevalent in most studied populations including patients with cancer and palliative care patients. The frequency of fatigue has been reported to be approximately 60–90% in patients with advanced cancer whereas prevalence of fatigue is around 20–30% in cancer survivors.7,9–15 The wide range of these estimates likely reflects variable diagnostic criteria used to define CRF. For example, using an International Classification of Diseases, 10th revision (ICD-10 definition criteria), the frequency of fatigue was reported to be 49.8%, far less than reported in previous studies using a number rating scale (NRS) of 0–10.16 Moderate-to-severe persistent fatigue affects the patients’ QOL and ability to perform activities that add meaning to their life. Fatigue has been associated with other symptoms, including pain, anxiety, depression, cachexia, and insomnia. However, assessment and treatment of this common symptom is difficult, as it is a complex, subjective symptom and is often underreported. Most commonly, the assessment of severity can be used to guide the management (Figure 43.1). The pathophysiology of fatigue has already been discussed in the previous chapters and it is clear that fatigue is usually multifactorial in patients receiving palliative care.4 Physiological, psychological, and situational factors can contribute to fatigue. The most frequent contributing factors in patients with advanced

Mechanism, Assessment, and Management of Fatigue cancer include weight loss, depression, dyspnea, deconditioning, isolation, and polypharmacy. 3,12,17 Chronic diseases can produce factors such as circulating cytokines, inflammation, and autonomic failure that may mediate fatigue.18,19 Although few published studies have correlated fatigue and cytokines near or at the end of life, several lines of evidence implicate cytokines in the pathophysiology of fatigue.20 First, cytokine levels are increased in nononcologic conditions characterized by fatigue, such as chronic fatigue syndrome. Second, fatigue is a major adverse effect of cytokines administered for therapeutic purposes including interleukins (IL), tumor necrosis factor α (TNF α), and interferon (INF).21 Finally, upregulation of pro-inflammatory cytokines is correlated with fatigue in several malignancies.11,18 In this chapter, we will discuss the mechanism, assessment, and management of fatigue in advanced cancer patients.

Mechanism of fatigue The etiology of fatigue is often unclear in the majority of patients with advanced-stage cancer. Several possible underlying etiologies of fatigue exist in most patients and the basic pathophysiology is not well understood. Infrequently, a predominant abnormality is a main driver to the symptom but more commonly, multiple abnormalities and other symptoms in cohort contribute to the genesis of fatigue. There are complex interactions between the host and tumor in patients with cancer. These interactions are not clearly understood and can result in fatigue in multiple ways. Figure 43.1 summarizes contributors to fatigue in cancer patients.

Tumors, host-derived factors, and cytokines

Tumors can produce multiple by-products, including proteolytic and lipolytic factors and cytokines capable of interfering with close metabolism and inducing fatigue.22 This may also have a role in the development of cancer-related cachexia. The relationship between cachexia and fatigue is discussed in another chapter 37.23 The current growing literature is increasingly supporting the prevailing hypothesis that the presence of a tumor and/or cancer related treatment, such as chemotherapy and/or radiotherapy, induces dysregulation of pro-inflammatory cytokines, such as TNF-α, IL-1, and IL-6.24 Furthermore, the cytokines have been implicated in the pathophysiology of fatigue by acting on multiple systems, including the brain (hypothalamic–pituitary–adrenal [HPA] axis, psychological and dopaminergic alterations, sleep), immune system (humoral and cellular changes), muscles (reductions in strength and mass), and metabolism.25 However, there are overall mixed, inconsistent, and nonpersistent outcomes when cytokine levels and fatigue burden are assessed. Pro-inflammatory cytokines are further regulated by hostrelated factors such as genetic factors. However, the lack of a clear consensus on the definition of CRF (phenotype), challenges the methodology used to measure the cytokines, and the lack of methodology for measuring these cytokines, along with a limited number of fatigue studies using animal models, contributes to our little understanding of the link between CRF and inflammation.26

Muscle abnormalities

Impaired muscle function may be a potential major underlying mechanism of fatigue.27 The cause of fatigue-related muscular abnormalities may be partially related to cytokine production,

403 but the production of other fatigue-inducing substances by the tumor or the host has only been hypothesized. Muscle alterations in patients with tumors are well known. Cachexia leads to a loss of muscle and fat, which may partially explain the relationship between cachexia and fatigue.28 Tumorfree muscle from tumor-bearing animals shows alterations in the activity of various enzymes, the distribution of isoenzymes, and the synthesis and breakdown of myofibrillar and sarcoplasmic proteins.28 Our group found decreased relaxation velocity, impaired maximal strength, and increased fatigue after electrical stimulation of the abductor pollicis muscle via the ulnar nerve in breast cancer patients compared with normal controls.29 In cancer patients, myopathies can also be induced by medications. Cyclosporine has been implicated as a cause of mitochondrial myopathy and corticosteroids can cause loss of muscle mass. A preliminary study comparing 10 patients with advancedstage cancer and 12 healthy volunteers determining the contribution of muscle fatigue to overall fatigue found no alterations in the muscle contractile property of advanced-stage cancer patients; therefore, the authors of the study postulated that the early motor task failure in CRF was primarily due to a central mechanism. 30 However, further studies are needed as more recent studies targeting the fatigue mechanisms involving muscle found no correlation between muscle alterations and fatigue. These studies included supplementation of adenosine triphosphate31 and L-carnitine. 32

Mitochondrial enzymes

There is a known association between the mitochondria and fatigue. Specifically, dysfunctions within the mitochondrial function (enzymes and oxidative/nitrosative stress), energy metabolism, structure, immune response, and genetics interplay with fatigue. Of the mitochondrial enzymes reviewed, only plasma CoQ10 levels were found to be significantly and consistently inversely correlated with fatigue expression. 33

Deconditioning

Prolonged bed rest and immobility lead to loss of muscle mass and reduced cardiac output. Deconditioning results in worsened muscle mass, which may be compounded by other muscle abnormalities in patients with cancer. Recent studies have found that endurance exercise training can reduce fatigue and improve physical performance in patients who have undergone bone marrow or autologous stem cell transplant, cancer survivors, and transplantation cancer patients undergoing chemotherapy. 34

Central nervous system abnormalities

The mechanisms by which fatigue is induced or perceived in the central nervous system (CNS) are poorly understood. Primary or secondary tumors involving the CNS and subsequent invasion of brain tissue (particularly the pituitary gland, with resulting endocrine abnormalities) appear to be possible causes of fatigue in cancer patients. Disturbed cognitive functioning may be caused by, but may also contribute, to fatigue. Brain tumors can cause cognitive dysfunction and other tumors, such as small cell lung cancers, can also affect brain function via production of neurotransmitters or hormones. Antineoplastic treatments, such as radiotherapy and chemotherapy, and medications used to treat complications of cancer, such as corticosteroids and opioids, can also impact the CNS. Recent research findings additionally suggest that inflammatory cytokines play a role in mental fatigue.

404 Other CNS mechanisms that have been proposed include: (a) circadian rhythm disruptions, which negatively impact arousal and sleep patterns (prior studies suggest that fatigue is positively correlated with decreased daytime activity and restless sleep at night); (b) dysregulation of serotonin and/or its receptors in the brain due to cancer or cancer treatment; and (c) dysregulation of the hypothalmo-pituitary axis. 35

Relationship between fatigue and cachexia Fatigue and cachexia coexist in the great majority of advancedstage cancer patients and it is likely that malnutrition is a major contributor to fatigue. The resulting loss of muscle mass from progressive cachexia can cause profound weakness and fatigue. As previously discussed, biochemical and structural muscle abnormalities are frequently found in advanced cancer patients. 36 Similar abnormalities often are used to explain fatigue associated with chronic respiratory and cardiac disease. It is important to note, however, that fatigue can exist independently of weight loss. Fatigue is common in patients with breast cancer and lymphomas, which has a low prevalence of cachexia. In nonmalignant conditions such as chronic fatigue syndrome and depression, profound fatigue is generally not associated with malnutrition. Our group found no correlation between nutritional status and fatigue or weight in a population of breast cancer patients. 37 However, severe malnutrition in the absence of fatigue can be observed in patients with anorexia nervosa and in some patient populations with solid tumors. Figure 12.1.2 illustrates the potential relationship between fatigue and cachexia. It has been proposed that fatigue and anorexia may be an expression of the major metabolic abnormalities that occur in patients with cancer, rather than simply be an expression of malnutrition per se. 38 This situation would be similar to the occurrence of a catabolic state owing to a viral infection or in the early postoperative period whereby patients experience anorexia and fatigue that are secondary to the metabolic abnormalities rather than being causes of those abnormalities.

Infection

Fatigue is frequently associated with infections, particularly those that are recurrent or protracted. It may occur as a prodrome, and it may outlast the infection by weeks or even months. Chronic infection and cancer induce the same mediators for cachexia, including inflammatory cytokines, 38 and they may share similar mediators for fatigue as well.

Anemia

Anemia is prevalent in cancer patients. Common causes of anemia in cancer patients are myelosuppression by chemotherapeutic agents, iron deficiency, bleeding, hemolysis, nutritional deficiencies, and anemia owing to chronic disease. Severe anemia (hemoglobin < 8 g/dL) is known to be a cause of profound fatigue. In patients receiving chemotherapy, treating less severe anaemia has been shown to improve energy levels, activity levels, and QOL. In a prospective, open-label study of epoetin-alpha in 2,342 anemic patients receiving chemotherapy, mean energy levels, activity levels, and QOL were found to improve with increases in mean hemoglobin levels from approximately 9 g/dL to 11 g/dL. 39 The improvements were independent of tumor response and correlated with the increases in hemoglobin levels. Although these data suggest an association between anemia and fatigue, there are limited studies that specifically assess this relationship in populations with advanced illness.

Textbook of Palliative Medicine and Supportive Care Autonomic dysfunction

Autonomic dysfunction is a common complication of advancedstage cancer. This syndrome includes malnutrition, delayed gastric emptying, chronic nausea, anorexia, and poor performance status.40 Postural hypotension has been documented in patients with a specific type of severe chronic fatigue syndrome. The association between fatigue and autonomic dysfunction has not been established in cancer patients and should be investigated in future research.41

Psychological issues

Anxiety, depression, and psychological distress may contribute to fatigue.42 However, the nature of these relationships is unclear. The diagnosis of a major depressive episode in patients with advanced-stage cancer is difficult because the patients frequently present with neurovegetative and somatic symptoms that are part of the disease itself. Nevertheless, cancer patients presenting with an adjustment disorder or a major depressive disorder can have fatigue as one of the prevalent symptoms. Therefore, the role of psychological factors, including anxiety and depression, in the development of fatigue among cancer patients needs further research.

Metabolic and endocrine disorders

Endocrine disorders (e.g., diabetes mellitus, Addison’s disease, and hypothyroidism) and electrolyte disorders (e.g., hyponatremia, hypokalemia, and hypercalcemia) are possible causes of fatigue and in many instances have relatively simple and effective treatments. Testosterone deficiency results in the loss of muscle mass, fatigue, reduced libido, and reduced hemoglobin.43 Androgen insufficiency in cancer patients can result from anorexia-cachexia syndrome.44 In addition, chemotherapy and radiotherapy can cause hypogonadism. Hormonal ablative therapy has been found to significantly increase the incidence of fatigue in patients with prostate cancer. In patients with testosterone insufficiency treatment with androgenic anabolic steroids, including testosterone and its derivatives, has been found to increase muscle mass, improve energy and libido,45 and increase hemoglobin levels.45 Androgenic anabolic steroids are regularly used for the treatment of hypogonadism in HIV-infected men. Abnormalities of the HPA axis concerning corticotrophinreleasing factor have been postulated as another possible endocrine-related cause of fatigue. Corticotrophin-releasing factor levels increase in situations of physical or emotional stress and thus may cause fatigue.19 The pro-inflammatory cytokines IL-1, IL-6, and TNF-α are central mediators of the inflammatory process that can result in the dysregulation of the HPA axis and the secretion of mediators that induce such symptoms as pain, fatigue, anxiety, and depression, leading to an impaired QOL. 35

Paraneoplastic neurological syndromes

Paraneoplastic neurological syndromes are rare but are important to recognize, as many of these syndromes can precede the clinical presentation of a malignancy. They may be partially reversible with primary treatment of the tumor. Table 43.1 summarizes some of the paraneoplastic neurological syndromes associated with fatigue.

Other cancer-related symptoms

Various correlative studies have shown that fatigue is associated with pain, psychological symptoms such as anxiety and depression, dyspnea, sleep disturbances, anorexia, and constipation.46

Mechanism, Assessment, and Management of Fatigue TABLE 43.1  Paraneoplastic Neurological Syndromes Associated with Fatigue Syndrome

Association

Progressive multifocal leukoencephalopathy Paraneoplastic encephalomyelitis Subacute motor neuropathy Subacute necrotic myelopathy Peripheral paraneoplastic neuropathy Ascending acute polyneuropathy (GBS) Dermatomyositis/polymyositis Eaton–Lambert syndrome Myasthenia gravis Amyotrophic lateral sclerosis

Lymphoma, leukemia 70% lung, 30% other malignancies e.g., after irradiation in lymphoma Lung cancer Often precedes the primary Lymphoma Associated with malignancy in 50% Small cell lung cancer Lymphoma, thymoma (30%) Primary disorder with fatigue

Abbreviation: GBS, Guillain–Barré syndrome.

However, the intensity of the individual symptoms in a given patient may determine the symptoms’ ultimate contribution to the fatigue.47

Side effects of cancer treatment

Treatments for both cancer and the symptoms and conditions caused by cancer can cause or aggravate fatigue. Worsening of fatigue is common during chemotherapy and radiotherapy.48 Radiotherapy can result in anemia, diarrhea, anorexia, and weight loss, and chemotherapy commonly causes anorexia, nausea, vomiting, and anemia; all these events may contribute to fatigue. In addition, these treatments have secondary effects that may cause or exacerbate fatigue; for instance, fatigue may be a consequence of chronic pain resulting from radiotherapyor chemotherapy-induced immunosuppression that predisposes patients to infection. Such effects may persist for months to years after the completion of treatment. Biological response-modifying agents have also been implicated in fatigue; for instance, INF-α was shown to cause fatigue in 70% of patients. In fact, fatigue is the most frequent dose-limiting side effect in patients receiving biological response-modifying treatments for cancer. Data from studies using of PD-1 checkpoint inhibitors and targeted agents in advanced cancer patients found significant increase in cancer related fatigue especially in the first few months of treatment.49,50 However, in these patients endocrinopathies (a complication with treatment) should be ruled out as a cause of CRF.49 Opioids such as morphine have significant effects on the reticular system and are capable of inducing sedation, cognitive changes, and fatigue in some patients. Box 43.1 outlines cancer therapies and drugs that frequently contribute to fatigue in patients with cancer.

Genetics and cancer-related fatigue

There is preliminary evidence that various single nucleotide polymorphisms of pro-inflammatory cytokine genes (which affect the gene expression levels) are associated with CRF.51 Prior studies found overrepresentation of the IL-1B—511 CC alleles among cancer survivors with fatigue.52 Another recent study found a significant association between polymorphisms in the TNF-alpha and IL-6 genes and fatigue.53

405 In summary, evidence clearly shows that fatigue is a complex, subjective, multidimensional syndrome that can be attributed to multiple causes. It is particularly important to note that not only cancer but also cancer treatments, cancer-related symptoms, metabolic causes, endocrine dysfunction, cytokine dysregulation, and neuromuscular dysfunction may be among those causes, making a comprehensive assessment of paramount importance.

Assessment of fatigue Fatigue is a complex, subjective, chronic multifactorial and multidimensional symptom.5,54,55 Therefore, a systematic evaluation is essential. Fatigue assessment involves characterizing its severity, temporal features (onset, course, duration, and daily pattern), exacerbating and relieving factors, associated distress, and impact on daily life; and identifying treatable causes.4,5 Several scales have been developed to quantify fatigue. These instruments measure the severity and assess various dimensions of fatigue. These include the Edmonton Symptom Assessment Scale (ESAS)-fatigue item, 56 which evaluates the average severity of fatigue in the last 24 hours (in 0–10 scale wherein “0” in no fatigue and “10” is the worst fatigue imaginable).5 In addition to the ESAS-fatigue item, various other scales are commonly used. These include EORTC-fatigue items, 57 Brief Fatigue Inventory, 58 Functional Assessment of Cancer Illness Therapy (FACIT)-fatigue subscale, 59 and most recent Patient-Reported Outcomes Measurement Information System (PROMIS)-item Bank-Fatigue Short Form (PROMIS-SF).60–62 CRF has been classified into various subtypes based on severity, or cut-off scores. The NCCN guidelines on CRF recommend a simple 0–10 NRS be used to assess CRF intensity during past week (0 = no fatigue; 10 = worst fatigue you can imagine).2 Patients can be grouped by their severity responses into subtypes: 0 = none; 1 to 3 = mild; 4 to 6 = moderate; and 7 to 10 = severe. A CRF severity score of 4 or more can be used to indicate that further workup, referrals, and treatment may be needed.2,3 Cut-off scores are sometimes used to identify the optimal level for detecting cases of clinically significant fatigue defined by exceeding the established threshold of “caseness.” The cut-off scores, however, vary according to how they are used to define a subgroup and by the CRF measure used. For example, a FACIT-F score of 43 or less indicates clinically significant fatigue, and on a 0–10 NRS scale a cut off score of 4 or greater has been used as an eligibility criteria for entry into clinical trials.12,63 The PROMIS-SF is a novel, validated, and efficient scale that consists of seven items that measure both the experience of fatigue and the interference of fatigue on daily activities over the prior week, scores range from 7 to 35 with higher scores reflecting greater fatigue burden.60 A potential benefit of PROMIS is that as a multidimensional, accurate, and standardized tool, it allows the opportunity to link legacy CRF measures such as FACIT-F to the PROMIS fatigue measure and vice versa, thus enabling comparisons across research results.64 Several multidimensional instruments are more frequently used in research rather than routine clinical settings. These include multidimensional fatigue symptom inventory-MFSI-SF, Fatigue symptom inventory, Multidimensional fatigue Inventory.

Assessment of fatigue in clinical practice Assessment of fatigue in palliative practice might be a challenge, and fatigue is probably often neglected or overlooked.65 Physicians’ neglect of fatigue might have historical reasons, but

Textbook of Palliative Medicine and Supportive Care

406 it is probably related to the non-specificity of fatigue as a symptom and also due to the fact that there are limited effective treatments available. By asking, the physician might fear ending up in a long consultation, taking several tests, not finding any treatment options and end up with presenting general advice. For these reasons, physicians probably don’t address fatigue, and the lack of documentation on treatment alternatives might further support such a nihilistic or avoidant approach. The physicians’ beliefs about fatigue are therefore of relevance.66 However, the prevalence of fatigue, the overall aim of palliative care to prioritize the patients’ QOL, and the burden fatigue imposes on the patients and their families both psychologically and functionally do not support an avoidant approach. In fact, many patients are relieved just by being asked, they feel assured by adequate information tailored to their level of knowledge, and many are well aware of the limited possibilities for documented treatment alternatives. The clinical assessment of

fatigue as a symptom follows general guidelines for symptom assessment in palliative care.4,5 Fatigue assessment involves characterizing its severity, temporal features (onset, course, duration, and daily pattern), exacerbating and relieving factors, associated distress, and impact on daily life. To measure fatigue severity, routine use of a simple NRS such as the fatigue item in the ESAS might be both useful for the physician and patient. The PROMIS-F is also another crucial and validated tool in assessing fatigue for both clinical practice and research. Fatigue is for most the complex subjective experience, and hence in patients who are deemed to have clinically significant fatigue it is essential to further assess the predominant dimension, physical, psycho-social or cognitive domain that is interfering with optimal function. However, evaluation should include a detailed history and focused physical examination and laboratory investigations based on clinical suspicion so as to identify treatable causes (Tables 43.2 and 43.3). 5

TABLE 43.2  Fatigue Specific Instruments in Cancer Patientsǂ

Instruments

Reliability, Cronbach Coefficient

Population Base

No. of Items

Comments

Unidimensional Instruments Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Edmonton Symptom Assessment Scale

0.930.95, Patients with cancer and receiving Testretest treatment reliability r = 0.87 over 37 days 0.79, Testretest Elderly patients receiving palliative care reliability 0.65

Profile of Mood 0.89, Testretest Patients with cancer and many chronic States (vigor and reliability conditions fatigue) r = 0.65 Short Form36Version 0.87 Adults with cancer and other populations 1 Vitality (Energy/ Fatigue) Subscale35 PROMIS Fatigue 0.994 Adults with cancer and other populations Short Form

Brief Fatigue Inventory

0.820.97

Patients with cancer and receiving treatment

Fatigue Symptom Inventory31

0.90

Patients with cancer and receiving treatment

EORTC QLQ (FS)

0.80–0.85

Patients with cancer and receiving treatment

41 items, self-administered Multidimensional fatigue subscales or interview, 10 minutes of Functional Assessment of Cancer Therapy, assesses global fatigue severity and quality of life Patients rate the severity of 9 symptoms including fatigue on 11-point (0–10) visual analog scales, self-administered or interview, 5 minutes 8 items for vigor, 7 items for fatigue

Global fatigue severity

1–2 min for 4-item subscale

Vitality, energy level, and fatigue

Global fatigue severity

Each question has five Fatigue frequency, duration and response options ranging intensity and Impact of fatigue on in value from one to five. physical, mental and social It assesses fatigue over activities* the past seven days 9 items, self-administered, Severity and effect of fatigue on 5 minutes daily functioning in the past 24 hours 13 items, Fatigue intensity and duration and self-administered interference in quality of life in the past week 3 items, self-administered It has been noted to have a ceiling effect in advanced cancer patients and is not recommended as a single measure in this group (Continued)

Mechanism, Assessment, and Management of Fatigue

407

TABLE 43.2  Fatigue Specific Instruments in Cancer Patientsǂ (Conitnued) Reliability, Cronbach Coefficient

Instruments

Population Base

No. of Items

Comments

Cancer patients receiving radiotherapy, patients with chronic fatigue syndrome, psychology students, medical students, army recruits, and junior physicians Adults with rheumatoid arthritis, human immunodeficiency virus-positive adults, multiple sclerosis, coronary heart disease, or cancer Patients with different types of cancer

20-item self-report instrument

Multidimensional scale including: general fatigue, physical fatigue, mental fatigue, reduced motivation, and reduced activity Subjective aspects of fatigue including quantity, degree, distress, impact, and timing are assessed

30-item instrument

Global, somatic, affective, cognitive, and behavioral symptoms of fatigue

Patients with cancer-related fatigue; or chronic hepatitis C infections

22-item measure

Adults with cancer and other populations

11-item instrument

Multidimensional, assesses global fatigue severity to evaluate the efficacy of intervention strategies One of the few multidimensional instruments that is brief, easy to use but also has robust psychometric properties

Unidimensional Instruments Multidimensional Instruments Multidimensional 0.80 validity Fatigue Inventory (r ≤ 0.78)

Multidimensional Assessment of Fatigue

0.93

Multidimensional 0.870.96 Fatigue Symptom Inventory (short form) Revised Piper Fatigue 0.85–0.97 Scale Fatigue Questionnaire

* ǂ

0.79–0.89

16 items, selfadministered, 5 minutes

http://www.assessmentcenter.net/documents/PROMIS%20Scoring%20SF%20Fatigue%207a.pdf Table in part was adapted from ref 5; see also ref. 55.

TABLE 43.3  Assessment Modalities for the Causes of Unexplained Fatigue at the End of Lifea Medical Condition

Assessment Modality

Anemia

Complete blood cell count, serum vitamin B12, folate, iron, transferrin saturation, ferritin levels, fecal occult blood tests, and, if abnormal test result, further evaluation for blood loss Anticholinergics, antihistamines, anticonvulsants, neuroleptics, opioids, central α-antagonists, β-blockers, diuretics, selective serotonin reuptake inhibitors and tricyclic antidepressants, muscle relaxants, and benzodiazepines Assessments such as ADL, IADL, MMSE, and “get up and go” test Assessment of depression and anxiety following the DSMIV criteria Recent radiation therapy, chemotherapy, surgery

Medication adverse effects and polypharmacy Cognitive or functional impairment Mood disorders Adverse effects of primary disease treatment Malnutrition Infections Other contributing medical conditions

Serum albumin, prealbumin, cholesterol Blood cultures, urine culture, chest radiography, HIV antibody, RPR, PPD skin test Directed based on clinical finding

Abbreviations: ADL, activities of daily living; DSMIV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; HIV, human immunodeficiency virus; IADL, instrumental activities of daily living; MMSE, MiniMental State Examination; PPD, purified protein derivative; RPR, rapid plasma reagin. a Evaluation of fatigue is based on ref. 5; see also ref. 74.

Management of fatigue To be able to manage fatigue adequately, the contributing factors, often multiple, need to be determined (Figure 43.1), some of which may be irreversible. Once appropriate assessment is completed, the therapeutic approach to fatigue can be divided into treating underlying causes and symptomatic treatment (Figure 43.2). Routine assessment and management of fatigue is essential for optimal management. The NCCN guidelines for cancer related fatigue recommend screening all patients at regular intervals. For

mild fatigue, educating the patient and their caregivers along with close monitoring at regular intervals is advised. When patients report moderate or severe cancer related fatigue, which is significant enough to affect their QOL, a focused history and evaluation helps to delineate contributing factors (medications/ side effects, cancer related symptoms such as pain, nausea, drowsiness, lack of appetite, shortness of breath, emotional distress, sleep disturbance, anemia, nutritional deficit/imbalance, decreased functional status, comorbidities). Treating the reversible factors with the use of evidence-based interventions tailored to individual needs is important to treating the underlying causes of fatigue

408

Textbook of Palliative Medicine and Supportive Care

FIGURE 43.2  Therapeutic approaches to the management of fatigue.

Cancer

The complex association between cancer and fatigue has not been completely defined. There is little doubt however, that most patients with cancer at some time in their illness develop fatigue, and especially in the terminal phase this is thought to be as a direct result of the cancer.67–69 In a cross-sectional follow-up study of 459 Hodgkin’s disease patients, fatigue was significantly higher than in controls from the general population.70 In patients with cancer, there is a complex interaction occurring between tumor and host, which is not well understood but is thought to result in fatigue in several ways. The mechanism of CRF is described more in detail in the previous section, but in brief, tumors produce proteolytic and lipolytic factors, which can interfere with host metabolism. These factors are thought to play a role in the development of cancer cachexia with which there is complex overlap and interplay with fatigue28 as discussed in other chapters in this book and also below. Moreover, there may be other substances induced or released directly by the tumor which can also lead to fatigue.19,71 Tumors can also act by direct invasion of brain tissue, particularly the pituitary gland, and cause fatigue by both direct (disturbance in cognition) or indirect (endocrine disturbances via the pituitary axis) mechanisms.19 Management in this case is essentially treating the cancer. The successful treatment of the malignancy can result in significant and sustained improvement in fatigue.72 Fatigue is generally perceived as a sign of the progression of disease by patient and family members, which adds to anxiety and unnecessary interventions. The patient and caregivers must be educated about how common fatigue is as a complication of cancer and its treatment. They must also be counseled and educated about what to anticipate during and after therapy is completed with regards to fatigue, and mechanisms by which this common symptom can be managed. Many of the cancer therapies and symptomatic treatments of other effects of the cancer, such as pain, can themselves result in transient and/or prolonged fatigue and management of this is discussed below.

Therapies and medications Chemotherapy and radiotherapy

These treatment modalities in patients with cancer cause a specific fatigue syndrome.48,73,74 In isolation they both can cause fatigue but this is augmented further when both modalities are given concurrently. Bower et al. in a longitudinal study in 763 breast carcinoma survivors found that the patients with both

radiation and chemotherapy were more likely to be fatigued than radiation alone.75 Fatigue associated with chemotherapy tends to have a cyclical pattern. It occurs within the first few days of starting therapy, gets to a peak at about the time the white blood cell count is at its lowest level then improves in the week or so thereafter. The cycle is repeated with each cycle of chemotherapy and worsens with subsequent cycles, suggestive of a cumulative dose-related toxic effect.73,76 Multiple chemotherapeutic agents have been studied in fatigue either in isolation or in combination with most generating some degree of fatigue. Different types of cancer have also been studied with specific chemotherapeutic regimens with varying degrees of fatigue noted depending on the cancer and the regimen.73,77–79 A longitudinal prospective controlled study assessed 104 women with breast cancer receiving adjuvant chemotherapy and 102 controls. Tools used included the Functional Assessment of Cancer Treatment-General Quality of Life questionnaire, with subscales for fatigue and endocrine symptoms and the High Sensitivity Cognitive Screen. Ninetyone and 83 patients, and 81 controls were assessable at the end of 1 and 2 years, respectively. Differences between patients and controls were significant for both scales. It showed that fatigue, menopausal symptoms and cognitive dysfunction were important adverse effects of chemotherapy that improved in most patients with time.79 Radiotherapy causes a different pattern of fatigue when given alone.74 It tends to start more abruptly soon after treatment and diminishes soon thereafter but may get progressively worse as therapy continues.80,81 Fatigue has been noted to diminish but not completely resolve when short breaks in therapy occur, for example at weekends.80

Biological therapy

Biological response modifying agents such as INF-α cause fatigue in 70% of patients who receive this therapy. 31 Fatigue is one of the most important dose-limiting side effects of this type of therapy. The mechanism here is unknown though some investigators have postulated diffuse encephalopathy may occur. 32,33 Management of fatigue in these situations is essentially symptomatic and nonpharmacological. Patients and their caregivers need to be counseled and educated prior to commencing therapy about the anticipated fatigue associated with the different treatment modalities and that treatment related fatigue is not necessarily correlates to disease progression. Exercise, without overexertion as well as physical and occupational therapy

Mechanism, Assessment, and Management of Fatigue during treatment can help minimize the sometimes-overwhelming fatigue and prevent deconditioning. One common side effect of chemotherapy, which may impact fatigue and has been associated with symptom improvement if treated early, is anemia. This will be discussed later in this chapter.

Opioids

A large proportion of cancer patients experiencing pain are on opioids. This group of medications has significant effects on the reticular system and can cause sedation, cognitive changes, and fatigue in some but not all patients. The central acting effects would explain the mental fatigue, but it is more likely that the drowsiness or somnolence is what is perceived as fatigue by some patients.42 A trial of dose reduction if pain is well controlled and fatigue is becoming the predominant symptom can be effective. Psychostimulants such as methylphenidate and donepezil have been used to improve opioid-induced fatigue.82,83 Chronic opioid use have been implicated in causing male hypogonadism and contributing to symptoms of fatigue.84 If treatment of hypogonadism by hormone replacement or decreasing dose of opioid is the best approach is yet to be identified.

Cytokine modulation

Circulating cytokines and inflammatory proteins are thought to be associated with many of the symptoms exhibited in patients with advanced cancer such as fatigue, pain, depression, cachexia, and sleep disorders.19,28,85 These products have also been associated with infections, the effects of cancer treatments including chemotherapy and radiation therapy, and with the presence of the cancer itself. One of the mechanisms shown in laboratory studies by which cytokines mediate symptoms is via a number of signals through the hypothalamic–pituitary–adrenal axis.86,87 Since fatigue is one of the most common symptoms in advanced cancer, researchers have proposed that one possible explanation for fatigue in this patient population is the increased secretion of pro-inflammatory cytokines, such as IL-2, IL-6, INF-α and TNFα, in response to both the disease and its treatment.41,42 Several lines of evidence support cytokines in the pathophysiology of fatigue. These include: • The occurrence of fatigue as a major side effect of cytokines used in the treatment of cancer patients.48,88 • The elevation of cytokine levels seen in chemotherapy treatments for cancer.89 • The upregulation of pro-inflammatory cytokines seen in several malignancies and their correlation with fati gue.42,48,49 Treatment in this case can be challenging and depends to some extent on the mechanism. Evidence to date strongly supports a role for cytokine modulation with agents such as corticosteroids, cyclooxygenase (COX) 1 and 2 inhibitors (nonsteroidal anti-inflammatory drugs, nabumetone) thalidomide, monoclonal antibodies (anti-TNF, infliximab), and specific soluble receptor antagonists, some of which are currently being studied to modulate the effects of cytokines on the brain and other sites.90,91

Treatment of cachexia

Cachexia has been covered in detail elsewhere in this book but there are a number of important points to note with cachexia in association with fatigue.28 There is a complex overlap between cachexia and fatigue, especially in advanced cancer. Cachexia can

409 be reversible when due to malnutrition or starvation, or in catabolic states such as acute or chronic infections. However, when due to underlying illness usually in the terminal phase such as cancer, AIDS, end-stage cardiac disease, or chronic obstructive airways disease, it is often more difficult to reverse.28,92 The significant loss of muscle mass in cachexia could explain the profound weakness and fatigue with which it is associated.93 Of note though is that fatigue can be present in the absence of significant weight loss and vice versa where profound cachexia and malnutrition may exist without fatigue. Treatment for cachexia secondary to malnutrition or starvation involves nutritional support. Though there is no evidence that aggressive nutritional therapy improves the QOL in advanced cancer patients or that parenteral feeding has much impact on fatigue,92 in patients where cachexia is deemed to be secondary to malnutrition these are exactly the measures that should be employed. In such patients, aggressive nutritional support can result in reversing the cachexia and associated fatigue. The majority of cachexia in palliative care patients is unfortunately irreversible and treatment is often symptomatic. In addition to established agents in use including progestins (megestrol acetate), corticosteroids, and prokinetics (metoclopramide), many newer agents are being studied such as thalidomide, cannabinoids and omega 3 fatty acids found in fish oils.94 Treatment of secondary cachexia by treating symptoms like constipation, nausea, dysguesia, dysphagia, early satiety with simple pharmacologic measures also helps with treatment of cachexia/anorexia and consequent weight gain.95

Management of autonomic failure

Autonomic failure is a common outcome of advanced cancer,96,97 but can also occur in other non-cancer diseases encountered in palliative care such as Parkinson’s disease. Symptoms associated with autonomic failure include postural hypotension with or without intermittent episodes of syncope, gastrointestinal symptoms such as nausea, vomiting, diarrhea or constipation, and anorexia.97 Some of these symptoms may contribute directly or indirectly to fatigue such as postural hypotension, anorexia, and persistent diarrhea. A subset of chronic fatigue syndrome has been associated with autonomic dysfunction, but this association has not been widely studied in advanced diseases encountered in palliative care. Low heart rate variability and increased norepinephrine levels have been associated with fatigue in advanced cancer population. Exercise is known to increase HRV, and hence might benefit with management of fatigue in advanced cancer population with autonomic failure.98 Autonomic failure is usually irreversible and can be difficult to treat in the setting of fatigue. Midodrine, a specific a1 sympathomimetic agent, has been used to manage autonomic failure in other conditions such as diabetes and might have a therapeutic role in autonomic failure in the palliative care population. In a double-blind randomized crossover study with midodrine and ephedrine, eight patients with refractory orthostatic hypotension secondary to autonomic failure were assessed. Midodrine produced a significant increase in both systolic and diastolic blood pressure with associated improved ability to stand as compared with ephedrine and placebo.99 Another double-blind, placebo controlled, four-way crossover trial looked at 25 patients with neurogenic orthostatic hypotension. Patients were randomized to receive either placebo or three different doses of midodrine (2.5, 10, or 20 mg) on successive days. Supine and standing blood pressures were measured sequentially and midodrine was shown

410

Textbook of Palliative Medicine and Supportive Care

to significantly increase standing systolic blood pressure (peaking at 1 hour after dosing) with a mean score of global improvement of symptoms being significantly higher for midodrine at doses of 10 and 20 mg compared with placebo.100 Other measures, including discontinuing all possible contributing medications, plasma volume expansion with increased salt intake and use of fludrocortisone, wearing pressure stockings and rising up in stages and slowly for patients with postural hypotension used in other causes of autonomic failure might also be applicable in this patient population.101

increase in mean self-rated scores of energy level, activity level, and overall QOL. These improvements correlated with the magnitude of the hemoglobin increase.105 Another prospective community-based study with 2,289 patients with nonmyeloid malignancies receiving chemotherapy received epoetin for 16 weeks. Patients reported improvement in QOL parameters which correlated with significant increases in hemoglobin levels independent of tumor response. 39 Some authors, however, believe that the improvement noted in treating this level of anemia may be secondary to improvement in exertional dyspnea rather than fatigue per se. Osterborg et al. conducted a placebo controlled randomised trial of epoetin alpha in severely anemic transfusion dependent patients with advanced haematologic malignancy. He concluded an improvement of QOL and anemia with most benefit seen ≥2 g/dl Hb. In 2008, FDA revisited the safety data and has black box warning on erythropoetin as several studies in breast, head and neck malignancies reported decreased survival, VTE and cardiac risks. The recommendation for use of Epo in cancer patients is at lowest dose possible to keep Hb around 12 g/ dl and dose reduction for Hb>12.106,107 B. Blood transfusion: In a Cochrane review by Preston NJ et al. the effect of blood transfusion for treating anemia in patients with advanced cancer was analyzed.108 12 studies with 653 participants were identified and the primary outcome in 5 studies was improvement of fatigue for two to seven days with the effect waning after 14 days. The studies used different measures for assesment and quantification of fatigue. Few patients in some studies died at or after 14 days of transfusion which could be attributed to transfusion or simply the patients being sicker. The result of this review demonstrated the short term response with concerns about risk and safety of blood transfusion in advanced disease. In managing fatigue thought to be associated with anemia, assessment of the underlying cause as well as the acuity of anemia becomes important as this may influence the choice of treatment. The goals of care need to be determined on an individual basis as well as overall prognosis since transfusions would give almost immediate results and erythropoietin could take up to 4 weeks to show response.109

Neurological disorders

A number of neurological disorders are associated with fatigue, some of which may be the primary disease such as amyotrophic lateral sclerosis, myasthenia gravis, Parkinson disease, multiple sclerosis, and other demyelinating diseases.2 On the other hand, some neurological disorders occur as a result of the terminal disease and may sometimes precede the disease by quite a long time, such as the paraneoplastic syndromes including Eaton–Lambert syndrome and dermatomyositis/polymyositis (Table 43.1).102 Treatment here is disease specific, though most of these diseases are progressive despite treatment and both the disease and associated fatigue become irreversible, at which point symptomatic therapies, both pharmacological and non-pharmacological, are introduced (see Figure 43.1).

Treating anemia

Anemia is a common entity seen in cancer patients, either as a complication of chemotherapy or as a disease presentation in itself, more so with hematological malignancies. Low hemoglobin and duration of anemia has been found to correlate with negative symptoms in patients with cancer, including fatigue, QOL, depression, vertigo. However, in the setting of advanced cancer the etiology of fatigue is multidimensional and the contribution of anemia is yet to be defined.17,103 In the patient group in which mild to moderate levels of anemia may exacerbate fatigue, there is evidence that treating less severe anemia improves energy levels and QOL, including those receiving chemotherapy. In patients with advanced disease and in the palliative care patient population, anemia is probably over-diagnosed as a cause for fatigue. Fatigue measured on a scale of 0–10 in a retrospective study of 147 patients seen in palliative care consultation with a median hemoglobin level of 11.6 g/dL did not show significant correlation between fatigue and hemoglobin level though there was a trend (p = 0.09).104 There is little doubt that anemia is prevalent in such disease states, especially advanced cancer, but it is unclear at what hemoglobin level the treatment of anemia either with blood transfusions or epoeitin impacts fatigue. Unfortunately, treatment of anemia in advanced cancer palliative settings has not been studied with randomized control trial. The two mainstays of treatment of anemia are blood transfusions or synthetic erythropoietin. A. Synthetic erythropoetin: Erythropoetin/darbopoetin are synthetic drugs administered subcutaneously either weekly or every three weeks. Several trials in the past have shown benefit of EPo with respect to decrease in need for RBC transfusions, improved QOL, Hb levels. In an open label study 2342 patients from community-based hospitals, with malignancies undergoing chemotherapy, were treated with epoetin alfa. A total of 1,047 patients completed the full 4 months of epoetin therapy and showed significant

Pain

Some authors have found a strong correlation between pain intensity/severity and fatigue in patients with cancer.110 It is more likely that there is an indirect correlation with chronic uncontrolled pain causing psychological distress, insomnia, thus impacting fatigue. Moreover, as mentioned above, some of the treatment modalities of pain can cause fatigue, for example opioids. As such, detailed assessment and targeting treatment toward the associated factors and symptoms, as well as achieving good pain control, would be the most appropriate management here.

Other comorbidities Infection

Patients with advanced cancer and other advanced disease states seen in palliative care are at increased risk of infection due to relative and sometimes profound immunosuppression. Fatigue is often associated with infections, especially when the course

Mechanism, Assessment, and Management of Fatigue is protracted or when infections are recurrent. Prolonged viral infections are especially notorious for producing longlasting episodes of fatigue.111–113 Fatigue may occur as a prodromal symptom and persist sometimes long after the infection has resolved. Chronic infection and cancer induce the same cytokine mediators for cachexia such as IL-6, TNF α,113,114 so it is possible that they share similar mediators for fatigue as well due to the overlap between cachexia and fatigue described earlier. Vigilance in avoiding recurrent infections is important here and having a low threshold for using appropriate antimicrobial therapy can minimize some of these infections.

Psychogenic disorders

Depression and anxiety are discussed in more detail elsewhere in this book but a few key points are worth mentioning here due to the strong correlation between these disorders and fatigue. Symptoms of psychological distress and adjustment disorders with depressive or anxious moods are much more common in this patient population than major psychiatric disorders.115 The incidence of depression in this group tends to be overestimated. Self-reported scales suggest a prevalence as high as 25%, but in fact only 6% of cancer patients are estimated to have major depression and 2% have anxiety disorders.116 Fatigue can be the prevalent symptom in any of these disorders. It is sometimes difficult to tease out cause and effect as depression for instance may be the cause of or occur as a result of fatigue. Some groups have found significant association between fatigue and psychological distress but again this is by no means the only variable causing fatigue, reiterating the multifactorial contributors to fatigue. Furthermore treatment of depression using antidepressant may not improve fatigue.117 Treatment here is by and large symptomatic with good expressive supportive counseling though antidepressants may sometimes be indicated especially when depressive mood makes up a large component of the adjustment disorder.118

Insomnia

Lack of sleep occurs for multiple reasons which themselves may be indirectly causing fatigue. Sleep may be disturbed because of uncontrolled symptoms such as pain, depression or anxiety, mild delirium with sleep cycle inversion, drugs and suboptimal conditions causing poor sleep hygiene. Insomnia is less likely therefore to be an independent variable in the etiology of fatigue and though it can cause fatigue does not cause physical weakness.89 Appropriately assessing the patient and treating the underlying contributing factors such as pain and psychogenic disorders, as well as teaching good sleep hygiene, can improve the insomnia and may sometimes be more effective in the long run than using hypnotics and sedatives which sometimes may be indicated for short-term use.118

Metabolic and endocrine abnormalities

These are often very reversible causes of fatigue, which can be easy to treat.5 It is therefore important when a patient presents with fatigue to run a simple chemistry panel as part of the work-up. Abnormalities such as hyponatremia, hypokalemia, hypomagnesemia, hypercalcemia, and hyper or hypoglycemia can be readily diagnosed and corrected with simple measures such as hydration and replacement therapy. A lot of these electrolyte disturbances cause physical/muscle weakness, which can cause significant fatigue. Endocrine disorders are easily missed but can also often be readily reversible or treatable causes of fatigue. Addison disease for instance causes significant fatigue and although this is

411 now uncommon in Western society, hypoadrenalism per se is still fairly common. Many drugs can cause secondary hypoadrenalism, which has identical symptoms to the primary disorder, e.g., steroids (when discontinued abruptly). Other common endocrine disorders such as diabetes and hypothyroidism should also be excluded and if diagnosed treated promptly with appropriate replacement therapies.

Hypogonadism

This condition deserves a separate mention from the other endocrine disorders due to recent research interest in this as a cause of fatigue with associated loss of muscle mass. Low testosterone results in loss of muscle mass, fatigue, reduced libido, and reduced hemoglobin.41,119 Two large patient groups encountered in palliative care, namely cancer patients and patients with AIDS, have been found to have testosterone deficiency which in males can often be easily reversible by replacement therapy with testosterone. Some antineoplastic therapies as well as both systemic and intrathecal opioids have been shown to cause hypogonadotropic hypogonadism41,44,120 and a low threshold for measuring testosterone levels and offering replacement therapy is key in managing fatigue in this patient population. Hormonal ablative therapy has been shown to double the incidence of fatigue in men with prostate cancer but of note is that this is one patient population in which testosterone replacement therapy is contraindicated.

Chronic hypoxia

The association here with fatigue is probably best studied in chronic airways disease where oxygen therapy has been shown to improve QOL in patients with fatigue as one of the symptoms. In a prospective longitudinal study of 43 consecutive chronic obstructive pulmonary disease patients fulfilling criteria for long-term oxygen therapy and 25 patients not fulfilling criteria, there was significant improvement noted in health-related QOL in patients on long-term oxygen therapy. This improvement in symptoms included fatigue, emotional, and mental function and was sustained over a 6-month period.121 The use of supplemental oxygen in decreasing dyspnea and fatigue or improving exercise tolerance has not been shown to be beneficial in cancer patients with mild hypoxemia. A double-blind, randomized controlled crossover trial with 31 lung cancer patients without severe hypoxemia (O2 saturation level > 90%) assessed whether or not oxygen is more effective than air in decreasing dyspnea and fatigue and increasing physical performance. There was no significant difference observed between treatment and control groups in dyspnea, fatigue, or physical performance.122 Earlier studies showed that patients with cancer who had hypoxemia and dyspnea at rest benefit from oxygen therapy, but further studies are required to determine whether oxygen therapy could improve fatigue or exercise tolerance in hypoxia patients with advanced disease.123

Symptomatic management of fatigue This can be divided into pharmacological and nonpharmacological management.

Pharmacological management

Pharmacological management can be further divided into established and emerging agents (Box 43.1).

Textbook of Palliative Medicine and Supportive Care

412 BOX 43.1  PHARMACOLOGICAL AGENTS FOR FATIGUE Established agents • Corticosteroids • Megestrol acetate • Psychostimulants, e.g., methylphenidate, modafinil, dextroamphetamine • Testosterone Emerging agents • Agents that inhibit cytokine action, e.g., thalidomide, COX-1 and COX-2 inhibitors (NSAIDs), selective COX-2 inhibitors, omega 3 fatty acids, a-melanocyte stimulating hormone • Agents that block cytokine release, e.g., pentoxifylline, bradykinin antagonists • Donepezil • Monoclonal antibodies, e.g., infliximab, soluble receptor antagonists • l-Carnitine

Established agents Unfortunately there is no single agent that can be used to treat fatigue in advanced diseases effectively. This is probably because of the multifactorial etiologies contributing to fatigue. However, a number of agents have been studied and shown to be effective in treating fatigue, often in combination targeting he multifactorial and multidimensional etiology of fatigue.

Corticosteroids

Corticosteroids are commonly used in palliative care for the management of symptoms. The mechanism of action of corticosteroids on fatigue is not well understood. Corticosteroids are presumed to decrease fatigue by their effect on: (a) inflammatory cytokines such as IL-1, IL-6, TNF-α which have been implicated in pathogenesis of cancer related fatigue; (b) effect on HPA axis as dysregulation of HPA axis has been associated with chronic fatigue syndrome. Some smaller studies have also implicated the altered cortisol response to stress in cancer patients related to persistent fatigue and symptom clusters. Studies have been done on steroids, dexamethasone, and methylprednisone and have shown improvement in fatigue. Moertel et al. in a double-blind controlled study with 116 patients with advanced gastrointestinal cancer, dexamethasone given at a dose of 0.75 and 1.5 mg four times daily showed improvement in appetite and sense of wellbeing.124 There was however, no associated weight gain or improvement in performance status. There was also initial symptomatic improvement in the placebo group but after 4 weeks this disappeared and at this point, dexamethasone showed a statistically significant advantage over placebo. Other groups found methylprednisolone caused improvement in activity level quite rapidly but this was not sustained over a 3-week period. A newer study by Paulsen et al. revealed methylprednisolone 16 mg twice daily improved fatigue, anorexia, and patient satisfaction 7 days post administration when compared to placebo.125 Forty terminally ill cancer patients were studied in a 14-day randomized

double-blind, crossover trial comparing methylprednisolone with placebo. The daily dose was 32 mg and endpoints studied were pain, appetite, nutritional status, psychiatric status, daily activity, and performance. Appetite and daily activity increased in 77 and 21% of patients, respectively, with 71 and 57% reduction in depression and analgesic use, respectively.126 In a recent randomized placebo controlled study by Yennurajalingam et al. 2013 with 84 advanced cancer patients, oral dexamethasone 8 mg/day for 14 days was found to be effective in relieving cancer related fatigue as compared to placebo. The mean (standard deviation) improvement in the FACIT-F fatigue subscale at day 15 was significantly higher in the dexamethasone group than in the placebo (9 [10.3] vs. 3.1 [9.59], p = 0.008). The numbers of grade ≥3 adverse effects did not differ between groups (17/62 vs. 11/58, p = 0.27. Corticosteroids to treat fatigue are probably best used on a short-term basis, as long-term use is associated with increased incidence of side effects including myopathy which could potentially make fatigue worse. Moreover, studies have shown that the beneficial effects generally last between 2 and 4 weeks. Other beneficial effects of steroids that may impact fatigue include the effect on nausea, appetite, and pain.91

Progestational steroids

Cancer cachexia is known to contribute to fatigue in cancer patients and weight loss has been associated with increased mortality. A number of studies in terminally ill patients given megestrol acetate have shown a rapid improvement within 1 week to 10 days, in a number of symptoms including fatigue, appetite, calorie intake, and nutritional status. Doses used range from 160 to 480 mg per day. In a randomized, double-blind crossover study with 53 evaluable patients with advanced solid tumors not responsive to hormone therapy, megestrol acetate given at a dose of 160 mg three times daily for 10 days reported a significant improvement in appetite, activity, and wellbeing. There was also significant improvement in overall fatigue score. There was no significant change in nausea, nutrition, or energy intake. The mechanism of action of megestrol acetate is unclear and may be due to the glucocorticoid or anabolic activity or due to effects on cytokine release or a combination. In a Cochrane review by Minton et al. involving three studies on progestational steroids, no benefit of these for treatment of fatigue was found. Known side effects of these agent include thromboembolic events), adrenal suppression with insufficiency upon abrupt discontinuation, hypertension, hyperglycemia, breakthrough uterine bleeding, and skin photosensitivity.127

Psychostimulants

Methylphenidate is a known drug therapy for ADD, used mainly in children and is the most well researched psychostimulant drug used for the treatment of fatigue as well as additional symptoms such as sedation and depression in advanced-stage cancer.128 Prior studies found that MP blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron by its action on the dopamine transporter and this results in the increased release of these monamines into the extraneuronal space.129 While prior studies have suggested that methylphenidate may result in significant improvement in activity level in patients on large doses of opioids,131–135 and otherwise heterogeneous studies with mixed results thought so due to small sample sizes due to underpowering,133,134 more recent meta-analysis of larger studies have found no statistically significant benefit of methylphenidate for fatigue compared to placebo.133,132 Despite these overall negative results,

Mechanism, Assessment, and Management of Fatigue future studies are needed to assess the benefits of psychostimulants in a subset of fatigued patients with predominant depressed mood or sedation.132 Other psychostimulants studied in noncancer palliative groups include modafinil and amantadine in multiple sclerosis,136 and armodafinil in human immunodeficiency virus (HIV)137 and amyotrophic lateral sclerosis (ALS).138 Both agents are postulated to enhance catecholaminergic signaling and decreased gamma aminobutyric acid release, primarily at the anterior hypothalamus, for the benefits of the treatment of impaired cognition139 and severe fatigue.140 Effect of modafinil on fatigue in cancer patient was studied by Jeanne-Pierre et al. in a phase III double blind placebo controlled randomised trial with 631 patients on chemotherapy.135 Modafinil 200 mg once a day was used and BFI-3 was utilised as a measure of fatigue in this study. The results showed a statistically significant response for those with severe fatigue (BFI score ≥ 7) with average BFI-3 scores 7.2 in modafinil group as compared to placebo with average score 7.6 (p = 0.033), although there were no significant differences in BFI-3 in the patients with mild to moderate fatigue. In a newer, randomized, well-designed study in non-small cell cancer patients, there were no significant benefits of modafinil when compared to placebo.141 Modafinil, a psychostimulant, is effective and well tolerated for the treatment of excessive daytime sleepiness (EDS) in patients with narcolepsy, and conditions such as Parkinson’s disease and obstructive sleep apnea. It was studied in HIV positive and ALS patients, and was found to improve symptoms of fatigue, depression and sleepiness.142 The newest literature reiterates insufficient evidence to use psychostimulants for the management of fatigue in cancer patients with or without opioid-related sedation.131

Testosterone

Low testosterone is common in men with advanced cancer. Low testosterone has been associated with high inflammatory markers and high symptom burden in patients with advanced cancer.143 Treatment with testosterone replacement has been beneficial in management of symptoms in non-cancer patients. The use of testosterone and its derivatives and other androgenic anabolic steroids have been shown, predominantly in patients with hypogonadism due to HIV disease, to increase muscle mass, improve energy and libido and increase hemoglobin levels. In a prospective longitudinal study over a 3-year period, 18 hypogonadal men who had never been treated were given transdermal testosterone. The mean testosterone level reached the normal range by 3 months of treatment and remained normal for the duration of treatment. Outcomes measured were bone mineral density, fat free mass, prostate volume, erythropoiesis, energy, and sexual function. The full effect on bone mineral density took 24 months but the full effects on the other tissues and energy levels took 3–6 months.45 A randomized, double-blind, placebo controlled study in a group of hypogonadal men with AIDS wasting looked at the effect of testosterone administration on the depression score. Fifty-two hypogonadal males with AIDS demonstrated significantly higher scores on the Beck Depression Inventory (BDI) than matched eugonadal men also with AIDS. The hypogonadal men were then treated with testosterone and there was a significant decrease noted in the BDI score for the 39 patients who completed the study.144 The correlation between depression and fatigue has been made earlier and hence by improving depression in this way, fatigue could potentially improve. Testosterone deficiency has also been shown to occur as a result of cancer therapy

413 including radiation and chemotherapy as well as in the hormonal treatment of certain cancers such as prostate cancer (where testosterone replacement is not possible). A preliminary randomized controlled study was recently conducted by Del Fabbro et al. to evaluate the efficacy of testosterone replacement for fatigue in male hypogonadic patients with advanced cancer.145 A total of 26 patients were evaluated with 12 on replacement and 14 on placebo for the primary outcome at Day 29. The intervention group had improvement in fatigue scores (mean [SD] −5.5±19 for placebo and 3.9 ± 14 for testosterone, p = 0.09). Adverse events were similar between groups.

Emerging pharmacological agents

Fatigue, as stated earlier in this chapter, is the most common symptom in palliative patients and yet is probably one of the most difficult symptoms to treat. Multiple agents have been studied and found not to be effective in the treatment of fatigue, such as mazindol, donepezil,146 and L-carnitine.147 With regards the established agents, results are often short term or they are associated with unacceptable side effects, e.g., corticosteroids with myopathy in long-term use or megestrol acetate with associated thrombotic risk. This often makes them unsuitable for many in this patient population. Moreover because of the multifactorial complex etiology of fatigue, it has been challenging to find a single effective pharmacological agent to treat fatigue. Currently a number of agents are under investigation for the treatment of fatigue some of which are discussed below. Ginseng is a Chinese herbal medicine, which comes in three forms: Asian (Panax ginseng) and American (Panax quiquefo­ lium), and the Siberian (Eleutherococcus senticosus) variety. It is presumed to help fatigue by reducing the impact on environmental stress (adaptogen). However, there are limited studies conducted in cancer patients. Other emerging and proposed agents for targeting the treatment of fatigue in palliative care include a-melanocyte-stimulating hormone, monoclonal antibodies against TNF-α such as infliximab, COX-1 and COX-2 inhibitors, to name a few. Herbal remedies are often used by patients with CRF. Ginkgo biloba, for example, has some activity against TNF and the potential benefits of natural products in fatigue should also be explored with good clinical studies.51

Nonpharmacological management

Of the various treatment strategies, exercise has the strongest empirical support in patients with early cancer and cancer survivors, with several recent meta-analyses concluding that physical activity has a moderate beneficial effect on CRF.150 There is also some support for psychological interventions, with a metaanalysis showing a small to moderate beneficial effect (standardized mean difference in the range of 0.10 to 0.30).42 The few trials that explicitly focused on fatigue, providing education about fatigue and instruction in self-care, coping techniques, and activity management, were more effective than nonspecific interventions.151

Physical activity or exercise

A recent Cochrane review confirmed the beneficial effects of exercise in the management of CRF.34 In a total of 56 studies in which 1,461 participants received an exercise intervention and with 1,187 control participants, exercise was seen to be statistically more effective than the control intervention (standardized

414 mean difference, −0.27, 95% confidence interval −0.37 to −0.17). Both aerobic and resistance exercises, such as brisk walking, cycling, swimming, and weight lifting, are helpful; at least one 30-minute episode per day (at least 150 minutes per week) has been shown to reduce fatigue levels. In addition, they found that aerobic exercise significantly reduced fatigue but that resistance training did not. There is limited evidence of beneficial effects of exercise in palliative care patients.152 In a randomized controlled study in advanced-stage cancer patients, 121 patients were referred to exercise and 110 were referred to usual care. After 8 weeks of a standardized 60-minute, twice-a-week intervention, no significant differences were found in the primary outcome of physical fatigue as assessed by a fatigue questionnaire. Statistically significant results were noted in the physical performance measures, including a shuttle walk test and a hand grip strength test; however, this study had a relatively lower adherence rate (69%) and a high dropout rate (36%).153 Further research is necessary to determine the most effective type (aerobic vs. resistance), frequency, duration, and intensity of exercise in palliative care patients. In general, exercise should be prescribed for patients with advanced-stage cancer, if appropriate, as exercise may be beneficial to maintain muscle mass and physical strength, which are commonly affected due to cachexia related to progressive cancer.153 Increase in physical activity may further be beneficial in improving outcomes, including maintaining independence, self-reported physical functioning, well-being, self-esteem, and energy.154 In cases of deconditioning, the physiotherapist can suggest suitable exercises and encourage increased activity, which may have beneficial effects from both physical and psychosocial perspectives. In addition, if the patient is immobile, a physiotherapist can perform passive movements that will help the patient maintain flexibility and decrease painful tendon retraction. Occupational therapists can allow patients to remain safe and increase their activity at home by providing such resources as ramps, wheelchairs and walkers, elevated toilets, safety devices for bathrooms, and hospital beds. In addition, these therapists can give patients and families useful tips that enhance mobility and help prevent further muscle atrophy, tendon retraction, and pressure ulcers.

Acupuncture

Several studies have been conducted using acupuncture as an intervention for CRF (see Chapter 75 Integrative Medicine in Supportive and Palliative Care).155 Of these, a recent study by Malossitis et al.156 of patients with breast cancer shows the most promise. In this study, 75 patients were randomly assigned to usual care and 227 patients to acupuncture plus usual care. Treatment was delivered by acupuncturists once a week for 6 weeks through needling three pairs of acupoints for 6 weeks. The usual care group received a booklet with information about fatigue and its management. The difference in the mean General Fatigue score of the multidimensional fatigue inventory, which was the primary outcome, between those who received the intervention and those who did not was −3.11 (95% confidence interval, −3.97 to −2.25; p < 0.001). The intervention also improved all other fatigue aspects including Physical Fatigue and Mental Fatigue, anxiety and depression1 and QOL. The authors of this study concluded that acupuncture is an effective intervention for managing CRF and improving patients’ QOL.157

Textbook of Palliative Medicine and Supportive Care Recent studies also suggest that integrative interventions such as massage therapy, Qigong/Tai Chi, and Yoga are beneficial in the treatment of fatigue in cancer patients.158 Further studies are needed in advanced cancer patients.

Cognitive behavorial therapy

Cognitive behavioral therapy (CBT) and psychosocial interventions (including mindfulness-based stress reduction) have been known to be effective for improving insomnia in cancer survivors, but have also been shown to be effective modalities for the treatment of CRF.159,160 Since daytime sleepiness and sleep disturbances contribute to CRF,90,161 interventions targeting sleep disturbances could improve CRF. In a recent four arm study of 96 cancer patients with chronic insomnia, it was found that CBT, or the combination of CBT with armodafinil was associated with greater reduction in fatigue scores.162 However, further welldesigned studies are needed in a broad variety of palliative care patients before this approach can be recommended in advanced serious illnesses other than cancer.

Neurofeedback

Cancer survivors typically experience ongoing symptoms such as fatigue and cognitive impairments. Neurofeedback is a noninvasive form of brain training that is noninvasive with minimal side effects. However, there is currently insufficient data to utilize neurofeedback as effective therapy for management of these symptoms in cancer survivors though there are promising results based on a meta-analysis review of multiple randomized control trials in utilizing this modality.163

Light therapy

Light has a known strong effect of sleep and circadian rhythms in other medical conditions but its effects on CRF are largely unknown. Preliminary studies in breast cancer patients have suggested that bright white light (BWL) prevented CRF from worsening during chemotherapy when compared to dim red light (DRL).164 Another preliminary study assessed 36 cancer survivors who were either post chemotherapy or chemotherapy and radiation for breast cancer, post completion of treatment for gynecologic cancer, or post hematopoietic stem cell transplantation in which BWL showed a reduction in fatigue whereas DRL did not. In addition, 55% of patients in the DRL group still reported residual fatigue post light therapy whereas the BWL arm did not report any residual fatigue.165

Nutritional supplements

For patients with moderate to severe fatigue who are undergoing cancer treatment, a therapeutic course of American ginseng is reasonable, as long as there are no potential contraindications such as drugs that may interact unfavorably with ginseng (such as anticoagulants). There is some literature that illustrates the benefits of ginseng. In a randomized, double blind, dose evaluation pilot study by Barton et al. with 282 cancer patients, Wisconsin Ginseng (Panax quiquefolium) was tried in a dose of 750, 1,000, and 2,000 mg/day in twice daily dosing versus placebo.148 There was no difference in symptom improvement in patients on 750 mg versus placebo. Although 40% of patients who completed 8 weeks of treatment with the 1,000 and 2,000 mg doses noted moderate benefit as

Mechanism, Assessment, and Management of Fatigue compared to 17% of the patients on the placebo arm. No significant toxicities were noted despite patients being on cytotoxic therapy. In a recently completed study, Wisconsin Ginseng at a dose of 2,000 mg daily for 2 months was found to effective compare to placebo in reducing fatigue in cancer patients. In a subset of patients receiving chemotherapy, it was found to be effective in 4 weeks.149 There were no significant side effects between the treatment and placebo arm. In another randomized controlled study, 2,000 mg/day of American ginseng (Panax quinquefolius) in 364 participants undergoing active treatment across the United States was associated with improvement in fatigue after 8 weeks of treatment compared to placebo, especially in patients receiving active treatment (versus those who had completed treatment) with no statistically significant differences in toxicities between the arms.149 Another study examined 50 mg twice daily of guarana (a stimulant derived from the extract of seeds from a plant in the Paullinia cupana) revealed that there was a significant improvement in fatigue at days 21 and 49 post administration with no resulting toxicities.166 Randomized control trials assessing the efficacy of Korean ginseng (Panax ginseng) however have demonstrated less clear benefits. In one randomized control trial, Asian ginseng (800 mg daily) was shown to be non-superior to placebo after 4 weeks of treatment in 112 patients with advanced cancer.167 By contrast, another randomized control trial in which 438 patients with colorectal cancer being treated with combination chemotherapy received 2,000 mg/day of Korean ginseng and had improved fatigue scores at 16 weeks without discernable toxicities.168 These findings support Ginseng as a promising nutraceutical agent in the treatment of cancer related fatigue. Further studies are necessary to characterize the dose, duration, and selection of patient population of who would most benefit from ginseng administration.

Education

Educating the patient and caregivers about the possible causes of fatigue and informing them of how frequent a symptom it is at this stage in their disease may help them have more realistic expectations. Also providing them with information about the different modalities of treatment, some of which can be self-implemented, such as education about sleep hygiene and progressive limitation in physical activity can help empower the patient.118,169 In a study by Carolina et al. of colon or gastric cancer from a comprehensive cancer center, 40 eligible patients were randomly allocated to intervention which consisted of a patient education program delivered by nurses aiming to study perception of fatigue with nursing education. The program included one-to-one education, training and counseling, as well as audio-visual and computerized educational materials. The comparison of symptoms was done between patients who received same treatment and had same type of cancer. Using FACT-F scale, the nursing intervention group had decrease in level of fatigue as compared to control group (please complete the data descriptions using p values). Cognitive behavioral therapy has shown benefit in chronic fatigue syndrome, neurological disorders, primary insomnia. The benefits of this therapy in cancer population have been studied as well. Gielissen et al. conducted a study with 112 cancer survivors with unexplained fatigue, who were randomly allocated to intervention (CBT) versus no intervention (waiting list)and assessed at baseline and 6 months. There was significant improvement in fatigue severity (−13.3; 95% CI, 8.6 to 18.1) and in functional impairment (−38.2; 95% CI, 197.1 to 569.2) in CBT versus no

415 intervention group. 54% of CBT group had clinically significant improvement in fatigue severity as compared to 4% of waiting list group. Similar results were seen with regards to improvement in functional impairment (50 vs 18% in CBT vs waiting list respectively). In another RCT by Espie et al., with 150 cancer patients, CBT was used as an intervention to study the effect on sleep quality with fatigue, QOL as secondary measures. Patients with CBT intervention had statistically significant improvement in physical fatigue measured by FACT scale as well as FSI, post-treatment and at 6 month follow up.

Counseling

Patient education and CBT were found to improve fatigue in patients with advanced-stage cancer.150 Patients frequently underestimate the side effect burden at the beginning of cancer therapy. In one study, only 8% of patients expected tiredness but 86% experienced it.170 This result suggests that many patients undergo treatment without sufficient information to develop realistic expectations about what that treatment entails. Counseling regarding the possible causes of fatigue and the types of therapeutic options available may allow the patient the opportunity to develop realistic expectations which may need to change as the disease progresses. Patients should be empowered by receiving correct and full information and by undergoing counseling. They may combat fatigue by: 1. Adapting their activities of daily living by reducing the amount of housework they do or by enlisting the help of others to perform physical duties; 2. Spending more time in bed or, alternatively, exercising more (the latter if deconditioning is considered to be a contributor to the fatigue); 3. Rearranging their schedules within the day, depending on their fatigue patterns; 4. Requesting changes in medications perceived to be causing a loss of energy; and 5. Avoiding expending energy on unnecessary activities. Counseling a patient about what symptoms to expect, including fatigue, with disease progression or with cancer treatment helps to better prepare them for the symptom when it occurs. Studies have shown that only a small percentage of patients expect fatigue from their therapy whereas up to 89% of them experience it.121 Counseling for coping with other symptoms, such as adjustment disorder with depressed mood and anxiety, which may impact fatigue could also help with improving fatigue. CBT for insomnia helps with fatigue Exercise (overexertion/deconditioning) has been discussed in detail in other chapters of this book. It is important however, to mention this again briefly here as it does impact the management of fatigue. Impaired muscle function may be one of the underlying mechanisms in fatigue (at least the physical component to fatigue). There are a number of studies showing muscle alterations in cancer patients and the association between reduced muscle mass in cachexia and fatigue.122 Prolonged bed rest or immobility has been shown to cause deconditioning with associated loss of muscle mass and decreased cardiac output. This state results in reduced endurance both for normal activities of daily living and exercise. Normal exercise has been shown to have a beneficial effect on muscle and cardiovascular fitness; however, overexertion is a frequent cause of fatigue in non-cancer patients.

Textbook of Palliative Medicine and Supportive Care

416 This is an important problem to recognize in younger cancer patients who are trying to maintain their social and professional lives while receiving aggressive antineoplastic therapies such as chemotherapy and radiotherapy. 3 Several meta-analysis now support the benefits of exercise for treatment of fatigue in patients receiving cancer treatment and in cancer survivors. In a Cochrane analysis by Cramp et al. in 2008, involving 28 RCTs, similar results were compiled. Most of these studies show a clear benefit of exercise on fatigue are in cancer survivors, patients with breast cancer, and in patients with less advanced disease. In a randomized control trial by Oldervoll et al. in 2011, 231 patients with advanced cancer and life expectancy ≤2 years were randomized to a physical exercise under supervision versus usual care. The exercise included warm up, circuit training, stretching and relaxation for 60 minutes twice a week for 8 weeks. The primary outcome was physical fatigue measured by the Fatigue Questionnaire and physical performance was a secondary outcome measured by the Shuttle Walk Test (SWT) and hand grip strength (HSG) test. Analyses showed fatigue was not significantly reduced (P-0.2) but physical performance (SWT and HGS test) was significantly improved (p = 0.001 for both) after 8 weeks of exercise. In a smaller study by Bass et al. with 49 hospice patients with 30 patients receiving kinesitherapy and 19 without kinesitherapy the results were different. In this study patients exercised under physiotherapist’s supervision three times a week, for 20–30 minutes, for 3–4 weeks. The patients in exercise group had significant improvement in fatigue after 3 weeks (p < 0.0001) as compared to the control group in which the fatigue deteriorated. Hence based of the prior studies exercise improves fatigue and physical functioning in patients with less advanced disease, cancer survivors although with advanced illness the type and amount of exercise needs to be defined. Exercise is recommended as part of the therapy for fatigue in cancer patients,123,124 and physiotherapists and occupational therapists can suggest suitable exercises and help achieve increased activity. The precaution here, however, is that the level of exercise is appropriate for the patient and does not result in overexertion and subsequent worsening of the fatigue.125

Multimodal and personalized therapy

In patients with advanced cancer, due to the multidimensional nature of fatigue, it is unlikely that fatigue can be effectively treated using a single intervention. A multimodal approach of combination of pharmacological and non-pharmacological treatments simultaneously should be considered on the basis of a predominant pathophysiologic mechanism for a given patient.171 For example, a patient with a significant component of physical fatigue may benefit from a combination of a short course of dexamethasone and physical activity tailored to the patient’s needs. On the other hand fatigue patients with anxiety/depression or drowsiness may benefit from interventions such as methylphenidate, and counseling with or without physical activity. Similarly, various combinations of treatment that have shown preliminary beneficial effects on fatigue in patients with advanced-stage cancer should be considered on an individual basis. These may include interventions such as cognitive behavioral therapy, educational interventions, anti-inflammatory drugs, and exercise. However, further well-designed studies are needed to investigate the efficacy of multimodal approach in patients with fatigue. Further studies should also investigate the benefit of personalizing fatigue management by targeting both the reversible causes,

KEY LEARNING POINTS • Fatigue is a common yet complex multifactorial symptom in palliative care. • To offer appropriate treatment a detailed assessment is important. • Treat reversible causes then add in symptomatic treatment if indicated—pharmacological as well as nonpharmacological. • Multiple agents are emerging with constant research, but it will be difficult to find a single agent to manage this complex symptom.

as well as nonreversible factors by a combination of treatments for reversible causes (e.g., hypokalemia), and symptomatic treatments (e.g., use of steroids or methylphenidate).

Conclusion Fatigue is a multifactorial symptom that is extremely common in advanced cancer patients. Approach to the management of this complex symptom must therefore be multidimensional to be effective. Detailed assessment is key to appropriate management and, as noted here, there is still a lot of research to be done to offer adequate therapy to this patient population for such a common symptom.

References



1. Berger AM, Mooney K, Alvarez-Perez A, et al. Cancer-related fatigue, Version 2.2015. J Natl Comprehens Cancer Netw: JNCCN 2015;13(8):1012–1039. 2. Piper BF, Cella D. Cancer-related fatigue: definitions and clinical subtypes. J Natl Comprehens Cancer Netw 2010;8(8):958–966. 3. Berger AM, Abernethy AP, Atkinson A, et al. Cancer-related fatigue. J Natl Comprehens Cancer Netw 2010;8(8):904–931. 4. Radbruch L, Strasser F, Elsner F, et al. Fatigue in palliative care patients: an EAPC approach. Palliat Med 2008;22(1):13–32. 5. Yennurajalingam S, Bruera E. Palliative management of fatigue at the close of life. JAMA 2007;297(3):295–304. 6. Butt Z, Rosenbloom SK, Abernethy AP, et al. Fatigue is the most important symptom for advanced cancer patients who have had chemotherapy. J Natl Comprehens Cancer Netw 2008;6(5):448–455. 7. Hofman M, Ryan JL, Figueroa-Moseley CD, Jean-Pierre P, Morrow GR. Cancer-related fatigue: the scale of the problem. Oncologist 2007;12(suppl 1):4–10. 8. Lundh Hagelin C, Wengström Y, Åhsberg E, Fürst C. Fatigue dimensions in patients with advanced cancer in relation to time of survival and quality of life. Palliat Med 2009;23(2):171–178. 9. de Raaf PJ, Sleijfer S, Lamers CH, Jager A, Gratama JW, van der Rijt CC. Inflammation and fatigue dimensions in advanced cancer patients and cancer survivors: an explorative study. Cancer 2012;118(23):6005–6011. 10. Cella D, Lai J-S, Chang C-H, Peterman A, Slavin M. Fatigue in cancer patients compared with fatigue in the general United States population. Cancer 2002;94(2):528–538. 11. Okuyama T, Tanaka K, Akechi T, et al. Fatigue in ambulatory patients with advanced lung cancer: prevalence, correlated factors, and screening. J Pain Symptom Manage 2001;22(1):554–564. 12. Spichiger E, Müller-Fröhlich C, Denhaerynck K, Stoll H, Hantikainen V, Dodd M. Prevalence and contributors to fatigue in individuals hospitalized with advanced cancer: a prospective, observational study. Int J Nurs Stud 2012;49(9):1146–1154. 13. Su W-H, Yeh E-T, Chen H-W, Wu M-H, Lai Y-L. Fatigue among older advanced cancer patients. Int J Gerontol 2011;5(2):84–88.

Mechanism, Assessment, and Management of Fatigue 14. Cella D, Davis K, Breitbart W, Curt G, Fatigue Coalition. Cancerrelated fatigue: prevalence of proposed diagnostic criteria in a United States sample of cancer survivors. J Clin Oncol 2001;19(14):3385–3391. 15. Wang XS, Zhao F, Fisch MJ, et al. Prevalence and characteristics of moderate to severe fatigue: a multicenter study in cancer patients and survivors. Cancer 2014;120(3):425–432. 16. Yeh ET, Lau SC, Su WJ, Tsai DJ, Tu YY, Lai YL. An examination of cancer-related fatigue through proposed diagnostic criteria in a sample of cancer patients in Taiwan. BMC Cancer 2011;11:387. 17. Yennu S, Urbauer D, Bruera E. Factors associated with the severity and improvement of fatigue in patients with advanced cancer presenting to an outpatient palliative care clinic. BMC Palliat Care 2012;11(1):16. 18. Bower JE, Ganz PA, Irwin MR, Kwan L, Breen EC, Cole SW. Inflammation and behavioral symptoms after breast cancer treatment: do fatigue, depression, and sleep disturbance share a common underlying mechanism? J Clin Oncol 2011;29(26):3517–3522. 19. Miller AH, Ancoli-Israel S, Bower JE, Capuron L, Irwin MR. Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer. J Clin Oncol 2008;26(6):971–982. 20. Inagaki M, Isono M, Okuyama T, et al. Plasma Interleukin-6 and fatigue in terminally ill cancer patients. J Pain Symptom Manage 2008;35(2):153–161. 21. Haroon E, Anand R, Chen X, et al. 178. Interferon-alpha-induced fatigue is associated with alterations in CNS glutamate metabolism as measured by magnetic resonance spectroscopy. Brain Behav Immunity 2012;26, Supplement 1(0):S49–S50. 22. Santos JC, Pyter LM. Neuroimmunology of behavioral comorbidities associated with cancer and cancer treatments. Front immunol 2018;9:1195. 23. Sadeghi M, Keshavarz-Fathi M, Baracos V, Arends J, Mahmoudi M, Rezaei N. Cancer cachexia: diagnosis, assessment, and treatment. Crit Rev Oncol Hematol 2018;127:91–104. 24. Renner M, Saligan LN. Understanding cancer-related fatigue: advancing the science. Fatigue: Biomed Health Behav 2016;4(4):189–192. 25. Saligan LN, Olson K, Filler K, et al. The biology of cancer-related fatigue: a review of the literature. Support Care Cancer 2015;23(8):2461–2478. 26. Wolff BS, Renner MA, Springer DA, Saligan LN. A Mouse Model of Fatigue Induced by Peripheral Irradiation. J Vis Exp 2017;(121):55145. 27. Neefjes EC, van der Vorst MJ, Blauwhoff-Buskermolen S, Verheul HM. Aiming for a better understanding and management of cancer-related fatigue. Oncologist 2013;18(10):1135–1143. 28. Fearon KCH, Glass DJ, Guttridge DC. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab 2012;16(2):153–166. 29. Bruera E, Brenneis C, Michaud M, Jackson PI, MacDonald RN. Muscle electrophysiology in patients with advanced breast cancer. J Natl Cancer Inste 1988;80(4):282–285. 30. Kisiel-Sajewicz K, Davis MP, Siemionow V, et al. Lack of muscle contractile property changes at the time of perceived physical exhaustion suggests central mechanisms contributing to early motor task failure in patients with cancer-related fatigue. J Pain Symptom Manage 2012;44(3):351–361. 31. Beijer S, Hupperets PS, van den Borne BE, et al. Randomized clinical trial on the effects of adenosine 5’-triphosphate infusions on quality of life, functional status, and fatigue in preterminal cancer patients. J Pain Symptom Manage 2010;40(4):520–530. 32. Cruciani RA, Dvorkin E, Homel P, et al. L-Carnitine supplementation in patients with advanced cancer and carnitine deficiency: a double-blind, placebo-controlled study. J Pain Symptom Manage 2009;37(4):622–631. 33. Filler K, Lyon D, Bennett J, et al. Association of mitochondrial dysfunction and fatigue: a review of the literature. BBA Clin 2014;1:12–23. 34. Cramp F. Daniel J. Exercise for the management of cancer-related fatigue in adults. Cochrane Database Syst Rev 2008:CD006145. 35. Bower JE, Ganz PA, Dickerson SS, Petersen L, Aziz N, Fahey JL. Diurnal cortisol rhythm and fatigue in breast cancer survivors. Psychoneuroendocrinology 2005;30(1):92–100. 36. Petruzzelli M, Wagner EF. Mechanisms of metabolic dysfunction in cancer-associated cachexia. Genes Dev 2016;30(5):489–501. 37. Bruera E, Brennies C, Michaud M, Rafter J, et al. Association between asthenia and nutritional status, lean body mass, anemia, psychological status, and tumor mass in patients with advanced breast cancer. J Pain Symptom Manage 1989;4(2):59–63. 38. Seruga B, Zhang H, Bernstein LJ, Tannock IF. Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Cancer 2008;8(11):887–899.

417 39. Demetri GD, Kris M, Wade J, Degos L, Cella D. Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: results from a prospective community oncology study. Procrit Study Group. J Clin Oncol 1998;16(10):3412–3425. 40. Bruera E, Chadwick S, Fox R, Hanson J, MacDonald N. Study of cardiovascular autonomic insufficiency in advanced cancer patients. Cancer Treat Rep 1986;17(12):1383–1387. 41. Strasser F, Palmer JL, Schover LR, et al. The impact of hypogonadism and autonomic dysfunction on fatigue, emotional function, and sexual desire in male patients with advanced cancer. Cancer 2006;107(12):2949–2957. 42. Yennurajalingam S, Palmer J, Zhang T, Poulter V, Bruera E. Association between fatigue and other cancer-related symptoms in patients with advanced cancer. Support Care Cancer 2008;16(10):1125–1130. 43. Basaria S, Wahlstrom JT, Dobs AS. Anabolic-androgenic steroid therapy in the treatment of chronic diseases. J Clin Endocrinol Metab 2001;86(11):5108–5117. 44. Burney BO, Hayes TG, Smiechowska J, et al. Low testosterone levels and increased inflammatory markers in patients with cancer and relationship with cachexia. J Clin Endocrinol Metab 2012;97(5):E700–E709. 45. Snyder PJ, Peachey H, Berlin JA, et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab 2000;85(8):2670–2677. 46. Yennu S, Urbauer DL, Bruera E. Factors associated with the severity and improvement of fatigue in patients with advanced cancer presenting to an outpatient palliative care clinic. BMC Palliat Care 2012;11:16. 47. Respini D, Jacobsen PB, Thors C, Tralongo P, Balducci L. The prevalence and correlates of fatigue in older cancer patients. Crit Rev Oncol/ Hematol 2003;47(3):273–279. 48. Wang XS, Shi Q, Williams LA, et al. Inflammatory cytokines are associated with the development of symptom burden in patients with NSCLC undergoing concurrent chemoradiation therapy. Brain Behav Immunity 2010;24(6):968–974. 49. Nagasaka M, Abdallah N, Samantray J, Sukari A. Is this really just “fatigue”? A case series of immune-related central adrenal insufficiency secondary to immune checkpoint inhibitors. Clin Case Rep 2018;6(7):1278–1281. 50. Naidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PDL1 immune checkpoint antibodies. Ann Oncol: Off J Eur Soc Med Oncol 2015;26(12):2375–2391. 51. Bower JE, Ganz PA, Irwin MR, Arevalo JMG, Cole SW. Fatigue and gene expression in human leukocytes: oncreased NF-κB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue. Brain Behav Immunity 2011;25(1):147–150. 52. Jim HSL, Park JY, Permuth-Wey J, et al. Genetic predictors of fatigue in prostate cancer patients treated with androgen deprivation therapy: preliminary findings. Brain Behav Immunity 2012;26(7):1030–1036. 53. Wright F, Hammer M, Paul SM, et al. Inflammatory pathway genes associated with inter-individual variability in the trajectories of morning and evening fatigue in patients receiving chemotherapy. Cytokine 2017;91:187–210. 54. Barnes EA, Bruera E. Fatigue in patients with advanced cancer: a review. Int J Gynecol Cancer 2002;12(5):424–428. 55. Minton O, Stone P. A systematic review of the scales used for the measurement of cancer-related fatigue (CRF). Ann Oncol 2009;20(1):17–25. 56. Bruera E KN, Miller MJ, Selmser P, Macmillan K. The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care 1991;7(2):6. 57. Knobel H, Loge JH, Brenne E, Fayers P, Hjermstad MJ, Kaasa S. The validity of EORTC QLQ-C30 fatigue scale in advanced cancer patients and cancer survivors. Palliat Med 2003;17(8):664–672. 58. Mendoza TR, Wang XS, Cleeland CS, et al. The rapid assessment of fatigue severity in cancer patients. Cancer 1999;85(5):1186–1196. 59. Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol 1993;11(3):570–579. 60. Ameringer S, Elswick RK, Jr., Menzies V, et al. Psychometric evaluation of the Patient-Reported Outcomes Measurement Information System Fatigue-Short Form across diverse populations. Nurs Res 2016;65(4):279–289. 61. Yost KJ, Eton DT, Garcia SF, Cella D. Minimally important differences were estimated for six Patient-Reported Outcomes Measurement Information System-Cancer scales in advanced-stage cancer patients. J Clin Epidemiol 2011;64(5):507–516.

418 62. Barsevick AM, Irwin MR, Hinds P, et al. Recommendations for highpriority research on cancer-related fatigue in children and adults. J Natl Cancer Inst 2013;105(19):1432–1440. 63. Butt Z, Wagner L, Beaumont J, et al. Use of a single-item screening tool to detect clinically significant fatigue, pain, distress, and anorexia in ambulatory cancer practice. J Pain Symptom Manage 2008;35:20–30. 64. Smith E, Lai JS, Cella D. Building a measure of fatigue: the functional assessment of Chronic Illness Therapy Fatigue Scale. PM & R: J Injur Function Rehabil 2010;2(5):359–363. 65. Passik SD. Abstract: impediments and solutions to improving the management of cancer-related fatigue. JNCI Monographs 2004;2004(32):136. 66. Portenoy RK. Cancer-related fatigue: an immense problem. Oncologist 2000;5(5):350–352. 67. Stone P, Hardy J, Broadley K, Tookman AJ, Kurowska A, A’Hern R. Fatigue in advanced cancer: a prospective controlled cross-sectional study. Br J Cancer 1999;79(9-10):1479–1486. 68. Coyle N, Adelhardt J, Foley KM, Portenoy RK. Character of terminal illness in the advanced cancer patient: pain and other symptoms during the last four weeks of life. J Pain Symptom Manage 1990;5:83–93. 69. Donnelly S, Walsh D. The symptoms of advanced cancer. Semin Oncol 1995;22:67–72. 70. Loge JH, Abrahamsen AF, Ekeberg Ø, Kaasa S. Hodgkin’s disease survivors more fatigued than the general population. J Clin Oncol 1999;17(1):253. 71. Barsevick A, Frost M, Zwinderman A, Hall P, Halyard M. I’m so tired: biological and genetic mechanisms of cancer-related fatigue. Qual Life Res 2010;19(10):1419–1427. 72. Goldstein D, Bennett BK, Webber K, et al. Cancer-related fatigue in women with breast cancer: outcomes of a 5-year prospective cohort study. J Clin Oncol 2012;30(15):1805–1812. 73. Wang XS, Fairclough DL, Liao Z, et al. Longitudinal study of the relationship between chemoradiation therapy for non–small-cell lung cancer and patient symptoms. J Clin Oncol 2006;24(27):4485–4491. 74. Hickok JT, Morrow GR, Roscoe JA, Mustian K, Okunieff P. Occurrence, severity, and longitudinal course of twelve common symptoms in 1129 consecutive patients during radiotherapy for cancer. J Pain Symptom Manage 2005;30(5):433–442. 75. Bower JE, Ganz PA, Desmond KA, et al. Fatigue in long-term breast carcinoma survivors. Cancer 2006;106(4):751–758. 76. Wang XS, Shi Q, Williams LA, et al. Serum interleukin-6 predicts the development of multiple symptoms at nadir of allogeneic hematopoietic stem cell transplantation. Cancer 2008;113(8):2102–2109. 77. Jacobsen PB, Hann DM, Azzarello LM, Horton J, Balducci L, Lyman GH. Fatigue in women receiving adjuvant chemotherapy for breast cancer: characteristics, course, and correlates. J Pain Symptom Manage 1999;18(4):233–242. 78. Brant JM, Beck SL, Dudley WN, Cobb P, Pepper G, Miaskowski C. Symptom trajectories during chemotherapy in outpatients with lung cancer colorectal cancer, or lymphoma. Eur J Oncol Nurs 2011;15(5):470–477. 79. Fan HGM, Houédé-Tchen N, Yi Q-L, et al. Fatigue, menopausal symptoms, and cognitive function in women after adjuvant chemotherapy for breast cancer: 1- and 2-year follow-up of a prospective controlled study. J Clin Oncol 2005;23(31):8025–8032. 80. Miaskowski C, Paul SM, Cooper BA, et al. Trajectories of fatigue in men with prostate cancer before, during, and after radiation therapy. J Pain Symptom Manage 2008;35(6):632–643. 81. Dirksen SR, Kirschner KF, Belyea MJ. Association of symptoms and cytokines in prostate cancer patients receiving radiation treatment. Biol Res Nurs 2013;16(3):250–257. 82. Bruera E, Fainsinger R, MacEachern T, Hanson J. The use of methylphenidate in patients with incident cancer pain receiving regular opiates. A preliminary report. Pain 1992;50(1):75–77. 83. Bruera E, Strasser F, Shen L, et al. The effect of donepezil on sedation and other symptoms in patients receiving opioids for cancer pain: a pilot study. J Pain Symptom Manage 2003;26(5):1049–1054. 84. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, Kaur G, Bruera E. Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer 2004;100(4):851–858. 85. Bower JE, Lamkin DM. Inflammation and cancer-related fatigue: mechanisms, contributing factors, and treatment implications. Brain Behav Immunity 2013;30, Supplement(0):S48–S57. 86. Chrousos GP. The hypothalamic–pituitary–adrenal axis and immunemediated inflammation. N Engl J Med 1995;332(20):1351–1363.

BK-TandF-BRUERA_9780367642037-200160-Chp43.indd 418

Textbook of Palliative Medicine and Supportive Care 87. Miller A, Ancoli-Israel S, Bower J, Capuron L, Irwin M. Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer. J Clin Oncol 2008;26:971–982. 88. Bower JE, Ganz PA, Tao ML, et al. Inflammatory biomarkers and fatigue during radiation therapy for breast and prostate cancer. Clin Cancer Res 2009;15(17):5534–5540. 89. Liu L, Mills PJ, Rissling M, et al. Fatigue and sleep quality are associated with changes in inflammatory markers in breast cancer patients undergoing chemotherapy. Brain Behav Immunity 2012;26(5):706–713. 90. Lee BN, Dantzer R, Langley KE, et al. A cytokine-based neuroimmunologic mechanism of cancer-related symptoms. Neuroimmu­ nomodulation 2004;11(5):279–292. 91. Yennurajalingam S, Frisbee-Hume S, Palmer JL, et al. Reduction of cancer-related fatigue with dexamethasone: a double-blind, randomized, placebo-controlled trial in patients with advanced cancer. J Clin Oncol 2013;31(25):3076–3082. 92. Stewart GD, Skipworth RJ, Fearon KC. Cancer cachexia and fatigue. Clin Med 2006;6(2):140–143. 93. Blum D, Omlin A, Baracos VE, et al. Cancer cachexia: a systematic literature review of items and domains associated with involuntary weight loss in cancer. Crit Rev Oncol/Hematol 2011;80(1):114–144. 94. Mantovani G, Madeddu C. Cancer cachexia: medical management. Support Care Cancer 2010;18(1):1–9. 95. Del Fabbro E HD, Dalal S, Dev R, Nooruddin ZI, Bruera E. Clinical outcomes and contributors to weight loss in a cancer cachexia clinic. J Palliat Med 2011;14(9):1004–1008. 96. Fadul N, Strasser F, Palmer JL, et al. The association between autonomic dysfunction and survival in male patients with advanced cancer: a preliminary report. J Pain Symptom Manage 2010;39(2):283–290. 97. Walsh D, Nelson K. Autonomic nervous system dysfunction in advanced cancer. Support Care Cancer 2002;10(7):523–528. 98. Fagundes CP, Murray DM, Hwang BS, et al. Sympathetic and parasympathetic activity in cancer-related fatigue: more evidence for a physiological substrate in cancer survivors. Psychoneuroendocrinology 2011;36(8):1137–1147. 99. Fouad-Tarazi FM, Okabe M, Goren H. Alpha sympathomimetic treatment of autonomic insufficiency with orthostatic hypotension. Am J Med 1995;99(6):604–610. 100. Low PA, Gilden JL, Freeman R, Sheng K, McElligott M. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension: a randomized, double-blind multicenter study. JAMA 1997;277(13):1046–1051. 101. Shibao C, Okamoto L, Biaggioni I. Pharmacotherapy of autonomic failure. Pharmacol Ther 2012;134(3):279–286. 102. Wokke JHJ. Fatigue is part of the burden of neuromuscular diseases. J Neurol 2007;254(7):948–949. 103. Hwang SS, Chang VT, Rue M, Kasimis B. Multidimensional independent predictors of cancer-related fatigue. J Pain Symptom Manage 2003;26(1):604–614. 104. Munch T, Zhang T, Willey J, Palmer J, Bruera E. The association between anemia and fatigue in patients with advanced cancer receiving palliative care. J Palliat Med 2005;8:1144–1149. 105. Glaspy J, Bukowski R, Steinberg D, Taylor C, Tchekmedyian S, VadhanRaj S. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. J Clin Oncol 1997;15(3):1218–1234. 106. Fishbane S, Jhaveri KD. The New Label for Erythropoiesis Stimulating Agents: The FDA’S Sentence. Semin Dialysis 2012;25(3):263–266. 107. Smith RE, Aapro MS, Ludwig H, et al. Darbepoetin alfa for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study. J Clin Oncol 2008;26(7):1040–1050. 108. Preston NJ, Brine J, Bennett MI. Blood transfusions for anaemia in patients with advanced cancer. Cochrane Database Syst Rev 2012(2):CD009007. 109. Mercadante S FP, Villari P, David F, Giarratano A, Riina S. Effects of red blood cell transfusion on anemia-related symptoms in patients with cancer. J Palliat Med 2009;12(1):60–63. 110. Fishbain DA, Cole B, Cutler RB, Lewis J, Rosomoff HL, Fosomoff RS. Is pain fatiguing? A structured evidence-based review. Pain Med 2003;4(1):51–62. 111. Kenyon JC, Lever AML. XMRV, prostate cancer and chronic fatigue syndrome. Br Med Bull 2011;98(1):61–74.

24/06/21 11:48 AM

Mechanism, Assessment, and Management of Fatigue 112. Piraino B, Vollmer-Conna U, Lloyd AR. Genetic associations of fatigue and other symptom domains of the acute sickness response to infection. Brain Behav Immun 2012;26(4):552–558. 113. Harden LM, du Plessis I, Poole S, Laburn HP. Interleukin-6 and leptin mediate lipopolysaccharide-induced fever and sickness behavior. Physiol Behav 2006;89(2):146–155. 114. Dantzer R. Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity. Eur J Pharmacol 2004;500(1–3):399–411. 115. Wilson KG, Chochinov HM, Graham Skirko M, et al. Depression and anxiety disorders in palliative cancer care. J Pain Symptom Manage 2007;33(2):118–129. 116. Brenne E, Loge JH, Kaasa S, Heitzer E, Knudsen AK, Wasteson E. Depressed patients with incurable cancer: which depressive symptoms do they experience? Palliat Support Care 2013;11(6):491–501. 117. Morrow GR, Hickok JT, Roscoe JA, et al. Differential effects of paroxetine on fatigue and depression: a randomized, double-blind trial from the University of Rochester Cancer Center Community Clinical Oncology Program. J Clin Oncol 2003;21(24):4635–4641. 118. de Raaf PJ, de Klerk C, Timman R, Busschbach JJV, Oldenmenger WH, van der Rijt CCD. Systematic monitoring and treatment of physical symptoms to alleviate fatigue in patients with advanced cancer: a randomized controlled trial. J Clin Oncol 2013;31(6):716–723. 119. Garcia JM, Li H, Mann D, et al. Hypogonadism in male patients with cancer. Cancer 2006;106(12):2583–2591. 120. Blick G, Khera M, Bhattacharya RK, Nguyen D, Kushner H, Miner MM. Testosterone replacement therapy outcomes among opioid users: the Testim Registry in the United States (TRiUS). Pain Med 2012;13(5):688–698. 121. Eaton T, Lewis C, Young P, Kennedy Y, Garrett JE, Kolbe J. Long-term oxygen therapy improves health-related quality of life. Respiratory Med 2004;98(4):285–293. 122. Bruera E, Sweeny C, Willey J, Palmer JL, Strasser F, Morice RC, Pisters K. A randomized controlled trial of supplemental oxygen versus air in cancer patients with dyspnea. Palliat Med 2003;17(8):659–663. 123. Bruera E, de Stoutz N, Velasco-Leiva A, Schoeller T, Hanson J. Effects of oxygen on dyspnoea in hypoxaemic terminal-cancer patients. Lancet 1993;342(8862):13–14. 124. Moertel CG, Schutt AJ, Reitemeier RJ, Hahn RG. Corticosteroid therapy of preterminal gastrointestinal cancer. Cancer 1974;33(6):1607–1609. 125. Paulsen O, Klepstad P, Rosland JH, et al. Efficacy of methylprednisolone on pain, fatigue, and appetite loss in patients with advanced cancer using opioids: a randomized, placebo-controlled, double-blind trial. J Clin Oncol 2014;32(29):3221–3228. 126. Bruera E, Roca E, Cedaro L, Carraro S, Chacon R. Action of oral methylprednisolone in terminal cancer patients: a prospective randomized double-blind study. Cancer Treat Rep 1985;69(7-8):751–754. 127. Minton O, Richardson A, Sharpe M, Hotopf M, Stone P. Drug therapy for the management of cancer-related fatigue. Cochrane Database Syst Rev 2010;7(7):CD006704. 128. Minton O, Richardson A, Sharpe M, Hotopf M, Stone P. A systematic review and meta-analysis of the pharmacological treatment of cancerrelated fatigue. J Natl Cancer Inst 2008;100:1155–1166. 129. Volkow ND, Wang G-J, Fowler JS, et al. Relationship between blockade of dopamine transporters by oral methylphenidate and the increases in extracellular dopamine: therapeutic implications. Synapse 2002;43(3):181–187. 130. Bruera E, Chadwick S, Brenneis C, Hanson J, MacDonald RN. Methylphenidate associated with narcotics for the treatment of cancer pain. Cancer Treat Rep 1987;7(1):67–70. 131. Minton O, Richardson A, Sharpe M, Hotopf M, Stone PC. Psychostimulants for the management of cancer-related fatigue: a systematic review and meta-analysis. J Pain Symptom Manage 2011;41(4):761–767. 132. Bruera E, Yennurajalingam S, Palmer JL, et al. Methylphenidate and/or a nursing telephone intervention for fatigue in patients with advanced cancer: a randomized, placebo-controlled, phase II trial. J Clin Oncol 2013;31(19):2421–2427. 133. Moraska AR, Sood A, Dakhil SR, et al. Phase III, randomized, double-blind, placebo-controlled study of long-acting methylphenidate for cancer-related fatigue: North Central Cancer Treatment Group NCCTG-N05C7 trial. J Clin Oncol 2010;28(23):3673–3679. 134. Yennurajalingam S, Palmer JL, Chacko R, Bruera E. Factors associated with response to methylphenidate in advanced cancer patients. Oncologist 2011;16(2):246–253.

419 135. Jean-Pierre P, Morrow GR, Roscoe JA, et al. A phase 3 randomized, placebo-controlled, double-blind, clinical trial of the effect of modafinil on cancer-related fatigue among 631 patients receiving chemotherapy. Cancer 2010;116(14):3513–3520. 136. Vucic S, Burke D, Kiernan MC. Fatigue in multiple sclerosis: mechanisms and management. Clin Neurophysiol 2010;121(6):809–817. 137. Rabkin JG, McElhiney MC, Rabkin R. Treatment of HIV-related fatigue with armodafinil: a placebo-controlled randomized trial. Psychosomatics 2011;52(4):328–336. 138. Rabkin JG, Gordon PH, McElhiney M, Rabkin R, Chew S, Mitsumoto H. Modafinil treatment of fatigue in patients with ALS: a placebo-controlled study. Muscle Nerve 2009;39(3):297–303. 139. Lundorff L, Jønsson B, Sjøgren P. Modafinil for attentional and psychomotor dysfunction in advanced cancer: a double-blind, randomised, cross-over trial. Palliat Med 2009;23(8):731–738. 140. Jean-Pierre P, Figueroa-Moseley CD, Kohli S, Fiscella K, Palesh OG, Morrow GR. Assessment of cancer-related fatigue: implications for clinical diagnosis and treatment. Oncologist 2007;12(suppl 1):11–21. 141. Spathis A, Fife K, Blackhall F, et al. Modafinil for the treatment of fatigue in lung cancer: results of a placebo-controlled, double-blind, randomized trial. J Clin Oncol 2014;32(18):1882–1888. 142. Tyne H, Taylor J, Baker G, Steiger M. Modafinil for Parkinson’s disease fatigue. J Neurol 2010;257(3):452–456. 143. Dev R, Hui D, Dalal S, et al. Association between serum cortisol and testosterone levels, opioid therapy, and symptom distress in patients with advanced cancer. J Pain Symptom Manage 2011;41(4):788–795. 144. Grinspoon S, Corcoran C, Askari H, et al. Effects of androgen administration in men with the AIDS Wasting syndrome: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998;129(1):18–26. 145. Fabbro E, Garcia JM, Dev R, et al. Testosterone replacement for fatigue in hypogonadal ambulatory males with advanced cancer: a preliminary double-blind placebo-controlled trial. Support Care Cancer 2013;21(9):2599–2607. 146. Bruera E, El Osta B, Valero V, et al. Donepezil for cancer fatigue: a double-blind, randomized, placebo-controlled trial. J Clin Oncol 2007;25(23):3475–3481. 147. Cruciani RA, Zhang JJ, Manola J, Cella D, Ansari B, Fisch MJ. L-Carnitine supplementation for the management of fatigue in patients with cancer: an Eastern Cooperative Oncology Group phase III, randomized, double-blind, placebo-controlled trial. J Clin Oncol 2012;30(31):3864–3869. 148. Barton D, Soori G, Bauer B, et al. Pilot study of Panax quinquefolius (American ginseng) to improve cancer-related fatigue: a randomized, double-blind, dose-finding evaluation: NCCTG trial N03CA. Support Care Cancer 2010;18(2):179–187. 149. Barton DL, Liu H, Dakhil SR, et al. Wisconsin ginseng (Panax quin­ quefolius) to improve cancer-related fatigue: a randomized, doubleblind trial, N07C2. J Natl Cancer Institute 2013;105(16):1230–1238. 150. Mustian KM, Alfano CM, Heckler C, et al. Comparison of pharmaceutical, psychological, and exercise treatments for cancer-related fatigue: a meta-analysis. JAMA Oncol 2017;3(7):961–968. 151. Jacobsen PB, Donovan KA, Vadaparampil ST, Small BJ. Systematic review and meta-analysis of psychological and activitybased interventions for cancer-related fatigue. Health Psychol 2007;26(6):660–667. 152. Ligibel JA, Giobbie-Hurder A, Shockro L, et al. Randomized trial of a physical activity intervention in women with metastatic breast cancer. Cancer 2016;122(8):1169–1177. 153. Oldervoll LM, Loge JH, Lydersen S, et al. Physical exercise for cancer patients with advanced disease: a randomized controlled trial. Oncologist 2011;16(11):1649–1657. 154. Segal R, Reid R, Courneya K, et al. Randomized controlled trial of resistance or aerobic exercise in men receiving radiation therapy for prostate cancer. J Clin Oncol 2009;27:344–350. 155. Garcia MK, McQuade J, Haddad R, et al. Systematic review of acupuncture in cancer care: a synthesis of the evidence. J Clin Oncol 2013;31(7):952–960. 156. Molassiotis A, Bardy J, Finnegan-John J, et al. Acupuncture for cancerrelated fatigue in patients with breast cancer: a pragmatic randomized controlled trial. J Clin Oncol 2012;30(36):4470–4476. 157. Zhang Y, Lin L, Li H, Hu Y, Tian L. Effects of acupuncture on cancer-related fatigue: a meta-analysis. Support Care Cancer 2018;26(2):415–425.

420 158. Hilfiker R, Meichtry A, Eicher M. Exercise and other non-pharmaceutical interventions for cancer-related fatigue in patients during or after cancer treatment: a systematic review incorporating an indirect-comparisons meta-analysis. Br J Sports Med 2018;52(10):651–658. 159. Bower JE, Crosswell AD, Stanton AL, et al. Mindfulness meditation for younger breast cancer survivors: a randomized controlled trial. Cancer 2015;121(8):1231–1240. 160. Johns SA, Brown LF, Beck-Coon K, et al. Randomized controlled pilot trial of mindfulness-based stress reduction compared to psychoeducational support for persistently fatigued breast and colorectal cancer survivors. Support Care Cancer 2016;24(10):4085–4096. 161. Berger AM, Mitchell SA. Modifying cancer-related fatigue by optimizing sleep quality. J Natl Comprehens Cancer Netw: JNCCN 2008;6(1):3–13. 162. Heckler CE, Garland SN, Peoples AR, et al. Cognitive behavioral therapy for insomnia, but not armodafinil, improves fatigue in cancer survivors with insomnia: a randomized placebo-controlled trial. Support Care Cancer 2016;24(5):2059–2066. 163. Luctkar-Flude M, Groll D. A systematic review of the safety and effect of neurofeedback on fatigue and cognition. Integrat Cancer Ther 2015;14(4):318–340. 164. Neikrug AB, Rissling M, Trofimenko V, et al. Bright light therapy protects women from circadian rhythm desynchronization during chemotherapy for breast cancer. Behav Sleep Med 2012;10(3):202–216.

Textbook of Palliative Medicine and Supportive Care 165. Redd WH, Valdimarsdottir H, Wu LM, et al. Systematic light exposure in the treatment of cancer-related fatigue: a preliminary study. Psychooncology 2014;23(12):1431–1434. 166. de Oliveira Campos MP, Riechelmann R, Martins LC, Hassan BJ, Casa FB, Del Giglio A. Guarana (Paullinia cupana) improves fatigue in breast cancer patients undergoing systemic chemotherapy. J Alternat Complement Med 2011;17(6):505–512. 167. Yennurajalingam S, Tannir NM, Williams JL, et al. A double-blind, randomized, placebo-controlled trial of Panax Ginseng for cancerrelated fatigue in patients with advanced cancer. J Natl Comprehens Cancer Netw: JNCCN 2017;15(9):1111–1120. 168. Kim YH, Lim Y, Cho JY, et al. Korean red ginseng to improve cancer-related fatigue in colorectal cancer patients with FOLFOX chemotherapy: a randomized, double-blind, placebo-controlled, parallel, multicenter trial, NCT02039635. J Clin Oncol 2017;35(15_suppl):10008–10008. 169. Reif K, de Vries U, Petermann F, Görres S. A patient education program is effective in reducing cancer-related fatigue: a multi-centre randomised two-group waiting-list controlled intervention trial. Eur J Oncol Nurs 2013;17(2):204–213. 170. Kirsh KL, Passik S, Holtsclaw E, Donaghy K, Theobald D. I get tired for no reason: a single item screening for cancer-related fatigue. J Pain Symptom Manage 2001;22(5):931–937. 171. Bruera E, Yennurajalingam S. Challenge of managing cancer-related fatigue. J Clin Oncol 2010;28(23):3671–3672.

44

BREATHLESSNESS

Claudia Bausewein, Sara Booth

Contents Definition.............................................................................................................................................................................................................................421 Experience of breathlessness.......................................................................................................................................................................................... 422 Epidemiology..................................................................................................................................................................................................................... 423 Pathophysiology of breathlessness................................................................................................................................................................................ 423 Assessment and identification of causes of breathlessness...................................................................................................................................... 424 Symptomatic management of dyspnea......................................................................................................................................................................... 425 Nonpharmacological therapies...................................................................................................................................................................................... 425 Interventions affecting the breathing domain....................................................................................................................................................... 425 Breathing techniques and positioning.............................................................................................................................................................. 425 Hand-held fan........................................................................................................................................................................................................ 425 Acupressure/acupuncture................................................................................................................................................................................... 426 Interventions affecting the thinking domain......................................................................................................................................................... 426 Psychotherapy........................................................................................................................................................................................................ 426 Mind–body interventions.................................................................................................................................................................................... 426 Music........................................................................................................................................................................................................................ 426 Interventions affecting the functioning domain................................................................................................................................................... 426 Physical exercise.................................................................................................................................................................................................... 426 Mobility aids........................................................................................................................................................................................................... 426 Neuromuscular electrical stimulation.............................................................................................................................................................. 426 Multicomponent/complex interventions���������������������������������������������������������������������������������������������������������������������������������������������������������������426 Pulmonary rehabilitation..................................................................................................................................................................................... 426 Breathlessness support services..........................................................................................................................................................................427 Pharmacological therapies...............................................................................................................................................................................................427 Opioids...........................................................................................................................................................................................................................427 Anxiolytics.....................................................................................................................................................................................................................427 Benzodiazepines.....................................................................................................................................................................................................427 Antidepressants..................................................................................................................................................................................................... 428 Oxygen................................................................................................................................................................................................................................ 428 References........................................................................................................................................................................................................................... 429

Definition Dyspnea is a common and burdensome symptom for patients with advanced disease. The American Thoracic Society describes dyspnea as “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity. The experience derives from interactions among multiple physiological, psychological, social, and environmental factors, and may induce secondary physiological and behavioural responses.”1 It is important to note that the subjective nature of the symptom is stressed along the multidimensional components, which go beyond solely physical condition and support the importance of the psychological, social, and spiritual/existential component. Similar to the concept of “total pain” as described by Dame Cicely Saunders, “total dyspnea” or “total breathlessness” have been suggested.2,3 Various terms are used in the context of dyspnea: difficult breathing, shortness of breath, breathing discomfort, or simply breathlessness. The term breathlessness is now widely used in the palliative care and breathlessness literature in preference to the biomedical “dyspnea” to emphasize the focus on the

daily experience of breathlessness from the patient’s perspective. 3 Therefore, this term is used in this chapter also. When breathlessness is persisting despite management of the underlying disease, it is sometimes referred to as “refractory breathlessness.” As this term is implying therapeutic nihilism, Johnson et al. suggested to name it “chronic breathlessness syndrome” to recognize possibilities of management and raise awareness among patients, clinicians, service providers, researchers, and research funders.4 The chronic breathlessness syndrome is described as “experience of breathlessness that persists despite optimal treatment of the underlying pathophysiology and results in disability for the patient.”4 Breathlessness presents as continuous breathlessness alone or in combination with episodic breathlessness. The latter is characterized by a severe worsening of breathlessness intensity or unpleasantness beyond usual fluctuations in the patient’s perception. 5 Such episodes are time-limited (seconds to hours) and occur intermittently with or without underlying continuous breathlessness. Episodes of breathlessness can be predictable with known triggers such as exertion, emotions, comorbidities, or 421

422

Textbook of Palliative Medicine and Supportive Care

external environment or may apparently be unpredictable.5 Linde et al. stated that many ostensibly inexplicable episodes are driven by “fear” or “panic” when investigated.6

• Thinking domain: Misconceptions about the nature of breathlessness, e.g., its causation, and previous experiences and memories of breathlessness having a profound impact on the present experience. These negative cognitions and memories can lead to anxiety, distress, feelings of panic, and thoughts about dying. • Functioning domain: People suffering from breathlessness frequently reduce their physical activity to avoid the sensation which leads to social isolation, the need for more help from others and deconditioning of limbs, chest wall, and accessory muscles.10

Experience of breathlessness Breathlessness not only impacts on patients’ physical condition, but also imposes psychological distress, changes social relationships, and often provokes spiritual-existential concerns for patients and carers. In the early stages, patients suffer from the invisibility of breathlessness, later on living with breathlessness is often seen as an ongoing struggle with unexpected transitions into acute illness in form of acute exacerbations.7,8 Breathlessness is frightening and distressing, and many patients suffer from anxiety and panic leaving them feeling vulnerable and open to attack by their breathlessness.9 Breathlessness affects individuals in different ways and in different dimensions which is well demonstrated by the Breathing– Thinking–Functioning (BTF) model.10,11 This clinical model conceptualizes the three predominant cognitive and behavioral reactions to breathlessness that, by causing vicious cycles, worsen and maintain the symptom as demonstrated in Figure 44.1. The three domains relating to the model are described in more detail here: • Breathing domain: Breathlessness associated with dysfunctional breathing patterns with an increased respiratory rate, the need for the use of accessory muscles and dynamic hyperinflation, leading to inefficient breathing and increased work of breathing.

When patients are suffering from breathlessness, this affects informal carers—families and friends supporting the patient— as well. However, their burden and anxieties are often overlooked and their presence is taken for granted. Carers of breathless patients carry out many roles and tasks of caring such as washing, dressing, managing symptoms, administering medications, or managing home oxygen as along with doing all the everyday household work.12 Besides this practical help, they also provide emotional support.12 The support of carers is not only a daytime job but includes disturbed nights as well, as described by Booth et al.13 Carers are lying awake, watching the patient breathing and observing whether he is still alive. Thus, it is not surprising that caregivers report severe problems with sleep quality which have much in common with those of shift workers and mothers of young children.14 Therefore, when treating patients with breathlessness, the focus also needs to be on the carers and their needs, acknowledging their role and providing education, support, and resources to them as well as

FIGURE 44.1  The Breathing–Thinking–Functioning clinical model. (From Reference [10] with permission.)

Breathlessness

423

the patients. Carers need to be encouraged to look after their own health, both physical and mental.

Epidemiology Breathlessness is a common symptom in the general population with higher prevalence in older age, female sex, and chronic malignant and non-malignant conditions.15–17 The prevalence varies across conditions from 16–77% in cancer, 56–98% in chronic obstructive pulmonary disease (COPD), 18–88% in chronic heart failure, 11–82% in end-stage renal disease, 12–52% in dementia, and 81–88% in motor neuron disease.18 Large variations are due to different ways of measurement and different disease stages. In the last months of life, breathlessness intensity increases as death approaches, especially in patients with primary lung cancer.19,20 Based on the Global Burden of Diseases, Injuries and Risk Factors Study, in 2016, deaths from cancer and noncancer conditions likely associated with breathlessness were as follows: cancer overall 8.9 million; lung cancer 1.7 million; cardiovascular disease 17.6 million; chronic respiratory diseases 3,5 million (with COPD 2.9 million; asthma 0.4 million).21 Breathlessness is associated with shorter survival,22 reduced will to live,23 reduced physical activity,24 increased emergency room visits,25 and other health services use.

Pathophysiology of breathlessness Breathlessness—the uncomfortable awareness of the need to breathe—is a complex, individual experience of the mind and the body.26–28 This helps to explain the clear evidence that

breathlessness severity is a better predictor of prognosis than disease severity measured by quantitative assessments such as pulmonary function tests.29 Respiration is the only vital function that is both unconscious and under voluntary control, enabling an individual to talk, sing, eat, or breathe-hold to swim under water, for example.30 The respiratory (breathing) center in the medulla and pons generates a respiratory rhythm which is then modified by connections through the brain stem and upper spinal cord. It coordinates the activity of the diaphragm, the intercostal muscles, and accessory muscles of respiration (see Figure 44.2). The links between different parts of the brain and brain stem and respiratory muscles continue to be very controversial—it is clear that “the sensation of breathlessness originates from complex neurophysiological interplays between the automaticity of the breathing center in the brain stem, the generation of fear/anxiety in the amygdala and limbic system and the influence of the higher, cortical thinking and feeling areas” (very much simplified in Figure 44.2). 31 The sensation of breathlessness is integrated throughout the central nervous system (CNS), influenced by “peripheral generators,” such as fluid in the pleural space, fear, and anxiety (originating in the limbic system) and cognitions and memories associated with breathlessness from the higher cortical centers. The breathlessness associated with planned activities in health, such as running, is not distressing although it may require much effort and cause discomfort, because it is interpreted in a different way from the breathlessness of disease. 33 In neuroimaging studies, breathlessness is associated with activity in these specific brain areas, but these will feed into distributive brain networks, rather than acting as discrete entities. The areas particularly associated with the generation of

FIGURE 44.2  Schematic diagram to outline the genesis of breathlessness. (Reproduced with permission from Reference [32].)

424

Textbook of Palliative Medicine and Supportive Care TABLE 44.1  Causes of Breathlessness

FIGURE 44.3 The Bayesian brain. (Reproduced from Reference [35] under Open Access.) breathlessness within the limbic system and the cerebral cortex are: (i) the amygdala, an area associated with perceiving threats to self and arousing anxiety and fear, (ii) the cingulate cortex— strongly associated with motivation, memory and action, (iii) the medial-dorsal thalamus, associated with memory all part of the limbic system, and (iv) the anterior insula, (cerebral cortex) associated with interpreting the body’s own perception of “how it is” known as “interoception.” In the 1950s, Comroe postulated that breathlessness, “like pain,” involved not only a “sensory component” from disease but also the patients “reaction to the sensation,” now called the affective component. 34 This historic definition is consistent with the current Bayesian brain hypothesis, 35 see Figure 44.3, which rejects the idea of the brain as a mere “stimulus conversion” organ, proposing a model that proposes that the brain “forms predictions based on previous experience28 and continuously generating a top-down cascade of neutrally encoded (mostly non-conscious) hypotheses about the body and the world.” 35 The stimulus conversion model would imply that a given quantitative amount of pathology would always generate the same breathlessness severity, and this is demonstrably untrue. It is likely that in order for a person to react instantly to the environment around them, the brain works on a number of “prior” interpretations of the world, based on previous experiences and so individuals react to the “brain’s best guess” of what it is happening to them. 35 These “top-down” interpretations work in concert with “bottom-up” sensory information and can be modified over time by new information including education, so that treating “breathlessness via the brain” has been proposed. 28,36 Certainly, the idea of “stimulus of the failing organ” 37 as the sole approach to palliating the symptom has been rejected although treatment of the underlying disease is fundamental to managing breathlessness. A schematic representation of the generation of breathlessness is shown in Figure 44.2. The presence of the physical consequences of disease, such as the distortion, stretching, or stiffening of lung tissue by fluid, inflammation or tumor, or hypoxemia are transmitted to the breathing center by, for example, pulmonary stretch receptors and large vessel chemoreceptors (see Table 44.1, pathology associated with breathlessness). It is thought that the medullary breathing center sends out a corollary discharge of the sensation being generated, and the perception of breathlessness is then modulated by the influences of the higher cortical centers and the limbic system, including “prior” interpretations of the experience of breathlessness. It is clear that the respiratory center receives sensory information from multiple sources and breathlessness encompasses many different qualitative dimensions. Two principle sensations are (i)

Infection Anemia Deconditioning Hypoxia Hypercapnia Metabolic acidosis Bronchospasm Pulmonary edema Pleural effusion Restrictive processes (chest wall restriction, decreased lung compliance) Pneumothorax Pulmonary embolus Muscle weakness (neuromuscular diseases, cachexia, steroid myopathy, and phrenic nerve paralysis) Airway mechanical obstruction Lymphangitic carcinomatosis Pulmonary hypertension Pericardial effusion Ascites

increased sense of effort, or work of breathing, from, for example, stiff lungs or narrowed airways; and (ii) air hunger, from changes in blood gases. Air hunger is far more frightening. It follows that the impact of breathlessness for a person will be linked to their individual characteristics as well as disease severity, and that some of these will be modifiable by physical, educational, and psychological interventions. These include the person’s health beliefs, previous experiences, and associations with breathlessness, psychological status, degree of social connectedness or isolation, poverty, nutritional status, and the support given by the health-care system. In someone who has been breathless for some time, secondary behavioral responses, sometimes resulting from the actions of others, such as admonitions to rest, may have become established. Some of these, although apparently helpful, may actually increase the impact or severity of breathlessness. The central role of the CNS in the perception of breathlessness including the importance of cognitions in interpreting it as well the possibility of altering peripheral generators (e.g., muscle deconditioning) are consistent with a holistic palliative care approach to managing breathlessness.

Assessment and identification of causes of breathlessness A comprehensive clinical history of a patient with breathlessness should include the following aspects:38 1. Pattern of breathlessness (onset, aggravating factors, characteristics, episodes, triggers) 2. Presence of other symptoms and their importance compared to breathlessness 3. Impact on a person’s quality of life including physical activities (e.g., walking), ability to self-care, social life, and psychological status

Breathlessness 4. Current symptomatic treatments for breathlessness (e.g., hand-held fan) and their efficacy for that person 5. Adverse effects of any treatments used currently or in the past 6. All comorbidities 7. The person’s understanding and interpretation of the symptom 8. Carer burden Assessment of breathlessness needs to incorporate the subjective experience of the patient; thus, self-report of the symptom is essential. This should include the sensory component with intensity and severity, the emotional burden reflected in the unpleasantness of breathlessness and the impact on daily life. 3 There is currently no universally accepted outcome measure in either the clinical or research setting which is an obvious barrier to routine clinical assessment and monitoring of breathlessness. 3 Two validated measures, the Dyspnoea 12 and the Multidimensional Dyspnoea Profile (MDP) are suitable for use in the clinical and research setting and are short enough for assessment and monitoring. 39–42 The Dyspnoea 12 is a 12-item measure with 7 physical items and 5 affective items not related to physical activity. The answering options are on a scale of none (0), mild (1), moderate (2), or severe (3). The time period relates to “these days.”39 The MDP is also a 12-item scale using NRS scores (0–10).41 Seven items relate to overall intensity, unpleasantness, and other qualitative sensory descriptions of breathlessness (increased muscle work of breathing, tight chest, air hunger, breathing a lot, requires mental effort), and five rate emotional responses to the breathlessness (depression, anxiety, frustration, anger, and fear).41,42 An assessment of a patient with breathlessness should also include a physical examination with vital signs, cardiac and pulmonary examination, ascites, and peripheral edema. Additional studies may include blood tests, pulse oximetry, echocardiogram, and imaging studies (chest X-ray, computed tomography, magnetic resonance imaging, positron-emission tomography, ventilation-perfusion scan). Although additional diagnostic tests may be important to identify any treatable causes of breathlessness, one should be aware that more objective assessments such as respiratory rate, blood gas analyses, or lung function tests do not measure breathlessness and only correlate moderately with the patient’s subjective experience of breathlessness. For optimal management of breathlessness, treatment of the underlying disease and the exclusion of reversible symptoms are the first step. A list of common causes of breathlessness associated with malignant and non-malignant processes causing breathlessness is presented in Table 44.1.43

Symptomatic management of dyspnea When breathlessness persists despite optimal management of the underlying condition, symptomatic treatment is mandatory. This comprises both nonpharmacological and pharmacological measures. Earlier in the disease trajectory, nonpharmacological treatments are the first choice with the aim to improve patients’ self-management and increase physical activity. Later in the disease when patients suffer from breathlessness at slight exertion or at rest, the addition of pharmacological measures will often be necessary.

425

Nonpharmacological therapies The abovementioned BTF model is helpful to classify available nonpharmacological interventions for breathlessness as demonstrated in Table 44.2. These should be proactively introduced to patients as they are the cornerstone for breathlessness management. Not all available interventions will be suitable for every patient. Thus, it is important to identify the domains of the BTF model where the patient is most affected and select individually interventions together with the patient.

Interventions affecting the breathing domain Breathing techniques and positioning

As breathlessness is causing dysfunctional breathing with excessive accessory muscle use and upper chest dominance, readaptation of breathing patterns is essential in breathlessness management. Breathing control and diaphragmatic breathing are two commonly used techniques. Diaphragmatic breathing prolongs and slows inspiration and deliberately increases tidal volume but should not be advocated in patients with severe COPD.45 In contrast, breathing control techniques maintain normal tidal breathing with relaxed upper chest and shoulders.46 Pursed lip breathing is a further frequently used breathing technique and is frequently and often instinctively used by patients as it is a potential strategy to reduce respiratory rate and aid recovery, especially in COPD patients.46 For improving their breathing, physiotherapy is essential for patients to teach them the right techniques and provide instructions for regular exercise. Many patients with COPD adopt a rapid, shallow breathing pattern, frequently with chest wall and abdominal asynchrony.46 Inspiratory muscles are constantly in a shortened position and may need to be augmented by accessory muscles with fixation of the shoulder girdle.46 Patients need to be advised on passively fixing the shoulder girdle for optimizing ventilatory muscle efficiency and relief of breathlessness.46

Hand-held fan

Airflow directed to the face reduces breathlessness by altering ventilation.47 This is potentially mediated through cold receptors in the nose arising from the second and third branch of the trigeminal nerve which give sensory input to affect respiration and decrease breathlessness.47,48 A simple device to produce such an airflow is a hand-held fan. Its effectiveness has TABLE 44.2  Nonpharmacological Interventions in Relation to Breathing-Thinking-Functioning Domain44 Patient Focus

Breathing

Thinking

Functioning

Breathlessness domain

Sensory perceptive

Affective distress

Symptom impact or burden Physical exercise Mobility aids Neuromuscular electrical stimulation

Treatment by Breathing Psychotherapy primary target techniques and and cognitive or mechanism of positioning therapies effect Hand-held fan Mind–body Acupressure/ interventions acupuncture Music Multicomponent/ Pulmonary rehabilitation complex Breathlessness support services interventions

426 been tested in three randomized controlled trials (RCTs) 49–51 and reduction of breathlessness has been shown in two of them.49,51 The fan has been reported as a helpful self-management strategy and aiding recovery. 52,53 Patients need sound instructions on how to use the fan and the mechanism of action behind it. 54

Acupressure/acupuncture

Acupuncture is widely used in traditional Chinese medicine and its efficacy and practice has been demonstrated.55 A systematic review examining the effects of acupuncture in breathless patients suffering from advanced disease, included 12 studies with 597 patients with COPD or advanced cancer and demonstrated that breathlessness severity decreased significantly. 56 Median treatment duration was 25 days ranging from a single acupuncture session to treatment over 12 weeks with better treatment effects in treatment duration of at least 2 weeks.56

Interventions affecting the thinking domain

As anxiety and panic are highly prevalent in patients suffering from breathlessness, psychosocial support and interventions addressing these symptoms are crucial. For many patients, active listening and promotion of the therapeutic alliance is an intervention in itself. 31 Also, education about breathlessness and that breathlessness in itself does not harm or inevitably means that the patient is dying. There is limited evidence of studies testing psychosocial interventions as most do not measure breathlessness but focus on anxiety and panic.

Psychotherapy

Different types of psychotherapies have been tested either with personalized psychoeducational interventions57,58 or cognitive behavioral therapy (CBT).59–61 In CBT, two studies reported a significant reduction of breathlessness following CBT, 59,60 but in one, the effect did not persist during the follow-up period.59 In Bove’s study, a trend in favor of CBT was shown but results were not significant after 12 weeks of follow-up.61 In the studies testing personalized psychoeducational interventions, self-reported breathlessness was unchanged.57,58

Mind–body interventions

Norweg et al. reported in her systematic review small to large dyspnea improvements resulting from yoga (ES = 0.2–1.21 for intensity; 0.67 for distress; 0.07 for mastery; and −8.37 for functional burden). 62 In a study evaluating an 8-week mindfulness-based breathing therapy (MBBT) program, the intervention group did not show any significant reduction of breathlessness. 63

Music

Studies testing music are referred to as distractive auditory stimuli (DAS). Two small studies tested DAS in combination with exercise (either walking or an upper extremity program) in COPD patients.64,65 In the study testing DAS during walking, a nonsignificant decrease was observed in the intervention group, and a nonsignificant increase in the control group.64 In the second study, no significant differences between or within groups were shown.65 Singh et al. compared the effects of music with progressive muscle relaxation and demonstrated that both groups

Textbook of Palliative Medicine and Supportive Care were clinically effective in immediately reducing breathlessness. The improvements in breathlessness and anxiety were higher in the music group than in the PMR group.66

Interventions affecting the functioning domain Physical exercise

As many patients experience unpleasant breathlessness especially with exertion, they reduce physical activity which in consequence leads to muscle deconditioning which drives further breathlessness at lower levels of activity.54 Therefore, physical exercise should be encouraged in patients with breathlessness. Exercise leads to improvement of fitness and muscular performance among people living with and cured of cancer.67 By improving physical capacity, the level of exertion for any given physical task or activity relative to capacity becomes proportionally lower, and the level of perceived exertion and symptoms, e.g., breathlessness and fatigue, is reduced.54 Exercise training has been proposed as the most powerful means of desensitization to breathlessness.1 A variety of exercise programs have been studied, but rates of uptake and completion vary widely, and benefit from intensive, supervised exercise training may be limited to selected patients, often those who are fitter and less symptomatic.68 Physical exercise is also a key component in pulmonary rehabilitation programs.

Mobility aids

Mobility aids such as rollators or walking sticks offer the breathless patient additional support and not only allow for walking longer distances but also improving breathlessness.69,70 An increased maximal voluntary ventilation by bracing the arms on the walking aid and adopting a lean forward position are probably responsible for the positive effect of a walking aid on breathlessness.71 In addition, stabilizing the ribcage may improve accessory muscle function allowing these muscles to be engaged in respiratory activities.71

Neuromuscular electrical stimulation

Deconditioning due to physical activity also leads to breathlessness and peripheral muscle weakness.72 Therefore, exercise training is a key component of pulmonary rehabilitation programs but not all participants with severe COPD are capable of exercise and exercise training.73 Neuromuscular electrical stimulation (NMES) provides an interesting alternative to improve lower limb muscle performance. Low current is applied to leg muscles, mainly the quadriceps muscle, by a device causing the muscle to contract. NMES does not have the same effect as aerobic or weight training but the aim is to prevent or slow the downward spiral that can affect the breathless patient, not to reduce breathlessness directly.54 Jones et al. demonstrated in a systematic review including 18 studies with 933 participants in chronic respiratory disease, chronic heart failure and thoracic cancer that NMES led to a statistically significant improvement in quadriceps muscle strength as compared to control equating to approximately 1.1 kg, and an improvement in exercise performance with mixed results in breathlessness.74

Multicomponent/complex interventions Pulmonary rehabilitation

There is strong evidence that pulmonary rehabilitation has a significant effect on breathlessness, increases functional exercise, and improves quality of life in COPD patients as demonstrated in a Cochrane Review including 65 RCTs with 3,822 participants.75

Breathlessness Programs usually last 8–12 weeks and encompass exercise training for at least 4 weeks with or without education and/or psychological support.75

Breathlessness support services

For optimal management of breathlessness several management strategies outlined above need to be tailored to the individual patients’ needs. Also, many patients with advanced disease are not fit enough to participate in a longer pulmonary rehabilitation program. Therefore, breathlessness services have been developed and evaluated over the past 20 years for patients with advanced disease following the Medical Research Council (MRC) Framework for complex interventions.76 These relatively new multi-professional services are usually provided by palliative care, sometimes in close collaboration with respiratory medicine.77 Services comprise expertise from a medical and physiotherapy and/or nursing or social work background.77–79 Most services provide 4–6 contacts over 4–6 weeks.80 Interventions provided to the patients are physiotherapy including breathing techniques and positioning, relaxation techniques, self-management strategies, and medical review. In a meta-analysis of studies testing breathlessness services, reductions in Numeric Rating Scale distress due to breathlessness (n = 324; mean difference [MD] = −2.30, 95% CI −4.43 to −0.16, p = 0.03) and depression scores measured by the Hospital Anxiety and Depression Scale (HADS) (n = 408, MD = −1.67, 95% CI −2.52 to −0.81, p < 0.001) favored the intervention.80 Statistically nonsignificant effects were observed for Chronic Respiratory Questionnaire (CRQ) mastery (n = 259, MD = 0.23, 95% CI −0.10 to 0.55, p = 0.17) and HADS anxiety scores (n = 552, MD = −1.59, 95% CI −3.22 to 0.05, p = 0.06).80

Pharmacological therapies Opioids

Opioids are the preferred treatment for breathlessness with good evidence.81,82 Endogenous opioids have a modulatory effect on breathlessness which appears to be mediated by binding to central rather than peripheral opioid receptors in the respiratory tract.83 Their effect can be reduced by naloxone as demonstrated in a cohort of COPD patients who had a significant increase in circulating beta-endorphin after exercise which was reversed by naloxone leading to higher levels of breathlessness.84 Recently, sustained-release morphine has been licensed in Australia in patients with distressing breathlessness due to severe COPD, cardiac failure, malignancy or other cause, after treatments for the underlying cause(s) of the breathlessness have been optimized and nonpharmacological treatments are not effective. 31 Over the past 30 years, a number of clinical trials evaluated the efficacy of opioids in patients with advanced disease. Jennings et al. published the first systematic review on the effectiveness of opioids in breathlessness due to advanced disease including nine studies with 116 participants.85 The review supported the use of oral and parenteral opioids to treat breathlessness in patients with advanced disease but concluded that nebulized opioids are not better than nebulized saline.85 The Jennings review was updated by Barnes et al. in 2016 including 26 studies with 526 participants.81 The meta-analyses with fixed-effects model demonstrated a standardized mean difference (SMD) of −0.09 [95% CI −0.36 to 0.19] in the opioid group. The review resulted in the conclusion that there was only low-quality evidence that shows benefit for the use of oral or parenteral opioids to palliate

427 breathlessness and no evidence to support the use of nebulized opioids.81 This review was criticized for the conflicting findings as they did not account for matched data of crossover trials.82 Ekström et al. reanalyzed the data with a random effects model and accounted for crossover data. They concluded that opioids decreased breathlessness (SDM = −0.32; 95% CI −0.18 to −0.47; I2 = 44.8%) representing a clinically meaningful reduction of 0.8 points (0–10 numerical rating scale) which was consistent across all meta-analyses.82 For other than oral or parenteral modes of application, such as intranasal or transmucosal, there are only case series or pilot RCTs and clinical observations.86–88 Most studies testing opioids on breathlessness included patients suffering from COPD and breathlessness at rest or minimal exertion limiting daily activities despite optimized treatment.89 In a pooled analysis, younger people or those with worse breathlessness are more likely to benefit.90 Overall, opioid doses to relieve breathlessness are much lower compared to analgesic doses. In a dose titration study, 70% of patients experiencing relief of breathlessness needed 10 mg/24 hours sustained release morphine and 90% responded to 20 mg or less daily.91 As slow-release opioids with steady state of the opioid showed slightly larger reductions in breathlessness than non-steady states,92 starting with sustained-release morphine seems preferable to short-acting morphine. In opioid-naïve patients, an adequate dose would be 10 mg/24 hours with dose titration upward over days and weeks. Similar to pain management, immediate-release opioids should be prescribed in addition for acute episodes of breathlessness but unlike pain management the titration rate is much lower. In patients who are already on opioids, e.g., for pain relief, a 25% increase in the baseline opioid dose for cancer pain provided relief of breathlessness for up to 4 hours.93 In patients with non-oncological disease, e.g., COPD, lower doses of opioids have been suggested if patients are opioidnaïve. A starting dose of 1 mg morphine once a day, increasing to twice daily during the next week and further upward titration were recommended.94 This is in contrast to the slow-release doses mentioned above and based on studies mainly with COPD patients but it might indicate that very low doses are sufficient for some of these patients. Side effects are those expected with opioid therapy. In Barnes’ systematic review, participants were 4.73 times more likely to experience nausea and vomiting compared to placebo, three times more likely to experience constipation, and 2.86 times more likely to experience drowsiness.81 Therefore, the same proactive prophylaxis as in pain management is necessary, e.g., regular laxatives to prevent constipation. More importantly, none of the studies testing opioids in breathlessness reported respiratory depression or other serious adverse events resulting in hospital admission or death.85,91 Therefore, regular, low dose, sustainedrelease opioids seems to be safe in patients with advanced and terminal disease.89

Anxiolytics Benzodiazepines

Benzodiazepines are frequently prescribed for the management of breathlessness hoping to reduce coexisting anxiety in these patients. Furthermore, it is assumed that benzodiazepines are active at brain structures implicated in the perception of breathlessness.95 However, a Cochrane review failed to show any benefit of benzodiazepines.96 Eight RCTs with 214 participants were included (COPD n = 66; cancer n = 148). Only one

428 study demonstrated a significant positive effect of midazolam compared to morphine.97 However, this result is conflicting with another study of the same author group were midazolam was less effective than morphine.98 In all the other studies, no significant effect could be demonstrated. Despite the limited evidence and because of the good clinical experience, benzodiazepines are recommended as secondline therapy when opioids and other pharmacological measures are not effective or when patients suffer from additional anxiety and panic.99 In advanced stages of the disease and in the terminal phase, a combination of opioids and benzodiazepines is recommended.98,100 Other psychoactive agents such as phenothiazines (promethazine or chlorpromazine) have been studied in patients with breathlessness.101–103 The potential mechanism of action is thought to be reduction of anxiety and agitation. Most studies are quite old (all published before 1990), with small numbers of participants and of low quality. Only one study demonstrated a small effect of promethazine for the relief of breathlessness which was not confirmed in other studies.101

Antidepressants

More recently, antidepressants have come more into a focus of interest for the relief of breathlessness. Serotonin, a neurotransmitter, plays an important role in the central control of respiration via multiple receptor subtypes, contributing to chemosensitivity and mediating ventilatory response to changes in CO2/pH, and by maintaining regulatory function as part of respiratory neuroplasticity.104 The perceived benefit does not appear to relate to antidepressant or anxiolytic effects, as patients without concurrent anxiety and/or depression also reported improvements in breathlessness.105,106 In consequence, selective serotonin reuptake inhibitors (SSRIs) could be a potential new treatment option, especially as there is some upcoming evidence. Two observational studies using sertraline, an SSRI, reported a subjective decrease in breathlessness in patients with COPD.105,107 However, a fully powered RCT in 223 patients with chronic breathlessness did not show a benefit of 25–100 mg (titrated upward over nine days) sertraline over placebo.108 Another commonly used and well-tolerated antidepressant is mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA). Besides action at the α2-receptor, it is also an antagonist at serotonin (5HT2A/2C/3) and histamine (H1) receptors.109 Mirtazapine may have direct beneficial effects as it impacts rapidly on neural circuits involved in vigilance and the perception of, and the emotional response to, unpleasant stimuli (of which breathlessness is one) through the process of interoception.104 This assumption is supported by a case series of six patients who received 15 mg mirtazapine.110 All patients reported less breathlessness and being able to do more. These effects need to be tested in a larger randomized controlled study which is currently underway.

Oxygen

Oxygen is commonly administered to patients suffering from breathlessness due to advanced disease, often in the belief that it is beneficial to patients. However, evidence is mixed regarding the effectiveness of oxygen in relieving breathlessness. In patients with COPD and chronic hypoxemia, long-term oxygen therapy (LTOT) is an established measure and recommended in numerous guidelines for prolongation of survival.

Textbook of Palliative Medicine and Supportive Care In breathless patients with mild or no hypoxemia, evidence is rather limited. In mildly hypoxemic and non-hypoxemic COPD patients who would not otherwise qualify for home oxygen therapy, oxygen can relieve breathlessness when given during exercise.111 In chronic heart failure, Asano et al. concluded in a systematic review including 11 studies, that there are scant data to justify the use of oxygen in individuals with non-hypoxemic chronic heart failure and chronic breathlessness.112 In interstitial lung disease, Bell et al. demonstrated in a further systematic review that there are no effects of oxygen therapy on breathlessness during exercise, although exercise capacity was increased.113 A systematic review in cancer patients confirmed the lack of evidence to support the use of oxygen for breathlessness.114 Most systematic reviews criticize mainly small and underpowered studies. Abernethy et al. studied a mixed population of 239 palliative care patients with PaO2 > 55 mmHg who were breathless at rest or with minimal exertion.115 Patients received oxygen or room air via a concentrator through a nasal cannula at 2 L per min for 7 days. Both groups experienced a similar reduction of breathlessness but without a significant difference. The authors concluded that oxygen provided no additional symptomatic benefit for the relief of refractory breathlessness compared with

KEY LEARNING POINTS • Breathlessness is a subjective experience that derives from interactions among multiple physiological, psychological, social, and environmental factors. Informal caregivers are severely burned and need attention of professionals. • The BTF model conceptualizes the three predominant cognitive and behavioral reactions to breathlessness that, by causing vicious cycles, worsen and maintain the symptom. • Breathlessness is a complex interaction of mind and body influences both by peripheral changes in the lungs as well as cognition and memories. • Assessment of a patient with breathlessness should include pattern of breathlessness, impact on patients’ quality of life including physical activities, and the person’s understanding and interpretation of the symptom. • Treatment of the underlying disease and the reversible causes are the first step in breathlessness management. • A variety of nonpharmacological therapies are available with good evidence that can be individually tailored to the patients. They should be employed before starting with pharmacological treatment. • For pharmacological therapies, opioids are the drugs of choice with good evidence. Benzodiazepines should only be used in combination with opioids as their evidence is limited. • Oxygen should only be prescribed to hypoxic patients. Otherwise, a draught of cool air, e.g., generated by a hand-held fan, should be introduced to patients as there is good evidence for the relief of breathlessness.

Breathlessness

429

room air and that less burdensome strategies should be considered after brief assessment of the effect of oxygen therapy on the individual patient.115 Abernethy’s study implies that airflow also has a beneficial effect on patients’ breathlessness. This has been confirmed by a systematic review examining the effect of airflow on chronic breathlessness. Swan et al. included 16 studies with overall 929 participants which used airflow as an intervention or a comparator.47 Airflow via a fan at rest, medical air via nasal cannulae, and medical airflow during a constant load exercise test before and after rehabilitation all offered significant benefit for breathlessness intensity.47 The potential mechanism of effect are stimulation of the second and third branches of the trigeminal nerve and/or stimulation of nasal mucosa and upper airway “flow” receptors.47 As the application of oxygen has known side effects (dry mouth and nose, immobility, CO2 retention, perceived stigma), is expensive and laborious to organize at home, the indication should be critically reviewed and restricted to patients with proven hypoxemia. In patients with mild or no hypoxemia, a hand-held fan should be introduced to the patient with clear instructions about its use.

References









1. American Thoracic Society. Dyspnea: mechanisms, assessment and management: a consensus statement. Am J Respir Crit Care Med 1999;159:321–340. 2. Abernethy AP, Wheeler JL. Total dyspnoea. Curr Opin Support Palliat Care 2008;2(2):110–113. 3. Johnson MJ, Currow DC, Booth S. Prevalence and assessment of breathlessness in the clinical setting. Expert Rev Respir Med 2014;8(2):151–161. 4. Johnson MJ, Yorke J, Hansen-Flaschen J, Lansing R, Ekstrom M, Similowski T, et al. Towards an expert consensus to delineate a clinical syndrome of chronic breathlessness. Eur Respir J 2017;49(5):1602277. 5. Simon ST, Weingartner V, Higginson IJ, Voltz R, Bausewein C. Definition, categorization, and terminology of episodic breathlessness: consensus by an international Delphi survey. J Pain Symptom Manage 2014;47(5):828–838. 6. Linde P, Hanke G, Voltz R, Simon ST. Unpredictable episodic breathlessness in patients with advanced chronic obstructive pulmonary disease and lung cancer: a qualitative study. Support Care Cancer 2018;26(4):1097–1104. 7. Gysels M, Higginson IJ. Access to services for patients with chronic obstructive pulmonary disease: the invisibility of breathlessness. J Pain Symptom Manage 2008;36(5):451–460. 8. Gysels M, Bausewein C, Higginson IJ. Experiences of breathlessness: a systematic review of the qualitative literature. Palliat Support Care 2007;5(3):281–302. 9. Hutchinson A. Patient and Carer Experience of Breathlessness. In: Bausewein C, Currow D, Johnson M, eds. Palliative Care in Respiratory Disease. Sheffield: European Respiratory Society, 2016. 10. Spathis A, Booth S, Moffat C, Hurst R, Ryan R, Chin C, et al. The breathing, thinking, functioning clinical model: a proposal to facilitate evidence-based breathlessness management in chronic respiratory disease. NPJ Primary Care Respir Med 2017;27(1):27. 11. Booth S, Burkin J, Moffat C, Spathis A. Managing Breathlessness in Clinical Practice. Springer, 2014. 12. Farquhar M. Supporting Informal Carers. In: Bausewein C, Currow D, Johnson M, eds. Palliative Care in Respiratory Disease. Sheffield: European Research Society, 2016. 13. Booth S, Silvester S, Todd C. Breathlessness in cancer and chronic obstructive pulmonary disease: using a qualitative approach to describe the experience of patients and carers. Palliat Support Care 2003;1(4):337–344. 14. Malik F. Breathlessness in Patients with Advanced Disease: The Experiences of Caregivers. London: King’s College London, 2011. 15. Currow DC, Plummer JL, Crockett A, Abernethy AP. A community population survey of prevalence and severity of dyspnea in adults. J Pain Symptom Manage 2009;38(4):533–545.

16. Figarska SM, Boezen HM, Vonk JM. Dyspnea severity, changes in dyspnea status and mortality in the general population: the Vlagtwedde/ Vlaardingen study. Eur J Epidemiol 2012;27(11):867–876. 17. van Mourik Y, Rutten FH, Moons KG, Bertens LC, Hoes AW, Reitsma JB. Prevalence and underlying causes of dyspnoea in older people: a systematic review. Age Ageing 2014;43(3):319–326. 18. Moens K, Higginson IJ, Harding R. Are there differences in the prevalence of palliative care-related problems in people living with advanced cancer and eight non-cancer conditions? A systematic review. J Pain Symptom Manage 2014;48(4):660–677. 19. Currow DC, Smith J, Davidson PM, Newton PJ, Agar MR, Abernethy AP. Do the trajectories of dyspnea differ in prevalence and intensity by diagnosis at the end of life? A consecutive cohort study. J Pain Symptom Manage 2010;39(4):680–690. 20. Seow H, Barbera L, Sutradhar R, Howell D, Dudgeon D, Atzema C, et al. Trajectory of performance status and symptom scores for patients with cancer during the last six months of life. J Clin Oncol 2011;29(9):1151–1158. 21. Foreman KJ, Marquez N, Dolgert A, Fukutaki K, Fullman N, McGaughey M, et al. Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016-40 for 195 countries and territories. Lancet 2018;392(10159):2052–2090. 22. Palmer JL, Fisch MJ. Association between symptom distress and survival in outpatients seen in a palliative care cancer center. J Pain Symptom Manage 2005;29(6):565–571. 23. Tataryn D, Chochinov HM. Predicting the trajectory of will to live in terminally ill patients. Psychosomatics 2002;43(5):370–377. 24. Troosters T, Sciurba F, Battaglia S, Langer D, Valluri SR, Martino L, et al. Physical inactivity in patients with COPD, a controlled multi-center pilot-study. Respir Med 2010;104(7):1005–1011. 25. Barbera L, Taylor C, Dudgeon D. Why do patients with cancer visit the emergency department near the end of life? CMAJ 2010;182(6):563–568. 26. Booth S, Moosavi SH, Higginson IJ. The etiology and management of intractable breathlessness in patients with advanced cancer: a systematic review of pharmacological therapy. Nat Clin Pract Oncol 2008;5(2):90–100. 27. Carel H. Illness. 2nd edn. Oxford: Routledge, 2012. 28. Herigstad M, Faull OK, Hayen A, Evans E, Hardinge FM, Wiech K, et al. Treating breathlessness via the brain: changes in brain activity over a course of pulmonary rehabilitation. Eur Respir J 2017;50(3):1701029. 29. Nishimura K, Izumi T, Tsukino M, Oga T. Dyspnea is a better predictor of 5-year survival than airway obstruction in patients with COPD. Chest 2002;121(5):1434–1440. 30. Moosavi SH, Paydarfar D, Shea SA. Suprapontine Control of Breathing. In: Ward DS, Dahan A, Teppema L, eds. Pharmacology and Pathophysiology of the Control of Breathing. Boca Raton: Taylor & Francis Group, 2005. 31. Booth S, Johnson MJ. Improving the quality of life of people with advanced respiratory disease and severe breathlessness. Breathe (Sheff). 2019;15(3):198–215. 32. Moosavi S, Booth S. The Cambridge BIS Breathlessness Intervention Service Manual. Cambridge, 2011. 33. Booth S, Fallon M, Hollis G. Rhetoric and reality: matching palliative care services to meet the needs of patients of all ages, with any diagnosis. Palliat Med 2016;30(1):3–5. 34. Comroe JH. Some Theories of the Mechanisms of Dyspnoea. Howell JBL, Campbell EJM, eds. Blackwell Scientific, 1966 Oxford. 35. Ongaro G, Kaptchuk TJ. Symptom perception, placebo effects, and the Bayesian brain. Pain 2019;160(1):1–4. 36. Booth S. Science supporting the art of medicine: improving the management of breathlessness. Palliat Med 2013;27(6):483–485. 37. Coats AJ. Teaching heart-failure patients how to breathe. Lancet 1998;351(9112):1299–1300. 38. Bausewein C, Booth S, Higginson IJ. Measurement of dyspnoea in the clinical rather than the research setting. Curr Opin Support Palliat Care 2008;2(2):95–99. 39. Yorke J, Moosavi SH, Shuldham C, Jones PW. Quantification of dyspnoea using descriptors: development and initial testing of the Dyspnoea-12. Thorax 2010;65(1):21–26. 40. Yorke J, Horton M, Jones PW. A critique of Rasch analysis using the Dyspnoea-12 as an illustrative example. J Adv Nurs 2012;68(1):191–198. 41. Meek PM, Banzett R, Parsall MB, Gracely RH, Schwartzstein RM, Lansing R. Reliability and validity of the multidimensional dyspnea profile. Chest 2012;141(6):1546–1553.

430 42. Parshall MB, Meek PM, Sklar D, Alcock J, Bittner P. Test-retest reliability of multidimensional dyspnea profile recall ratings in the emergency department: a prospective, longitudinal study. BMC Emerg Med 2012;12:6. 43. Thomas J. Dyspnea. In: Bruera E, Higginson I, van Gunten CF, Morita T, eds. Textbook of Palliative Medicine and Supportive Care. CRC Press Taylor & Francis Group, 2015 London. 44. Johnson M, Barbetta C, Currow D, Maddocks M, McDonald V, Mahadeva R, et al. Management of Chronic Breathlessness. In: Bausewein C, Currow D, Johnson M, eds. Palliative Care in Respiratory Disease. ERS Monogr. Sheffield: European Respiratory Society, 2016, pp. 153–171. 45. Holland AE, Hill CJ, Jones AY, McDonald CF. Breathing exercises for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012;10:CD008250. 46. Bott J, Blumenthal S, Buxton M, Ellum S, Falconer C, Garrod R, et al. Guidelines for the physiotherapy management of the adult, medical, spontaneously breathing patient. Thorax 2009;64(Suppl 1): i1–i52. 47. Swan F, Newey A, Bland M, Allgar V, Booth S, Bausewein C, et al. Airflow relieves chronic breathlessness in people with advanced disease: an exploratory systematic review and meta-analyses. Palliat Med 2019;33(6):618–633. 48. Schwartzstein RM, Lahive K, Pope A, Weinberger SE, Weiss JW. Cold facial stimulation reduces breathlessness induced in normal subjects. Am Rev Respir Dis 1987;136(1):58–61. 49. Galbraith S, Fagan P, Perkins P, Lynch A, Booth S. Does the use of a handheld fan improve chronic dyspnea? A randomized, controlled, crossover trial. J Pain Symptom Manage 2010;39(5):831–838. 50. Bausewein C, Booth S, Gysels M, Kuhnbach R, Higginson IJ. Effectiveness of a hand-held fan for breathlessness: a randomised phase II trial. BMC Palliat Care 2010;9:22. 51. Puspawati N, Sitorus R, Herawati T. Hand-held fan airflow stimulation relieves dyspnea in lung cancer patients. Asia Pac J Oncol Nurs 2017;4(2):162–167. 52. Johnson MJ, Booth S, Currow DC, Lam LT, Phillips JL. A mixed-methods, randomized, controlled feasibility trial to inform the design of a phase III trial to test the effect of the handheld fan on physical activity and carer anxiety in patients with refractory breathlessness. J Pain Symptom Manage 2016;51(5):807–815. 53. Luckett T, Phillips J, Johnson MJ, Farquhar M, Swan F, Assen T, et al. Contributions of a hand-held fan to self-management of chronic breathlessness. Eur Respir J 2017;50(2):1700262. 54. Booth S, Chin C, Spathis A, Maddocks M, Yorke J, Burkin J, et al. Non-pharmacological interventions for breathlessness in people with cancer. Exp Rev Qual Life Cancer Care 2018 https://doi.org/10.1080/ 23809000.2018.1524708. 55. Kaptchuk TJ. Acupuncture: theory, efficacy, and practice. Ann Intern Med 2002;136(5):374–383. 56. von Trott P, Oei SL, Ramsenthaler C. Acupuncture for breathlessness in advanced diseases: a systematic review and meta-analysis. J Pain Symptom Manage 2020;59(2):327–338. 57. Alexopoulos GS, Kiosses DN, Sirey JA, Kanellopoulos D, Novitch RS, Ghosh S, et al. Personalised intervention for people with depression and severe COPD. Br J Psychiatry 2013;202(3):235–236. 58. Chan CW, Richardson A, Richardson J. Managing symptoms in patients with advanced lung cancer during radiotherapy: results of a psychoeducational randomized controlled trial. J Pain Symptom Manage 2011;41(2):347–357. 59. Kunik ME, Veazey C, Cully JA, Souchek J, Graham DP, Hopko D, et al. COPD education and cognitive behavioral therapy group treatment for clinically significant symptoms of depression and anxiety in COPD patients: a randomized controlled trial. Psychol Med 2008;38(3):385–396. 60. Livermore N, Dimitri A, Sharpe L, McKenzie DK, Gandevia SC, Butler JE. Cognitive behaviour therapy reduces dyspnoea ratings in patients with chronic obstructive pulmonary disease (COPD). Respir Physiol Neurobiol 2015;216:35–42. 61. Bove DG, Lomborg K, Jensen AK, Overgaard D, Lindhardt BO, Midtgaard J. Efficacy of a minimal home-based psychoeducative intervention in patients with advanced COPD: a randomised controlled trial. Respir Med 2016;121:109–116. 62. Norweg A, Collins EG. Evidence for cognitive-behavioral strategies improving dyspnea and related distress in COPD. Int J Chronic Obstruct Pulm Dis 2013;8:439–451.

Textbook of Palliative Medicine and Supportive Care 63. Mularski RA, Munjas BA, Lorenz KA, Sun S, Robertson SJ, Schmelzer W, et al. Randomized controlled trial of mindfulness-based therapy for dyspnea in chronic obstructive lung disease. J Altern Complement Med 2009;15(10):1083–1090. 64. Bauldoff GS, Hoffman LA, Zullo TG, Sciurba FC. Exercise maintenance following pulmonary rehabilitation: effect of distractive stimuli. Chest 2002;122(3):948–954. 65. Bauldoff GS, Rittinger M, Nelson T, Doehrel J, Diaz PT. Feasibility of distractive auditory stimuli on upper extremity training in persons with chronic obstructive pulmonary disease. J Cardiopulm Rehabil 2005;25(1):50–55. 66. Singh VP, Rao V, Prem V, Sahoo RC, Keshav Pai K. Comparison of the effectiveness of music and progressive muscle relaxation for anxiety in COPD: a randomized controlled pilot study. Chron Respir Dis 2009;6(4):209–216. 67. Silver JK, Baima J, Mayer RS. Impairment-driven cancer rehabilitation: an essential component of quality care and survivorship. CA Cancer J Clin 2013;63(5):295–317. 68. Maddocks M, Mockett S, Wilcock A. Is exercise an acceptable and practical therapy for people with or cured of cancer? A systematic review. Cancer Treat Rev 2009;35(4):383–390. 69. Gupta R, Goldstein R, Brooks D. The acute effects of a rollator in individuals with COPD. J Cardiopulm Rehabil 2006;26(2):107–111. 70. Honeyman P, Barr P, Stubbing DG. Effect of a walking aid on disability, oxygenation, and breathlessness in patients with chronic airflow limitation. J Cardiopulm Rehabil 1996;16(1):63–67. 71. Probst VS, Troosters T, Coosemans I, Spruit MA, Pitta FO, Decramer M, et al. Mechanisms of improvement in exercise capacity using a rollator in patients with COPD. Chest 2004;126(4):1102–1107. 72. Reardon JZ, Lareau SC, ZuWallack R. Functional status and quality of life in chronic obstructive pulmonary disease. Am J Med 2006;119(10 Suppl 1):32–7. 73. Vivodtzev I, Pepin JL, Vottero G, Mayer V, Porsin B, Levy P, et al. Improvement in quadriceps strength and dyspnea in daily tasks after 1 month of electrical stimulation in severely deconditioned and malnourished COPD. Chest 2006;129(6):1540–1548. 74. Jones S, Man WD, Gao W, Higginson IJ, Wilcock A, Maddocks M. Neuromuscular electrical stimulation for muscle weakness in adults with advanced disease. Cochrane Database Syst Rev 2016;10:CD009419. 75. McCarthy B, Casey D, Devane D, Murphy K, Murphy E, Lacasse Y. Pulmonary rehabilitation for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2015;(2):CD003793. 76. Craig P, Dieppe P, Macintyre S, Michie S, Nazareth I, Petticrew M. Developing and evaluating complex interventions: the new Medical Research Council guidance. BMJ 2008;337:a1655. 77. Higginson IJ, Bausewein C, Reilly CC, Gao W, Gysels M, Dzingina M, et al. An integrated palliative and respiratory care service for patients with advanced disease and refractory breathlessness: a randomised controlled trial. Lancet Respir Med 2014;2(12):979–987. 78. Farquhar MC, Prevost AT, McCrone P, Brafman-Price B, Bentley A, Higginson IJ, et al. Is a specialist breathlessness service more effective and cost-effective for patients with advanced cancer and their carers than standard care? Findings of a mixed-method randomised controlled trial. BMC Medicine 2014;12:194. 79. Farquhar MC, Prevost AT, McCrone P, Brafman-Price B, Bentley A, Higginson IJ, et al. The clinical and cost effectiveness of a Breathlessness Intervention Service for patients with advanced nonmalignant disease and their informal carers: mixed findings of a mixed method randomised controlled trial. Trials 2016;17:185. 80. Brighton LJ, Miller S, Farquhar M, Booth S, Yi D, Gao W, et al. Holistic services for people with advanced disease and chronic breathlessness: a systematic review and meta-analysis. Thorax 2019;74(3):270–281. 81. Barnes H, McDonald J, Smallwood N, Manser R. Opioids for the palliation of refractory breathlessness in adults with advanced disease and terminal illness. Cochrane Database Syst Rev 2016;3:CD011008. 82. Ekstrom M, Bajwah S, Bland JM, Currow DC, Hussain J, Johnson MJ. One evidence base; three stories: do opioids relieve chronic breathlessness? Thorax. 2018;73(1):88–90. 83. Mahler DA, Gifford AH, Waterman LA, Ward J, Kraemer WJ, Kupchak BR, et al. Effect of increased blood levels of beta-endorphin on perception of breathlessness. Chest 2013;143(5):1378–1385. 84. Mahler DA, Murray JA, Waterman LA, Ward J, Kraemer WJ, Zhang X, et al. Endogenous opioids modify dyspnoea during treadmill exercise in patients with COPD. Eur Respir J 2009;33(4):771–777.

Breathlessness 85. Jennings AL, Davies AN, Higgins JP, Broadley K. Opioids for the palliation of breathlessness in terminal illness. [Review] [70 refs]. Cochrane Database Syst Rev 2001;(4):CD002066. 86. Jensen D, Alsuhail A, Viola R, Dudgeon DJ, Webb KA, O’Donnell DE. Inhaled fentanyl citrate improves exercise endurance during highintensity constant work rate cycle exercise in chronic obstructive pulmonary disease. J Pain Symptom Manage 2012;43(4):706–719. 87. Hui D, Hernandez F, Larsson L, Liu D, Kilgore K, Naberhuis J, et al. Prophylactic fentanyl sublingual spray for episodic exertional dyspnea in cancer patients: a pilot double-blind randomized controlled trial. J Pain Symptom Manage 2019:58(4):605–613. 88. Hui D, Kilgore K, Park M, Williams J, Liu D, Bruera E. Impact of prophylactic fentanyl pectin nasal spray on exercise-induced episodic dyspnea in cancer patients: a double-blind, randomized controlled trial. J Pain Symptom Manage 2016;52(4):459–468 e1. 89. Ekstrom MP, Abernethy AP, Currow DC. The management of chronic breathlessness in patients with advanced and terminal illness. BMJ 2015;349:g7617. 90. Johnson MJ, Bland JM, Oxberry SG, Abernethy AP, Currow DC. Opioids for chronic refractory breathlessness: patient predictors of beneficial response. Eur Respir J 2013;42(3):758–766. 91. Currow DC, McDonald C, Oaten S, Kenny B, Allcroft P, Frith P, et al. Once-daily opioids for chronic dyspnea: a dose increment and pharmacovigilance study. J Pain Symptom Manage 2011;42(3):388–399. 92. Ekstrom M, Nilsson F, Abernethy AA, Currow DC. Effects of opioids on breathlessness and exercise capacity in chronic obstructive pulmonary disease. A systematic review. Ann Am Thorac Soc 2015;12(7):1079–1092. 93. Allard P, Lamontagne C, Bernard P, Tremblay C. How effective are supplementary doses of opioids for dyspnea in terminally ill cancer patients? A randomized continuous sequential clinical trial. J Pain Symptom Manage 1999;17(4):256–265. 94. Booth S, Bausewein C, Higginson IJ, Moosavi SH. Pharmacological treatment of refractory breathlessness. Expert Rev Resp Med 2009;3(1):21–36. 95. Paulus MP, Feinstein JS, Castillo G, Simmons AN, Stein MB. Dosedependent decrease of activation in bilateral amygdala and insula by lorazepam during emotion processing. Arch Gen Psychiatry 2005;62(3):282–288. 96. Simon ST, Higginson IJ, Booth S, Harding R, Weingartner V, Bausewein C. Benzodiazepines for the relief of breathlessness in advanced malignant and non-malignant diseases in adults. Cochrane Database Syst Rev 2016;10:CD007354. 97. Navigante AH, Castro MA, Cerchietti LC. Morphine versus midazolam as upfront therapy to control dyspnea perception in cancer patients while its underlying cause is sought or treated. J Pain Symptom Manage 2010;39(5):820–830. 98. Navigante AH, Cerchietti LC, Castro MA, Lutteral MA, Cabalar ME. Midazolam as adjunct therapy to morphine in the alleviation of severe dyspnea perception in patients with advanced cancer. J Pain Symptom Manage 2006;31(1):38–47. 99. Leitlinienprogramm Onkologie. Erweiterte S3 Leitlinie Palliativmedizin für Patienten mit einer nicht heilbaren Krebserkrankung. Onkologie Leitlinienprogramm; 2019. Contract No.: AWMF-Registernummer: 128/001OL.

431 100. Allcroft P, Margitanovic V, Greene A, Agar MR, Clark K, Abernethy AP, et al. The role of benzodiazepines in breathlessness: a single site, open label pilot of sustained release morphine together with clonazepam. J Palliat Med 2013;16(7):741–744. 101. Woodcock AA, Gross ER, Geddes DM. Drug treatment of breathlessness: contrasting effects of diazepam and promethazine in pink puffers. Br Med J (Clin Res Ed) 1981;283(6287):343–346. 102. Rice KL, Kronenberg RS, Hedemark LL, Niewoehner DE. Effects of chronic administration of codeine and promethazine on breathlessness and exercise tolerance in patients with chronic airflow obstruction. Br J Dis Chest 1987;81(3):287–292. 103. O’Neill PA, Morton PB, Stark RD. Chlorpromazine: a specific effect on breathlessness? Br J Clin Pharmacol 1985;19(6):793–797. 104. Lovell N, Wilcock A, Bajwah S, Etkind SN, Jolley CJ, Maddocks M, et al. Mirtazapine for chronic breathlessness? A review of mechanistic insights and therapeutic potential. Expert Rev Respir Med 2019;13(2):173–180. 105. Smoller JW, Pollack MH, Systrom D, Kradin RL. Sertraline effects on dyspnea in patients with obstructive airways disease. Psychosomatics 1998;39(1):24–29. 106. Perna G, Cogo R, Bellodi L. Selective serotonin re-uptake inhibitors beyond psychiatry: are they useful in the treatment of severe, chronic, obstructive pulmonary disease? Depress Anxiety 2004;20(4):203–204. 107. Papp LA, Weiss JR, Greenberg HE, Rifkin A, Scharf SM, Gorman JM, et al. Sertraline for chronic obstructive pulmonary disease and comorbid anxiety and mood disorders. Am J Psychiatry 1995;152(10):1531. 108. Currow DC, Ekstrom M, Louw S, Hill J, Fazekas B, Clark K, et al. Sertraline in symptomatic chronic breathlessness: a double blind, randomised trial. Eur Respir J 2019;53(1):1801270. 109. Anttila SA, Leinonen EV. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev 2001;7(3):249–264. 110. Lovell N, Bajwah S, Maddocks M, Wilcock A, Higginson IJ. Use of mirtazapine in patients with chronic breathlessness: A case series. Palliat Med 2018;32(9):1518–1521. 111. Ekstrom M, Ahmadi Z, Bornefalk-Hermansson A, Abernethy A, Currow D. Oxygen for breathlessness in patients with chronic obstructive pulmonary disease who do not qualify for home oxygen therapy. Cochrane Database Syst Rev 2016;11:CD006429. 112. Asano R, Mathai SC, Macdonald PS, Newton PJ, Currow DC, Phillips J, et al. Oxygen use in chronic heart failure to relieve breathlessness: a systematic review. Heart Fail Rev. 2020 Mar;25(2):195-205. doi: 10.1007/s10741-019-09814-0. 113. Bell EC, Cox NS, Goh N, Glaspole I, Westall GP, Watson A, et al. Oxygen therapy for interstitial lung disease: a systematic review. Eur Respir Rev: Off J Eur Respir Soc 2017;26(143):160080. 114. Uronis HE, Currow DC, McCrory DC, Samsa GP, Abernethy AP. Oxygen for relief of dyspnoea in mildly- or non-hypoxaemic patients with cancer: a systematic review and meta-analysis. Br J Cancer 2008;98(2):294–299. 115. Abernethy AP, McDonald CF, Frith PA, Clark K, Herndon JE, 2nd, Marcello J, et al. Effect of palliative oxygen versus room air in relief of breathlessness in patients with refractory dyspnoea: a double-blind, randomised controlled trial. Lancet 2010;376(9743):784–793.

45

OTHER RESPIRATORY SYMPTOMS (COUGH, HICCUP, AND SECRETIONS)

Regina M. Mackey and Francisco Loaiciga

Contents Introduction....................................................................................................................................................................................................................... 433 Cough.................................................................................................................................................................................................................................. 433 Physiology..................................................................................................................................................................................................................... 433 Pathogenesis................................................................................................................................................................................................................. 434 Etiologies....................................................................................................................................................................................................................... 434 Assessment................................................................................................................................................................................................................... 434 Management strategies.............................................................................................................................................................................................. 435 Supportive: speech therapy................................................................................................................................................................................. 435 Pharmacological: cough suppressor or protrusive or cough enhancers.................................................................................................... 435 Hiccup................................................................................................................................................................................................................................. 436 Physiology..................................................................................................................................................................................................................... 436 Pathophysiology.......................................................................................................................................................................................................... 436 Management strategies...............................................................................................................................................................................................437 Nonpharmacological strategies...........................................................................................................................................................................437 Secretions.................................................................................................................................................................................................................437 Physiopathology of increased respiratory secretions including bronchorrhea.............................................................................................. 438 Management................................................................................................................................................................................................................ 438 Nonpharmacological approach.......................................................................................................................................................................... 438 Pharmacological approach.................................................................................................................................................................................. 438 References............................................................................................................................................................................................................................439

Introduction In this chapter, we approach other respiratory symptoms besides dyspnea. Starting with the incidence of each symptom in the palliative medicine population, moving into physiology, pathogenesis, and then, we discuss the assessment and management options. We present each symptom with its section and the latest research evidence. In the end, we offer a summary of these symptoms and palliative care management approaches in tables to facilitate a quick consult.

Cough Cough is one of the most common complaints that motivates patients to seek medical attention in the United States. It is a natural mechanism that protects the respiratory tract with multiple roles: (1) an important defense mechanism that clears secretions or foreign body from the airways, (2) important factor of infection spreading, (3) a life-saving mechanism when keeping patient consciousness during a potentially lethal arrhythmia or converting back to the normal cardiac rhythm, or (4) one of the most common symptoms for which patients visit a healthcare provider.1 Chronic cough is a distressing symptom present in approximately 37% of patients with advanced cancer. Approximately 38% of these patients will rate this symptom from moderate to

severe.2,3 Persistent and chronic cough can impact the lives of patients and their families. It can cause insomnia, fatigue, vomiting, worsening of pain, and anxiety.

Physiology

Cough can be a voluntary act or a spontaneous reflex. In the latter, it involves a complex reflex arc with receptors, an afferent pathway, a center for process information, the efferent pathway, and this reflex arc ends with effectors.4 These receptors are located in the respiratory tree and lesser extent in other areas such as the esophagus, pericardium, diaphragm, pleura, ear, and paranasal sinuses.4 Sensory nerves from larynx, pharynx, and upper respiratory tract join the vagus nerve, and then enter the nerves system near the respiratory center, terminating in the medullary cough center. The efferent part of the reflex arc is a cholinergic pathway going to the effectors, located on pharyngeal and respiratory muscles.5 The cough reflex act has four phases; the first one is part of afferent, all others are in the efferent pathway. It begins with the receptorial phase when the cough receptors are stimulated and send the signal through the vagus nerve. The next is the inspiratory phase that consists of a contraction of the arytenoid cartilage resulting in the glottis opening with rapid inhalation. This phase will require an average of 50% of the vital capacity with some variation depending on the stimulation. Following is the compressive phase, happening with the closure of the glottis after the contraction of the adductor muscle of the arytenoid cartilage,

433

434 which results in the adduction of the vocal cords. At this time, the abdominal muscles will exhibit a strong contraction, resulting in an intrapulmonary pressure increase and compression of bronchioles and alveolar sacs. The expiratory phase is the final phase, with the action of abductor muscle of arytenoid cartilages, which will cause a sudden opening of epiglottis and vocal cords. It will cause the explosive leakage of air to the outside, with complete exhalation and relaxation of the diaphragm.4 An effective cough is determined by the operational lung volume, which relies on the coordination of respiratory and laryngeal muscles and lung mechanics.6

Pathogenesis

The ineffectiveness of the cough reflex may occur when respiratory and laryngeal muscles are weakened or uncoordinated, decreasing the driving pressure, which will result in a low expiratory volume and flows during cough. Neuromuscular disease such as Parkinson’s disease, quadriplegia, multiple sclerosis, poliomyelitis, motor neuron disease, Guillain–Barre syndrome, Charcot-Marie-Tooth disease, myasthenia, Lambert–Eaton syndrome, Duchenne muscular dystrophy, etc. may have weakness or dysfunction of respiratory muscle.4 The other important factor for an effective cough is the tenacity of the mucus and the effectivity of the mucociliary transport system. The mucus needs to be dispersed into the expiratory gas. The physical properties of the mucous slug also affect cough efficiency. Cough effectiveness is directly proportional to the depth of the mucus and is inversely proportional to mucus tenacity (the product of adhesiveness and cohesiveness).7 The normal function of the mucociliary apparatus is critical in maintaining an effective cough, as it is needed to transport secretions from the periphery to the more proximal airways where they can then be cleared by cough.4 It is also important to understand the innervation related to the cough reflex. The majority of bronchopulmonary vagal afferent nerves are unmyelinated C fibers. 8 These fibers are further differentiated from lung stretch receptors by their sensitivity to several different substances such as bradykinin and activators of the ion channels, transient receptor potential vanilloid 1 (TRPV1) (e.g., capsaicin, protons), and transient receptor potential ankyrin 1 (TRPA1) (e.g., ozone, allyl isothiocyanate). Several other inflammatory mediators found in the environment, for instance, prostaglandin E2, ozone, nicotine, adenosine, and serotonin can play a role as irritants of bronchopulmonary C fibers. 8 Mechanical stimulus can be due to touching or displacement. Because cough can be the result of an affective behavior, the social and psychological issues of the patient must be clarified as a possible cause or effect of coughing.9

Etiologies

The most common etiologies of chronic cough are upper airway cough syndrome (previously postnasal drip), asthma, and gastroesophageal reflux.9,10 Cough may also be a complication of drug therapy, particularly with angiotensin-converting enzyme (ACE) inhibitors. Other less common causes of chronic cough include a number of disorders affecting the airways (non-asthmatic eosinophilic bronchitis, chronic bronchitis, bronchiectasis, neoplasm, foreign body) or the pulmonary parenchyma (interstitial lung disease, lung abscess). A cause is identified in 75–90% of patients with chronic cough.11,12 However, some patients may experience chronic cough

Textbook of Palliative Medicine and Supportive Care of unclear etiology for years, despite extensive evaluation. The etiology of so-called chronic idiopathic cough is unknown; exaggerated cough reflex sensitivity has been suggested. In a palliative care population, there are many malignant and non-malignant diseases related to chronic cough, for instance, cardiopulmonary source (tumor, asthma, infection, pulmonary edema, decompensated congested heart failure (CHF), lymphadenopathy, etc.), esophageal origin (gastroesophageal reflux), medication angiotensin-converting enzyme (ACE) inhibitors, and treatment-related (radiation therapy to the chest).5 Cough caused by cancer can be direct (anatomical) or indirect (as the result of complications). For example, tumor mass obstructing, lymphangitic carcinomatosis, and related to treatment. An indirect cause could lead to infections (such as pneumonia and bronchitis empyema and post obstructive pneumonia, pulmonary embolism, compressive atelectasis, pleural effusion, or effusion of the pericardium in superior vena cava syndrome).13 Fistulas from the esophagus to the respiratory tract in radiation to the chest can cause cough with swallowing in about 50% of the patients with this type of lesions.14 Malignant disease from lungs, pleura, airway, mediastinum, and metastatic to the thorax is likely to cause cough. In patients with advanced head and neck cancer or lung cancer, cough is present in 90% of the patients.15

Assessment

Based on duration, cough can be acute, lasting less than 3 weeks or chronic, lasting from 3–8 weeks or longer. Acute cough is mostly due to infection; chronic cough is more often simultaneously due to more than one condition1 It can also be subdivided in acute, subacute (3–8 weeks), and chronic after 8 weeks. As with other symptoms, a detailed history and physical examination remain the key to diagnosing cough. Starting by trying to distinguish between acute and chronic cough is very important. Several of the algorithms of evaluation and management of cough have been published.13,16 It can be helpful to follow a systematic assessment approach. Identifying important associated symptoms, such as nausea, vomiting, pain (odynophagia, dysphagia), insomnia, weight loss, lack of appetite, dyspnea, and cough characteristics and timing, may help elucidate the diagnosis. However, cough characteristics and timing may not yield significant predictive value in diagnosis.9 Searching for benign causes is still important, even in the cancer population. Questions should begin with the most common causes of cough, regardless of the population. Medication and smoking history should always be part of the encounter. Chest X-ray is the main diagnostic test in evaluating cough when history and physical examination are insufficient. Other tests and imaging should be followed to rule out life-threatening diseases. While looking for underlying causes, the provider should be able to determine the frequency and effectiveness of the cough. In patients with chronic cough, the optimal evaluation should include both subjective and objective methods because they are potential methods to measure different things.9 The patient’s subjective response will be measured by the intensity of the cough. It is recommended to use a reliable quality of life instrument to assess this symptom and treatment. Some assessment tools have been studied to evaluate cough. Leicester Cough Questionnaire (LCQ) and the Cough-Specific Quality-of-Life Questionnaire (CQLQ) were valid and reliable, showing high interclass and test–retest correlations. Unfortunately, these tools are being used

Other Respiratory Symptoms (Cough, Hiccup, and Secretions) inconsistently. Because health-related quality-of-life instruments have been psychometrically tested and visual analog scales have not, the cough-specific health-related quality-of-life instruments are recommended as the primary subjective outcome measure. More studies are needed.17

Management strategies

When planning the management, the treatment of the underlying diseases is recommended as the first step, when possible. Stop offending agents: for example, for patients with ACE inhibitor-induced cough, the medication should be discontinued or replaced with another medication from a different class. The incidence of ACE inhibitor-induced cough has been reported to be in the range of 5–35% among patients treated with these agents. The onset of ACE inhibitor-induced cough ranges from within hours of the first dose to months after the initiation of therapy. Resolution typically occurs within 1–4 weeks after the cessation of therapy, but the cough may linger for up to 3 months. The only uniformly effective treatment for ACE inhibitor-induced cough is the cessation of treatment with the offending agent. Treatment of underlying disease when possible: • Upper airway cough syndrome: antihistaminic and/or decongestants. Cough is caused by the nasal and sinuses secretion dripping down and stimulating the cough reflex. There is no diagnostic test for it. The confirmation will be the response to treatment. Antihistaminic with sedating property has shown good results, but the provider needs to be aware of sedation and anticholinergic effects these medications may have, especially in the elderly population.18,19 • Asthma: bronchodilator and/or steroids. Asthma and its variants will respond to B2 agonist and corticoids with different degrees of relief.20,72 • Gastroesophageal reflux: treat as the general population with proton pump inhibitor.9 • Oncological treatment when appropriate: radiotherapy may improve cough in non-small-cell lung cancer in about 50% of patients.21 Chemotherapy may also provide cough palliation, with studies showing 75% of patients achieving improvement of the cough.22 Other oncology invasive procedures can be helpful to palliative cough.23 If a cancer patient presenting with cough is no longer followed by oncology, it would be important to discuss with the patient’s previous oncologist and consider referring back for evaluation.

Supportive: speech therapy

Chronic cough that does not respond to medical treatment may respond to speech therapy. There is some evidence that speech therapy might improve cough with counseling, breathing exercise, and cough suppression techniques.24 Consultation with physical therapy may also be helpful. Chest physiotherapy teaches techniques to the patient to improve the clearance of the airway, especially in patients with neuromuscular diseases.25

Pharmacological: cough suppressor or protrusive or cough enhancers

Pharmacological treatment of the chronic cough can be either antitussive, to prevent or eliminate cough, or protrusive, to make cough more effective. When the cough serves no useful purposes

435

like cleaning airways, the antitussive is used. When the therapy is directed to the symptom rather than the cause, a nonspecific antitussive is employed. If the cough is performing a helpful function, like with bronchiectasis and cystic fibrosis, for instance, the protrusive can be employed to encourage the cough.9 Using the cough severity to guide the treatment, a mild cough should be first trial non-pharmacological management, such as breathing exercises, education, and counseling.24 A peripheral acting antitussive such as benzoate may be tried if not responsive to non-pharmacological methods. Benzoate has also been used on cancer patients with opioid-resistant cough. Benzonatate presumably anesthetizes stretch receptors in the lungs and pleura. The recommended dose is 100–200 mg three times daily.5 If the latter does not produce an acceptable response, or if the cough is moderate to severe, a centrally acting medication like opioid could be tried. They are the primary medication for moderate-tosevere cough in palliative care. Morphine 5 mg every 4 hours as needed can be started in a naïve person. If the patient is already on opioids for pain, for instance, a slow increase of the dose can be trialed. Although widely used in the past, codeine is metabolized to morphine by a cytochrome P450 enzyme system, and patients who have variants of this enzyme are at risk of experiencing adverse effects of codeine without the benefit.26 Some patients with advanced disease are taking opioids for pain when they present cough. The dose might be adjusted to try to control the cough, but there is no evidence supporting a second opioid added for the chronic cough. Hydrocodone, a codeine metabolite, can be an alternative for morphine. A study showed that hydrocodone was well-tolerated in advanced cancer patients, who presented a greater than 50% improvement on their cough using hydrocodone 10 mg a day.27 Patients with moderate-to-severe cough unable to take opioid, gamma-aminobutyric acid analogs, such as gabapentin and pregabalin, are recommended. The evidence for these medications was from a study conducted on a general palliative care population. The initiation dose should be low (300 mg/day for gabapentin and 75 mg/day for pregabalin) and carefully titrated watching for sedation and dizziness. Other side effects such as nausea, weakness, tremor, peripheral edema, and others can also be observed.28 A randomized trial showed improvement of the cough in patients with idiopathic pulmonary fibrosis (IPF). Thalidomide is an anti-inflammatory medication with the antiemetic and immunomodulatory effect that can be potentially helpful for a cough from IPF.29 Guaifenesin is an expectorant shown in a systematic review, to have very limited benefit in reducing cough intensity and no benefit from mucolytics. 30 It is important to remember that dehydrated patients may need additional fluid to be able to effectively use an expectorant. An efficient cough is also required, which is not always possible, for instance, in patients with weak muscles due to cachexia or diseases causing muscular weakness. Mucolytics are expectorants, which means they facilitate the sputum elimination by breaking the polymer network of the mucin or the DNA-actin. This way is helping with the mucus clearance. 31 Carbocysteine is a type of mucolytic with some benefit for patients with cough due to bronchitis but no benefit for advanced cancer patients. Another type of mucolytic is the recombinant DNase, which is not recommended by the American College of

Textbook of Palliative Medicine and Supportive Care

436 Chest Physicians in their 2006 guidelines for use in patients with cystic fibrosis. 32 Dextromethorphan, an antitussive antagonist of the N-methylD-aspartate receptor (found in most over-the-counter cough syrups), is not indicated for the treatment of chronic cough due to limited evidence of efficacy. 33 Lidocaine or bupivacaine, both local anesthetics, have been studied, but they have an unpleasant taste, risk of aspiration, risk of bronchospasm, short duration of action and frequent tachyphylaxis. 34,35 Several other therapies have been tried but with uncertain benefit or evidence to support the use.

Hiccup Hiccups, or singultus (medical term), are caused by synchronous, repetitive spasm (myoclonic jerks) of one of both hemidiaphragm and inspiratory intercostal muscle with the inhibition of the expiratory component of the latter (intercostal muscle). As soon as the contractions start, a sudden closure of the glottis produces the characteristic sound and sensation.40–43 Soon after the activation of the hiccup neural pathway, the recurrent laryngeal nerve stimulates the glottis closure, which gives the characteristic “hic” sound. It is more frequent in males than females and can occur every 2–60 minutes.44 Most of the hiccups are benign, and resolves in minutes to hours,45 but it can last longer, being described as persistent when lasting more than 48 hours or intractable, after 1 month. The incidence of this symptom in advance cancer patient is about 1–9%.45–47 This bothersome symptom can affect the quality of life the patient with serious illness. It can cause sleeping problems, decrease of oral intake, anxiety, worsen pain, fatigue, depression, etc.

Physiology

The function of hiccups in adults is still unknown. Hiccups are observed in fetuses after the 8 weeks of gestation also seen in neonates, decreasing frequency over time. Some postulated theories include protection of the respiratory tract against esophageal gastric reflux.41,44 A recent explanation by Howes in 2012 suggests that hiccups may have evolved along with other reflexes developed in mammals that allow them to coordinate suckling milk and breathing.48 Knowing the neural pathway that controls the reflex, or reflex arc, involved in the hiccup may help us to understand the possible causes. The afferent component of the arc reflex consists of the vagus and phrenic nerves (C2–C4), the pharyngeal branch of the glossopharyngeal nerve and sympathetic fibers from T6–12. The central mediation is thought to be located on the hypothalamus, brainstem near the respiratory center, medial and dorsal medullary nuclei, and cervical spinal cord somewhere between C3 and C5 segment.40,41,44,45 The efferent pathway of the arc is given by the phrenic and intercostal nerves.44

Pathophysiology

Like the hiccup function, the pathophysiology of chronic hiccup is poorly understood. There are more than 110 diseases and several medications that may be associated with persistent intractable hiccups, with disturbance of one or more components of the hiccup arc reflex (Table 45.1).41 The leading causes of hiccups can be: 1. Pathology of the gastrointestinal tract or thoracic structures: They are related to the anatomical location of the phrenic and vagus nerves. 2. Conditions involving the central nervous system (CNS) 3. Medication or metabolic causes

BOX 45.1  APPROACH TO MANAGING COUGH IN THE PALLIATIVE CARE POPULATION Assess with detailed history, examination, and when appropriate, complementary tests, which may be chest radiograph and spirometry. Stop ACE inhibitors. Consider smoking cessation counseling based on prognosis. It can be stressful for a long life smoker and may not add any meaningful result. Consider benign causes of cough, such as gastroesophageal reflux, upper respiratory infection, asthma, and treat appropriately: • Upper airway cough syndrome: antihistamines and/or decongestants • Asthma: most respond to inhaled bronchodilators and inhaled corticosteroids • Gastroesophageal reflux disease: prokinetics, antacids, and proton pump inhibitors/H2 antagonists36 Consider disease-directed treatment, such as chemotherapy, radiotherapy, etc. Commence other treatment protocols from Association for Palliative Medicine task group70 (reproduced with permission): • Inhaled sodium cromoglycate: There are only one small randomized controlled trial from 1996 for patent with lung cancer and chronic cough. 37 The main limitation is the need to use an inhaler device. New formulation of inhaled sodium cromoglycate has been studied in an RCT for idiopathic pulmonary fibrosis. 38 • Prescribe an opioid: a. Morphine: 5 mg every 4 hours PRN b. Gabapentoid: patient unable to take opioids, gabapentin or pregabalin should be tried. 39 If the patient has a very poor prognosis, consider cough suppression with opioid alone.

Other Respiratory Symptoms (Cough, Hiccup, and Secretions)

437

TABLE 45.1  Etiology of Chronic Hiccup (see further reference [41]) Peripheral Causes (Esophageal Disorders) Gastritis, gastric ulcer Gastric distension, foreign body, gastric bleeding Bowel obstruction Hepatic and biliary disorders Intestinal disease Pleural effusion Cardiac infarction, aneurysm, etc. Mediastinal disease Diaphragmatic hernia Post operatory

Central Causes

Metabolic/Toxic Causes

Psychiatric Causes

Brainstem infarction (in particular lateral medullary infarction) Demyelinating conditions: multiple sclerosis (MS), neuromyelitis optica (NMO) Neoplasia Cerebrovascular diseases Infections Epilepsy Sarcoidosis

Corticosteroids

Reaction to grief

Electrolyte imbalance

Personality disorder

Uremia Sepsis Renal failure Drugs Medication

malingering Anorexia nervosa Hysteria enuresis

Parkinson’s disease Tuberculoma Neurosyphilis

Diabetes ENT infection Goiter

Management strategies

After considering the possible etiology (Table 45.1), the first step on management should be assessed for reversible causes.41 Nevertheless, sometimes the cause cannot be found. The next is the assessment and documentation of how the symptom is impacting the patient and his/her family, and consideration of treatment. The evidence on hiccup treatment is sparse and mostly based on case reports, probably because it is rare and self-limiting.

Nonpharmacological strategies

Launois et al. have a list of possible nonpharmacological management for the hiccup.40 Finally, treatment with medication might need to be tried (Table 45.2). In 1932, Mayo stated that the knowledge about hiccups was inversely proportional to the available treatments. In patients with advanced cancer, the most common causes are gastroesophageal reflux, irritation of the diaphragm all the phrenic nerve, gastric distention, CNS tumors in toxic, metabolic, infection, and iatrogenic.47 While there are many “traditional” remedies for acute bouts of hiccups, they often involve some form of pharyngeal stimulation or diaphragmatic splinting, for example, a cold key on the back of the neck or drinking water from the wrong side of a cup, these are unlikely to be successful for the intractable hiccup.41 Nonpharmacological interventions that used with success include phrenic nerve stimulation 52 and phrenic nerve block. 53 Acupuncture at pressure points has also proven successful. 54

Secretions The accumulation of secretions within the respiratory tract of a patient around the later stages of a terminal disease can become a burden for the patient and the caregiver(s); it is also known as “death rattle” due to its association with imminent death (16–60 hours before death).55–58 In this chapter, we will approach this subject based on the following classifications/terminology: predominantly salivary secretions (type I), predominantly bronchial secretions (type II); as well as terms such as death rattle versus pseudo death rattle.

Classification: The respiratory airway is a complex system, hence the necessity to understand a symptom so ubiquitous toward end of life has been a challenge within the medical community, and the following two classifications; even though TABLE 45.2  Medications Used to Treat Hiccup (see further reference [41]) Drug

Evidence

Gabapentin: Starting Reported to be effective dose 100–300 mg in several case series50 TID49 Baclofen: 5–60 mg Case series and a small TID PO, increasing randomized crossover dose by 5 mg every 3 trial days until effective or maximum dose reached Metoclopramide: 10 Used with success mg IV then 10–40 in a case series mg PO daily of 14 patients with a variety of conditions51 Haloperidol: 5–10 mg Licensed for use in daily PO intractable hiccup but evidence for efficacy in case reports only. Commonly used in palliative care Chlorpromazine: Licensed for use in 25–50 mg IV in intractable hiccup, 30–60 minutes then, small evidence for 50–60 mg daily PO efficacy Nifedipine: 10–80 Four patients in a series mg/day (orally) of seven gained complete relief and a fifth felt improvement with nifedipine

Common Side Effects Drowsiness, sedation, ataxia, and anxiety Sedation, drowsiness, careful with renal impairment

Few side effects and not a sedative

Extrapyramidal side effects and sedation (usually at higher doses)

Hypotension, dizziness, and sedation Headache, vasodilatation, and peripheral edema

Textbook of Palliative Medicine and Supportive Care

438 they share similarities, cite important factors that help us understand the physiopathological basis of the symptom in question, such as level of consciousness and other types of secretions, besides the ones innate to the respiratory tract: 1. Noisy respiratory secretions (Bennet):57 • Type I due to predominantly salivary secretions: accumulation of upper respiratory tract secretions secondary to an impaired swallowing reflex or inability to swallow. • Type II due to accumulated bronchial secretions: secondary to inability to satisfactorily clear the lower respiratory tract, due to weakness or absence of cough reflex. 2. Death rattle (Wildiers and Menten): • Type 1 real death rattle: accumulation of respiratory secretions, associated mainly to a decline in the swallowing reflex or consciousness, due to nonpathological secretions. • Type 2 pseudo-death rattle: bronchial or pathological pulmonary secretions (e.g., pulmonary effusion secondary to congestive heart failure or pulmonary edema). This specific category is likely to not respond well to ant muscarinic regimens. 55

Physiopathology of increased respiratory secretions including bronchorrhea

It is defined as the sound caused by the oscillatory movement of the upper respiratory airway secretions along with the expiratory and inspiratory phases of respiration. As mentioned above, different authors tend to agree that the presence or combination of the accumulation of upper respiratory tract secretions in the bronchi and oropharynx due to loss or decreased cough or swallow reflexes as well as increased M2 and M3 muscarinic acetylcholine receptors leading to partial obstruction of the airways. 59 The airflow through the secretions produces the characteristic “death rattle,” which is the result of airway resistance and respiratory rate; decreased expiratory flow of air subsequently augments airway resistance causing an audible noise. This mechanism is considered hypothetical at the moment and more research in this regard is recommended by different authors.60

Bronchorrhea, also a common cause of increased respiratory secretions, has a similar symptomatic and broad differential diagnosis to noisy upper respiratory secretions. Defined as the production of more than 100 ml of sputum per day, can be found in chronic obstructive pulmonary disease, pancreatic cancer, colorectal carcinoma, cervical adenocarcinoma, as well as lung cancer (most commonly broncoalveolar carcinoma [BAC]).60–63 When it comes to BAC, the airway mucin gene MUSC5AC is highly expressed. Epidermal growth factor (EGF) ligands also stimulate mucin production, explaining why EGFR-TK inhibitors have reported rapid and complete resolution of bronchorrhea.64–67

Management Nonpharmacological approach

Repositioning the patient in a lateral position, and a more upright fashion as tolerated, while trying to achieve the maximum level of comfort with the intervention, providing scheduled mouth care, and keeping the amount of parenteral fluids to the minimum. The use of suctioning is appropriate only if the secretions are easy to reach, as it has been associated with pain and distress. Also, the most important aspect in the management of secretions toward end of life is to provide reassurance that the sounds are not distressing for the patient and that their pharmacological treatment or lack of is not contributing to his/her life expectancy. Some healthcare systems recur to educational pamphlets to support this intervention.

Pharmacological approach

The antisecretory properties of anticholinergic medications are related to their antagonism with muscarinic receptors. The most common drugs used for the management of terminal secretions are the tertiary amines (e.g., hyoscine, atropine, and hyoscine hydrobromide) and the quaternary amines (e.g., glycopyrronium bromide [glycopyrrolate]) and hyoscine butylbromide). The smaller size of the tertiary amines make them easier to the medication to cross the brain–blood barrier promoting agitation, sedation, and confusion, whereas both quaternary and tertiary amines can cause more peripheral effects such as rhythm disturbances, and urinary retention (see Table 45.3). 68 Special medical management considerations: bronchorrhea secondary to malignancy (specifically BAC) responds to EGFR-TK inhibitors such as gefitinib and erlotinib, as well as the use of nebulized indomethacin for malignant and nonmalignant bronchorrhea (eg, panbronchiolitis).69

TABLE 45.3  Anticholinergic medications used in Death Rattle (see further references [67,69,70]) Medication

Recommended starting dose (adult)

Side effects

comments

Scopolamine base transdermal (hyoscine)

1 patch every 72h May use 1-3 patches

Dry mouth, drowsiness, dizziness, confusion

Glycopyrrolate

0.2 mg SC every 4-6 hours as needed. 1 mg PO, then 1-2 mg every 4-6 Sublingual (1% ophthalmic solution): Initial: 1 to 2 drops every 2 to 4 hours; usual dose range: 2 to 4 drops every 2 to 4 hours) 0.125 mg SC/SL then 0.125-0.25 mg every 4-6h

Severe xerostomia, decrease absorption of other SL medication Delirium, flushing, tachycardia hypotension.

Known in the United States as Scopolamine, generic name is hyoscine. The high volume for PO route maybe cause difficulty to administer There is no sufficient evidence to support use as first line treatment, please consider if no alternative available.

Atropine

Hyoscyamine (Levsin)

Dry mouth, drowsiness, dizziness, constipation

Other Respiratory Symptoms (Cough, Hiccup, and Secretions) KEY LEARNING POINTS COUGH • Chronic cough can be very stressful for patients and their families. • Careful assessment to identify the cause is essential, when possible. • Remember benign and common causes of cough. • For mild cough, start with nonpharmacological treatment. • Antitussive agents are available and the reason for the treatment choice should be weighed carefully with patient prognosis and medications side effects. • Opioids are the most widely available antitussive therapy, especially for cancer patients, but may not be appropriate in early disease. HICCUP • Assessment for the underlying cause and remove, when possible. Check medication profile and electrolytes (see Box 45.1). • Also evaluate for gastric distension and reflux, and start prokinetics and proton pump inhibitors, if indicated. Be aware of medication side effects, for instance, metoclopramide, a good prokinetic, may not be used in malignant bowel obstruction. • No response to the aforementioned, gabapentin is becoming the recommended second-line medication for intractable hiccups. SECRETIONS • Noisy respiratory secretions in the setting of advanced disease are a strong predictor of imminent death. • Identify differential, as increased secretions in the end of life setting may be related to other causes, such as infections, gastrointestinal diseases, or extra pulmonary tumors, that might not respond to the most common interventions. • Nonpharmacological interventions such as repositioning and frequent mouth care should be the first attempted. • Consider discontinuation or decrease of intravenous fluids, as they might worsen secretions. • No antisecretory medication is better compared to another, also data show that pharmacological management might not be useful or necessary; this topic is in need of further research.

References



1. Irwin RS, Boulet LP, Cloutier MM, Fuller R, Gold PM, Hoffstein V, et al. Managing cough as a defense mechanism and as a symptom. A consensus panel report of the American College of Chest Physicians. Chest 1998; 133S–181S. 2. Donnelly S. The symptoms of advanced cancer. Semin Oncol 1995; 67–72.

BK-TandF-BRUERA_9780367642037-200160-Chp45.indd 439

439



3. Donnelly DWS. The symptoms of advanced cancer: identification of clinical priorities by assessment of prevalence and severity. J Pallit Care 1995; 27–32. 4. Andrani Francesco, et al. Cough, a vital reflex. Mechanisms, determinants and measurements. Acta Biomed 2018; 477–480. 5. Doona Marie, et al. Benzoate for opioid-resistant cough in advanced cancer. Palliative Medicine 1998; 55–58. 6. Smith JA, et al. Chest wall dynamics during voluntary and induced cough in health volunteers. J Physiol 2012; 563–574. 7. McCool FD. Global Physiology and Pathophysiology of Cough: ACCP Evidence-Based Clinical Practice Guidelines Supplement Diagnosis and Management of Cough: ACCP Evidence-Based Clinical Practice Guidelines|HYPERLINK “https://journal.chestnet.org/issue/S00123692(15)X6430-0” Volume 129, ISSUE 1, SUPPLEMENT, 48S-53S, January 01, 2006. 8. Brendan P, et al. Anatomy and Neurophysiology of Cough. Chest 2014; 1633–1648. 9. Irwin RS, et al. Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest 2006; 129. 10. Iyer VN, et al. Chronic cough: an update, Mayo Clin Proc 2013; 1115–1126. 11. Irwin RS, et al. Chronic cough. The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Am Rev Respir Dis 1990; 141(3):640. 12. Kastelik JA, et al. Investigation and management of chronic cough using a probability-based algorithm. Eur Respir J 2005; 25(2):235. 13. Bassam Estfan, et al. Management of cough in advanced cancer. Supportive Oncology 2004; 523–527. 14. Burt M, et al. Malignant esophageal respiratory fistula: management options and survival. Ann Thorac Surgery 1991; 1222–1228. 15. Iyer S, et al. Symptom burden and quality of life in advanced non-small cell lung cancer patients in France and Germany. Lung cancer 2013; 288–293. 16. Dubois M. James, et al. An algorithmic approach to chronic cough. An Intern Med 1993; 119: 977–983. 17. Coeytaux R, et al. Evaluating cough assessment tools: a systematic review. Chest 2013; 1819–1826. 18. Irwin SI, et al. Managing cough as a defence mechanism and as a symptom: a consensus panel report of the American College of Chest Physicians. Chest 1998. 19. Curley FJ, et al. Cough and the common cold. Am Rev Respir Dis 1988. 20. de Benedictis FM, et al. Methacholine inhalational challenge in the evaluation of chronic cough in children. J Asthma 1986. 21. Langendijk JA, et al. Quality of life after palliative radiotherapy in nonsmall cell lung cancer: a prospective study. Int J Radiat Oncol Biol Phys 2000; 149–155. 22. Thatcher N, et al. Gemcitabine: symptomatic benefit in advanced nonsmall cell lung cancer. Semin Oncol 1997; S8-6–S8-12. 23. Paul AK. Chronic cough due to lung tumors: ACCP evidence-based clinical practice guidelines. Chest 2006; 147S–153S. 24. Gibson PG, et al. Speech patheology for chronic cough: a new approach. Pulm Pharmacol 2009; 159–162. 25. Bento J, et al. Indications and compliance of home mechanical insufflation-exsufflation in patients with neuromuscular diseases. Arch Bronconeumol 2010. 26. Smith HS, Opioid metabolism. Mayo Clin Proc 2009; 613–624. 27. Homsi J, et al. A phase II study of hydro-codone for cough in advanced cancer. Am J Hosp Palliat Care, 2002. 28. Gibson P, et al. Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest 2016; 27–44. 29. Horton MR, et al. Thalidomide for the treatment of cough in idiopathic pulmonary fibrosis: a randomized trial. Ann Intern Med 2012. 30. Yancy WS Jr, et al. Efficacy and tolerability of treatments for chronic cough: a systematic review and meta-analysis. Chest 2013; 1827. 31. Rubin BK. The pharmacologic approach to airway clearance: mucoactive agents. Respir Care 2002. 32. Bolser DC. Cough suppressant and pharmacologic protussive therapy: ACCP evidence-based clinical practice guidelines. Chest 2006. 33. Matthys H, et al. Dextromethorphan and codeine: objective assessment of antitussive activity in patients with chronic cough. J Int Med Res 1983; 92. 34. Truesdale K, et al. Nebulized lidocaine in the treatment of intractable cough. Am J Hosp Palliat Care 2013; 587.

24/06/21 11:48 AM

440 35. Slaton RM, et al. Evidence for therapeutic uses of nebulized lidocaine in the treatment of intractable cough and asthma. Ann Pharmacother 2013; 578–585. 36. BeeWee A, et al. Management of chronic cough in patients receiving palliative care: review of evidence and recommendations by a task group of the Association for Palliative Medicine of Great Britain and Ireland. Palliat Med 2012; 780–787. 37. Moroni GM, et al. Inhaled sodium cromoglycate to treat cough in advanced lung cancer patients. Br J Cancer 1996; 309–311. 38. Birring SS, et al. A novel formulation of inhaled soudium cromoglycate (PA101) in idiophatic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial. Lancet Respir Med 2017. 39. Launois S, et al. Hiccups in adults: an overview. Eur Resp J 1993; 563–575. 40. Walker P, et al. Baclofen, a treatment for chronic hiccup. J Pain Symptom Manage 1998; 125–132. 41. Krakauer EL, et al. Case records of the Massachusetts general Hospital: weekly clinical pathological exercise. Case 6-2005. A 58-year-old male with esophageal cancer in nausea vomiting, and intractable hiccups. N Englk J Med 2005; 817–825. 42. Moretti R, et al. Gabapentin as a drug therapy of intractable hiccup because of vascular lesion: a 3 year follow-up. Neurologist 2004; 102–106. 43. Davis J. An experimental study of the hiccup. Brain 1970; 851–872. 44. Marinella M. Diagnosis and management of hiccups in the patient with advanced cancer. J Support Oncol 2009; 52–54. 45. Porzio G, Aielli F, Verna L, Aloisi P, Galletti B, Ficorella C. Gabapentin in the treatment of hiccups in patients with advanced cancer of 5 years experience. Clin Neuropharma 2010; 179–180. 46. Riapmonti C, et al. Respiratory problems in advanced cancer. Support Care Center 2002; 204–216. 47. Howes D. A recent explanation by Howes in 2012 suggests that hiccups may have evolved along with other reflexes developed in mammals that allow them to coordinate suckling milk and breathing. BioEssays 2012; 451–453. 48. Thompson D. Gabapentin therapy of hiccups. Ann Pharmacother 2013; 897–903. 49. Tegeler ML. Baumrucker SJ. Gabapentin for intractable hiccups in palliative care. Am J Hosp Palliat Care 2008; 52–54. 50. Madanagopolan N. Metoclopramide in hiccup. Curr Med Res Opin 1975; 371–374. 51. Fodstad H. et al. Phrenic nerve stimulation (diaphragm pacing) in chronic singultus. Neurochirurgia (Stuttg) 1984; 115–116. 52. Kuusniem K. Phrenic nerve block with ultrasound-guidance for treatment of hiccups: a case report. J Med Case Reports 2011;5:493.

Textbook of Palliative Medicine and Supportive Care 53. Ge A. Acupuncture treatment for persistent hiccups in patients with cancer. J Altern Complement Med 2010; 811–816. 54. Wildiers H, et al. Death rattle: prevalence, prevention and treatment. J Pain Symptom Manage 2002; 310–317. 55. Ellershaw JE, et al. Dehydration and the dying patient. J Pain Symptom Manage 1995; 192–197. 56. Bennett M. Death rattle: an audit of hyoscine (scopolamine) use and review of management. J Pain Symptom Manage 1996; 229–233. 57. Morita T, et al. Risk factors for death rattle in terminally ill cancer patients: a prospective exploratory study. Palliat Med 2000; 19–23. 58. Clark MBK. Noisy respiratory secretions at the end of life. Curr Opin Support Palliat Care 2009; 120–124. 59. Lembo T, et al. A case of pancreatic carcinoma causing massive bronchial fluid production and electrolyte abnormalities. Chest 1995; 1161–1163. 60. Wee RHB. Interventions for noisy breathing in patients near to death. Cochrane Database Syst Rev 2008; 2008(1):CD005177. 61. Shimura S, Takishima T. Bronchorrhea from diffuse, lymphangitic metastasis of colon carcinoma to the lung. Chest 1994; 308–310. 62. Epaulard O, et al. Bronchorrhea revealing cervix adenocarcinoma metastatic to the lung. Lung Cancer 2001; 331–334. 63. Kitazaki T, et al. Novel effects of gefitinib on mucin production in bronchioloalveolar carcinoma; two case reports. Lung Cancer 2005; 125–128. 64. Popat N, et al. Severe bronchorrhea in a patient with bronchioloalveolar carcinoma. Chest 2012;141:513–514. 65. Milton D, et al. Prompt control of bronchorrhea in patients with bronchioloalveolar carcinoma treated with gefitinib. Support Care Cancer 2005; 70–72. 66. Thotathil Z. Erlotinib effective against refractory bronchorrhea from advanced non small cell lung cancer. J Thoracic Oncol 2007; 881–882. 67. Prommer E. Anticholinergics in palliative medicine: an update. Am J Hosp Palliat Care 2013;30(5):490–498. 68. Homma S, et al. Successful treatment of refractory bronchorrhea by inhaled indomethacin in two patients with bronchioloalveolar carcinoma. Chest 1999;115:1465–1468. 69. Hugel H, et al. Respiratory tract secretions in the dying patient: a comparison between glycopyrronium and hyoscine hydrobromide. J Palliat Med 2006; 279. 70. Protus BM, et al. Evaluation of atropine 1% ophthalmic solution administered sublingually for the management of terminal respiratory secretions. Am J Hosp Palliat Care 2013; 388–392. 71. Bennett M, et al. Using anti-muscarinic drugs in the management of death rattle: evidence-based guidelines for palliative care. Palliat Med 2002;369. 72. Cheriyan S, et al. Outcome of cough variant asthma treated with inhaled steroids. Ann Allergy 1994;73(6):478–480.

46

DEPRESSION/ANXIETY

Tatsuo Akechi

Contents Introduction....................................................................................................................................................................................................................... 441 Prevalence, effect, and assessment of depression....................................................................................................................................................... 441 General medical patients................................................................................................................................................................................................. 441 Cancer: A paradigm for serious chronic illness.......................................................................................................................................................... 442 Challenges in the assessment of depression in cancer patients............................................................................................................................... 442 Treatment of depression.................................................................................................................................................................................................. 443 General medical patients........................................................................................................................................................................................... 443 Cancer patients............................................................................................................................................................................................................ 444 Choosing patients for treatment........................................................................................................................................................................ 444 Treatment options................................................................................................................................................................................................. 445 Randomized trials................................................................................................................................................................................................. 446 Unique issues in end-of-life care........................................................................................................................................................................ 447 Managing anxiety.................................................................................................................................................................................................. 448 Conclusion.......................................................................................................................................................................................................................... 450 References........................................................................................................................................................................................................................... 450

Introduction The length and quality of life of patients with serious chronic illnesses, such as cancer, are influenced not only by their malignant disease but also by comorbid medical and psychological conditions, such as depression and anxiety. For example, previous study investigating the effect of cancer diagnosis demonstrates that cancer diagnosis can produce acute stress associated with higher suicide rate and cardiovascular death especially in the first weeks, and these effects prolong at least 6 months after diagnosis.1 The complexity of care for these patients makes it particularly challenging to ascertain whether a patient is struggling with serious depression. Moreover, compared with the statistics on the overall population of general medical patients, there are fewer data to draw upon that would help clinicians determine what treatments are effective for depression in the advanced cancer or other advanced disease settings. This chapter will examine the assessment and treatment of depression and anxiety in general medical patients and in patients with cancer.

Prevalence, effect, and assessment of depression General medical patients

To better understand how to recognize and treat depression in patients with cancer, it is useful to first review the existing paradigms for finding and treating depression in the primary care setting. Depression is estimated to affect 121 million people worldwide, and 5.8% of men and 9.5% of women experience a depressive episode every year.2 The prevalence of major depression in primary care setting is 5–9%. 3 Depression is two to three times more common in patients with chronic medical illnesses.4

Physicians recognize psychological distress in about two-thirds of the general medical patient population and prescribe antidepressants for about half of those distressed patients. 5 Major depressive disorders can cause severe decrement in health.6 Depressive symptoms are associated with a higher-than-normal risk of physical decline and with long-term mortality in older adults;7,8 depression is also a risk factor for diabetes, coronary heart disease, and stroke,4,9 and it is associated with a greater use of health-care services.10 In addition, comorbid depression is associated with increased medical symptom burden, functional impairment, medical costs, poor adherence to self-care regimens, and increased risk of morbidity and mortality in patients with chronic medical disorders.4 The standard paradigm for identifying depression in the primary care setting is to view depression as a syndromal diagnosis made on the basis of patient history and the exclusion of competing diagnoses, using criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5.11 Major depression is defined as depressed mood or anhedonia (loss of interest in pleasurable activities) that lasts for at least 2 weeks plus the presence of three or four other specific psychological or somatic symptoms. If two to four rather than more than five symptoms are present, then the patient may be defined as having minor depression, an other specified diagnosis in the DSM-IV-TR,12 while this criteria is not mentioned in DSM-5. The U.S. Preventive Services Task Force recommends depression screening in clinical practices that have systems in place to ensure accurate diagnosis and effective treatment and follow-up. 3 Unfortunately, such systems are not available in most primary care practices or oncology/hematology subspecialty practices. The decision regarding whether to treat a patient for depression in the primary care setting is not always made on the basis of rigid diagnostic criteria; it often arises from clinical judgment

441

442 about the severity and duration of symptoms and the likelihood of spontaneous recovery within a supportive environment.13 Between 50 and 60% of cases of major depression respond to initial therapy with antidepressants, psychotherapy, or both.13 Although previous study suggests that minor depression has similar response rates to antidepressants or psychotherapy over placebo, recent meta-analysis investigating the effect of antidepressants on minor depression reveals that there is unlikely to be a clinically important advantage for antidepressants.14 Depression may be treated by a patient’s primary care physician, who can use either a collaborative care model that involves augmentation with one or more visits with a mental health-care provider or a stepped-care approach in which patients whose depression does not respond to initial therapy are referred to a mental health-care provider.15 Depression is the 15th leading cause of disability adjusted life years (DALY) in the world according to the most recent estimates.16 Moreover, this burden is expected to rise in the next 10 years. Thus, depression is now recognized as an important cause of long-term disability and dependency.17 It not only produces serious suffering,18 but also worsens quality of life,19,20 reduces adherence to medical treatments,21,22 can lead to suicide,23 is a psychological burden on the family,24,25 and prolongs hospitalization.26 Fortunately, depression is treatable, and thus, costeffective interventions to improve the detection and treatment of depression are important.

Cancer: A paradigm for serious chronic illness

Mitchell et al. reported findings with regard to meta-analysis including 70 studies with 10,071 individuals across 14 countries in oncological and hematological settings, and they demonstrated that prevalence of major depression was 14.9% (95% confidence interval: 12.2–17.7), minor depression 19.2% (9.1–31.9), adjustment disorders 19.4% (14.5–24.8), and dysthymia 2.7% (1.7–4.0).27 In palliative care settings studies including 24 studies with 4,007 individuals across seven countries, they also found that prevalence of major depression was 14.3% (11.1–17.9), minor depression 9.6% (3.6–18.1), and adjustment disorders 15.4% (10.1–21.6).27 Thus, the best estimate is that major depression has a point prevalence of 10–20% in cancer patients, irrespective of cancer stage. This prevalence is similar to that seen in patients with other chronic medical illnesses. Although some comprehensive cancer centers have adequate behavioral health-care resources, most hospitals and oncology clinics rely on general psychiatry and psychology staff and resources. Limited funding for mental health-care resources is a serious problem, and care is often fragmented among private practitioners, for-profit and not-for-profit clinics, and community mental health centers.28 This is a report by American psycho-oncologist: the situations, however, are similar or even much worse in other countries including Asian nations.29 Limited resources in standard areas of care also affect the research environment. Even though it may be ideal to use a two-stage strategy that combines an assessment of severity with an assessment of the number of depressive symptoms, it is far more common to perform only a short instrument to assess symptom severity in the typical environment where time and resources are limited. Numerous symptom scales have been used to assess depression symptom severity at a specific time or over time. The most commonly reported instruments are shown in Box 46.1.

Textbook of Palliative Medicine and Supportive Care BOX 46.1  SELF-REPORT MEASURES USED TO ASSESS DEPRESSIVE SYMPTOMS IN CANCER PATIENTS • Hospital and Anxiety Depression Scale (HADS) • Zung Self-Rating Depression Scale (ZSRDS) • Brief version, Zung Self-Rating Depression Scale (BZSDRS) • Beck Depression Inventory (BDI) • Beck Depression Inventory, Short Form (BDI-SF) • Center for Epidemiologic Studies Depression Scale (CES-D) • Brief Symptom Inventory (BSI) • Rotterdam Symptom Checklist (RSCL) • Geriatric Depression Scale (GDS) • Profile of Mood States (POMS) • Profile of Mood States, Short Form (POMS-SF) • General Health Questionnaire (GHQ) • Edinburg Postnatal Depression Scale (EPD)

Challenges in the assessment of depression in cancer patients

Patients, family members, and health-care providers sometimes believe that feeling down, depressed, or hopeless is perfectly natural and understandable in the context of living with cancer. Clinicians are encouraged to acknowledge the difficulty and disappointment that often confront cancer patients and their families, 30 but depression and hopelessness are not accepted by expert clinicians as an inevitable consequence of living with cancer. In addition, cancer patients often have physical symptoms of depression (so-called neurovegetative symptoms), such as sleep disturbance, psychomotor retardation, appetite disturbance, poor concentration, and low energy, as a consequence of their underlying illness or treatment, thus confounding the diagnosis of depression. Indeed, depression is just one of the many symptoms that clinicians must recognize and manage in inpatients and outpatients with cancer. For example, roughly two-thirds of outpatients with cancer experience pain, and more than a third report significant disruption in daily function associated with the pain. 31 For patients with advanced cancer, fatigue, pain, lack of energy, weakness, and appetite loss are the most frequent symptoms, occurring in more than 50% of patients. 32 It may be that the problem of concurrent symptoms is the most relevant difference between depression in the general medical setting and in the cancer care setting. Relatively few cancer care providers have sufficient knowledge and skills to assess and treat depression in this context, and it is often difficult to decide whether the depressive symptoms should be the primary focus of treatment or whether these symptoms may improve if other problems are better managed. The large number of instruments and techniques used to assess cancer patients for depression does not seem to translate into an overall improvement in the assessment of depression in this complex population of patients. A “Don’t ask, don’t tell” policy appears to be in place all too often.28 A list of 11 of the most significant barriers to the assessment of depression is presented in Box 46.2. With a growing appreciation for the need to simplify the starting point in assessing depression, the use of 1- or 2-item screening techniques has become popular (Box 46.3). Chochinov et al. 33

Depression/Anxiety BOX 46.2  COMMON BARRIERS TO THE ASSESSMENT OF DEPRESSION IN PATIENTS WITH CANCER • Overlap of physical symptoms of depression and symptoms of cancer or its treatment • Clinician’s underrecognition of hopelessness, feelings of worthlessness, or suicidal ideation • Clinician’s uncertainty about how to interpret screening instrument cut-offs • Lack of clinician’s routine discussion with patients and family about low mood, not like pain assessment • Limited understanding by cancer professionals regarding which patients are most at risk • Time constraints in busy oncology settings • Cost constraints limiting access to professionals with behavioral health training • Few mental health programs and specialists connecting with oncology • Poor continuity of care over the trajectory of illness • Stigma concerning mental illness or weakness perceived by the patient/family • Patient/family fear that revealing depression will lead to undertreatment of the cancer

have studied a simple 1-item survey and found it to have acceptable psychometric properties in patients with advanced cancer. Akizuki et al. 34 have described a clever 1-item survey that was tested in 275 patients and was found to correlate well with both the Hospital Anxiety and Depression Scale (HADS) (r = 0.66) and the Distress Thermometer (r = 0.71). At optimal cut-offs, the sensitivity (80%) and specificity (61%) for diagnosing major depression and adjustment disorders for this 1-item survey were similar to those of the HADS and Distress Thermometer. Finally, Whooley et al. 35 have used 2-item screening in medically ill patients who did not

BOX 46.3  EXAMPLES OF 1- OR 2-QUESTION SCREENING METHODS FOR DEPRESSION One question • “Are you depressed?” (Chochinov et al. 33) • “Please grade your mood during the past week by assigning it a score from 0 to 100, with a score of 100 representing your usual relaxed mood. A score of 60 is considered a passing grade.” (Akizuki et al. 34) Two questions • “Have you often been bothered by feeling down, depressed, or hopeless?”35 • “Have you often been bothered by having a lack of interest or pleasure in doing things?” (Whooley et al. 35)

443 have cancer with an approach that targeted depressed mood and anhedonia. This 2-item screening approach has been endorsed by the U.S. Preventive Health Task Force for use in primary care settings. 3,36 Recent meta-analysis investigating the screening performance of one or two simple verbal questions in the detection of depression in cancer settings demonstrated the findings as follows: a simple 1-item “depression” survey, sensitivity of 72%, specificity of 83%; a simple 1-item “loss of interest” survey, sensitivity of 83%, specificity of 86%; two questions “depression and loss of interest” survey; sensitivity of 91%, specificity of 86%. 37 The author concluded that simple surveys perform well at excluding depression in the nondepressed but perform poorly at confirming depression and that the “two question” method is significantly more accurate than either single question. In addition, based on this finding, the author emphasizes that clinicians should not rely on these simple questions alone and should be prepared to assess the patient more thoroughly. The HADS38 has also been investigated as a screening tool for depression and anxiety in cancer patients and this instrument has been translated into more than 20 languages. A meta-analysis published in 2010 investigating the accuracy of the HADS as a screening tool in cancer patients demonstrates that the HADS had a sensitivity of 82% and a specificity of 77% for depression (no studies for anxiety). 39 The authors conclude that the HADS is recommended as a screening tool but not case-finding instrument. In addition to brief screening approaches specific to depression, a more global approach to distress screening has been developed by Holland and endorsed by the National Comprehensive Cancer Network.40,37 This approach involves a thermometer with a numerical scale ranging from 0 to 10 for the patient to indicate “How much distress you have been experiencing in the past week, including today?” This is coupled with a 34-item checklist organized into practical areas, family issues, emotional issues, spiritual/religious issues, and physical symptoms. This approach embeds depression screening in a broad context that can be less stigmatizing to some patients. The drawback of this approach is that it is not easy to use in face-to-face discussions between the physician and the patient. Rather, it is well suited to a practice setting in which other providers are available to do the screening and initiate an appropriate response to the patient on the basis of the information provided. In general, the distress screening approach works best in a resource-rich environment. Now distress thermometer approach is introduced and used in several countries.41–46 Non-Western, for example, Japanese, patients still had difficulty with Western biopsychiatric concepts of depression. Sadness, worry, and stress, not depression, were more commonly used terms; thus, mental health providers need more euphemisms: worry, maybe sadness, stress, anxiety. These patients are reluctant to discuss with psychological issues, especially emotional disclosure to their physicians. They would like not to view their condition as an individual issue. Focusing on community and contextual factors, such as family, work, financial, and housing issues, was seen as more acceptable. The physicians might avoid the term “depression” during these discussions.47

Treatment of depression General medical patients

Antidepressant therapy and psychotherapy seem to be equally effective for treating mild-to-moderate depression in the general

Textbook of Palliative Medicine and Supportive Care

444 medical population.48,49 For treating severe depression, antidepressant therapy combined with psychotherapy may be better than psychotherapy alone.48,49 Antidepressants are also effective for treating depression in patients with concomitant physical illnesses.50 In 2011, a systematic review of randomized trials comparing antidepressants with placebo to treat depression in patients with life-threatening illness was published; the review comprised 25 studies including more than 1,100 patients with a variety of life-threatening illness including cancer, renal failure, chronic obstructive pulmonary disease, chronic heart failure, Parkinson’s disease, multiple sclerosis, and HIV/AIDS.51 Depression treated with antidepressants was significantly more likely to improve than that treated with placebo (4–5 weeks, odds ratio: 1.93; 95% CI: 1.15–3.42; 6–8 weeks, odds ratio: 2.25; 95% CI: 1.38–3.67; 9–18 weeks, odds ratio: 2.71; 95% CI: 1.50–4.91). However, at 4–5 weeks, the study also showed that approximately nine patients would need to be treated to produce one recovery

that would not have occurred with placebo alone (number needed to treat [NNT] 9; 95% CI: 4.3–81.0). The NNT decreased over time: 6–8 weeks NNT 6; 95% CI: 3.9–8.8; 9–18 weeks NNT 5; 95% CI: 2.9–9.9.51 Approximately 40 different antidepressants that work by at least 8 distinct mechanisms of action are available. However, no single drug or category of drugs has proved most effective for relieving depressive symptoms or treating the syndrome of major depression (see Box 46.4, for a summary of antidepressant agents),48,52 although several previous studies suggest existence of differences for efficacy and acceptability among second-generation antidepressants.53,54

Cancer patients Choosing patients for treatment

The largest barrier to the effective treatment of depression in patients with cancer is the difficulty in recognizing patients who

BOX 46.4  COMMONLY USED ANTIDEPRESSANTS GROUPED BY MECHANISM OF ACTION Selective serotonin reuptake inhibitors (SSRIs) • • • •

Sertraline Citalopram Escitalopram Fluoxetine

Comment: These agents are frequently used. They have few anticholinergic or cardiovascular side effects and, therefore, not fatal in overdose. Sexual dysfunction, insomnia, headache, or nausea may occur with any of these agents. Noradrenergic and specific serotonergic antidepressants (NaSSA) • Mirtazapine Comment: This agent is frequently used for patients with poor appetite and/or insomnia, because they cause sedation and weight gain. For this reason, it can be dosed at night to improve sleep and given to patients who have poor appetite. Serotonin and norepinephrine reuptake inhibitor (SNRIs) • Venlafaxine • Duloxetine Comment: In addition to their effect on depression, these agents have been used to decrease the frequency and intensity of hot flashes and neurotoxicity induced by chemotherapy in cancer patients. Dose-related sustained hypertension is an important possible side effect to monitor. These may cause sexual dysfunction, insomnia, headache, constipation, or nausea. Dopamine and norepinephrine reuptake inhibitor • Bupropion Comment: This agent is also indicated to improve rates of successful smoking cessation. Sometimes used to avoid the sexual dysfunction seen with other agents. Does not treat anxiety. Known to lower the seizure threshold. May cause insomnia, agitation, confusion, headache, or weight loss. Psychostimulants • Methylphenidate • Pemoline • Dextroamphetamine Comment: These agents are known for the rapid onset of action in terms of antidepressant efficacy. They are activating agents also used to counteract opioid-induced sedation. Generally given in the waking hours (morning and early afternoon). Should be avoided in patients with unstable ischemia or cardiac arrhythmias. Drug tolerance, abuse, and dependence can occur. May cause nervousness, agitation, insomnia, or nausea.

Depression/Anxiety

445

Tricyclic antidepressants • • • •

Nortriptyline Amitriptyline Doxepin Desipramine

Comment: These agents are generally not used because they can cause cardiac arrhythmias, and overdoses are lethal. Baseline electrocardiography is recommended. Often used as adjuvant analgesics at doses subtherapeutic for depression. May cause sexual dysfunction, weight gain, anticholinergic effects (dry mouth, sedation, or constipation), or orthostatic hypotension. Novel antidepressants • Agomelatine Comment: This agent is approved in 2009 for use in the European Union. This drug is thought to act through a combination of antagonist activity at 5-HT 2c receptor and agonist activity at melatonergic MT1/MT2 receptors. • vortioxetine Comment: This agent is first approved in 2013 for use in United States. vortioxetine is a multimodal antidepressant with two different types of pharmacologic targets: serotonin receptors and transporters including 5-HT1a receptor agonist, 5-HT3, 5-HT7, 5-HT1D receptor agnosist, 5-HT1B receptor partial agonist, and inhibitor of 5-HT transporter.

are depressed and need treatment.55,56 The factors associated with increased risk of depression in cancer patients are shown in Box 46.5. Because of the complexity of assessing patients in modern cancer care environments, many cases of depression are missed, and the patients with more severe symptoms, ironically, are more easily overlooked. Investigators in Indiana, USA, working in the community setting evaluated 1,109 outpatients with cancer and found that physicians were most accurate at correctly identifying the absence of depression.56 However, when depression was severe, only 13% of affected patients were correctly classified by their oncologists. In general, oncologists and oncology nurses appear to be most responsive to sad, tearful patients with minor depression rather than patients with a flat affect, feelings of pervasive guilt or worthlessness, or suicidal thoughts. In a sense, sicker patients may create thicker smokescreens that impede easy recognition of the underlying problem. These patients are particularly vulnerable, and their inability to advocate for themselves may be part of the illness.28 Symptom research is an emerging interest within the discipline of academic general medicine.57,58 Within this new paradigm, symptoms are conceptualized in terms of a functional disturbance of the nervous system. There is a growing appreciation for the physical changes in the nervous system associated with depression and its treatment.59,60,51,52 Understanding depressive symptoms in the context of symptom science rather than solely within the standard psychiatric paradigm is being explored in the context of cancer care to try to overcome some of the barriers to recognition and management of depression in this population.

Treatment options

Drugs used to treat depression in cancer patients are quite similar to those used in the primary care setting; these include selective

BOX 46.5  RISK FACTORS FOR DEPRESSION IN CANCER Social and environmental factors • • • • •

Recent losses (e.g., spouse, family, friends, animals) Financial stressors Poor social support Sexual and/or physical abuse Childhood trauma or parental loss

Psychiatric factors • Family and own history of depressive disorder • History of substance abuse Cancer-related factors • Advanced stage of disease • Poor performance status • Poor pain control Cancer treatment factors • • • • • • •

Corticosteroids Interferon α Interleukin-2 Amphotericin-B Procarbazine L-Asparaginase Paclitaxel

Textbook of Palliative Medicine and Supportive Care

446 serotonin reuptake inhibitor (SSRIs), serotonin and norepinephrine reuptake inhibitor (SNRIs), noradrenergic and specific serotonergic antidepressants (NaSSA), newer antidepressants, tricyclic antidepressants, and psychostimulants. The essential medicines recommended by the International Association for Hospice and Palliative Care for treatment of depression in palliative care are amitriptyline, citalopram (or any other SSRIs except paroxetine and fluvoxamine), and mirtazapine (or any other generic dual action noradrenergic and specific serotonergic antidepressants or SNRIs).61 Specific examples of commonly used antidepressants grouped by mechanism of action are presented in Box 46.4. The National Institutes of Health consensus statement regarding symptom management in cancer states that “depression related to cancer is not substantially different from depression in other medical conditions, but treatments may need to be adapted or refined for cancer patients.”62 One refinement for patients with cancer, particularly in the palliative care setting, is the growing interest in the use of psychostimulants to treat depression.63–65 Especially depressive terminally ill patients with estimated prognosis of less than a couple of weeks are best treated by psychostimulants. Another refinement that is often important to cancer patients is being mindful of potentially important drug interactions that can occur with antidepressants that are metabolized using the cytochrome P450 (CYP) enzyme system of the liver.66 In particular, agents such as fluoxetine and nefazodone that inhibit the CYP 3A4 enzyme system may increase the effects of some commonly used chemotherapeutic agents. Fluoxetine may also influence and paroxetine (CYP 2D6 inhibitors) can probably affect on the effect of tamoxifen that is the usual endocrine therapy for hormone receptor-positive breast cancer in premenopausal women.67,68 Moreover, because many patients with cancer are older adults with complex medical problems, other coadministered drugs may be influenced by the antidepressants. Among commonly used antidepressants for physically ill patients, sertraline and citalopram may be recommended for

first-line treatment, because these drugs appear to be less potential for serious pharmacokinetic drug interaction.69 Psychological therapies include psychoeducational interventions, behavioral therapy including relaxation training, cognitive behavioral therapy, interpersonal psychotherapy, supportive psychotherapy, group therapy, and supportive-expressive psychotherapy. In practice, all psychological therapies are patient-centered but very flexibly provided depending on each patient’s physical condition and needs.70 Electroconvulsive therapy, an invasive modality known to be effective for severe depression, is rarely used and has not been studied for depression in the context of cancer care. Some recent studies have demonstrated the effectiveness of ketamine71 and scopolamine,72 commonly used drugs in palliative care setting, and light therapy 73 on depression in physically healthy people. These therapies may be worth for testing their efficacy for the treatment of depression among cancer patients. Finally, both pharmacological and psychological therapies have been shown to be efficacious in treating depression in cancer; it is unknown that their relative and combined efficacy and their role in the treatment that is less severe and occurs in association with advanced disease.74

Randomized trials

With all of these challenges in mind, it is not surprising that data from controlled trials regarding the efficacy of treatment of depression in cancer patients are sparse. Fifteen published controlled randomized trials have investigated the effects of an antidepressant drug for depression in cancer patients (Table 46.1). A total of 1824 patients were included; none of these studies included children, and eight studies75–83 included women only. The trend in these studies was in favor of the treatment arm than placebo, but the small sample size of the individual trials, short follow-up duration, and lack of reporting of adverse events/tolerability limit

TABLE 46.1 Clinical Trials Comparing Antidepressant with Placebo or Other Antidepressants for Depression in Patients with Cancer Author

Antidepressants

Subjects

Inclusion Criteria for Depression

Costa (1985)75

A. Mianserin (N = 36) B. Placebo (N = 37) A. Mianserin (N = 28) B. Placebo (N = 27)

Women with cancer

Major depression

Early breast cancer patients receiving radiation therapy Mixed cancer patients

Major depression

Van Heeringen (1996)76

Razavi (1996)82 Holland (1998)77 Pezzella (2001)78 Tasmuth (2002)79

A. Fluoxetine (N = 45) B. Placebo (N = 46) A. Fluoxetine (N = 21) B. Desipramine (N = 17) A. Paroxetine (N = 88) B. Amitriptyline (N = 87) Venlafaxine (N = 13) Placebo (N = 13)

Morrow (2003)99

A. Paroxetine (N = 277) B. Placebo (N = 272)

Fisch (2003)100

A. Fluoxetine (N = 83) B. Placebo (N = 80)

Adult women with advanced cancer Adult women with breast cancer Patients with breast cancer and neuropathic pain Fatigued patients with cancer receiving chemotherapy Advanced cancer patients

Main Findings Depression is more improved in mianserin group Depression is more improved in mianserin group

Major depression or adjustment disorders Major depression or adjustment disorders Major depression

NS

None

NS

None

Depression is more improved in paroxetine group

Depressed mood and/or anhedonia revealed by 2-question survey

Depression is more improved in fluoxetine group

NS NS

(Continued)

Depression/Anxiety

447

TABLE 46.1  Clinical Trials Comparing Antidepressant with Placebo or Other Antidepressants for Depression in Patients with Cancer (Continued) Inclusion Criteria for Depression

Author

Antidepressants

Subjects

Roscoe (2005)80

A. Paroxetine (N = 44) B. Placebo (N = 50)

None

Depression is more improved in paroxetine group

Musselman (2006)81

A. Paroxetine (N = 13) B. Desipramine (N = 11) C. Placebo (N = 11) A. Sertraline (N = 95) B. Placebo (N = 94) A. Mirtazapine (N = 20) B. Imipramine (N = 13)

Breast cancer patients receiving chemotherapy Breast cancer patients

Major depression

NS

Advanced cancer patients Cancer patients

Depressive but not with major depression Major depression or adjustment disorders or anxiety disorders Without major depression Positive after two-item depression screening

NS

Major depression (DSM-IV)

Depressed symptoms are more improved in methylphenidate group

Stockler (2007)101 Cankurtaran (2008)102

Lydiatt (2008)103 Navari (2008)83

Ng (2014)65

A. Citalopram (N = 13) B. Placebo (N = 12) A. Fluoxetine (N = 90) B. Placebo (N = 90) A. Methylphenidate + mirtazapine (N = 44) B. Placebo + mirtazapine (N = 44)

Head and neck cancer patients Early breast cancer patients beginning adjuvant treatment Terminally ill cancer patients defined as an estimated life expectancy of less than 3 months

Main Findings

Depression is more improved in mirtazapine group NS Depressed symptoms are more improved in fluoxetine group

Abbreviation: NS, not statistically significant.

the conclusions that can be made from this body of research. In addition, no specific antidepressant has proved more effective for relieving depression in cancer patients. As the previous systematic review investigating the effectiveness of pharmacological treatment for depression in cancer patients suggested, there is some evidence that cancer patients with depression are responsive to pharmacological treatment although more data are needed regarding the safety and efficacy of antidepressants.84,85 Even though there is some evidence that patients with cancer with depression may respond to antidepressants in general, more data are needed regarding the most commonly prescribed antidepressants including SSRIs and SNRIs because physicians tend to treat patients with cancer in similar way they treat other depressed patients without comorbidity.86 Psychological therapies are most often applied in addition to drug treatments for depressed patients, but this kind of therapy can also be used alone to treat moderate to severe depression.15 In fact, there are very few studies in the medically ill in which the effect of psychotherapy has been described with sufficient methodological detail.87 There are several published systematic reviews and meta-analyses of controlled trials of psychological interventions for decreasing psychological distress in cancer patients (Table 46.2). Although the findings of these reviews are not consistent probably due to differences in the focus of the reviews, the methods used to summarize findings across studies, and the manner in which recommendations were reached, psychoeducational interventions, behavioral therapy, cognitive behavioral therapy, and supportive and supportive-expressive psychotherapy are effective for ameliorating depression for cancer patients.88 It is useful to note that application of unwanted (but received) intervention has been uniquely associated with poor psychosocial adjustment.89 As such, clinicians would do well to make support

available to cancer patients but to respect the boundaries that some patients set regarding such services. A recent study, investigating the effect of provision of early palliative care by palliative care team consisting of board-certified palliative care physicians and advanced-practice nurses for advanced lung cancer patients on quality of life and psychological distress including depression, demonstrated that early palliative care itself contributes to improvement in quality of life and ameliorating depression.90 This study suggests the usefulness of patient-centered early palliative care itself for reducing depression in cancer patients. In addition, some recent studies demonstrate that collaborative care interventions are also useful for depression among cancer patients.91–93

Unique issues in end-of-life care

Ambiguity surrounding the definition of end-of-life care makes this particular literature difficult to interpret and apply. The 1-item screening question “Are you depressed?” explored by Chochinov involved a cohort of 197 palliative care inpatients and had perfect sensitivity and specificity of 1.0 in this single study.33,94 However, in a palliative care cohort of 74 patients in the United Kingdom receiving only palliative and supportive day care, LloydWilliams et al. found that 27% of patients had depression by semistructured interview criteria, and the single-item screening question had a sensitivity of 55%, a specificity of 74%, a positive predictive value of 44%, and a negative predictive value of 82%.94 The similar findings with regard to poor screening performance of the 1-item screening question are also shown in Japanese study (a sensitivity of 47%, a specificity of 97%).95 Nevertheless, even use of the 14-item HADS had significant limitations in another UK study in a hospice population, as the positive predictive value of this instrument using a cut-off threshold of 20 was only 48% with

Textbook of Palliative Medicine and Supportive Care

448

TABLE 46.2  Systematic Reviews and Meta-Analysis of Psychotherapy for Depression and Anxiety in Cancer Patients Effect Size or Results Author

Psychotherapy

Included Studies

Depression

Anxiety

Main Findings

Devine

Psychoeducation

R and Non-R

Sheard119

Psychological intervention

R

d = 0.56 (95% CI 0.42 to 0.70) d = 0.42 (95% CI: 0.08–0.74)

Luebbert120

Relaxation training

R

Redd121

Behavioral intervention for side effects Psychoeducation

R and Non-R

d = 0.54 (95% CI: 0.43–0.65) d = 0.36 (95% CI: 0.06–0.66) (d = 0.19 with positive outliers removed) d = 0.54 (95% CI: 0.30–0.78) NA

Psychoeducation is effective for both depression and anxiety Preventative psychological interventions may have a moderate clinical effect upon anxiety but not depression Relaxation training is effective for both depression and anxiety Behavioral intervention is effective for ameliorating anxiety associated with aversive side effects Psychoeducation is effective for depression

Newell123

Psychological intervention

R

Ross124

Psychological intervention

R

Positive results reported in 9 of 17 studies

Positive results reported in 10 of 24 studies

Akechi125

Psychological intervention for advanced cancer Psychological intervention for advanced cancer

R

SMD = –0.44 (95% CI: –0.08 to –0.80)

SMD = –0.68 (95% CI: 0.01 to –1.37)

R

SMD = –0.67 (95% CI: –1.06 to –0.29)

SMD = –0.68 (95% CI: 0.01 to –1.37)

118

Barsevick122

Okuyama126

R and Non-R

Positive results reported in 29 of 46 studies No intervention strategy can be recommended

d = 0.45 (95% CI: 0.23–0.67) Positive results reported in 17 of 19 studies NA

Music therapy can be tentatively recommended

Music therapy can be tentatively recommended for reducing anxiety, although no intervention strategy can be recommended for reducing depression The question of whether psychosocial intervention among cancer patients has a beneficial effect remains unresolved Psychotherapy is effective for depression in advanced cancer patients Psychotherapy is effective for depression in advanced cancer patients

Abbreviations: R, randomized studies; Non-R, nonrandomized studies; CI, confidence interval; SMD, standardized mean difference.

a sensitivity of 77% and specificity of 89%.96 Overall, there are insufficient data in end-of-life patient populations to distinguish the assessment issues from those that have been described for cancer patients in general.97 It should be noted, however, that the occurrence of counter-transference of hopelessness on the part of families and clinicians may discourage dying patients from seeking assessment and treatment for depression.98 Regarding the treatment of patients with depression toward the end of life, several consensus statements have been publis hed.18,87,98,104 These statements are limited by the paucity of evidence, but several themes emerge across these statements. First, there should be a low threshold for treating patients with suspected depression using short-term therapeutic trials of carefully selected interventions.18,87 In addition, the rapid onset of the action of psychostimulants makes this class of drugs particularly appealing in patients toward the very end of life although one guideline does not recommend the use of psychostimulants due to three being evidence of adverse effects and inadequate evidence of efficacy.104 At all events, because patients’ survival time largely determines susceptibility to pharmacological treatment and it is hard to achieve drug response in patients whose survival time is very limited, possible symptom management including sleep disturbance and agitation, even not focused on depression fundamentally, should be provided.105 In addition, novel psychotherapeutic interventions focused on issues related to meaning

and/or dignity106–109 have shown promising results in the terminally ill. Finally, one of the more dreaded issues in managing patients with serious illness toward the end of life is the problem of patients who express desire for death. Desire for death statements may indicate that a patient is depressed or suicidal, but may also be a way of coping or expressing suffering.110,111 Depressive disorders and delirium are the most common underlying psychiatric disorders of suicidal ideation in patients with potentially fatal illnesses.112,113 However, the presence of a potentially fatal illness, by itself, only carries a modest two- to fourfold increased risk for suicide.23,114 Challenging aspects of assessing patients with desire for death include evaluation and treatment of depression and delirium, assessing the adequacy of palliative care overall, and dealing with broader issues such as personality, family dynamics, as well as important ethnic and cultural issues.115,116 It is important to understand that most patients appreciate being asked about their mood in depth, including questions about desire for death or suicide.117

Managing anxiety

Because anxiety is a response to threat, most patients living with cancer or a serious chronic illness experience some kinds of anxiety. Thus, anxiety is an inevitable human reaction to serious

Depression/Anxiety medical illness. On the other hand, anxiety ranges from adaptive to pathological ones. In psychiatry, clinically pathological anxiety is diagnosed with anxiety disorders including generalized anxiety disorders (GAD), panic disorders, and so on11 and a certain amount of cancer patients actually have these disorders.127,128 However, in practice, these criteria may be difficult to apply to cancer patients (e.g., A diagnosis of a DSM-5 (11) defines GAD requires excessive anxiety and worry, difficulty in controlling the worry, plus 3 or more additional symptoms of anxiety occurring more days than not for at least 6 months). Rather anxiety may be encountered as a component of trauma- and stressor-related disorders including adjustment disorders and posttraumatic disorders, depressive disorders, delirium, or organic anxiety disorder.129–132 In oncology setting, the estimated prevalence of clinical anxiety is within a range 15–30%.27,133 Symptoms that are uniquely attributable to anxiety include physical symptoms such as tremor, sweating, tachycardia, hyperventilation, and restlessness. Psychological symptoms of anxiety include worry, rumination, and fear.134,135 In the palliative care setting, it may not be easy to distinguish the somatic causes of anxiety from the psychological ones.135 The common causes of anxiety symptoms in palliative care are outlined in Box 46.6.

BOX 46.6  COMMON CAUSES OF ANXIETY SYMPTOMS IN PALLIATIVE CARE Situational • • • • •

Recent diagnosis of serious illness Impending surgery or chemotherapy Impending diagnostic imaging Perceived risk for receiving bad news Fear of death/existential anxiety

449 Psychiatric disorders • • • • • •

For patients with pervasive worry and autonomic hyperreactivity, pharmacotherapy may be indicated. The categories of medications used to treat anxiety are listed in Box 46.7. The essential medicines recommended by the International Association for Hospice and Palliative Care for treatment of anxiety in palliative care are diazepam, lorazepam, and midazolam.61 Unfortunately, there is an overall lack of evidence on the role of benzodiazepines and most other anxiolytics including antidepressants in palliative care patients.82,136–138 Benzodiazepines are the most commonly prescribed agents, and they are effective first-line agents. These medications may cause significant sedation or trigger delirium in patients who are on other psychoactive medications (including opioids) or who are particularly frail. These drugs should be used cautiously and, when feasible, should be discontinued. The shortacting benzodiazepines lorazepam and alprazolam are used most frequently. For patients with coexisting delirium, risperidone, quetiapine, or other neuroleptic agents are useful for the management of symptoms. Antihistamines and other sedative hypnotic agents can also provide useful anxiolysis, particularly at night when insomnia is an issue. Finally, most psychotherapies shown as effective for reducing depression are also useful for ameliorating anxiety in cancer patients.88

Symptom-related • • • •

Pain Dyspnea Palpitations Nausea

Metabolic disturbances • • • • •

Hypercalcemia Hypoglycemia Carcinoid syndrome Pulmonary embolus Paraneoplastic syndrome

Drug-associated • Akathisia due to antipsychotics or antiemetics (dopamine-2 antagonists) • Steroids • Bronchodilators • Psychostimulants • Thyroid replacement • Allergic reactions • Substances or withdrawal from substances

Delirium Depressive disorders Panic disorder Posttraumatic stress disorder Phobias Generalized anxiety disorder

BOX 46.7  DRUG THERAPY OF ANXIETY Benzodiazepines • • • • •

Alprazolam Diazepam Lorazepam Clonazepam Midazolam

Antidepressant agents • SSRI and newer antidepressants Neuroleptic agents • Haloperidol • Atypical antipsychotics Other drug therapies • • • •

Buspirone β blockers (for autonomic symptom relief) Sedative hypnotics (for relief of insomnia) Antihistamines

Textbook of Palliative Medicine and Supportive Care

450 KEY LEARNING POINTS



• Depression and anxiety are common in patients with serious illness. • Despite a body of research that spans several decades and includes hundreds of clinical trials, one can make no strong recommendations about the effectiveness of antidepressants or psychological interventions at improving depression or anxiety outcomes for patients with cancer and other serious chronic illnesses. • Simple, direct questions to explore issues about mood, anxiety, or desire for death are important and appreciated by patients. • An awareness of the potential for drug interactions with antidepressants and some other drugs commonly used in palliative care is important. • Patients with serious chronic illnesses would benefit from multidisciplinary care that includes access to specialists in behavioral health when needed.

Conclusion Depression and anxiety are the most common psychological and/or psychiatric issues experienced by patients with serious physical disease including cancer. The best estimate is that major depression has a point prevalence of 10–20% in cancer patients, irrespective of cancer stage. This prevalence is similar to that seen in patients with other chronic medical illnesses. The estimated prevalence of clinical anxiety is within a ranger 15–30%. Appropriate management of depression and anxiety is essential for maintaining optimal medical care, as these distress can lead to serious and far-reaching negative consequences in patients with serious physical disease. These psychological and/or psychiatric problems can reduce patients’ quantity and quality of life and cause severe suffering and suicide, as even though both psychotherapies and pharmacotherapies are useful treatments for depression and anxiety among these patients, one can make no strong recommendations about the effectiveness of antidepressants or psychological interventions at improving depression or anxiety outcomes for patients with cancer and other serious chronic illnesses. Patients with serious chronic illnesses would benefit from multidisciplinary collaborative care.

References



1. Fang F, Fall K, Mittleman MA, Sparen P, Ye W, Adami HO, et al. Suicide and cardiovascular death after a cancer diagnosis. N Engl J Med 2012;366(14):1310–1318. 2. Barley EA, Murray J, Walters P, Tylee A. Managing depression in primary care: a meta-synthesis of qualitative and quantitative research from the UK to identify barriers and facilitators. BMC Fam Pract 2011;12:47. 3. U.S. Preventive Services Task Force. Screening for depression: recommendations and rationale. Ann Intern Med 2002;136(10):760–764. 4. Katon WJ. Epidemiology and treatment of depression in patients with chronic medical illness. Dialogues Clin Neurosci 2011;13(1):7–23. 5. Hirschfeld RM, Keller MB, Panico S, Arons BS, Barlow D, Davidoff F, et al. The National Depressive and Manic-Depressive Association consensus statement on the undertreatment of depression. JAMA 1997;277(4):333–340.



















6. Moussavi S, Chatterji S, Verdes E, Tandon A, Patel V, Ustun B. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet 2007;370(9590):851–858. 7. Kazama M, Kondo N, Suzuki K, Minai J, Imai H, Yamagata Z. Early impact of depression symptoms on the decline in activities of daily living among older Japanese: Y-HALE cohort study. Environ Health Prev Med 2011;16(3):196–201. 8. Gallo JJ, Bogner HR, Morales KH, Post EP, Ten Have T, Bruce ML. Depression, cardiovascular disease, diabetes, and two-year mortality among older, primary-care patients. Am J Geriatr Psychiatry 2005;13(9):748–755. 9. Pan A, Sun Q, Okereke OI, Rexrode KM, Hu FB. Depression and risk of stroke morbidity and mortality: a meta-analysis and systematic review. JAMA 2011;306(11):1241–1249. 10. Herrman H, Patrick DL, Diehr P, Martin ML, Fleck M, Simon GE, et al. Longitudinal investigation of depression outcomes in primary care in six countries: the LIDO study. Functional status, health service use and treatment of people with depressive symptoms. Psychol Med 2002;32(5):889–902. 11. American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders, 5th edn. Washington, DC: American Psychiatric Association, 2013. 12. Williams JW, Jr., Noel PH, Cordes JA, Ramirez G, Pignone M. Is this patient clinically depressed? JAMA 2002;287(9):1160–1170. 13. Whooley MA, Simon GE. Managing depression in medical outpatients. N Engl J Med 2000;343(26):1942–1950. 14. Barbui C, Cipriani A, Patel V, Ayuso-Mateos JL, van Ommeren M. Efficacy of antidepressants and benzodiazepines in minor depression: systematic review and meta-analysis. Br J Psychiatry 2011;198:11–16. 15. Kroenke K. A 75-year-old man with depression. JAMA 2002;287(12):1568–76. 16. GBD 2015 DALYs and HALE Collaborators. Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016;388(10053):1603–1658. 17. Prince M, Livingston G, Katona C. Mental health care for the elderly in low-income countries: a health systems approach. World Psychiatry 2007;6(1):5–13. 18. Block SD. Assessing and managing depression in the terminally ill patient. ACP-ASIM End-of-Life Care Consensus Panel. American College of Physicians—American Society of Internal Medicine. Ann Intern Med 2000;132(3):209–218. 19. Gonzalez-Saenz de Tejada M, Bilbao A, Bare M, Briones E, Sarasqueta C, Quintana JM, et al. Association between social support, functional status, and change in health-related quality of life and changes in anxiety and depression in colorectal cancer patients. Psycho-oncology 2017;26(9):1263–1269. 20. Reich M, Lesur A, Perdrizet-Chevallier C. Depression, quality of life and breast cancer: a review of the literature. Breast Cancer Res Treat 2008;110(1):9–17. 21. Colleoni M, Mandala M, Peruzzotti G, Robertson C, Bredart A, Goldhirsch A. Depression and degree of acceptance of adjuvant cytotoxic drugs. Lancet 2000;356(9238):1326–1327. 22. Mausbach BT, Schwab RB, Irwin SA. Depression as a predictor of adherence to adjuvant endocrine therapy (AET) in women with breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat 2015;152(2):239–246. 23. Henriksson MM, Isometsa ET, Hietanen PS, Aro HM, Lonnqvist JK. Mental disorders in cancer suicides. J Affect Disord 1995;36(1-2):11–20. 24. Hodges LJ, Humphris GM, Macfarlane G. A meta-analytic investigation of the relationship between the psychological distress of cancer patients and their carers. Soc Sci Med 2005;60(1):1–12. 25. McLean LM, Jones JM. A review of distress and its management in couples facing end-of-life cancer. Psycho-oncology 2007;16(7):603–616. 26. Prieto JM, Blanch J, Atala J, Carreras E, Rovira M, Cirera E, et al. Psychiatric morbidity and impact on hospital length of stay among hematologic cancer patients receiving stem-cell transplantation. J Clin Oncol 2002;20(7):1907–1917. 27. Mitchell AJ, Chan M, Bhatti H, Halton M, Grassi L, Johansen C, et al. Prevalence of depression, anxiety, and adjustment disorder in oncological, haematological, and palliative-care settings: a meta-analysis of 94 interview-based studies. Lancet Oncol 2011;12(2):160–174. 28. Greenberg DB. Barriers to the treatment of depression in cancer patients. J Natl Cancer Inst Monogr 2004(32):127–135.

Depression/Anxiety 29. Gotay CC. Disparities in the Impact of Cancer. In: Holland J, Brietbart W, Jacobsen PB, Lederberg MS, Loscalzo M, eds. Psyho-Onocology. N.Y.: Oxford University Press, 2010, p. 503–508. 30. Quill TE, Arnold RM, Platt F. “I wish things were different”: expressing wishes in response to loss, futility, and unrealistic hopes. Ann Intern Med 2001;135(7):551–555. 31. Cleeland CS, Gonin R, Hatfield AK, Edmonson JH, Blum RH, Stewart JA, et al. Pain and its treatment in outpatients with metastatic cancer. N Engl J Med 1994;330(9):592–596. 32. Teunissen SC, Wesker W, Kruitwagen C, de Haes HC, Voest EE, de Graeff A. Symptom prevalence in patients with incurable cancer: a systematic review. J Pain Symptom Manage 2007;34(1):94–104. 33. Chochinov HM, Wilson KG, Enns M, Lander S. “Are you depressed?” Screening for depression in the terminally ill. Am J Psychiatry 1997;154(5):674–676. 34. Akizuki N, Akechi T, Nakanishi T, Yoshikawa E, Okamura M, Nakano T, et al. Development of a brief screening interview for adjustment disorders and major depression in patients with cancer. Cancer 2003;97(10):2605–2613. 35. Whooley MA, Avins AL, Miranda J, Browner WS. Case-finding instruments for depression. Two questions are as good as many. J Gen Intern Med 1997;12(7):439–445. 36. Pignone MP, Gaynes BN, Rushton JL, Burchell CM, Orleans CT, Mulrow CD, et al. Screening for depression in adults: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2002;136(10):765–776. 37. Mitchell AJ. Are one or two simple questions sufficient to detect depression in cancer and palliative care? A Bayesian meta-analysis. Br J Cancer 2008;98(12):1934–1943. 38. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67(6):361–370. 39. Mitchell AJ, Meader N, Symonds P. Diagnostic validity of the Hospital Anxiety and Depression Scale (HADS) in cancer and palliative settings: a meta-analysis. J Affect Disord 2010;126(3):335–348. 40. Holland JC, Bultz BD. The NCCN guideline for distress management: a case for making distress the sixth vital sign. J Natl Compr Canc Netw 2007;5(1):3–7. 41. Carlson LE, Groff SL, Maciejewski O, Bultz BD. Screening for distress in lung and breast cancer outpatients: a randomized controlled trial. J Clin Oncol 2010;28(33):4884–4891. 42. Akizuki N, Yamawaki S, Akechi T, Nakano T, Uchitomi Y. Development of an Impact Thermometer for use in combination with the Distress Thermometer as a brief screening tool for adjustment disorders and/ or major depression in cancer patients. J Pain Symptom Manage 2005;29(1):91–99. 43. Grassi L, Rossi E, Caruso R, Nanni MG, Pedrazzi S, Sofritti S, et al. Educational intervention in cancer outpatient clinics on routine screening for emotional distress: an observational study. Psychooncology 2011;20(6):669–674. 44. Carlson LE, Waller A, Groff SL, Bultz BD. Screening for distress, the sixth vital sign, in lung cancer patients: effects on pain, fatigue, and common problems–secondary outcomes of a randomized controlled trial. Psycho-oncology 2013;22(8):1880–1888. 45. Geerse OP, Hoekstra-Weebers JE, Stokroos MH, Burgerhof JG, Groen HJ, Kerstjens HA, et al. Structural distress screening and supportive care for patients with lung cancer on systemic therapy: a randomised controlled trial. Eur J Cancer 2017;72:37–45. 46. Lazenby M, Dixon J, Bai M, McCorkle R. Comparing the distress thermometer (DT) with the Patient Health Questionnaire (PHQ)-2 for screening for possible cases of depression among patients newly diagnosed with advanced cancer. Palliat Support Care 2014;12(1):63–68. 47. Furler J, Kokanovic R, Dowrick C, Newton D, Gunn J, May C. Managing depression among ethnic communities: a qualitative study. Ann Fam Med 2010;8(3):231–236. 48. APA. Practice guideline for the treatment of patients with major depressive disorder, third edition. Am J Psychiatry 2010;167 Suppl:1–118. 49. Parikh SV, Quilty LC, Ravitz P, Rosenbluth M, Pavlova B, Grigoriadis S, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 2. Psychol Treatm. Can J Psychiatry [Revue canadienne de psychiatrie] 2016;61(9):524–539. 50. Rayner L, Price A, Evans A, Valsraj K, Higginson IJ, Hotopf M. Antidepressants for depression in physically ill people. Cochrane Database Syst Rev 2010(3):Cd007503.

451 51. Rayner L, Price A, Evans A, Valsraj K, Hotopf M, Higginson IJ. Antidepressants for the treatment of depression in palliative care: systematic review and meta-analysis. Palliat Med 2011;25(1):36–51. 52. Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3. Pharmacol Treatm. Can J Psychiatry [Revue canadienne de psychiatrie] 2016;61(9):540–560. 53. Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 2009;373(9665):746–758. 54. Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 2018;391(10128):1357–1366. 55. Akechi T, Ietsugu T, Sukigara M, Okamura H, Nakano T, Akizuki N, et al. Symptom indicator of severity of depression in cancer patients: a comparison of the DSM-IV criteria with alternative diagnostic criteria. Gen Hosp Psychiatry 2009;31(3):225–232. 56. Passik SD, Dugan W, McDonald MV, Rosenfeld B, Theobald DE, Edgerton S. Oncologists’ recognition of depression in their patients with cancer. J Clin Oncol 1998;16(4):1594–1600. 57. Aronowitz RA. When do symptoms become a disease? Ann Intern Med 2001;134(9 Pt 2):803–808. 58. Kroenke K, Harris L. Symptoms research: a fertile field. Ann Intern Med 2001;134(9 Pt 2):801–802. 59. Holden C. Neuroscience. Drugs and placebos look alike in the brain. Science 2002;295(5557):947. 60. Vastag B. Decade of work shows depression is physical. JAMA 2002;287(14):1787–1788. 61. De Lima L. International Association for Hospice and Palliative Care list of essential medicines for palliative care. Ann Oncol 2007;18(2):395–399. 62. NIH. State-of-the-Science Statement on symptom management in cancer: pain, depression, and fatigue. NIH Consens State Sci Statements 2002;19(4):1–29. 63. Rozans M, Dreisbach A, Lertora JJ, Kahn MJ. Palliative uses of methylphenidate in patients with cancer: a review. J Clin Oncol 2002;20(1):335–339. 64. Meyers CA, Weitzner MA, Valentine AD, Levin VA. Methylphenidate therapy improves cognition, mood, and function of brain tumor patients. J Clin Oncol 1998;16(7):2522–2527. 65. Ng CG, Boks MP, Roes KC, Zainal NZ, Sulaiman AH, Tan SB, et al. Rapid response to methylphenidate as an add-on therapy to mirtazapine in the treatment of major depressive disorder in terminally ill cancer patients: a four-week, randomized, double-blinded, placebo-controlled study. Eur Neuropsychopharmacol: J Eur Coll Neuropsychopharmacol 2014;24(4):491–498. 66. Miguel C, Albuquerque E. Drug interaction in psycho-oncology: antidepressants and antineoplastics. Pharmacology 2011;88(5-6):333–339. 67. Henry NL, Stearns V, Flockhart DA, Hayes DF, Riba M. Drug interactions and pharmacogenomics in the treatment of breast cancer and depression. Am J Psychiatry 2008;165(10):1251–1255. 68. Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin PC, et al. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ 2010;340:c693. 69. National Institute for Health and Clinical Excellence. Depression in adults with a chronic physical health problem: treatment and management. 2010. 70. Akechi T. Psychotherapy for depression among patients with advanced cancer. Jpn J Clin Oncol 2012;42(12):1113–1119. 71. Kishimoto T, Chawla JM, Hagi K, Zarate CA, Kane JM, Bauer M, et al. Single-dose infusion ketamine and non-ketamine N-methyl-daspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med 2016;46(7):1459–1472. 72. Drevets WC, Furey ML. Replication of scopolamine’s antidepressant efficacy in major depressive disorder: a randomized, placebo-controlled clinical trial. Biol Psychiatry 2010;67(5):432–438. 73. Golden RN, Gaynes BN, Ekstrom RD, Hamer RM, Jacobsen FM, Suppes T, et al. The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence. Am J Psychiatry 2005;162(4):656–662.

452 74. Li M, Fitzgerald P, Rodin G. Evidence-based treatment of depression in patients with cancer. J Clin Oncol 2012;30(11):1187–1196. 75. Costa D, Mogos I, Toma T. Efficacy and safety of mianserin in the treatment of depression of women with cancer. Acta Psychiatr Scand Suppl 1985;320:85–92. 76. van Heeringen K, Zivkov M. Pharmacological treatment of depression in cancer patients. A placebo-controlled study of mianserin. Br J Psychiatry 1996;169(4):440–443. 77. Holland JC, Romano SJ, Heiligenstein JH, Tepner RG, Wilson MG. A controlled trial of fluoxetine and desipramine in depressed women with advanced cancer. Psycho-oncology 1998;7(4):291–300. 78. Pezzella G, Moslinger-Gehmayr R, Contu A. Treatment of depression in patients with breast cancer: a comparison between paroxetine and amitriptyline. Breast Cancer Res Treat 2001;70(1):1–10. 79. Tasmuth T, Hartel B, Kalso E. Venlafaxine in neuropathic pain following treatment of breast cancer. Eur J Pain 2002;6(1):17–24. 80. Roscoe JA, Morrow GR, Hickok JT, Mustian KM, Griggs JJ, Matteson SE, et al. Effect of paroxetine hydrochloride (Paxil) on fatigue and depression in breast cancer patients receiving chemotherapy. Breast Cancer Res Treat 2005;89(3):243–249. 81. Musselman DL, Somerset WI, Guo Y, Manatunga AK, Porter M, Penna S, et al. A double-blind, multicenter, parallel-group study of paroxetine, desipramine, or placebo in breast cancer patients (stages I, II, III, and IV) with major depression. J Clin Psychiatry 2006;67(2):288–296. 82. Razavi D, Allilaire JF, Smith M, Salimpour A, Verra M, Desclaux B, et al. The effect of fluoxetine on anxiety and depression symptoms in cancer patients. Acta Psychiatr Scand 1996;94(3):205–210. 83. Navari RM, Brenner MC, Wilson MN. Treatment of depressive symptoms in patients with early stage breast cancer undergoing adjuvant therapy. Breast Cancer Res Treat 2008;112(1):197–201. 84. Laoutidis ZG, Mathiak K. Antidepressants in the treatment of depression/depressive symptoms in cancer patients: a systematic review and meta-analysis. BMC Psychiatry 2013;13:140. 85. Walker J, Sawhney A, Hansen CH, Ahmed S, Martin P, Symeonides S, et al. Treatment of depression in adults with cancer: a systematic review of randomized controlled trials. Psychol Med 2013:1–11. 86. Akechi T, Furukawa TA. Depressed with cancer can respond to antidepressants, but further research is needed to confirm and expand on these findings. Evid Based Ment Health 2015;18(1):28. 87. Stiefel R, Die Trill M, Berney A, Olarte JM, Razavi A. Depression in palliative care: a pragmatic report from the Expert Working Group of the European Association for Palliative Care. Support Care Cancer 2001;9(7):477–488. 88. Jacobsen PB, Jim HS. Psychosocial interventions for anxiety and depression in adult cancer patients: achievements and challenges. CA Cancer J Clin 2008;58(4):214–230. 89. Reynolds JS, Perrin NA. Mismatches in social support and psychosocial adjustment to breast cancer. Health Psychol 2004;23(4):425–430. 90. Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, et al. Early palliative care for patients with metastatic non-smallcell lung cancer. N Engl J Med 2010;363(8):733–742. 91. Sharpe M, Walker J, Holm Hansen C, Martin P, Symeonides S, Gourley C, et al. Integrated collaborative care for comorbid major depression in patients with cancer (SMaRT Oncology-2): a multicentre randomised controlled effectiveness trial. Lancet 2014;384(9948):1099–1108. 92. Strong V, Waters R, Hibberd C, Murray G, Wall L, Walker J, et al. Management of depression for people with cancer (SMaRT oncology 1): a randomised trial. Lancet 2008;372(9632):40–48. 93. Walker J, Hansen CH, Martin P, Symeonides S, Gourley C, Wall L, et al. Integrated collaborative care for major depression comorbid with a poor prognosis cancer (SMaRT Oncology-3): a multicentre randomised controlled trial in patients with lung cancer. Lancet Oncol 2014;15(10):1168–1176. 94. Lloyd-Williams M, Dennis M, Taylor F, Baker I. Is asking patients in palliative care, “are you depressed?” Appropriate? Prospective study. BMJ 2003;327(7411):372–373. 95. Akechi T, Okuyama T, Sugawara Y, Shima Y, Furukawa TA, Uchitomi Y. Screening for depression in terminally ill cancer patients in Japan. J Pain Symptom Manage 2006;31(1):5–12. 96. Le Fevre P, Devereux J, Smith S, Lawrie SM, Cornbleet M. Screening for psychiatric illness in the palliative care inpatient setting: a comparison between the Hospital Anxiety and Depression Scale and the General Health Questionnaire-12. Palliat Med 1999;13(5):399–407.

Textbook of Palliative Medicine and Supportive Care 97. Wasteson E, Brenne E, Higginson IJ, Hotopf M, Lloyd-Williams M, Kaasa S, et al. Depression assessment and classification in palliative cancer patients: a systematic literature review. Palliat Med 2009;23(8):739–753. 98. APM’s Ad Hoc Committee on End-of-Life Care. Psychiatric aspects of excellent end-of-life care: a position statement of the Academy of Psychosomatic Medicine. J Palliat Med. 1998;1(2):113–115. 99. Morrow GR, Hickok JT, Roscoe JA, Raubertas RF, Andrews PL, Flynn PJ, et al. Differential effects of paroxetine on fatigue and depression: a randomized, double-blind trial from the University of Rochester Cancer Center Community Clinical Oncology Program. J Clin Oncol 2003;21(24):4635–4641. 100. Fisch MJ, Loehrer PJ, Kristeller J, Passik S, Jung SH, Shen J, et al. Fluoxetine versus placebo in advanced cancer outpatients: a double-blinded trial of the Hoosier Oncology Group. J Clin Oncol 2003;21(10):1937–1943. 101. Stockler MR, O’Connell R, Nowak AK, Goldstein D, Turner J, Wilcken NR, et al. Effect of sertraline on symptoms and survival in patients with advanced cancer, but without major depression: a placebo-controlled double-blind randomised trial. Lancet Oncol 2007;8(7):603–612. 102. Cankurtaran ES, Ozalp E, Soygur H, Akbiyik DI, Turhan L, Alkis N. Mirtazapine improves sleep and lowers anxiety and depression in cancer patients: superiority over imipramine. Support Care Cancer 2008;16(11):1291–1298. 103. Lydiatt WM, Denman D, McNeilly DP, Puumula SE, Burke WJ. A randomized, placebo-controlled trial of citalopram for the prevention of major depression during treatment for head and neck cancer. Arch Otolaryngol Head Neck Surg. 2008;134(5):528–535. 104. Rayner L, Price A, Hotopf M, Higginson IJ. The development of evidence-based European guidelines on the management of depression in palliative cancer care. Eur J Cancer 2011;47(5):702–712. 105. Shimizu K, Akechi T, Shimamoto M, Okamura M, Nakano T, Murakami T, et al. Can psychiatric intervention improve major depression in very near end-of-life cancer patients? Palliat Support Care 2007;5(1):3–9. 106. Chochinov HM, Kristjanson LJ, Breitbart W, McClement S, Hack TF, Hassard T, et al. Effect of dignity therapy on distress and end-of-life experience in terminally ill patients: a randomised controlled trial. Lancet Oncol 2011;12(8):753–762. 107. Breitbart W, Poppito S, Rosenfeld B, Vickers AJ, Li Y, Abbey J, et al. Pilot randomized controlled trial of individual meaning-centered psychotherapy for patients with advanced cancer. J Clin Oncol 2012;30(12):1304–1309. 108. Breitbart W, Rosenfeld B, Pessin H, Applebaum A, Kulikowski J, Lichtenthal WG. Meaning-centered group psychotherapy: an effective intervention for improving psychological well-being in patients with advanced cancer. J Clin Oncol 2015;33(7):749–754. 109. Rodin G, Lo C, Rydall A, Shnall J, Malfitano C, Chiu A, et al. Managing Cancer and Living Meaningfully (CALM): a randomized controlled trial of a psychological intervention for patients with advanced cancer. J Clin Oncol 2018;36(23):2422–2432. 110. Nissim R, Gagliese L, Rodin G. The desire for hastened death in individuals with advanced cancer: a longitudinal qualitative study. Soc Sci Med 2009;69(2):165–1671. 111. Rodin G, Lo C, Mikulincer M, Donner A, Gagliese L, Zimmermann C. Pathways to distress: the multiple determinants of depression, hopelessness, and the desire for hastened death in metastatic cancer patients. Soc Sci Med 2009;68(3):562–569. 112. Chochinov HM, Wilson KG, Enns M, Mowchun N, Lander S, Levitt M, et al. Desire for death in the terminally ill. Am J Psychiatry 1995;152(8):1185–1191. 113. Akechi T, Nakano T, Akizuki N, Nakanishi T, Yoshikawa E, Okamura H, et al. Clinical factors associated with suicidality in cancer patients. Jpn J Clin Oncol 2002;32(12):506–511. 114. Harris EC, Barraclough BM. Suicide as an outcome for medical disorders. Medicine (Baltimore) 1994;73(6):281–296. 115. Cohen LM, Steinberg MD, Hails KC, Dobscha SK, Fischel SV. Psychiatric evaluation of death-hastening requests. Lessons from dialysis discontinuation. Psychosomatics 2000;41(3):195–203. 116. Mann JJ. A current perspective of suicide and attempted suicide. Ann Intern Med 2002;136(4):302–311. 117. Meyer HA, Sinnott C, Seed PT. Depressive symptoms in advanced cancer. Part 2. Depression over time; the role of the palliative care professional. Palliat Med 2003;17(7):604–607.

Depression/Anxiety 118. Devine EC, Westlake SK. The effects of psychoeducational care provided to adults with cancer: meta-analysis of 116 studies. Oncol Nurs Forum 1995;22(9):1369–1381. 119. Sheard T, Maguire P. The effect of psychological interventions on anxiety and depression in cancer patients: results of two meta-analyses. Br J Cancer 1999;80(11):1770–1780. 120. Luebbert K, Dahme B, Hasenbring M. The effectiveness of relaxation training in reducing treatment-related symptoms and improving emotional adjustment in acute non-surgical cancer treatment: a metaanalytical review. Psycho-oncology 2001;10(6):490–502. 121. Redd WH, Montgomery GH, DuHamel KN. Behavioral intervention for cancer treatment side effects. J Natl Cancer Inst 2001;93(11):810–823. 122. Barsevick AM, Sweeney C, Haney E, Chung E. A systematic qualitative analysis of psychoeducational interventions for depression in patients with cancer. Oncol Nurs Forum 2002;29(1):73–84; quiz 5-7. 123. Newell SA, Sanson-Fisher RW, Savolainen NJ. Systematic review of psychological therapies for cancer patients: overview and recommendations for future research. J Natl Cancer Inst 2002;94(8):558–584. 124. Ross L, Boesen EH, Dalton SO, Johansen C. Mind and cancer: does psychosocial intervention improve survival and psychological well-being? Eur J Cancer 2002;38(11):1447–1457. 125. Akechi T, Okuyama T, Onishi J, Morita T, Furukawa TA. Psychotherapy for depression among incurable cancer patients. Cochrane Database Syst Rev 2008(2):CD005537. 126. Okuyama T, Akechi T, Mackenzie L, Furukawa TA. Psychotherapy for depression among advanced, incurable cancer patients: A systematic review and meta-analysis. Cancer treatment reviews 2017;56:16–27. 127. Spencer R, Nilsson M, Wright A, Pirl W, Prigerson H. Anxiety disorders in advanced cancer patients: correlates and predictors of end-oflife outcomes. Cancer 2010;116(7):1810–1819. 128. Stark DP, House A. Anxiety in cancer patients. Br J Cancer 2000;83(10):1261–1267.

453 129. Akechi T, Okuyama T, Sugawara Y, Nakano T, Shima Y, Uchitomi Y. Major depression, adjustment disorders, and post-traumatic stress disorder in terminally ill cancer patients: associated and predictive factors. J Clin Oncol 2004;22(10):1957–1965. 130. Okamura H, Watanabe T, Narabayashi M, Katsumata N, Ando M, Adachi I, et al. Psychological distress following first recurrence of disease in patients with breast cancer: prevalence and risk factors. Breast Cancer Res Treat 2000;61(2):131–137. 131. Akechi T, Okamura H, Nishiwaki Y, Uchitomi Y. Psychiatric disorders and associated and predictive factors in patients with unresectable nonsmall cell lung carcinoma: a longitudinal study. Cancer 2001;92(10):2609–2622. 132. Andersen BL, DeRubeis RJ, Berman BS, Gruman J, Champion VL, Massie MJ, et al. Screening, assessment, and care of anxiety and depressive symptoms in adults with cancer: an American Society of Clinical Oncology guideline adaptation. J Clin Oncol 2014;32(15):1605–1619. 133. DieTrill M. Anxiety and sleep disorders in cancer patients. EJC supplements: EJC: official journal of EORTC, Eur Org Res Treatm Cancer 2013;11(2):216–224. 134. Stiefel F, Razavi D. Common psychiatric disorders in cancer patients. II. Anxiety and acute confusional states. Support Care Cancer 1994;2(4):233–237. 135. Roth AJ, Massie MJ. Anxiety and its management in advanced cancer. Curr Opin Support Palliat Care 2007;1(1):50–56. 136. Candy B, Jackson KC, Jones L, Tookman A, King M. Drug therapy for symptoms associated with anxiety in adult palliative care patients. Cochrane Database Syst Rev 2012;10:Cd004596. 137. Salt S, Mulvaney CA, Preston NJ. Drug therapy for symptoms associated with anxiety in adult palliative care patients. Cochrane Database Syst Rev 2017;5:Cd004596. 138. Jansen K, Haugen DF, Pont L, Ruths S. Safety and effectiveness of palliative drug treatment in the last days of life: a systematic literature review. J Pain Symptom Manage 2018;55(2):508–521.e3.

47

DELIRIUM

Yesne Alici and William S. Breitbart

Contents Introduction........................................................................................................................................................................................................................455 Delirium in palliative care settings................................................................................................................................................................................ 456 Prevalence of delirium................................................................................................................................................................................................ 456 Pathophysiology of delirium..................................................................................................................................................................................... 456 Diagnosing delirium................................................................................................................................................................................................... 456 Delirium screening and diagnostic tools................................................................................................................................................................ 457 Subtypes of delirium................................................................................................................................................................................................... 457 Differential diagnosis of delirium............................................................................................................................................................................ 458 Management of delirium in palliative care settings............................................................................................................................................. 458 Assessment of etiologies of delirium..................................................................................................................................................................459 Nonpharmacological interventions....................................................................................................................................................................459 Pharmacological interventions in delirium...................................................................................................................................................... 460 Prevention of delirium............................................................................................................................................................................................... 463 Controversies in the management of terminal delirium..................................................................................................................................... 463 Prognostic implications of delirium in the terminally ill.................................................................................................................................... 464 Conclusion.......................................................................................................................................................................................................................... 464 References........................................................................................................................................................................................................................... 464

Introduction A variety of psychiatric or mental syndromes can be seen in patients with advanced disease. These syndromes could fall under one of the following1: • Delirium, dementia (major neurocognitive disorder), and other neurocognitive disorders • Depressive disorder due to another medical condition • Bipolar and related disorder due to another medical condition • Anxiety disorder due to another medical condition • Psychotic disorder due to another medical condition • Substance-related disorders • Catatonic disorder due to another medical condition • Personality change due to another medical condition While virtually all of these mental syndromes can be seen in the patient with advanced disease, the most common are delirium, other neurocognitive disorders, and depressive and anxiety disorders due to another medical condition. Neurocognitive disorders are unfortunately all too common in patients with advanced illness. For cognitively intact or minimally impaired patients, the more prominent symptoms tend to consist of anxiety, mood disturbance, delusions, hallucinations, or personality change. For instance, the patient with mood disturbance meeting criteria for major depression who is severely hypothyroid or on high-dose corticosteroids is most accurately diagnosed as having a depressive disorder due to hypothyroidism or corticosteroid-induced depressive disorder, respectively (particularly if medical factors are judged to be the primary etiology related to the mood disturbance). Similarly, the patient with hyponatremia or patient

on acyclovir for central nervous system herpes who is experiencing visual hallucinations but has a normal level of alertness and attention span with minimal cognitive deficits is more accurately diagnosed as having a psychotic disorder due to another medical condition or a substance-induced psychotic disorder, respectively. Delirium is a common and often serious neuropsychiatric complication in palliative care settings that is characterized by concurrent disturbances in the level of alertness, awareness, attention, thinking, perception, memory, psychomotor behavior, mood, and sleep–wake cycle. Disorientation, fluctuation, and waxing and waning of these symptoms, as well as an acute or abrupt onset of such disturbances are other critical features of delirium. It is a sign of significant physiological disturbance, usually involving multiple causes, including infections, organ failure, and medication adverse effects. Delirium, in contrast with dementia, is conceptualized as a reversible process. Reversibility of the process of delirium is possible even in the patient with advanced illness; however, it may not be reversible in the last 24–48 hours of life and this influences the outcomes of its management.2 This is most likely due to the fact that irreversible processes, such as multiple organ failure, are occurring in the final hours of life. Delirium occurring in these last days of life is often referred to as terminal restlessness or terminal agitation in the palliative care literature. Delirium is associated with significant morbidity and mortality. Increased health-care costs, prolonged hospital stays, and long-term cognitive decline are well-recognized outcomes of delirium. 3–5 It is a harbinger of impending death in terminally ill patients, causing significant distress for patients, family members, and staff.5–9 In a study of the “Delirium Experience” of terminally ill cancer patients, Breitbart and colleagues found that 54% of patients recalled their delirium experience after recovery from delirium.6 Factors predicting delirium recall included the 455

456 degree of short-term memory impairment, delirium severity, and the presence of perceptual disturbances (the more severe factors, the less likely recall). The most significant factor predicting distress for patients was the presence of hallucinations and delusions. Patients with hypoactive delirium were just as distressed as patients with hyperactive delirium. Predictors of spouse distress included the patients’ Karnofsky Performance Status (the lower the Karnofsky status, the worse the spouse distress), and predictors of nurse distress included delirium severity and perceptual disturbances. A survey of 300 bereaved Japanese families showed that two-thirds of the families found delirium in the family members to be highly distressing.7 Symptoms that caused the most distress included agitation and cognitive impairment. In a study of 99 patients with advanced cancer who had recovered from delirium, 74% remembered their delirium episode.8 Patients who recalled their delirium episode reported a higher level of distress than patients with no recall. Family caregivers of those patients reported higher levels of distress compared to nurses and physicians caring for patients with delirium.8 Another study on caregivers has shown that the family members of delirious terminally ill patients were 12 times more likely to develop an anxiety disorder than caregivers of nondelirious patients.9 These findings highlight the importance of not only treating the causes and controlling the symptoms of delirium, but also educating the caregivers about the medical nature of delirium and the potential treatment options to reduce caregiver distress. Delirium can interfere dramatically with the recognition and control of other physical and psychological symptoms such as pain in later stages of illness.5 Uncontrolled pain can cause agitation. Patients with delirium use a significantly greater number of “breakthrough” doses of opioids at night compared with patients without delirium due to sleep–wake cycle reversal.11 On the other hand, agitation due to delirium may be misinterpreted as uncontrolled pain, resulting in inappropriate escalation of opioids, potentially worsening delirium.12 A retrospective study of 284 hospice patients sought to identify factors that contribute to impairment of communication capacity in terminally ill cancer patients.13 The study demonstrated that communication capacity was frequently impaired in terminally ill cancer patients and the degree of impairment was significantly associated with higher doses of opioids. Patients with delirium were also found to have difficulty in communicating their needs, emphasizing the importance of further investigations to explore new strategies for maintaining communication capacity in this population.13 Unfortunately, delirium is often underrecognized or misdiagnosed and inappropriately treated or untreated in terminally ill patients.5 The diversity of the signs and symptoms of delirium and the fluctuating clinical course primarily leads to underrecognition and mistreatment of delirium. Practitioners caring for patients with life-threatening illnesses must be able to diagnose delirium accurately, undertake appropriate assessment of the etiologies, and be familiar with the risks and benefits of the pharmacological and nonpharmacological interventions currently available in managing delirium among the terminally ill. Improved recognition of delirium with delirium assessment tools validated in palliative care settings and the terminally ill is the first step toward better management of delirium. Implementation of delirium assessment strategies to routine care should become the standard of care to rule out this disabling condition in palliative care settings.10 This chapter provides an overview of the prevalence as well as the main clinical features of delirium, including its

Textbook of Palliative Medicine and Supportive Care subtypes, differential diagnosis, and assessment of etiologies. Pharmacological and nonpharmacological interventions and controversies common to the management of delirium in palliative care settings are also summarized.

Delirium in palliative care settings Prevalence of delirium

Delirium is one of the most common mental disorders encountered in general hospital practice. Delirium is highly prevalent in cancer and AIDS patients with advanced disease, particularly in the terminally ill patients in the last weeks of life, with prevalence rates ranging from 20 to 88%.5,14–19 The wide range of prevalence reports in the literature is due to the diverse and complex nature of delirium and heterogeneity of sample populations, settings of care, and the assessment scales used.5 Prospective studies conducted in inpatient palliative care settings have found a delirium occurrence rate of 20–42% upon admission, and an incident delirium developing during admission in 32–62% of patients.14,15,17–19 Approximately, 25–50% of medically hospitalized cancer patients and about 85% of terminally ill cancer patients develop delirium.5,20

Pathophysiology of delirium

The study of the pathophysiology of delirium is vital to our understanding of the phenomenology, prognosis, treatment, and prevention of delirium.21,22 As reflected by its diverse phenomenology, delirium is a dysfunction of multiple regions of the brain, a global cerebral dysfunction characterized by concurrent disturbances in level of alertness, awareness, attention, perception, cognition, psychomotor behavior, mood, and sleep–wake cycle.21 Various hypotheses have been put forth as contributing to the pathophysiology of delirium, including but not limited to neuronal aging, neuroinflammation, oxidative stress, neuroendocrine, circadian rhythm dysregulation, and neurotransmitter hypotheses, none of them being mutually exclusive.22 Variable contribution of these hypotheses may lead to the development of various cognitive and behavioral dysfunctions characteristic of delirium. As detailed in a comprehensive review by Maldonado, 22 delirium is a neurobehavioral syndrome caused by the transient disruption of normal neuronal activity, mediated by alterations in the neurotransmitters and dysfunction of neuronal networks, secondary to systemic disturbances. Many neurotransmitter systems, such as the serotonergic, noradrenergic, opioidergic, glutamatergic, and histaminergic systems, may contribute to delirium as a syndrome.22 Literature on the pathophysiology of delirium has continued to expand in the past decade, yet remains limited.

Diagnosing delirium

The diagnostic “gold standard” is the clinician’s assessment using the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria for delirium.1 According to DSM-5, the essential features of delirium are: disrupted attention (e.g., difficulty directing, focusing, sustaining, or shifting attention) and awareness (i.e., reduced orientation to the environment); a change from baseline that develops over hours to days and fluctuates within a day; additional cognitive problems (e.g., in memory, orientation, language, visuospatial ability, or perception); the condition is not better explained by another neurocognitive disorder and is not associated with a state of severely reduced arousal such as coma; history, physical exam, or lab findings suggest the patient’s

Delirium mental state is a direct physiological result of another medical condition, substance intoxication or withdrawal, exposure to a toxin, or multiple etiological factors.1 The clinical features of delirium are quite numerous and include a variety of neuropsychiatric symptoms that are also common to other psychiatric disorders such as depression, dementia, and psychosis.5,23 Main features of delirium include prodromal symptoms (e.g., restlessness, anxiety, sleep disturbances, and irritability); rapidly fluctuating course; abrupt onset of symptoms, reduced attention span (easily distractible); altered level of alertness; increased or decreased psychomotor activity; disturbance of sleep–wake cycle; affective symptoms (e.g., emotional lability, sadness, anger, and euphoria); altered perceptions (e.g., misperceptions, illusions, delusions, and hallucinations); disorganized thinking and incoherent speech; disorientation to time, place, or person; and memory impairment (cannot register new material) or impairment in other cognitive domains (e.g., dysnomia, sensorimotor aphasia, dysgraphia, constructional apraxia, and executive dysfunction) (Table 47.1). The DSM-5 criteria for delirium does not address the prodromal or affective symptoms (i.e., depressed mood) of delirium, which might be more prominent in patients with delirium in palliative care settings and also associated with worse outcomes.5 Neurological examination abnormalities may include motor abnormalities (e.g., tremor, asterixis, myoclonus, and reflex and tone changes) and/or signs of frontal release (i.e., grasp, palmomental, glabellar tap, and snout reflexes).5 Cognitive impairment was found to be the most common symptom noted in phenomenology studies with disorientation occurring in 78–100%, attention deficits in 62–100%, memory deficits in 62–90%, and diffuse cognitive deficits in 77% of patients.24 Disturbance of consciousness was recorded in 65–100% of patients with delirium. In addition, disorganized thinking was found in 95%, language abnormalities in 47–93%, and sleep–wake cycle disturbances in 49–96% of patients.24 A phenomenology study by Meagher and colleagues has found the sleep–wake cycle abnormalities (97%) and inattention (97%) to be the most frequent symptoms in patients with delirium; disorientation was found to be the least common symptom.25 The clinical presentation of delirium may vary based on the age of the patients. A phenomenology study of different age groups has shown that childhood delirium presents more likely with severe perceptual disturbances, severe delusions, severe lability of mood, and agitation when compared with delirium in adult TABLE 47.1  Clinical Features of Delirium Disturbance in the level of awareness Attentional disturbances Rapidly fluctuating clinical course and abrupt onset of symptoms Disorientation Cognitive disturbances (i.e., memory impairment, executive dysfunction, apraxia, agnosia, visuospatial dysfunction, and language disturbances) Increased or decreased psychomotor activity Disturbance of sleep–wake cycle Mood symptoms (depression, mood lability) Perceptual disturbances (hallucinations or illusions) or delusions Disorganized thought process Incoherent speech Neurological findings (may include asterixis, myoclonus, tremor, frontal release signs, changes in muscle tone) Source:

Adapted from Breitbart W, Alici Y. JAMA 2008;300:2898.

457 and geriatric patient populations.26 More severe cognitive symptoms were observed in geriatric patients with delirium.26 It is important to emphasize that clinicians should assess for subsyndromal delirium (i.e., delirium that does not meet the full DSM-5 criteria for a diagnosis of delirium) or prodromal signs of delirium to timely recognize and treat this disabling condition in palliative care settings.27

Delirium screening and diagnostic tools

The diagnostic gold standard for delirium is the clinician’s assessment utilizing the DSM-5 criteria as outlined earlier.28–34 A number of scales or instruments have been developed that can aid the clinician in rapidly screening for neurocognitive disorders (dementia or delirium), establishing a diagnosis of delirium, and assessing delirium severity. A detailed review of these assessment tools is available elsewhere.28 Several examples of delirium assessment tools currently used in palliative care settings include the Memorial Delirium Assessment Scale (MDAS),29,30 the Delirium Rating Scale-Revised 98, 31 and the Confusion Assessment Method (CAM). 32,33 Of these, the MDAS and the CAM have been validated in palliative care settings. 30,33 Each of these scales has good reliability and validity.28–34

Subtypes of delirium

Three clinical subtypes of delirium, based on psychomotor behavior and the level of alertness, have been described. 35,36 These subtypes include the “hyperactive” subtype, the “hypoactive” subtype, and a “mixed” subtype with alternating features of hyperactive and hypoactive delirium.5,18,35–41 In the palliative care setting, hypoactive delirium is most common and is frequently misdiagnosed as depression or severe fatigue.5 Despite the frequency of hypoactive delirium, hypoactive delirium has been found to be underdetected when compared with the detection rates of hyperactive or mixed subtypes of delirium in palliative care settings. 37 Research suggests that the hyperactive form is most often characterized by hallucinations, delusions, hypervigilance, and psychomotor agitation, while the hypoactive form is characterized by psychomotor retardation, lethargy, sedation, and reduced awareness of surroundings.5 Delirium phenomenology studies suggest that cognitive performance is similar across motor subtypes of delirium. A study of 100 consecutive cases of DSM-IV-TR delirium across motor subtypes (33 patients with hypoactive, 18 with hyperactive, 26 with mixed, and 23 patients with no motor alteration were included) in a palliative care unit showed that patients with mixed motoric subtype had more severe delirium, with highest scores for DRS-R-98 sleep–wake cycle disturbance, hallucinations, delusions, and language abnormalities. 38 Cognitive performance did not differ across hyperactive, mixed, and hypoactive motor groups. Authors concluded that motor variants in delirium have similar cognitive profiles, but mixed cases differ in the expression of several noncognitive features. A phenomenology study showed that although perceptual disturbances and delusions were more prevalent in hyperactive (70.2 and 78.7%, respectively) than in hypoactive delirium (50.9 and 43.4%, respectively), the prevalence of perceptual disturbances and delusions in hypoactive delirium was much higher than previously reported, deserving clinical attention and intervention. 39 The mean prevalence of hypoactive delirium was reported to be 48% (ranging from 15 to 71%) in comparison to hyperactive delirium that occurred in 13–46% of patients in the palliative care settings.5,36,40 In a hospice setting, 29% of 100 acute admissions

458 were found to have delirium; 86% of these had the hypoactive subtype.18 The prototypically agitated delirious patient most familiar to clinicians may actually constitute less than half of patients with delirium in the terminally ill. There is evidence suggesting that specific delirium subtypes may be related to specific etiologies of delirium and may have unique pathophysiologies, differential responses to treatment, and prognosis.5,18,41–44 Hypoactive delirium has been shown to be associated with higher rates of mortality than hyperactive delirium.18,41 Hypoactive delirium has been found to occur with hypoxia, metabolic disturbances, and anticholinergic medications. Hyperactive delirium has been correlated with alcohol and drug withdrawal, drug intoxication, or medication adverse effects.5,18,41 A randomized controlled trial (RCT) of haloperidol and chlorpromazine found that both drugs were equally effective in hypoactive and hyperactive subtypes of delirium, whereas an open-label trial of olanzapine found poorer treatment response with hypoactive delirium.42,43 A case-matched study comparing the efficacy of haloperidol and aripiprazole in the treatment of delirium has shown no significant differences in treatment results between the two medications for patients with hypoactive or hyperactive delirium.44

Differential diagnosis of delirium

Many of the clinical features and symptoms of delirium can also be associated with other psychiatric disorders such as depression, mania, psychosis, and dementia. Delirium, particularly the “hypoactive” subtype, is often initially misdiagnosed as depression. Symptoms of major depression, including altered level of psychomotor activity (hypoactivity), insomnia, reduced ability to concentrate, depressed mood, and even suicidal ideation, can overlap with symptoms of delirium, making an accurate diagnosis more difficult. In distinguishing delirium from depression, particularly in the context of advanced disease, an evaluation of the onset and temporal sequencing of depressive and cognitive symptoms is particularly helpful. Importantly, the degree of cognitive impairment in delirium is much more severe and pervasive than in depression, with a more abrupt temporal onset. Moreover, in delirium the characteristic disturbance in the level of alertness is present, while it is usually not a feature of depression. Similarly, a manic episode may share some features of delirium, particularly a “hyperactive” or “mixed” subtype of delirium. Again, the temporal onset and course of symptoms, the presence of a disturbance in the level of alertness as well as of cognition, and the identification of a presumed medical etiology or medications for delirium are helpful in differentiating these disorders. Past psychiatric history or family history of mood disorders is usually evident in patients with depression or a manic episode. Symptoms such as severe anxiety and autonomic hyperactivity can lead the clinician to an erroneous diagnosis of panic disorder. Delirium that is characterized by vivid hallucinations and delusions must be distinguished from a variety of psychotic disorders. In delirium, such psychotic symptoms occur in the context of a disturbance in the level of alertness and impaired attention span, as well as memory impairment and disorientation, which is not the case in other psychotic disorders. Delusions in delirium tend to be poorly organized and of abrupt onset, and hallucinations are predominantly visual or tactile rather than auditory as is typical of schizophrenia. Finally, the development of these psychotic symptoms in the context of advanced medical illness makes delirium a more likely diagnosis. It is important to note that not all patients with agitation have delirium. Patients with uncontrolled pain, medication-induced akathisia, and panic attacks may also present with

Textbook of Palliative Medicine and Supportive Care agitation. The diagnosis of delirium is reserved for patients who meet the diagnostic criteria for delirium. The most challenging differential diagnostic issue is whether the patient has delirium, or dementia, or a delirium superimposed upon a preexisting dementia. Both delirium and dementia are cognitive impairment disorders and share common clinical features such as impaired memory, thinking, judgment, aphasia, apraxia, agnosia, executive dysfunction, and disorientation. Delusions and hallucinations can be seen in patients with dementia. The patient with dementia is alert and does not have a disturbance in the level of alertness that is characteristic of delirium. The temporal onset of symptoms in dementia is more subacute and chronically progressive. It is the abrupt onset, fluctuating course, and disturbances of consciousness that differentiate delirium from dementia. It is also important to note that delirium represents an acute change from the patient’s baseline cognitive functioning, even if the patient has dementia or other cognitive disturbances at baseline. Delirium superimposed on an underlying dementia can be encountered such as in the case of an older patient, an AIDS patient, or a patient with a paraneoplastic syndrome. Reversibility of the delirium is possible even in the patient with advanced illness as opposed to dementia. However, as noted previously, delirium may not be reversible in the last 24–48 hours of life. Clinically, a number of scales or instruments aid clinicians in the diagnosis of delirium, dementia, or delirium superimposed on dementia.28,34 Boettger and colleagues reviewed the treatment and phenomenological characteristics of 100 cancer patients with delirium superimposed on dementia (DD) in contrast to patients with delirium in the absence of dementia (ND).45,46 Patients in the DD (n = 18) group, compared to the ND group (n = 82), had significantly greater levels of disturbance of consciousness and impairments in all cognitive domains (i.e., orientation, short-term memory, and concentration). There were no significant differences between the DD and ND groups in terms of the presence or severity of hallucinations, delusions, psychomotor behavior, and sleep–wake cycle disturbances. The MDAS scores at baseline were significantly higher in DD group (21.1) compared to ND group (17.6). Over the course of treatment, MDAS scores were significantly higher in DD group with 11.7 compared with 7.0 in ND group. After 3 days of management, delirium resolution rates were significantly lower in DD group with 18.2% compared to 53.9% in ND group, and at 7 days, delirium resolution rates were 50 and 83%, respectively. Researchers concluded that when delirium is superimposed on dementia, it may present with more severe cognitive symptoms, may respond poorly to treatment, and may resolve at a lower rate when compared to nondemented patients with delirium.45,46

Management of delirium in palliative care settings

The standard approach to the management of delirium includes a search for underlying causes, correction of those factors, and management of the symptoms of delirium (utilizing both pharmacological and nonpharmacological interventions).10 Treatment of the symptoms of delirium should be initiated before, or in concert with, a diagnostic assessment of the etiologies to minimize distress to patients, staff, and family members. In the terminally ill patient who develops delirium in the last days of life (“terminal” delirium), the management of delirium is unique, presenting a number of dilemmas, and the dying process may significantly alter the desired clinical outcome. The desired and often achievable outcome is a patient who is awake, alert, calm, comfortable, cognitively intact, not psychotic, not in pain, and communicating coherently with family and staff.

Delirium Assessment of etiologies of delirium

The underlying etiologies of delirium are multiple (Table 47.2). In the medical setting, the diagnostic workup typically includes an assessment of potentially reversible causes, for example, dehydration or medication, as well as those that are potentially irreversible, for example, sepsis or major organ failure. The clinician should obtain a detailed history of the patient’s baseline mental status from the family and staff and verify the current fluctuating mental status. Predisposing delirium risk factors should be reviewed in detail, including old age, physical frailty, multiple medical comorbidities, dementia, admission to the hospital with infection or dehydration, visual impairment, deafness, polypharmacy, renal impairment, and malnutrition. 3 Physical examination should seek evidence of infection, dehydration, fecal impaction, urinary retention, or organ (e.g., liver, pulmonary, and renal) failure.5 Medication adverse effects should be reviewed as a possible cause. It is important to inquire about alcohol or other substance use disorders to be able to recognize and treat alcohol or other substance-induced withdrawal delirium. Opioids, corticosteroids, benzodiazepines, and anticholinergics are commonly associated with delirium particularly in the elderly and the terminally ill.5,47 In palliative care settings, medications used for symptom control (e.g., antihistamines, opioids, tricyclic antidepressants, and corticosteroids) have been shown to significantly increase the overall burden of anticholinergic adverse effects, increasing the risk for delirium.47,48 Laboratory tests can identify metabolic abnormalities (e.g., hypercalcemia, hyponatremia, hypoglycemia), hypoxia, or disseminated intravascular coagulation. In some instances, an electroencephalogram (to rule out seizures), brain imaging studies (to rule out brain metastases, intracranial bleeding, or ischemia), and lumbar puncture (to rule out leptomeningeal carcinomatosis or meningitis) may be appropriate.5 When confronted with delirium in the terminally ill or dying patient, a differential diagnosis should always be formulated as to the likely etiology or etiologies including underlying medical conditions, such as infections, electrolyte disturbances, organ failure, uncontrolled pain, and medication adverse effects. However, the clinician must take an individualized and judicious approach to such testing, consistent with the goals of care. There is an ongoing debate as to the appropriate extent of diagnostic evaluation that should be pursued in a dying patient with a terminal delirium. Most palliative care clinicians would undertake diagnostic studies only when a clinically suspected etiology can be identified easily, with TABLE 47.2 Causes of Delirium in Patients with Advanced Disease Direct central nervous system causes Primary brain tumors Metastatic spreads to brain Seizures (including nonepileptiform status epilepticus) Indirect causes Metabolic encephalopathy due to major organ failure Electrolyte imbalance Treatment side effects from chemotherapeutic agents, corticosteroids, radiation therapy, opioids, anticholinergics, antiemetics, antivirals, and other medications and therapeutic modalities Infections Hematological abnormalities Nutritional deficiencies Paraneoplastic syndromes

459 a minimal use of invasive procedures, and treated effectively with simple interventions that carry minimal burden or risk of causing further distress. A survey of 270 physicians from 4 disciplines (palliative care, medical oncology, geriatrics, and geriatric psychiatry) found that about 85% of specialists would order basic blood tests when confronted with delirium in patients with advanced cancer; more than 40% of specialists reported that they would not do any investigation in patients with terminal delirium.49 Diagnostic workup in pursuit of an etiology for delirium may be limited by either practical constraints such as the setting (home, hospice) or the focus on patient comfort so that unpleasant or painful diagnostics may be avoided. However, most often the etiology of terminal delirium is multifactorial or may not be determined. When a distinct cause is found for delirium in the terminally ill, it is often irreversible or difficult to treat. Studies, however, in patients with earlier stages of advanced cancer have demonstrated the potential utility of a thorough diagnostic assessment. When such diagnostic information is available, specific therapy may be able to reverse delirium. In a study of patients with advanced cancer admitted to hospice, the overall delirium reversibility rate was only 20% and the 30-day mortality rate was 83%.50 Reversibility of delirium was highly dependent on the etiology: hypercalcemia was reversible in 38%; medications in 37%; infection in 12%; and hepatic failure, hypoxia, disseminated intravascular coagulation, and dehydration each in less than 10% of patients. Leonard and colleagues found 27% recovery rate from delirium among patients in palliative care. Patients with irreversible delirium experienced greater disturbances of sleep and cognition. Mean (SD) time until death was 39.7 (69.8) days for 33 patients with reversible delirium versus 16.8 (10.0) days for 88 patients with irreversible delirium.2 In a prospective study of delirium in patients in a palliative care unit, investigators reported that the etiology of delirium was multifactorial in a majority of cases.51 Even though delirium occurred in 88% of dying patients in the last week of life, delirium was reversible in approximately 50% of episodes. Causes of delirium that were most associated with reversibility included dehydration and psychoactive or opioid medications. Major organ failure and hypoxic encephalopathies were less likely to be reversed in terminal delirium.51 In light of the several studies on the reversibility of delirium, the prognosis of patients who develop delirium is defined by the interaction of the patients’ baseline physiologic susceptibility to delirium (e.g., predisposing factors), the precipitating etiologies, and any response to treatment. If a patient’s susceptibility or resilience is modifiable, then targeted interventions may reduce the risk of delirium upon exposure to a precipitant and enhance the capacity to respond to treatment. Conversely, if a patient’s vulnerability is high and resistant to modification, then exposure to precipitants enhances the likelihood of developing delirium and may diminish the probability of a complete restoration of cognitive function.

Nonpharmacological interventions

In addition to seeking out and potentially correcting underlying causes of delirium, nonpharmacological and supportive therapies are important. Nonpharmacological and supportive therapies play an essential role in the treatment of patients with delirium, especially in patients with terminal delirium. In fact, in the dying patient, they may be the only steps that can be taken. Fluid and electrolyte balance, nutrition, measures to help reduce anxiety and disorientation, and interactions with and education of family

Textbook of Palliative Medicine and Supportive Care

460 TABLE 47.3  Summary of Nonpharmacological Interventions Used in the Prevention and Treatment of Delirium Reducing polypharmacy Control of pain Sleep hygiene (e.g., minimize noise and interventions at bedtime) Monitor for dehydration and fluid-electrolyte disturbances Monitor nutrition Monitor for sensory deficits, provide visual and hearing aids Encourage early mobilization Minimize the use of immobilizing catheters, IV lines, and physical restraints Monitor bowel and bladder functioning Reorient the patient frequently Place an orientation board, clock, or familiar objects in patient rooms Encourage cognitively stimulating activities Source:

Adapted from Breitbart W, Alici Y. JAMA 2008;300: 2898.

members may be useful. Measures to help reduce anxiety and disorientation (i.e., structure and familiarity) include a quiet, well-lit room with familiar objects, a visible clock or calendar, and the presence of family. In nonpalliative care settings, there is evidence that nonpharmacological interventions result in faster improvement in delirium and slower deterioration in cognition. However, these interventions were not found to have any beneficial effects on mortality or health-related quality of life when compared with usual care.52–57 Nonpharmacological interventions used in these studies include oxygen delivery, fluid and electrolyte administration, ensuring bowel and bladder function, nutrition, mobilization, pain treatment, frequent orientation, use of visual and hearing aids, and environmental modifications to enhance a sense of familiarity (Table 47.3).52–57 Low implementation rates of all the components of the interventions were identified as the main limiting factor in the interpretation of the study results in a majority of nonpharmacological intervention trials.58 Physical restraints should be avoided in patients who are at risk for developing delirium and for those with delirium. Physical restraints have been identified as an independent risk factor for the persistence of delirium at discharge.59 Evidence suggests that restraintfree management of patients should be the standard of care for prevention and treatment of delirium.60 One-to-one observation may be necessary while maintaining the safety of the patient without the use of any restraints.

Pharmacological interventions in delirium

Symptomatic treatment with psychotropic medications is often essential to control the symptoms of delirium.10 Since publication of the American Psychiatric Association (APA) guidelines for treatment of delirium in 1999, a number of systematic reviews and guidelines have been released based on evidence-based management of delirium. The guidelines highlight the importance of multicomponent nonpharmacological prevention strategies, education of health-care professionals, medical evaluation of delirium etiology, optimizing pain management, and avoiding high-risk medications. The guidelines include avoidance of drug treatment for hypoactive delirium and avoidance of benzodiazepines for treatment of delirium, except in cases of alcohol or benzodiazepine withdrawal. In palliative care settings, the evidence is supportive of shortterm low-dose use of antipsychotics in the control of symptoms of delirium with close monitoring for possible side effects,

especially in older patients with multiple medical comorbidities (Tables 47.4).10 It is also recommended that nonpharmacological interventions in the routine care of patients at risk for delirium and patients with delirium be implemented, based on the evidence from the medically ill older persons.10 Following is a brief description of each medication class with a review of the evidence of their use in the treatment of delirium in palliative care settings.

Antipsychotics

Antipsychotics, formerly known as neuroleptics, are a group of medications primarily indicated for schizophrenia, bipolar disorder, and other mood disorders. The mechanisms by which these drugs ameliorate disturbances of thought and affect in psychotic states are not fully understood, but presumably, they act by blocking the postsynaptic mesolimbic dopamine receptors. Typical (conventional or first-generation) and atypical (secondgeneration) antipsychotics differ in their effects on the different dopamine and serotonin receptor subtypes. Typical antipsychotics are traditionally known to be associated with a higher incidence of extrapyramidal side effects (EPS) due to their effects on the striatal dopamine 2 (D2) receptors. On the other hand, atypical antipsychotics (i.e., risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) have been associated with weight gain, and metabolic syndrome, but significantly less risk for EPS. APA provided guidance for the use of antipsychotics in the treatment of delirium in 1999. Since then antipsychotic use has been studied in many settings and different patient populations in the past two decades.42–44,61–65 Treatment with antipsychotic agents is the norm in the everyday management of symptoms of delirium across settings and different patient populations.10 Last decade has seen the biggest surge in the number of treatment trials on delirium. Several recent studies did not show benefit of antipsychotics in decreasing the duration or severity of delirium. A 2016 systematic review examined antipsychotic drugs including oral risperidone, oral olanzapine, oral quetiapine, intramuscular ziprasidone, and oral, intravenous, and intramuscular haloperidol61 and concluded that the current evidence does not support the use of antipsychotics for treatment (or prevention) of delirium in hospitalized older adults. There was no significant decrease in delirium incidence among 19 studies and no change in delirium duration, severity, hospital or intensive care length of stay, or reduction in mortality. Potential harm was demonstrated in two studies in which more patients required institutionalization after treatment with antipsychotics. In a more recent systematic review of antipsychotics in treatment of delirium, among 16 RCTs and 10 observational studies, there was no difference in sedation status, delirium duration, hospital length of stay, or mortality between haloperidol and atypical antipsychotics versus placebo.62 There was no difference in delirium severity and cognitive functioning for haloperidol versus secondgeneration antipsychotics. Significant heterogeneity was present among the studies in terms of dose, administration route of antipsychotics, outcomes, and measurement instruments. There was insufficient or no evidence regarding multiple clinically important outcomes. In an RCT63 of atypical antipsychotic drugs in palliative care settings, participants receiving oral risperidone or haloperidol had higher delirium symptom scores and were more likely to require breakthrough treatment compared with participants receiving placebo. This study was largely publicized due to the finding that participants in the placebo group had better overall survival compared to those in the haloperidol group. Interestingly, survival was not one of the primary study outcomes

Delirium

461

TABLE 47.4  Antipsychotic Medications Used in the Treatment of Delirium Medication

Dose Range

Routes of Administration

Haloperidol

0.5–2 mg every 2–12 h

Chlorpromazine

Side Effects

Comments

PO, IV, IM, SC

Extrapyramidal adverse effects can occur at higher doses. Monitor QT interval on electrocardiogram (EKG).

12.5–50 mg every 4–6 h

PO, IV, IM, SC, PR

Olanzapine

2.5–5 mg every 12–24 h

PO, IM

More sedating and anticholinergic compared with haloperidol. Monitor blood pressure for hypotension. More suitable for use in intensive care unit settings for closer blood pressure monitoring Sedation is the main doselimiting adverse effect in short-term use

Remains the gold standard therapy for delirium. May add lorazepam (0.5–1 mg every 2–4 h) for agitated patients. Double-blinded controlled trials support efficacy in the treatment of delirium. A pilot placebo-controlled trial suggests lack of efficacy when compared to placebo May be preferred in agitated patients due to its sedative effect. Doubleblind controlled trials support efficacy in the treatment of delirium. No placebo-controlled trials

Risperidone

0.25–1 mg every 12–24 h

PO

Quetiapine

12.5–100 mg every 12–24 h

PO

Ziprasidone

10–40 mg every 12–24 h

PO, IM

Monitor QT interval on EKG

Aripiprazole

5–30 mg every 24 hours

PO, IM

Monitor for akathisia

Source:

Extrapyramidal adverse effects can occur with doses >6 mg/ day. Orthostatic hypotension Sedation, orthostatic hypotension

Older age, preexisting dementia, and hypoactive subtype of delirium have been associated with poor response. Double-blind comparison trials with haloperidol and risperidone support efficacy in the treatment of delirium. A pilot placebo-controlled prevention trial suggested worsening in delirium severity. A placebo-controlled study is supportive of efficacy in reducing delirium severity and duration Double-blind comparison trials support efficacy in the treatment of delirium. No placebo-controlled trials. Sedating effects may be helpful in patients with sleep–wake cycle disturbance. Pilot placebo-controlled trials suggest efficacy in the treatment of delirium. However, studies allowed for the concomitant use of haloperidol, which makes the results difficult to interpret Placebo-controlled, double blind trial suggests lack of efficacy in the treatment of delirium Evidence is limited. A prospective open-label trial suggests comparable efficacy to haloperidol. No placebocontrolled trials

Adapted from Breitbart W, Alici Y. J Clin Oncol 2012 April 10;30(11):1206.

and the patients in the haloperidol arm were medically sicker with greater opioid use and more severe delirium. A Cochrane review on drug therapy for delirium in the terminally ill64 concluded that there was no high-quality evidence to support or refute the use of drug therapy for delirium symptoms in terminally ill adults. As noted eloquently in a debate article by Meagher et al.,65 evidence-based concerns must be applied to all interventions, both pharmacological and nonpharmacological, with equal vigilance. Nonpharmacological interventions can be effective in prevention of delirium in certain settings and may be a helpful tool in treatment of delirium; on the other hand, interventions such as early

mobilization or cognitive remediation may be more agitating to patients with severe delirium rather than being beneficial. Management of delirium in palliative care settings is nuanced. The judicious, most specifically short-term and low-dose, use of antipsychotics continues to be the mainstay of treatment of symptoms of delirium (e.g., severe agitation, delusions, and hallucinations interfering with care) in the palliative care settings with the understanding that antipsychotics are not expected to cure the underlying etiologies or prolong survival, but are expected to allow for patients to safely and successfully be managed. In light of the recent research on use of antipsychotics, it is important

462 to emphasize that in hypoactive delirium, or delirium of all subtypes that is of mild to moderate severity, antipsychotics are best avoided or only used if the benefits of medications clearly outweigh the risks associated with their use. Haloperidol is considered to be the preferred antipsychotic in the treatment of delirium in patients with advanced disease due to its efficacy and tolerability (e.g., few anticholinergic effects, lack of active metabolites, and availability in different routes of administration).5 In general, doses of haloperidol need not exceed 20 mg in a 24-hour period; however, some clinicians advocate higher doses (up to 250 mg/24 hour of haloperidol intravenously) in selected cases.66 Typically 0.5–1.0 mg haloperidol (PO, intravenous [IV], intramuscular [IM], subcutaneous [SC]) is administered, with repeat doses every 45–60 minutes titrated against target symptoms of agitation, paranoia, and fear.23 An IV route can facilitate rapid onset of medication effects. If IV access is unavailable, IM or SC routes of administration could be used with switch to the oral route when possible. The majority of delirious patients can be managed with oral haloperidol. Haloperidol is administered by the SC route by many palliative care practitioners.5 It is important to note that the Food and Drug Administration (FDA) has issued a warning about the risk of QTc prolongation and torsades de pointes on electrocardiogram with IV haloperidol; therefore, monitoring QTc intervals closely among medically ill patients on IV haloperidol has become the standard clinical practice.67 A common strategy in the management of symptoms related to delirium is to add parenteral lorazepam to a regimen of haloperidol.5 Lorazepam (0.5–1.0 mg every 1–2 hours PO or IV) along with haloperidol may be more effective in rapidly sedating the agitated delirious patient and may minimize EPS associated with haloperidol especially in palliative care settings.68 An alternative strategy is to switch from haloperidol to a more sedating antipsychotic such as chlorpromazine, especially in the intensive care unit setting where close blood pressure monitoring is feasible. It is important to monitor for anticholinergic and hypotensive adverse effects of chlorpromazine, particularly in elderly patients.5 Atypical antipsychotic agents (i.e., risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) are increasingly used in the treatment of delirium in palliative care settings due to decreased risk of extrapyramidal adverse effects. In the light of existing literature, risperidone may be used in the treatment of delirium, starting at doses ranging from 0.125 to 1 mg and titrated up as necessary with particular attention to the risks of EPS, orthostatic hypotension, and sedation at higher doses.

Textbook of Palliative Medicine and Supportive Care Olanzapine can be started between 2.5 and 5 mg nightly and titrated up with sedation being the major limiting factor, which may be favorable in the treatment of hyperactive delirium. The current literature on the use of quetiapine suggests a starting dose of 25–50 mg and a titration up to 100–200 mg a day (usually at twice daily divided doses). Sedation and orthostatic hypotension are the main dose-limiting factors. Findings to date and our clinical experience suggest a starting dose of 2 to 5 mg daily for aripiprazole, with a maximum dose of 15 mg daily. Important considerations in starting treatment with any antipsychotic for delirium should include EPS risk, sedation, anticholinergic side effects, cardiac arrhythmias, and possible drug–drug interactions (Table 47.5). Most importantly, the FDA has issued a “black box” warning of increased risk of death associated with the use of typical and atypical antipsychotics in elderly patients with dementia-related psychoses.69 Caution is advised when using antipsychotic medications, especially in elderly patients with dementia, due to the FDA warnings described earlier. Therefore, the use of nonpharmacological interventions is critical to reduce the need to use antipsychotic medications whenever possible. It is also important to recognize that antipsychotics have complex mechanisms of action, mostly affecting multiple neurotransmitter systems that can lead to unwanted side effects. Therefore, the benefits of initiating antipsychotic treatment for delirium should be weighed against risks associated with its use. As mentioned previously, in palliative care settings, the evidence is most clearly supportive of the shortterm low-dose use of antipsychotics for the control of the symptoms of delirium, with close monitoring for possible side effects, especially in older patients with multiple medical comorbidities.10 Delirium in pediatric settings is similarly managed through treatment of underlying medical etiologies and minimizing iatrogenic triggers.70 However, if the delirium persists and the child has agitated behaviors that are distressing or interfering with the medical care plan, pharmacologic therapies may be considered. Most experts recommend use of the atypical antipsychotics, such as quetiapine.70

Psychostimulants

The use of psychostimulants in the treatment of hypoactive subtype of delirium has been suggested.71,72 However, studies with psychostimulants in treating delirium symptoms are limited.71,72 The risks of precipitating agitation and exacerbating psychotic symptoms should be carefully evaluated when psychostimulants are considered in the treatment of delirium in palliative care settings.10

TABLE 47.5 Recommendations on Monitoring Patients with Delirium for Antipsychotic Side Effects in Palliative Care Settingsa EKGb: Baseline and with every dose increase [consider daily monitoring if on high doses (e.g., haloperidol > 5–10 mg daily), patients with underlying unstable cardiac disease, patients with electrolyte disturbances, patients on other QT-prolonging medications,11 medically frail, older patients; patients with unstable cardiac diseases or those on IV antipsychotics may require continuous monitoring in consultation with cardiology] Fasting blood glucose: Baseline and weekly Body mass index: Baseline and weekly EPS (including parkinsonism, dystonia, akathisia, neuroleptic malignant syndrome): Baseline and daily Blood pressure, pulse: Baseline and at least daily (continuous monitoring may be required in medically unstable patients; orthostatic measurements should be considered with antipsychotics with alpha-1 antagonist effects such as chlorpromazine, risperidone, and quetiapine) Source: Adapted from Breitbart W, Alici Y. J Clin Oncol 2012 April 10;30(11):1206. a Recommendations are based on the Consensus Development Conference on antipsychotic drugs and obesity and diabetes. b The risk of QT prolongation is directly correlated with higher antipsychotic doses, with parenteral formulations (e.g., IV haloperidol) of antipsychotics, and with certain medications (e.g., ziprasidone, thioridazine). In individual patients, an absolute QTc interval of > 500 ms or an increase of 60 ms (or more than 20%) from baseline is regarded as indicating an increased risk of torsades des pointes. Discontinuation of the antipsychotic and a consultation with cardiology should be considered, especially if there is continued need for the use of antipsychotics.

Delirium Cholinesterase inhibitors

Impaired cholinergic function has been implicated as one of the final common pathways in the neuropathogenesis of delirium.22 Despite case reports of beneficial effects of donepezil and rivastigmine, current evidence does not support use of cholinesterase inhibitors in the treatment of delirium.10

Alpha-2 agonists

Dexmedetomidine, an alpha-2 agonist, mostly studied for use postoperatively and in critical care settings, has been compared to standard sedatives such as midazolam and propofol, and to opioids and placebo in RCTs. A systematic review and meta-analysis with incidence of delirium and delirium resolution as the primary outcomes, showed that the administration of dexmedetomidine was associated with significantly lower overall incidence and duration of delirium when compared to placebo, propofol, midazolam, and opioids. The main side effects were increased risk of bradycardia and hypotension.73 It is important to emphasize that dexmedetomidine is used in postsurgical and critical care settings and primarily for mechanically ventilated patients. Evidence for its use in palliative care settings remains to be studied.

Other agents

While antipsychotics are most effective in diminishing agitation, clearing the sensorium and improving cognition are not always possible in delirium, which complicates the last days of life. Approximately 30% of dying patients with delirium do not have their symptoms adequately controlled with antipsychotic medications.74–76 Processes causing delirium may be ongoing and irreversible during the active dying phase. In such cases, a reasonable choice is the use of sedative agents such as benzodiazepines (e.g., midazolam and lorazepam), propofol, or opioids to achieve a state of quiet sedation.74–78 Delirium has, in fact, been identified as the main indication for the use of palliative sedation in up to 82% of cases in symptom control studies among the terminally ill.74–81 Clinicians are often concerned that the use of sedating medications may hasten death via respiratory depression, hypotension, or even starvation. However, studies have shown that the use of opioids and psychotropic agents in hospice and palliative care settings is associated with longer rather than shorter survival.79-81

Prevention of delirium

Several researchers have studied both pharmacological and nonpharmacological interventions in the prevention of delirium among older patient populations, particularly in surgical settings. The applicability of these interventions to the prevention of delirium in palliative care settings has not been widely studied.82 In a 2016 Cochrane review that examined prophylactic antipsychotics compared with control for preventing delirium in hospitalized non-ICU medical and surgical adult patients 16 years or older, there was no clear benefit of antipsychotics as a group.83 There is some evidence suggesting that both melatonin84 and ramelteon85 may be effective in reducing incidence of delirium in older patients admitted to acute care settings. Based on the current literature, no recommendations can be made regarding the use of medications in the prevention of delirium among palliative care patients. Prevention of delirium with nonpharmacological multicomponent approaches has been shown to be effective and has gained widespread acceptance as the most effective strategy for delirium. 86 In a meta-analysis of 14 interventional studies

463 based on the Hospital Elder Life Program, multicomponent approaches significantly reduced the risk of incident delirium by 53%, and the risk of falls by 62%, among hospitalized, nonICU patients who were 65 years and older.82 In oncology settings and in the terminally ill, the effect of these interventions on delirium incidence has been more limited. In a study of 1516 patients with terminal cancer, Gagnon et al. 87 were not able to reduce incidence of delirium with a multicomponent intervention including early assessment of patient risk factors, active engagement of physicians in planning for delirium, and education of family members.

Controversies in the management of terminal delirium

Several aspects of the use of antipsychotics and other pharmacological agents in the management of delirium in the dying patient remain controversial in some circles. A study by Agar and colleagues49 showed that physicians from different disciplines manage terminal delirium differently. According to a survey of 270 physicians from different disciplines, medical oncologists were found to be more likely to manage terminal delirium with benzodiazepines or benzodiazepine and antipsychotic combinations. On the other hand, palliative care physicians were more likely to use antipsychotics to manage delirium symptoms, including hypoactive subtype of delirium. Some have argued that pharmacological interventions with antipsychotics or benzodiazepines are inappropriate in the dying patient. Delirium is viewed by some as a natural part of the dying process that should not be altered. In particular, there are clinicians who care for the dying who view hallucinations and delusions, which involve dead relatives communicating with or in fact welcoming dying patients to heaven, as an important element in the transition from life to death. Clearly, there are many patients who experience hallucinations and delusions during delirium that are pleasant and in fact comforting, and many clinicians question the appropriateness of intervening pharmacologically in such instances. Another concern that is often raised is that these patients are so close to death that aggressive treatment is unnecessary. Parenteral antipsychotics or sedatives may be mistakenly avoided because of exaggerated fears that they might hasten death through hypotension or respiratory depression. Many are unnecessarily pessimistic about the possible results of neuroleptic treatment for delirium. They argue that since the underlying pathophysiological process often continues unabated (such as hepatic or renal failure), no improvement can be expected in the patient’s mental status. There is concern that antipsychotics or sedatives may worsen delirium by making the patient more confused or sedated. Clinical experience in managing delirium in dying patients suggests that the use of antipsychotics in the management of agitation, paranoia, hallucinations, and altered sensorium is safe, effective, and often quite appropriate.5 Management of delirium on a case-by-case basis seems wisest. The agitated delirious dying patient should probably be given antipsychotics to help restore calm. A “wait-and-see” approach, prior to using antipsychotics, may be appropriate with some patients who have a lethargic or somnolent presentation of delirium or those who have frankly pleasant or comforting hallucinations. Such a “wait-and-see” approach must, however, be tempered by the knowledge that a lethargic or “hypoactive” delirium may very quickly and unexpectedly become an agitated or “hyperactive” delirium that can threaten the serenity and safety of the patient, family, and staff.

Textbook of Palliative Medicine and Supportive Care

464 Similarly, hallucinations and delusions during a delirium that are pleasant and comforting can quickly become menacing and terrifying. It is important to remember that by their nature, the symptoms of delirium are unstable and fluctuate over time. Finally, perhaps the most challenging of clinical problems is management of the dying patient with a “terminal” delirium that is unresponsive to standard antipsychotic interventions, whose symptoms can only be controlled by sedation to the point of a significantly decreased level of consciousness. Before undertaking interventions, such as midazolam or propofol infusions, where the best achievable goal is a calm and comfortable but sedated and unresponsive patient, the clinician must first take several steps. The clinician must have a discussion with the family (and the patient if there are lucid moments when the patient appears to have capacity), eliciting their concerns and wishes for the type of care that can best honor their desire to provide comfort and symptom control during the dying process. The clinician should describe the optimal achievable goals of therapy as they currently exist. Family members should be informed that the goal of sedation is to provide comfort and symptom control, not to hasten death. They should also be told to anticipate that sedation may result in a premature sense of loss and that they may feel their loved one is in some sort of limbo state, not yet dead, but yet no longer alive in the vital sense. The distress and confusion that family members can experience during such a period can be ameliorated by including the family in the decision-making and emphasizing the shared goals of care. Sedation in such patients is not always complete or irreversible; some patients have periods of wakefulness despite sedation, and many clinicians will periodically lighten sedation to reassess the patient’s condition. Ultimately, the clinician must always keep in mind the goals of care and communicate these goals to the staff, patients, and family members. The clinician must weigh each of the issues outlined earlier in making decisions on how to best manage the dying patient who presents with delirium that preserves and respects the dignity and values of that individual and family.

KEY LEARNING POINTS • Delirium occurs in up to 85% of patients prior to death. • Hypoactive subtype of delirium is as common and as distressing as the hyperactive subtype of delirium. • There are typically three or more etiologies for delirium in the palliative care setting. • In the terminally ill, delirium is reversible in only 50% of cases compared with more than 80% of cases in patients with earlier stage disease. • The management of delirium involves the concurrent search for and treatment of the underlying etiology while actively controlling the symptoms of delirium. • Delirium often is a harbinger of impending death. Issues of end-of-life care treatment preferences are ideally dealt with prior to the onset of delirium. • Delirium is associated with high levels of distress in patients, family members, and nurses. Education of family members and nurses in the palliative care setting is important. • Current evidence is supportive of the short-term use of antipsychotics in the treatment of symptoms of delirium (i.e., agitation, sleep–wake cycle disturbances, delusions, hallucinations) with close monitoring for possible side effects especially in elderly patients with multiple medical comorbidities. The choice of antipsychotic medication for the treatment of delirium should be based on the clinical presentation of the patient and the side effect profile of each antipsychotic drug, as none of the antipsychotics were found to be superior to others in comparison trials. • It is strongly recommended to implement nonpharmacological interventions in the routine care of patients who are either at risk for delirium or have established delirium, based on the evidence from nonpalliative care settings. • Sedation may be necessary in up to 30% of patients with delirium unresponsive to antipsychotics.

Prognostic implications of delirium in the terminally ill

It is important to emphasize the prognostic value of delirium in terminally ill patients. Delirium is a relatively reliable predictor of approaching death in the coming days to weeks.58 The death rates among hospitalized elderly patients with delirium over the 3-month post-discharge period range from 22 to 76%, the wide range most likely reflecting the variability in underlying general medical conditions contributing to delirium in elderly patients.59 In the palliative care setting, several studies provide support that delirium reliably predicts impending death in patients with advanced cancer.88,89 Given prognostic significance of delirium, recognizing an episode of delirium in the late phases of palliative care is critically important in treatment planning and in advising family members on what to expect.

Conclusion Palliative care clinicians commonly encounter delirium as a major complication of terminal illness. Proper assessment, diagnosis, and management of delirium are essential in improving the quality of life and minimizing morbidity in palliative care settings for patients, families, and health-care professionals.

References

1. American Psychiatric Association.Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th ed. Washington, D.C.: American Psychiatric Association, 2013. 2. Leonard M, Raju B, Conroy M, et al. Reversibility of delirium in terminally ill patients and predictors of mortality. Palliat Med 2008;22(7):848–854. 3. Inouye SK, Westendorp RG, Saczynski JS. Delirium in elderly people. Lancet 2014 March 8;383(9920):911–922. 4. Leslie DL, Zhang Y, Holford TR, Bogardus ST, Leo-Summers LS, Inouye SK. Premature death associated with delirium at 1-year followup. Arch Intern Med 2005 July 25;165(14):1657–1662. 5. Breitbart W, Alici Y. Agitation and delirium at the end of life: “We couldn’t manage him.” JAMA 2008;300:2898–2910. 6. Breitbart W, Gibson C, Tremblay A. The delirium experience: delirium recall and delirium related distress in hospitalized patients with cancer, their spouses/caregivers, and their nurses. Psychosomatics 2002;43:183–194.

Delirium









7. Morita T, Hirai K, Sakaguchi Y, et al. Family perceived distress from delirium-related symptoms of terminally ill cancer patients. Psychosomatics 2004;45:107–113. 8. Bruera E, Bush SH, Willey J, et al. Impact of delirium and recall on the level of distress in patients with advanced cancer and their family caregivers. Cancer 2009 May 1;115(9):2004–2012. 9. Buss MK, Vanderwerker LC, Inouye SK, Zhang B, Block SD, Prigerson HG. Associations between caregiver-perceived delirium in patients with cancer and generalized anxiety in their caregivers. J Palliat Med 2007;10(5):1083–1092. 10. Breitbart W, Alici Y. Evidence-based treatment of delirium in patients with cancer. J Clin Oncol 2012 April 10;30(11):1206–1214. 11. Gagnon B, Lawlor PG, Mancini IL, Pereira JL, Hanson J, Bruera ED. The impact of delirium on the circadian distribution of breakthrough analgesia in advanced cancer patients. J Pain Symptom Manage 2001;22(4):826–833. 12. Coyle N, Breitbart W, Weaver S, Portenoy R. Delirium as a contributing factor to ‘Crescendo’ pain: three case reports. J Pain Symptom Manage 1994;9:44–47. 13. Morita T, Tei Y, Inouye S. Impaired communication capacity and agitated delirium in the final week of terminally ill cancer patients: prevalence and identification of research focus. J Pain Symptom Manage 2003;26:827–834. 14. Hosie A, Davidson PM, Agar M, Sanderson CR, Phillips J. Delirium prevalence, incidence, and implications for screening in specialist palliative care inpatient settings: a systematic review. Palliat Med 2013 June;27(6):486–498. 15. Pereira J, Hanson J, Bruera E. The frequency and clinical course of cognitive impairment in patients with terminal cancer. Cancer 1997;79(4):835–842. 16. Bond SM, Dietrich MS, Shuster JL Jr, Murphy BA. Delirium in patients with head and neck cancer in the outpatient treatment setting. Support Care Cancer 2012 May;20(5):1023–1030. 17. Lawlor PG, Gagnon B, Mancini IL, et al. Occurrence, causes, and outcome of delirium in patients with advanced cancer: a prospective study. Arch Intern Med 2000;160(6):786–794. 18. Spiller JA, Keen JC. Hypoactive delirium: assessing the extent of the problem for inpatient specialist palliative care. Palliat Med 2006;20(1):17–23. 19. Gagnon P, Charbonneau C, Allard P, et al. Delirium in terminal cancer: a prospective study using daily screening, early diagnosis, and continuous monitoring. J Pain Symptom Manage 2000;19(6):412–426. 20. Fann JR, Roth-Roemer S, Burington BE, et al. Delirium in patients undergoing hematopoietic stem cell transplantation. Cancer 2002;95:1971–1981. 21. Trzepacz PT. Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine. Semin Clin Neuropsychiatry 2000;5:132–148. 22. Maldonado JR. Delirium pathophysiology: an updated hypothesis of the etiology of acute brain failure. Int J Geriatr Psychiatry 2018 November;33(11):1428–1457. 23. American Psychiatric Association. Practice guidelines for the treatment of patients with delirium. Am J Psychiatry 1999;156(5 suppl):1–20. 24. Meagher DJ, Trzepacz PT. Delirium phenomenology illuminates pathophysiology, management, and course. J Geriatr Psychiatry Neurol Fall 1998;11(3):150–156. 25. Meagher DJ, Moran M, Raju B, Gibbons D, Donnelly S, Saunders J, Trzepacz PT. Phenomenology of delirium. Assessment of 100 adult cases using standardized measures. Br J Psychiatry 2007 February;190:135–141. 26. Leentjens AF, Schieveld JN, Leonard M, Lousberg R, Verhey FR, Meagher DJ. A comparison of the phenomenology of pediatric, adult, and geriatric delirium. J Psychosom Res 2008 February;64(2):219–223. 27. Gagnon PR. Treatment of delirium in supportive and palliative care. Curr Opin Support Palliat Care 2008 March;2(1):60–66. 28. Smith MJ, Breitbart WS, Platt MM. A critique of instruments and methods to detect, diagnose, and rate delirium. J Pain Symptom Manage 1994;10(1):35–77. 29. Breitbart W, Rosenfeld B, Roth A. The memorial delirium assessment scale. J Pain Symptom Manage 1997;13:128–137. 30. Lawlor P, Nekolaichuck C, Gagnon B, et al. Clinical utility, factor analysis and further validation of the Memorial Delirium Assessment Scale (MDAS). Cancer 2000;88:2859–2867. 31. Trzepacz PT, Mittal D, Torres R, Kanary K, Norton J, Jimerson N. Validation of the delirium rating scale-revised-98: Comparison with the delirium rating scale and the cognitive test for delirium. J Neuropsychiatry Clin Neurosci 2001;13(2):229–242.

465 32. Inouye B, Vandyck C, Alessi C. Clarifying confusion: The confusion assessment method, a new method for the detection of delirium. Ann Intern Med 1990;113:941–948. 33. Ryan K, Leonard M, Guerin S, et al. Validation of the confusion assessment method in the palliative care setting. Palliat Med 2009;23:40–55. 34. Wong CL, Holroyd-Leduc J, Simel DL, Straus SE. Does this patient have delirium?: Value of bedside instruments. JAMA 2010 August 18;304(7):779–786. 35. Meagher DJ, O’Hanlon D, O’Mahony E, Casey PR, Trzepacz PT. Relationship between symptoms and motoric subtype of delirium. J Neuropsychiatry Clin Neurosci 2000;12(1):51–56. 36. Stagno D, Gibson C, Breitbart W. The delirium subtypes: A review of prevalence, phenomenology, pathophysiology, and treatment response. Palliat Support Care 2004;2(2):171–179. 37. Fang CK, Chen HW, Liu SI, Lin CJ, Tsai LY, Lai YL. Prevalence, detection and treatment of delirium in terminal cancer inpatients: A prospective survey. Jpn J Clin Oncol January 2008;38(1):56–63. 38. Leonard M, Donnelly S, Conroy M, Trzepacz P, Meagher DJ. Phenomenological and neuropsychological profile across motor variants of delirium in a palliative-care unit. J Neuropsychiatry Clin Neurosci Spring 2011;23(2):180–188. 39. Boettger S, Breitbart W. Phenomenology of the subtypes of delirium: Phenomenological differences between hyperactive and hypoactive delirium. Palliat Support Care 2011;9:129–135. 40. Ross CA, Peyser CE, Shapiro I, Folstein MF. Delirium: phenomenologic and etiologic subtypes. Int Psychogeriatr 1991;3(2):135–147. 41. Kiely DK, Jones RN, Bergmann MA, Marcantonio ER. Association between psychomotor activity delirium subtypes and mortality among newly admitted postacute facility patients. J Gerontol A Biol Sci Med Sci 2007;62(2):174–179. 42. Breitbart W, Marotta R, Platt MM, Weisman H, Derevenco M, Grau C, Corbera K, Raymond S, Lund S, Jacobson P. Am J Psychiatry February 1996;153(2):231–237. 43. Breitbart W, Tremblay A, Gibson C. Psychosomatics May-June 2002;43(3):175–182. PMID:12075032. 44. Boettger S, Friedlander M, Breitbart W, et al. Aripiprazole and haloperidol in the treatment of delirium. Aust N Z J Psychiatry 2011;45:477–482. 45. Boettger S, Passik S, Breitbart W. Delirium super imposed on dementia versus delirium in the absence of dementia: Phenomenological differences. Palliat Support Care 2009 December;7(4):495–500. 46. Boettger S, Passik S, Breitbart W. Treatment characteristics of delirium super imposed on dementia. Int Psychogeriatr 2011 December;23(10):1671–1676. 47. Agar M, Currow D, Plummer J, et al. Changes in anticholinergic load from regular prescribed medications in palliative care as death approaches. Palliat Med 2009;23:257–265. 48. Gaudreau JD, Gagnon P, Harel F, et al. Psychoactive medications and risk of delirium in hospitalized cancer patients. J Clin Oncol 2005;23:6712–6718. 49. Agar M, Draper B, Phillips PA, Phillips J, Collier A, Harlum J, Currow D. Making decisions about delirium: a qualitative comparison of decision making between nurses working in palliative care, aged care, aged care psychiatry, and oncology. Palliat Med 2012 October;26(7):887–896. 50. Morita T, Tei Y, Tsunoda J, Inoue S, Chihara S. Underlying pathologies and their associations with clinical features in terminal delirium of cancer patients. J Pain Symptom Manage. 2001;22(6):997–1006. 51. Lawlor P, Gagnon B, Mancini I, et al. The occurrence, causes and outcomes of delirium in advanced cancer patients: A prospective study. Arch Intern Med 2002;160:786–794. 52. Cole MG, Primeau FJ, Bailey RF, et al. Systematic intervention for elderly inpatients with delirium: a randomized trial. CMAJ 1994;151(7):965–970. 53. Cole MG, McCusker J, Bellavance F, et al. Systematic detection and multidisciplinary care of delirium in older medical inpatients: a randomized trial. CMAJ 2002;167(7):753–759. 54. Pitkälä KH, Laurila JV, Strandberg TE, Tilvis RS. Multicomponent geriatric intervention for elderly in patients with delirium: a randomized, controlled trial. J Gerontol A Biol Sci Med Sci 2006;61(2):176–181. 55. Pitkala KH, Laurila JV, Strandberg TE, Kautiainen H, Sintonen H, Tilvis RS. Multicomponent geriatric intervention for elderly in patients with delirium: effects on costs and health-related quality of life. J Gerontol A Biol Sci Med Sci 2008;63(1):56–61. 56. Milisen K, Lemiengre J, Braes T, Foreman MD. Multicomponent intervention strategies for managing delirium in hospitalized older people: Systematic review. J Adv Nurs 2005;52(1):79–90.

466 57. Flaherty JH, Steele DK, Chibnall JT, et al. An ACE unit with a delirium room may improve function and equalize length of stay among older delirious medical inpatients. J Gerontol A Biol Sci Med Sci 2010;65:1387–1392. 58. Casarett DJ, Inouye SK. American College of Physicians-American Society of Internal Medicine End-of-Life Care Consensus Panel. Diagnosis and management of delirium near the end of life. Ann Intern Med 2001;135(1):32–40. 59. Inouye SK, Zhang Y, Jones RN, Kiely DK, Yang F, Marcantonio ER. Risk factors for delirium at discharge: Development and validation of a predictive model. Arch Intern Med 2007;167(13):1406–1413. 60. Flaherty JH, Little MO. Matching the environment to patients with delirium: Lessons learned from the delirium room, a restraint-free environment for older hospitalized adults with delirium. J Am Geriatr Soc 2011 November;59(Suppl 2):S295–S300. 61. Neufeld KJ, Yue J, Robinson TN, Inouye SK, Needham DM. Antipsychotic medication for prevention and treatment of delirium in hospitalized adults: a systematic review and meta-analysis. J Am Geriatr Soc 2016;64(4):705–714. 62. Nikooie R, Neufeld KJ, Oh ES, Wilson LM, Zhang A, Robinson KA, Needham DM. Antipsychotics for treating delirium in hospitalized adults: a systematic review. Ann Intern Med. 2019;171(7):485–495. 63. Agar MR, Lawlor PG, Quinn S, et al. Efficacy of oral risperidone, haloperidol, or placebo for symptoms of delirium among patients in palliative care: a randomized clinical trial. JAMA Intern Med 2017;177(1):34–42. 64. Finucane AM, Jones L, Leurent B, Sampson EL, Stone P, Tookman A, Candy B. Drug therapy for delirium in terminally ill adults. Cochrane Database Syst Rev 2020 January 21;1:CD004770. 65. Meagher D, Agar MR, Teodorczuk A. Debate article: Antipsychotic medications are clinically useful for the treatment of delirium. Int J Geriatr Psychiatry. 2018 November;33(11):1420–1427. 66. Fernandez F, Holmes V, Adams F, Kavanaugh J. Treatment of severe refractory agitation with a haloperidol drip. J Clin Psychiatry 1988;49(6):239–241. 67. U.S. Food and Drug Administration. Information for healthcare professionals: Haloperidol (marketed as Haldol, Haldol Decanoate and Haldol Lactate). 2007. http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/drugsafetyinformationforheathcareprofessionals/ucm085203.htm. (Accessed March 31, 2020). 68. Hui D, Frisbee-Hume S, Wilson A, Dibaj SS, Nguyen T, De La Cruz M, Walker P, Zhukovsky DS, Delgado-Guay M, Vidal M, Epner D, Reddy A, Tanco K, Williams J, Hall S, Liu D, Hess K, Amin S, Breitbart W, Bruera E. Effect of lorazepam with haloperidol vs haloperidol alone on agitated delirium in patients with advanced cancer receiving palliative care: a randomized clinical trial. JAMA 2017 September 19; 318(11):1047–1056. 69. U.S. Food and Drug Administration. Information for healthcare professionals: Antipsychotics. 2008 http://www.fda.gov/cder/drug/ InfoSheets/HCP/antipsychotics_conventional.htm. (Accessed March 31, 2020). 70. Patel AK, Bell MJ, Traube C. Delirium in pediatric critical care. Pediatr Clin North Am 2017 October;64(5):1117–1132. 71. Gagnon B, Low G, Schreier G. Methylphenidate hydrochloride improves cognitive function in patients with advanced cancer and hypoactive delirium: a prospective clinical study. J Psychiatry Neurosci 2005;30(2):100–107.

Textbook of Palliative Medicine and Supportive Care 72. Keen JC, Brown D. Psychostimulants and delirium in patients receiving palliative care. Palliat Support Care 2004;2(2):199–202. 73. Flükiger J, Hollinger A, Speich B, Meier V, Tontsch J, Zehnder T, Siegemund M. Dexmedetomidine in prevention and treatment of postoperative and intensive care unit delirium: a systematic review and meta-analysis. Ann Intensive Care 2018 September 20;8(1):92. 74. Fainsinger RL, Waller A, Bercovici M, et al. A multicentre international study of sedation for uncontrolled symptoms in terminally ill patients. Palliat Med 2000;14(4):257–265. 75. Rietjens JA, van Zuylen L, van Veluw H, van der Wijk L, van der Heide A, van der Rijt CC. Palliative sedation in a specialized unit for acute palliative care in a cancer hospital: comparing patients dying with and without palliative sedation. J Pain Symptom Manage 2008;36(3):228–234. 76. Connor SR, Pyenson B, Fitch K, Spence C, Iwasaki K. Comparing hospice and nonhospice patient survival among patients who die within a three-year window. J Pain Symptom Manage 2007;33(3):238–246. 77. Mercadante S, DeConno F, Ripamonti C. Propofol in terminal care. J Pain Symptom Manage 1995;10(8):639–642. 78. Lo B, Rubenfeld G. Palliative sedation in dying patients: “we turn to it when everything else hasn’t worked.” JAMA 2005;294(14):1810–1816. 79. Morita T, Chinone Y, Ikenaga M, et al. Efficacy and safety of palliative sedation therapy: a multicenter, prospective, observational study conducted on specialized palliative care units in Japan. J Pain Symptom Manage 2005;30(4):320–328. 80. Bercovitch M, Adunsky A. Patterns of high-dose morphine use in a home-care hospice service: should we be afraid of it? Cancer. 2004;101(6):1473–1477. 81. Vitetta L, Kenner D, Sali A. Sedation and analgesia-prescribing patterns in terminally ill patients at the end of life. Am J Hosp Palliat Care 2005;22(6):465–473. 82. Martinez F, Tobar C, Hill N. Preventing delirium: should non-pharmacological, multicomponent interventions be used? A systematic review and meta-analysis of the literature. Age Ageing 2015;44(2):196–204. 83. Siddiqi N, Harrison JK, Clegg A, et al. Interventions for preventing delirium in hospitalised non-ICU patients. Cochrane Database Syst Rev 2016;3:CD005563. 84. Al-Aama T, Brymer C, Gutmanis I, Woolmore-Goodwin SM, Esbaugh J, Dasgupta M. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial. Int J Geriatr Psychiatry 2011 July;26(7):687–694. 85. Hatta K, Kishi Y, Wada K, et al. Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial. JAMA Psychiatry 2014 April;71(4):397–403. 86. Hshieh T, Yue J, Oh E, et al. Effectiveness of multicomponent nonpharmacological delirium interventions: a meta-analysis. JAMA Intern Med 2015;175(4):512–520. 87. Gagnon P, Allard P, Gagnon B, Mérette C, Tardif F. Delirium prevention in terminal cancer: assessment of a multicomponent intervention. Psychooncology 2010 December;21:187–194. 88. Agar M, Quinn SJ, Crawford GB, et al. Predictors of mortality for delirium in palliative care. J Palliat Med 2016;19(11):1205–1209. 89. Bush et al. Delirium in adult cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 2018;29(supplement 4):iv143–iv165.

48

SLEEP DISTURBANCES IN ADVANCED CANCER PATIENTS

Delmer A. Montoya and Sriram Yennurajalingam

Contents Introduction....................................................................................................................................................................................................................... 467 Pathophysiology of sleep disorders in cancer patients.............................................................................................................................................. 469 Normal sleep architecture......................................................................................................................................................................................... 469 Mechanisms of cancer-related sleep disturbances................................................................................................................................................470 Assessment of sleep disorders.........................................................................................................................................................................................471 Treatment of sleep disturbances.....................................................................................................................................................................................472 Nonpharmacological interventions..........................................................................................................................................................................472 Pharmacological interventions..................................................................................................................................................................................473 Multimodal intervention for treatment of sleep disturbances in advanced cancer........................................................................................474 Conclusion...........................................................................................................................................................................................................................474 References............................................................................................................................................................................................................................474

Introduction Sleep disturbances (SDs) can be defined as any symptom or condition that interferes with normal sleep.1 They are very common in patients with advanced cancer,2 with a prevalence reported between 24 and 95% in this population. 3 However, this problem is usually neglected in treatment strategies for advanced cancer, as many studies have focused on patients with early-stage disease and survivors.4 SDs in the cancer population can present as a temporary symptom associated with the cancer or as part of depression or anxiety disorders, and physicians often assume that the SDs will resolve when the underlying problem is treated.4–6 The sleep disorders are a group of pathologic conditions that have been defined based on clinical presentation and diagnostic criteria.7 There is a classification system published by the American Academy of Sleep Medicine (AASM; see Table 48.1) that standardizes the diagnosis of sleep disorders and is especially useful in the research setting.8 This system recognizes six major sleep disorder categories: insomnia, sleep-related breathing disorders, hypersomnia, circadian rhythm sleep disorders, parasomnias, and sleep-related movement disorders. Of those disorder categories, the most common in advanced cancer patients, compared with the general population, is insomnia, which accounts for 35% of the diagnoses in these patients.9,10 Insomnia is a complex complaint that can be defined as a difficulty initiating sleep, trouble staying asleep, with prolonged nocturnal awakenings, early morning awakening with inability to resume sleep, or impairment of daytime functioning. Insomnia can appear as an isolated disorder or as a symptom that accompanies a different disorder. The Diagnostic and Statistical Manual of Mental disorders, fifth edition (DSM-5) and the International Classification of Sleep Disorders, third edition (ICSD-3) insomnia’s diagnostic criteria are similar because of collaborative efforts between the American Psychiatric Association and the AASM classification task forces. The DSM-IV distinction into primary and secondary insomnia is removed in DSM-5. Daytime distress or impairment in work, family, academic, and other vital areas of functioning account

for another key component. Other symptoms that commonly accompany insomnia include mood disturbance and irritability, anergia, and, especially in children, behavior problems such as hyperactivity, impulsivity, or aggression. ICSD-3 and DSM-5 both distinguish between short-term and chronic insomnia, with the latter continuing for 3 months or longer.75 The prevalence of sleep disorders in cancer patients is about twice that of the general population. Screening tests used for sleep disorder are heavily weighted toward diagnosing insomnia; therefore, it is not surprising that the most common SDs found by Sela et al. in palliative cancer patients were difficulty falling asleep (40%), difficulty staying asleep (63%), and not feeling rested in the morning (72%).1 Adjustment insomnia (acute insomnia) and insomnia due to medical conditions (comorbid insomnia) are the most common new-onset SD subtypes. The general criteria for insomnia in adults are presented in Table 48.2.12 The prevalence of SDs varies depending upon the type of cancer. For example, breast cancer patients have a high frequency of insomnia and fatigue, whereas lung cancer patients have the highest prevalence of SDs in general, owing to coughing, difficulty in breathing, and nocturia that lead to frequent awakenings that disrupt the patient’s sleep pattern. Proper diagnostic criteria and classification schemes have not been used when studying the frequency of sleep disorders in individuals with cancer, making it somewhat difficult to establish the incidence and prevalence of conditions other than insomnia.2 Some studies have suggested that a disrupted sleep–wake cycle is associated with a shorter survival rate in patients with advanced cancer,76,77 but these cross-sectional findings need to be interpreted cautiously, as a poorer prognosis could also lead to worse rest–activity rhythms. In this chapter, we will describe normal sleep architecture and discuss the mechanisms of cancer-related SD. We will then turn to assessment and diagnosis of SD, through subjective selfreports and more objective medical tests such as polysomnography (PSG). We will conclude by summarizing the treatments available, ranging from nonpharmacological methods to SD medications. 467

Textbook of Palliative Medicine and Supportive Care

468 TABLE 48.1  International Classification of Disorders 1.

2.

3.

4.

Insomnia a. Adjustment insomnia (acute insomnia) b. Psychophysiological insomnia c. Paradoxical insomnia d. Idiopathic insomnia e. Insomnia due to mental disorder f. Inadequate sleep hygiene g. Behavioral insomnia of childhood h. Insomnia due to drug or substance i. Insomnia due to medical condition j. Insomnia not due to substance or known physiological condition, unspecified (nonorganic insomnia, not otherwise specified (NOS)) k. Physiological (organic) insomnia, unspecified Sleep-related breathing disorders a. Central sleep apnea syndromes i. Primary central sleep apnea ii. Central sleep apnea due to Cheyne–Stokes breathing pattern iii. Central sleep apnea due to high-altitude periodic breathing iv. Central sleep apnea due to medical condition, not Cheyne–Stokes v. Central sleep apnea due to drug or substance vi. Primary sleep apnea of infancy b. Obstructive sleep apnoa (OSA) syndromes i. OSA, adult ii. OSA, pediatric c. Sleep-related hypoventilation/hypoxemic syndromes i. Sleep-related nonobstructive alveolar hypoventilation, idiopathic ii. Congenital central alveolar hypoventilation syndrome d. Sleep-related hypoventilation/hypoxemia due to medical conditions i. Sleep-related hypoventilation/hypoxemia due to pulmonary parenchymal or vascular pathology ii. Sleep-related hypoventilation/hypoxemia due to lower airway obstruction iii. Sleep-related hypoventilation/hypoxemia due to neuromuscular and chest wall disorders e. Other sleep apnea/sleep-related breathing disorders Hypersomnia of central origin not due to a circadian rhythm disorder or other cause of disturbed nocturnal sleep a. Narcolepsy with cataplexy b. Narcolepsy without cataplexy c. Narcolepsy due to medical conditions d. Narcolepsy unspecified e. Recurrent hypersomnia i. Kleine–Levin syndrome ii. Menstrual-related hypersomnia f. Idiopathic hypersomnia with long sleep time g. Idiopathic hypersomnia without long sleep time h. Behaviorally induced insufficient sleep syndrome i. Hypersomnia due to medical conditions j. Hypersomnia due to drug or substance k. Hypersomnia not due to substance or known physiological condition (nonorganic hypersomnia, NOS) l. Physiological (organic) hypersomnia, unspecified (organic hypersomnia, NOS) Circadian rhythm sleep disorder a. Circadian rhythm disorder, delayed sleep-phase type (delayed sleep-phase disorder) b. Circadian rhythm disorder, advanced sleep-phase type (advanced sleep-phase disorder) c. Circadian rhythm disorder, irregular sleep–wake type (irregular sleep–wake rhythm) d. Circadian rhythm disorder, free-running type (nonentrained type) e. Circadian rhythm disorder, jet lag type (jet lag disorder) f. Circadian rhythm disorder, shift work type (shift work disorder) g. Circadian rhythm disorder, due to medical conditions h. Other circadian rhythm disorder (circadian rhythm disorder, NOS) i. Other circadian rhythm disorder due to drug or substance

Sleep Disturbances in Advanced Cancer Patients

469

TABLE 48.1  International Classification of Disorders (Continued) 5.

6.

7.

8.

Parasomnia a. Disorders of arousal from non-rapid eye movement (NREM) sleep i. Confusional arousals ii. Sleepwalking iii. Sleep terrors b. Parasomnias usually associated with REM sleep i. REM sleep behavior disorder ii. Recurrent isolated sleep paralysis iii. Nightmare disorder c. Other parasomnias i. Sleep-related dissociative disorders ii. Sleep enuresis iii. Sleep-related groaning (catathrenia) iv. Exploding head syndrome v. Sleep-related hallucinations vi. Sleep-related eating disorder vii. Parasomnia, unspecified viii Parasomnias due to drug or substance ix. Parasomnias due to medical conditions Sleep-related movement disorder a. Restless legs syndrome b. Periodic limb movement disorder c. Sleep-related leg cramps d. Sleep-related bruxism e. Sleep-related rhythmic movement disorder f. Sleep-related movement disorder, unspecified g. Sleep-related movement disorder due to drug or substance h. Sleep-related movement disorder due to medical conditions Isolated symptoms, apparently normal variants and unresolved issues a. Long sleepers b. Short sleepers c. Snoring d. Sleep talking e. Sleep starts (hypnic jerks) f. Benign sleep myoclonus of infancy g. Hypnagogic foot tremor and alternating leg muscle activation during sleep h. Propriospinal myoclonus at sleep onset i. Excessive fragmentary myoclonus Other sleep disorders a. Other physiological (organic) sleep disorder b. Other sleep disorder not due to substance or known sleep disorder c. Environmental sleep disorder

Sources: Adapted from American Academy of Sleep Medicine. International Classification of Sleep Disorders: Diagnostic and Coding Manual, 2nd edn. Westchester, IL: American Academy of Sleep Medicine, 2005; Freedom T. Classification of sleep disorders. Disease-a-Month 2011;57: 323.

Pathophysiology of sleep disorders in cancer patients Normal sleep architecture

The normal sleep physiology has been divided into two distinct physiologic types: rapid eye movement (REM) and non-rapid eye movement (NREM) sleep. The latter is subdivided in stages numbered from N1 to N3. The last stage is known as slow-wave sleep based on the electroencephalography. Perhaps the most important difference between NREM and REM sleep is the presence

of voluntary muscle paralysis with evidence of electroencephalographic activity in the latter. During REM sleep, people experience dreams and significant autonomic variability.13 Sleepers experience complete paralysis of voluntary skeletal muscles, which is mediated through changes in the brain stem that causes activation of descending inhibitory pathways on the brain stem and spinal cord.14 During a normal sleep night, individuals progress between different sleep stages, from light (stage 1) to deep or slow-wave sleep, returning to more light stages and to REM sleep in between.

Textbook of Palliative Medicine and Supportive Care

470 TABLE 48.2  General Criteria for Insomnia in Adults

1. Difficulty initiating sleep, difficulty maintaining sleep, or waking up too early or sleep that is chronically nonrestorative or poor in quality 2. Sleep difficulty occurring despite adequate opportunities and circumstances for sleep 3. Patient reports at least one of the following forms of daytime impairment related to the nighttime sleep difficulty: • Fatigue or malaise • Attention, concentration, or memory impairment—social or vocational dysfunction • Mood disturbance or irritability • Daytime sleepiness • Motivation, energy, or initiative reduction • Proneness for errors or accidents at work or while driving • Tension, headache, or gastrointestinal symptoms in response to sleep loss • Concerns or worries about sleep Source:

Adapted from American Academy of Sleep Medicine. International Classification of Sleep Disorders: Diagnostic and Coding Manual, 2nd edn. Westchester, IL: American Academy of Sleep Medicine, 2005.

A normal night sleep consists of several of these fluctuations (between 4 and 6). The distinction between the physiological stages of sleep is important because certain pathologies present exclusively during certain stages (parasomnias) or are exacerbated during specific phases (such as sleep-disordered breathing during REM sleep).15,16

Mechanisms of cancer-related sleep disturbances

Just as many aspects of sleep physiology are still not understood, the precise mechanism by which cancer leads to SDs also remains unknown. Several models have been developed to explain sleep– wake disorders in the context of cancer. All these models appear to coincide in the multifactorial nature of the disorder and the hypothesis that physiological, psychological, and behavioral phenomena play an important role in the development of deviations from normal sleep and pathologic changes.17 The most commonly cited hypothesis in patients with cancer is based on the Speilman three-factor model: (1) predisposing factors that increase the individual’s vulnerability to insomnia (gender, age, and a family history of insomnia); (2) precipitating factors that trigger the onset of insomnia (disease-specific biological factors, cancer-related emotional factors, functional loss, treatment, pain, and delirium); and (3) perpetuating factors that maintain insomnia over time

(maladaptive sleep behaviors and misconceptions about sleep). The most important contributors for each category of factors are summarized in Table 48.3.10 This model assumes that predisposing factors are rarely modifiable and that many cancer patients may have preestablished sleep disorders, thus making the determination of true risk factors difficult, especially since some populations have been studied preferentially (e.g., breast cancer patients). The cancer-specific-related risk factors for SDs may be subdivided into disease-specific, treatment-related, or associated phenomenon. Patients with cancer share demographic and age risk factors for SDs with the normal population. The single most important unmodifiable risk factor for sleep–wake disturbances is age, especially since cancer tends to be diagnosed in older patients. The cancer-specific factors may be subdivided into disease-specific, treatment-related, or associated phenomena.12 These cancer-specific factors have been divided into pathophysiological changes induced by the disease, symptoms that may interfere with normal sleep initiation or maintenance, and changes in lifestyle that could contribute to disturbances in the sleep–wake cycle. Cancer can affect the patient’s sleep by contributing to symptoms that are known to cause sleep–wake disruption. Changes in sleep architecture have been described with decrease in

TABLE 48.3  Key Etiologic Factors of Insomnia in Cancer Patients Predisposing Factors

Precipitating Factors

• Psychiatric disorders

• Pain

• • • •

• • • • •

Female sex Advancing age Hyperarousability Family history of insomnia • Personal history of insomnia • Misconceptions about the causes of insomnia

Medical illness Mutilating surgery Hospitalization Radiation therapy Bone marrow transplantation

Perpetuating Factors • Poor sleep habits (excessive time spent in bed, napping, irregular sleep schedules)

• • Dysfunctional reactions to sleep (anxiety associated with the act of sleeping)

• Medications (antiemetic drugs, hormonal therapy, chemotherapy)

•

• • Delirium

Source:

Adapted from Savard J, Morin CM. J Clin Oncol 2001February 1;19: 895.

• Unrealistic sleep requirements • • Misattributions of daytime impairments

Sleep Disturbances in Advanced Cancer Patients slow-wave sleep and REM sleep and corresponding increases in stages N1 and N2 sleep.18 Symptoms such as urinary disturbances can cause patients to awaken frequently, disturbing their sleep cycles. Several agents used to treat malignancies also can lead to symptoms such as neuropathy or pain that can further disrupt the sleep–wake cycle. Pain has been proposed as an important factor leading to insomnia, although there have been very few trials to support this widely accepted association.2,19 Likewise, inadequate pain management can lead to significant changes in insomnia occurrence and severity. In a study of symptom assessment, Meuser et al. showed that adequate pain control may actually be associated with a decrease in the incidence of insomnia.20 Another important aspect of pain in cancer patients is that it is frequently treated with opioids, which can cause changes in the normal sleep physiology and lead to respiratory depression with exacerbation of other sleep disorders.21 Mood and anxiety disorders, which appear to interfere significantly with normal sleep, are the most common psychiatric diagnoses in cancer patients and have been demonstrated to cause disruption of the sleep architecture, as in depression.22–24 In contrast, anxiety can lead to increased arousal with patients experiencing difficulty falling asleep. Despite the extensive association between affective problems and anxiety with SDs, there is very little evidence that this association is exclusive to the cancer population, suggesting that the symptoms may precede the cancer diagnosis.25,26 Severe emotional distress, not uncommon in this group of patients, may further alter the patient’s ability to maintain sleep. There is growing interest in the potential role of cytokines in the development of specific symptoms in cancer patients. Elevated levels of proinflammatory cytokines have been found in patients with cancer.27 Cytokines exert their effect in the brain through different pathways including the liberation of prostaglandin E2 thus elevating the body temperature and stimulating the hypothalamic–pituitary–adrenal axis that in turn may lead to changes in the sleep–wake cycle. As symptoms experienced by this population may resemble those suffered by individuals with infections, cytokines have been studied as potential mediators of most chemotherapy and cancer-related symptoms.28,29 Some cancer patients receiving interleukin-2 and tumor necrosis factor alpha (TNF-α) as treatment for their underlying malignancy develop systemic signs of inflammation and the appearance of symptoms such as fever, fatigue, anorexia, and insomnia.2 Further experimental data from animal models suggest the important role of these cytokines in sleep. For example, interleukin-1 and TNF-α increased intracellular calcium concentrations in gamma amino butyric acid (GABA)-producing cultured rat hypothalamic neurons. 30 In addition, studies done in rats have shown that the administration of interleukin-1 or TNF-α can induce and increase slow-wave sleep when administered topically to the somatosensory cortex under the dura. 31 It also appears that the effects of the cytokines on sleep may be modulated through the serotonin system, since the dorsal raphe, the main serotoninergic system in the brain, has receptors for interleukin-1 and exposure to cytokines increases NREM sleep in rats. 32 In addition, most of the effects of interleukin-1 on sleep are lost with disruption of the serotoninergic system in the brain. 33,34 Finally, other animal models have demonstrated that the infusion of interleukin-1 to the preoptic nucleus of the hypothalamus can change the firing rates of active neurons, further substantiating the potential role of these cytokines in sleep. 35

471 Interleukin-6, another cytokine that may be involved in the regulation of sleep, is important in the modulation of response to interleukin-1 among other functions. Interleukin-6 shows a normal diurnal variation in levels that mirror changes in the sleep– wake cycle36 and can also increase slow-wave sleep and reduce REM sleep in humans. 37 Interestingly, clinical studies using the TNF-α receptor antagonist etanercept have shown a decrease in plasma interleukin-6 levels as well as daytime sleepiness in sleep apnea patients. 38 There are clinical studies showing that interleukin-6 levels may correlate with the amount of sleep and that sleep deprivation may change the normal temporal pattern of circadian interleukin-6 secretion. 39 Thus, growing evidence supports the role of cytokines as sleep modulatory substances. Most of the data come from animal experiments, but some clinical data are slowly appearing. One important aspect from a therapeutic standpoint is the modulation potential of these protein levels as a treatment for SD.

Assessment of sleep disorders The most important aspect during assessment of SD in cancer patients is characterizing the sleep difficulty and identifying the causes, exacerbating factors, and comorbidities that trigger the SD. Taking into consideration that cancer patients occasionally do not report SD to their physicians, a thorough history is essential to identify the factors that contribute to SD. The patients should be able to provide this information, and their partners should be asked to contribute to the sleep history to rule out other sleep disorders such as restless legs syndrome or obstructive sleep apnea (OSA).40,41 Several screening and evaluation tests are available for detecting and diagnosing SD. The first group of the tests relies on selfreports about sleep latency, quality, satisfaction, and awakenings. This information is usually gathered with sleep quality questionnaires, sleep history questionnaires, sleep diaries, and daytime sleepiness questionnaires.13 The Pittsburgh Sleep Quality Index (PSQI), the standard for self-reported sleep data, is a frequently used tool in clinical research. The PSQI measures the quality and patterns of sleep and differentiates “poor” from “good” sleep by measuring subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, SD, use of sleeping medication, and daytime dysfunction.42 The Edmonton Symptom Assessment Scale (ESAS) evaluates the prevalence and severity of 10 self-reported symptoms commonly experienced by cancer patients over the previous 24 hours: pain, fatigue, nausea, depression, anxiety, drowsiness, dyspnea, loss of appetite, sense of well-being, and sleep. The severity of each symptom is rated on a numerical scale of 0–10, where 0 means that the symptom is absent, and 10 indicates the worst possible severity.43 The cutoff point of the presence of ESAS sleep symptom is 3 out of 10 for the screening of SD. This cutoff has a sensitivity of 86% and a specificity of 53%. 3 Another way to document SDs and monitor the effect of interventions is with sleep diaries, which are more objective than patient or partner recall. Several sleep diary models collect various kinds of data, but in general, the patient records daily information on time of initiation of sleep, total sleep time, and number of awakenings. Daytime sleepiness and sleep-related habits are recorded as well.44 The daytime sleepiness inventories are aimed at finding the repercussions of impaired sleep on the patient’s daytime functioning. Because of the subjective nature of the self-reported instruments, it is often recommended that researchers and physicians

Textbook of Palliative Medicine and Supportive Care

472 also use objective measures of SD. The standard for detection of specific sleep and wake states is PSG.45 PSG records several bioelectrical signals such as electroencephalogram (EEG), heart rate, respiratory rate, upper airway flow, presence of snoring, EMG, and leg movement to characterize the sleep architecture and detect SD. Another frequently used test in the diagnosis of SD is actigraphy which uses an accelerometer to monitor activity throughout the day. With the use of computer algorithms, actigraphy calculates sleep time, latency, and awakenings. Unlike subjective measures, which can differ significantly from the polysomnogram, actigraphy correlates well with polysomnographic data.46 Both PSG and actigraphy complement the self-reported SD. These tests help us gather more objective information about stages of sleep in hospital settings or sleep–wake patterns of patients in their own homes.47 Laboratory investigations may be considered when associated medical conditions are causing SD. For example, ferritin measurement can help diagnose restless legs syndrome, and a physical examination of the head and neck can help identify OSA as a cause of daytime tiredness and fatigue secondary to SD. The STOP-Bang (snoring, tired, observed, blood pressure–BMI, age, neck circumference, gender) questionnaire was developed as a screening tool for OSA in surgical patients and preoperative clinics. This questionnaire is short and easy to apply and has sensitivity between 93 and 100% for moderate-to-severe OSA.48

Treatment of sleep disturbances SD has a negative effect on quality of life in patients suffering from advanced cancer and other diseases, emphasizing the need to treat this condition.49 Management of the underlying pathology is paramount in order to lessen the somatic, psychological, and social effects of SD experienced by cancer patients. Symptoms such as fatigue, impaired daytime functioning, and mood disturbances are commonly reported by advanced cancer patients and could be secondary to SD.10 Therefore, the development of interventions aimed at improving SD can help alleviate these symptoms and increase patients’ coping capacity.10 A multimodal approach with pharmacological and nonpharmacological interventions has been used to treat SD in advanced cancer patients, but data on the effectiveness of these measures in this specific population are limited.50 Although there are no prospective studies that inform an evidence-based approach, for many patients a combined approach is most helpful.

Nonpharmacological interventions

The AASM strongly recommends educating patients about sleep hygiene measures51 (see Table 48.4). These interventions alone have not been demonstrated to be effective against insomnia but are easy to implement and have a high possibility of improving sleep when combined with other therapeutic interventions such as cognitive behavioral treatment (CBT). Awareness of good sleep hygiene may also help the patient identify abnormal behavior that can interfere with restful sleep. Several nonpharmacological therapies to treat insomnia have been tried in the general population. The most commonly evaluated modalities include behavioral and CBTs. CBT is a supportive counseling intervention aimed at eliminating factors associated with chronic insomnia, reducing the severity of perpetuating factors below the insomnia threshold, and deactivating the hyperarousal.12 Importantly, two meta-analyses revealed that some of these interventions might have efficacy against insomnia.10 Not all measures of sleep quality have responded equally well to CBT. The largest therapeutic effects have been obtained for sleep-onset latency, sleep quality ratings, and duration of awakenings. The National Institutes of Health State-of-the-Science Conference on Insomnia concluded that CBT is as effective as hypnotic medications are for the short-term management of insomnia.2 CBT’s effects are also longer lasting than those of pharmacological agents, and in general, CBT may have other benefits for the patient’s quality of life. The American Academy of Sleep Medicine’s Practice Parameters, published in 2006, recommended behavioral and psychological interventions as a standard for the treatment of chronic comorbid insomnia.12 Other techniques that have proven beneficial include stimulus control, relaxation, sleep restriction, and multicomponent therapy that are part of CBT. Several studies have evaluated the effectiveness of CBT for the treatment of insomnia in the cancer population. A recent review reports that four randomized controlled trials and nine quasi-experimental studies have shown that in general, CBT is an effective intervention that leads to improvement of several sleep outcome measures including sleep quality using the PSQI.12 These studies have been performed in different cancer populations, including patients undergoing active treatment and survivors. Among other interventions, supportive expressive group therapy showed an increase in the wake-latency time in breast cancer patients.52 Objective measures, such as actigraphy, and subjective measures, such as sleep diaries and questionnaires, showed improvement with CBT in a randomized controlled crossover study done by Fiorentino et al.53

TABLE 48.4  Commonly Recommended Sleep Hygiene Measures 1. Maintain a regular bed and wake time schedule including weekends. 2. Establish a regular, relaxing bedtime routine such as soaking in a hot bath and then reading a book or listening to soothing music. 3. Create a sleep-conducive environment that is dark, quiet, comfortable, and cool. 4. Sleep on a comfortable mattress and pillows. 5. Use your bedroom only for sleep and sex. 6. Finish eating at least 2–3 hours before your regular bedtime. 7. Exercise regularly. It is best to complete your workout at least a few hours before bedtime. 8. Avoid caffeine (e.g., coffee, tea, soft drinks, chocolate etc.) close to bedtime. It can keep you awake. 9. Avoid nicotine (e.g., cigarettes, tobacco products). When used close to bedtime, it can lead to poor sleep. 10. Avoid alcohol close to bedtime. Sources: Adapted from National Sleep Foundation. Healthy Sleep Tips. http://www.sleepfoundation.org/article/sleep-topics/healthy-sleep-tips. (Accessed May 23, 2012); American Academy of Sleep Medicine. International Classification of Sleep Disorders: Diagnostic and Coding Manual, 2nd edn. Westchester, IL: American Academy of Sleep Medicine, 2005.

Sleep Disturbances in Advanced Cancer Patients

473

Complementary interventions that have been tested include progressive muscle relaxation, which decreased sleep latency in patients with multiple cancers; hypnosis interventions, which decreased hot flashes in breast cancer patients; and bright light therapy, which may improve SD and fatigue in breast cancer patients during chemotherapy.2,12 Exercise interventions such as stretching, concentrating, and strengthening affect the circadian phase (evening exercise produced substantial phase advances for evening exercises). Regular exercise for a sustained period of time may help to improve sleep latency and quality.47 Exercise may prove beneficial for cancer patients, but further studies are required before these interventions can be widely recommended.12 Although not all studies found benefit from combining specific interventions, layering different approaches appears to be helpful to at least some patients, and they are all low-risk interventions.

Pharmacological interventions

The approach to SD should take into account the patient’s overall clinical condition. Patients receiving palliative care but who maintain a relatively better prognosis and have minimal comorbid conditions will likely tolerate pharmacological treatments for insomnia similar to medically healthy individuals. However, patients approaching end of life or who are more debilitated may be more susceptible to the side effects of pharmacological treatment due to drug–drug interactions or the presence of end organ impairment.71 Pharmacotherapy is the most common SD intervention in the general population and cancer patients. Table 48.5 summarizes the most commonly used hypnotic agents in the cancer population. The newer, short-acting benzodiazepines have a more selective hypnotic effect with less residual side effects than the long-acting benzodiazepines. Benzodiazepines interact with the GABA-A receptor, increasing the conductance to chloride and

therefore hyperpolarizing the neurons.54 In general, benzodiazepines cause central nervous system depression, with amnestic and hypnotic effects, and have been shown to decrease sleep latency and duration in short-term studies in the general population.55,56 However, objective data from polysomnographic studies show that self-reported measures may overestimate the effect on sleep latency.57 There are many different benzodiazepines with variable half-lives depending on their metabolism. This becomes important when using long half-life medications, since residual effects with impairment of daytime functioning may occur, especially in the elderly, leading to an increased risk of falls and hip fractures.58 Another important concern in elderly cancer patients is the potential of benzodiazepines to cause delirium, cognitive impairment, and respiratory depression when combined with opioids.59–62 These adverse interactions have been described with methadone even at a low dose.63 In addition, very little information is available on the long-term efficacy of these agents, and the well-known pharmacological effects, such as the patient’s tolerance and dependence on these agents, may make them undesirable for long-term use.64 Antidepressant medications with sedative properties, such as trazodone, amitriptyline, and doxepin, can be beneficial for depressed patients with SD.10 Since selective serotonin reuptake inhibitors (SSRIs) have very low sedative effects, the use of SSRIs is limited to depression-related insomnia. Venlafaxine can be used to treat both hot flashes and SD in breast cancer patients; however, no beneficial effects for sleep have been reported. SSRI and serotonin norepinephrine reuptake inhibitors (SNRIs) can produce SD as well owing to their pharmacological action over the 5-HT2 and 5-HT3 receptors.65 Side effects associated with antidepressants, such as orthostasis (mostly with trazodone), anticholinergic activity, nausea, and constipation, should be considered before prescribing these

TABLE 48.5  Commonly Used Hypnotic Medications Activity

Initial Dose (mg)

Ultrashort acting Short-onset brief duration Short-onset, intermediate duration of action

Intermediate onset, duration Longer latency to onset, prolonged activity

Longer latency to onset, prolonged activity (off-label for insomnia)

Variable activity (off-label for insomnia)

Source:

Zaleplon Triazolam Alprazolam Zolpidem Zopiclone Eszopiclone Lorazepam Temazepam Clonazepam Chlordiazepoxide Diazepam Amitriptyline Imipramine Doxepin Trazodone Mirtazapine Haloperidol Risperidone Olanzapine Quetiapine

5–10 0.125 0.5–1 5–10 5–7.5 3 0.5–4 7.5–15 0.5–2 50–100 5–10 25–100 25–100 25–100 25–100 15–30 0.5–5 0.5–1 5–10 25

considerations Little to no anxiolytic effect; costly Rapid sleep induction; limited effect on sleep maintenance No clear advantage over benzodiazepines; costly; minimal anxiolytic effect Adequate effect on sleep induction and maintenance; risk of daytime drowsiness Slow sleep induction with increased risk of accumulation of metabolites; high risk of daytime sedation Increased risk of daytime sedation, confusion, constipation, and cardiac conduction abnormalities

Used in sleep disturbance related to psychosis or delirium

Adapted from Delgado-Guay M, Yennurajalingam S. Oxford American Handbook of Hospice and Palliative Medicine, Yennurajalingam S, Bruera E (eds.). New York: Oxford University Press, 2011, pp. 115–126.

Textbook of Palliative Medicine and Supportive Care

474 medications to cancer patients.65 Tricyclic antidepressants can decrease sleep latency, reduce awakenings, and increase sleep quality, but they also can cause concerning side effects, such as daytime sedation, an anticholinergic effect, and cardiovascular problems, especially in older patients.65–67 Mirtazapine is a good option for managing multiple distressing symptoms in cancer patients. A noradrenergic and specific serotonergic antidepressant with antagonistic effects on 5-HT2 and 5-HT3 receptors, mirtazapine can improve nausea, vomiting, and insomnia. An advantageous side effect associated with mirtazapine is weight gain because this agent increases appetite and thus improves anorexia in cancer patients. Benzodiazepines should not be used with mirtazapine because of the risk of sedation.68 Diphenhydramine is an over-the-counter antihistamine with sedating properties. However, the side effects, primarily related to the anticholinergic action (e.g., dry mouth, decreased cognitive function, delirium etc.), the rapid development of tolerance, and the lack of safety data in palliative care patients should discourage their widespread use, particularly in the palliative care context.74 Melatonin, a naturally existing hormone produced in the pineal gland, regulates circadian rhythm by regulating the suprachiasmatic nucleus of the hypothalamus through G-protein-coupled receptors (MT1–MT3). The use of melatonin in the treatment of sleep disorders is still controversial. Data from several metaanalyses suggest that melatonin’s effects are limited to delayed sleep-phase syndrome.69 One of the suggested reasons for melatonin’s failure to achieve results against insomnia in clinical trials is the lack of consistency in the melatonin presentations, which has led to the development of specific melatonin (MT1–MT2) agonists that have received Food and Drug Administration approval for the treatment of insomnia. An example is Ramelteon, a selective melatonin receptor agonist that can potentially be helpful in patients with sleep onset problems or sleep phase disruption. In contrast to benzodiazepines and benzodiazepine receptor agonists, it is non-habit forming and does not appear to have the side effects associated with other hypnotics.73 Ramelteon does, however, have important drug–drug interactions that should be carefully considered, especially in palliative care patients who may be on a number of different agents. It is metabolized primarily through the CYP450 1A2 pathway, thus it should not be coadministered with other potent inhibitors of this pathway, such as ciprofloxacin and fluvoxamine. Because of the lack of conclusive data for melatonin use in the cancer population, the routine use of this supplement or its agonists cannot be recommended, 50 even though melatonin appears to be very safe with few side effects.

Multimodal intervention for treatment of sleep disturbances in advanced cancer

In patients with advanced cancer, due to the multidimensional nature of sleep disturbances including sleep quality disturbance, it is unlikely that sleep disturbance can be effectively treated using a single intervention. A multimodal approach of combination of pharmacological and nonpharmacological treatments simultaneously should be considered on the basis of a predominant pathophysiologic mechanism for a given patient. We recently completed a study (five to obtain feasibility data and effect sizes for various known treatments, including bright light therapy, melatonin, methylphenidate, their placebos, and combinations thereof to improve sleep quality, as measured by change in PSQI scores from baseline to day 15 and day 30 [NCT01628029]). We described these treatment combinations

as multimodal therapy. For the conduct of the study, we only included cancer patients with sleep quality disturbance (PSQI ≥ 5). Using a double-blind randomized factorial study design, patients were randomized into one of the eight arms of the study, which included combinations of interventions or their corresponding placebo treatments for 2 weeks. All patients received three sessions of standardized psychoeducation intervention based on the principles of CBT to control for insomnia counseling. We found that 84% (54 of 64) of randomized patients completed the study. There were no differences in the demographics and baseline sleep quality scores between groups, and there were no significant differences in adverse events by groups (p = 0.80). The adherence rates for bright light therapy, melatonin, methylphenidate, and CBT were 93, 100, 100, and 100%, respectively. The effect size for change in PSQI scores for bright light therapy (N = 29) was 0.46, p = 0.017; for melatonin (N = 26) was 0.24, p = 0.20; and for methylphenidate (N = 26) was 0.06, p = 0.46. Based on these results, we concluded that the use of multimodal therapy interventions to treat sleep quality disturbance was feasible. Most importantly, bright light therapy+ melatonin+ CBT showed the most promising effect size (0.64) in improvement in sleep quality. In addition, we found that most of the patients wanted an opportunity to receive the active treatment, i.e., bright light therapy+ melatonin+ CBT, after the randomized phase. However, further studies are needed to validate these findings.

Conclusion SDs have a negative effect on quality of life in the advanced cancer patients. Fatigue, impaired daytime functioning, and mood disturbances are commonly reported in this population and could be secondary to SDs. Both subjective and objective screening tools are available for evaluation of SD in the cancer population. Interventions that are aimed at improving SDs help alleviate these symptoms and increase the copying capacity. Management of these symptoms usually requires a multimodality approach with the use of nonpharmacological and pharmacological measures to obtain long-lasting results.

References





1. Sela RA, Watanabe S, Nekolaichuk CL. Sleep disturbances in palliative cancer patients attending a pain and symptom control clinic. Palliat Support Care 2005 March;3:23. 2. Liu L, Ancoli-Israel S. Sleep disturbances in cancer. Psychiatr Ann 2008 September 1;38:627. 3. Delgado-Guay M, Yennurajalingam S, Parsons H, Palmer JL, Bruera E. Association between self-reported sleep disturbance and other symptoms in patients with advanced cancer. J Pain Symptom Manage 2011;41:819. 4. Akechi T, et al. Associated and predictive factors of sleep disturbance in advanced cancer patients. Psycho-Oncology 2007 October;16:888. 5. Morin CM, et al. Cognitive behavioral therapy, singly and combined with medication, for persistent insomnia: a randomized controlled trial. J Am Med Assoc 2009 May 20;301:2005. 6. Savard J, Simard S, Ivers H, Morin CM. Randomized study on the efficacy of cognitive-behavioral therapy for insomnia secondary to breast cancer, part I: sleep and psychological effects. J Clin Oncol: Official J Am Soc Clin Oncol 2005 September 1;23:6083. 7. American Academy of Sleep Medicine. International Classification of Sleep Disorders: Diagnostic and Coding Manual, 2nd edn. Westchester, IL: American Academy of Sleep Medicine, 2005. 8. Freedom T. Classification of sleep disorders. Disease-a-Month 2011 July;57:323. 9. Hearson B, Sawatzky JA. Sleep disturbance in patients with advanced cancer. Int J Palliat Nurs 2008 January;14:30.

Sleep Disturbances in Advanced Cancer Patients 10. Savard J, Morin CM. Insomnia in the context of cancer: a review of a neglected problem. J Clin Oncol 2001 February;19:895. 11. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: American Psychiatric Association, 2000. 12. Berger AM. Update on the state of the science: sleep–wake disturbances in adult patients with cancer. Oncol Nurs Forum 2009 July;36:E165. 13. Vena C, Parker K, Cunningham M, Clark J, McMillan S. Sleep–wake disturbances in people with cancer. Part I: an overview of sleep, sleep regulation, and effects of disease and treatment. Oncol Nurs Forum 2004 July;31:735. 14. Hishikawa Y, Shimizu T. Physiology of REM sleep, cataplexy, and sleep paralysis. Advance Neurol 1995;67:245. 15. Goldstein CA. Parasomnias. Disease-a-Month 2011;57:364. 16. Primhak R, Kingshott R. Sleep physiology and sleep-disordered breathing: the essentials. Arch Disease Childhood 2012 January 1;97:54. 17. Otte JL, Carpenter JS. Theories, models, and frameworks related to sleep–wake disturbances in the context of cancer. Cancer Nurs 2009 March–April;32:90. 18. Stepanski EJ, Burgess HJ. Sleep and cancer. Sleep Med Clin 2007;2:67. 19. Silberfarb PM, Hauri PJ, Oxman TE, Schnurr P. Assessment of sleep in patients with lung cancer and breast cancer. J Clin Oncol: Official J Am Soc Clin Oncol 1993 May;11:997. 20. Meuser T, et al. Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology. Pain 2001 September;93:247. 21. Dimsdale JE, Norman D, DeJardin D, Wallace MS. The effect of opioids on sleep architecture. J Clin Sleep Med: Official Pub Am Acad Sleep Med 2007 February 15;3:33. 22. Bottomley A. Depression in cancer patients: a literature review. Eur J Cancer Care 1998 September;7:181. 23. Fleming J. Sleep architecture changes in depression: interesting finding or clinically useful. Prog Neuropsychopharmacol Biol Psychiatry 1989;13:419. 24. Derogatis LR, et al. The prevalence of psychiatric disorders among cancer patients. J Am Med Assoc 1983 February 11;249:751. 25. Breslau N, Roth T, Rosenthal L, Andreski P. Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry 1996 March 15;39:411. 26. Cimprich B. Pretreatment symptom distress in women newly diagnosed with breast cancer. Cancer Nurs 1999 June;22:185. 27. Dunlop RJ, Campbell CW. Cytokines and advanced cancer. J Pain Symptom Manage 2000 September;20:214. 28. Wood LJ, Nail LM, Gilster A, Winters KA, Elsea CR. Cancer chemotherapy-related symptoms: evidence to suggest a role for proinflammatory cytokines. Oncol Nurs Forum 2006 May;33:535. 29. Rich T, et al. Elevated serum cytokines correlated with altered behavior, serum cortisol rhythm, and dampened 24-hour rest-activity patterns in patients with metastatic colorectal cancer. Clin Cancer Res: Official J Am Assoc Cancer Res 2005 March 1;11:1757. 30. De A, Churchill L, Obal F, Jr, Simasko SM, Krueger JM. GHRH and IL1 beta increase cytoplasmic Ca(2+) levels in cultured hypothalamic GABAergic neurons. Brain Res 2002 September 13;949:209. 31. Yoshida H, et al. State-specific asymmetries in EEG slow wave activity induced by local application of TNF alpha. Brain Res 2004 May 29;1009:129. 32. Manfridi A, et al. Interleukin-1 beta enhances non-rapid eye movement sleep when microinjected into the dorsal raphe nucleus and inhibits serotonergic neurons in vitro. Eur J Neurosci 2003 September;18:1041. 33. Imeri L, Mancia M, Opp MR. Blockade of 5-hydroxytryptamine (serotonin)-2 receptors alters interleukin-1-induced changes in rat sleep. Neuroscience 1999;92:745. 34. Gemma C, Imeri L, de Simoni MG, Mancia M. Interleukin-1 induces changes in sleep, brain temperature, and serotonergic metabolism. Am J Physiol 1997 February;272:R601. 35. Alam MN, et al. Interleukin-1 beta modulates state-dependent discharge activity of preoptic area and basal forebrain neurons: role in sleep regulation. Eur J Neurosci 2004 July;20:207. 36. Bauer J, et al. Interleukin-6 serum levels in healthy persons correspond to the sleep–wake cycle. Clin Invest 1994 March;72:315. 37. Spath-Schwalbe E, et al. Acute effects of recombinant human interleukin-6 on endocrine and central nervous sleep functions in healthy men. J Clin Endocrinol Metab 1998 May;83:1573.

475 38. Vgontzas AN, et al. Marked decrease in sleepiness in patients with sleep apnea by etanercept, a tumor necrosis factor-alpha antagonist. J Clin Endocrinol Metab 2004 September;89:4409. 39. Redwine L, Hauger RL, Gillin JC, Irwin M. Effects of sleep and sleep deprivation on interleukin-6, growth hormone, cortisol, and melatonin levels in humans. J Clin Endocrinol Metab 2000 October;85:3597. 40. Sateia MJ, Doghramji K, Hauri PJ, Morin CM. Evaluation of chronic insomnia. An American Academy of Sleep Medicine review. Sleep 2000 March 15;23:243. 41. Chesson A, Jr. et al. Practice parameters for the evaluation of chronic insomnia. An American Academy of Sleep Medicine report. Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep 2000 March 15;23:237. 42. Buysse DJ, Reynolds CF, 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989 May;28:193. 43. Bruera E, Kuehn N, Miller MJ, Selmser P, Macmillan K. The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care 1991 Summer;7:6. 44. Babkoff H, Weller A, Lavidor M. A comparison of prospective and retrospective assessments of sleep. J Clin Epidemiol 1996 April;49:455. 45. de Souza L, et al. Further validation of actigraphy for sleep studies. Sleep 2003 February 1;26:81. 46. Cole RJ, Kripke DF, Gruen W, Mullaney DJ, Gillin JC. Automatic sleep/ wake identification from wrist activity. Sleep 1992 October 1;15:461. 47. Berger A, et al. Sleep/wake disturbances in people with cancer and their caregivers: state of the science. Oncol Nurs Forum 2005;32:E98. 48. Chung F, et al. STOP questionnaire: a tool to screen patients for obstructive sleep apnea. Anesthesiology 2008 May;108:812. 49. Fortner BV, Stepanski EJ, Wang SC, Kasprowicz S, Durrence HH. Sleep and quality of life in breast cancer patients. J Pain Symptom Manage (2002;24:471. 50. Delgado-Guay M, Yennurajalingam S. Symptom Assessment. In: Yennurajalingam S, Bruera E, eds., Oxford American Handbook of Hospice and Palliative Medicine. New York: Oxford University Press, 2011, pp. 115–126. 51. Morgenthaler T, et al. Practice parameters for the psychological and behavioral treatment of insomnia: An update. An american academy of sleep medicine report. Sleep 2006 November;29:1415. 52. Fobair P, et al. Psychosocial intervention for lesbians with primary breast cancer. Psycho-Oncology 2002 September–October;11:427. 53. Fiorentino L, et al. Individual cognitive behavioral therapy for insomnia in breast cancer survivors: a randomized controlled crossover pilot study. Nature Sci Sleep 2009 December 1;2010:1. 54. Polc P. Enhancement of GABAergic inhibition: a mechanism of action of benzodiazepines, phenobarbital, valproate and L-cycloserine in the cat spinal cord. Electroencephalogr Clin Neurophysiol Suppl 1982;36:188. 55. Nowell PD, et al. Benzodiazepines and zolpidem for chronic insomnia: a meta-analysis of treatment efficacy. J Am Med Assoc 1997 December 24–31;278:2170. 56. Parrino L, Terzano MG. Polysomnographic effects of hypnotic drugs. A review. Psychopharmacology 1996 July;126:1. 57. Holbrook AM, Crowther R, Lotter A, Cheng C, King D. Meta-analysis of benzodiazepine use in the treatment of insomnia. Canad Med Assoc J (journal de I’Association medicale canadienne) 2000 January 25;162:225. 58. Wagner AK, et al. Benzodiazepine use and hip fractures in the elderly: who is at greatest risk? Arch Inter Med 2004 July 26;164:1567. 59. Foy A, et al. Benzodiazepine use as a cause of cognitive impairment in elderly hospital inpatients. J Gerontol Series A Biol Sci Med Sci 1995 March;50:M99. 60. Hanlon JT, et al. Benzodiazepine use and cognitive function among community-dwelling elderly. Clin Pharmacol Ther 1998 December;64:684. 61. Paterniti S, Dufouil C, Alperovitch A. Long-term benzodiazepine use and cognitive decline in the elderly: the epidemiology of vascular aging study. J Clin Psychopharmacol 2002 June;22:285. 62. Tune LE, Bylsma FW. Benzodiazepine-induced and anticholinergic-induced delirium in the elderly. Int Psychogeriatr/IPA 1991 Winter;3:397. 63. Corkery JM, Schifano F, Ghodse AH, Oyefeso A. The effects of methadone and its role in fatalities. Human Psychopharmacol 2004 December;19:565. 64. Busto U, Sellers EM. Pharmacologic aspects of benzodiazepine tolerance and dependence. J Substance Abuse Treatment 1991;8:29.

476 65. Fava M, et al. Acute efficacy of fluoxetine versus sertraline and paroxetine in major depressive disorder including effects of baseline insomnia. J Clin Psychopharmacol 2002 April;22:137. 66. Saletu-Zyhlarz GM, et al. Insomnia in depression: differences in objective and subjective sleep and awakening quality to normal controls and acute effects of trazodone. Prog Neuropsychopharmacol Biol Psychiatry 2002 Febreuary;26:249. 67. Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 1999 December;83:389. 68. Kim SW, et al. Effectiveness of mirtazapine for nausea and insomnia in cancer patients with depression. Psychiatry Clin Neurosci 2008 February;62:75. 69. Sanchez-Barcelo EJ, Mediavilla MD, Tan DX, Reiter RJ. Clinical uses of melatonin: evaluation of human trials. Curr Med Chem 2010;17:2070. 70. National Sleep Foundation. Healthy Sleep Tips. http://www.sleepfoundation.org/article/sleep-topics/healthy-sleep-tips (Accessed May 23, 2012). 71. Bloom HG. Evidence based recommendations for assessment and management of sleep disorders in older persons. J Am Geriatr Soc 2009 May;57(5):761–789.

Textbook of Palliative Medicine and Supportive Care 72. Alessi CA. A randomized trial of a combined physical activity and environmental intervention in nursing home residents: do sleep and agitation improve? J Am Geriatr Soc 1999;47(7):784. 73. Hatta K, Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial. JAMA Psychiatry 2014;71(4):397. 74. Sateia MJ. Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med 2017;13(2):307. 75. Sateia MJ. International Classification of Sleep Disorders-third edition: highlights and modifications. Chest 2014;146:1387–1394. 76. Chang WP, Lin CC. Correlation between rest–activity rhythm and survival in cancer patients experiencing pain. Chronobiol Int 2014;31:926–934. 77. Lévi F, Dugué PA, Innominato P, et al. Wrist actimetry circadian rhythm as a robust predictor of colorectal cancer. Chronobiol Int 2014 October;31(8):891–900. 78. Yennurajalingam S, Carmack C, Balachandran D, et al. Sleep disturbance in patients with cancer: a feasibility study of multimodal therapy. BMJ Support Palliat Care 2020. Epub 2020/01/12.

49

COUNSELING IN PALLIATIVE CARE

Sophie A. McGilvray and David W. Kissane

Contents What issues present for counseling?..............................................................................................................................................................................477 What diagnoses potentially underpin these concerns?..............................................................................................................................................478 Indications for counseling................................................................................................................................................................................................478 Models of counseling.........................................................................................................................................................................................................479 Psychoeducational interventions..............................................................................................................................................................................479 Supportive psychotherapy..........................................................................................................................................................................................479 Grief therapy.................................................................................................................................................................................................................479 Existential psychotherapy.......................................................................................................................................................................................... 480 Cognitive behavioral therapy.....................................................................................................................................................................................481 Mindfulness-based interventions.............................................................................................................................................................................481 Psychodynamic psychotherapy, including Managing Cancer and Living Meaningfully (CALM) therapy...............................................481 Life narrative, biography, and dignity-conserving therapies...............................................................................................................................481 Meaning-centered psychotherapy........................................................................................................................................................................... 482 Systemic therapies....................................................................................................................................................................................................... 482 Therapist and process issues........................................................................................................................................................................................... 482 Effectiveness of counseling and limitations................................................................................................................................................................. 482 References........................................................................................................................................................................................................................... 483 Psychotherapeutic interventions and support may be offered not only to the individual palliative care patient, but also to their families and caregivers. Although the incidence of distress found in studies varies, approximately 15–40% of palliative care patients will develop significant symptoms of anxiety, demoralization or depression, with rates rising higher at the end of life.1,2 Similar rates are found among caregivers.3 Systematic reviews have shown the benefit of psychological treatments, especially for patients and families at high risk.4,5 The approach to counseling will vary according to needs and clinical indications. Services may be delivered individually, some will be more effective when targeting the couple, and meeting with the immediate or extended caregiving family is both helpful and cost-effective. Self-help or professionally led groups are beneficial in promoting support, while focused family therapy and multifamily groups present other options. In this chapter, the indications for counseling, varied models of intervention, issues for therapists, and process challenges in the delivery of the counseling will be reviewed alongside the evidence for effectiveness of outcome.

What issues present for counseling? Patients present often with a concern or worry, sometimes with a symptom and rarely with a labeled disorder. The concern may be phrased as a question, buried in a bewildered maze of thoughts and feelings or projected as a problem onto another family member. Whatever the presentation—whether emotional, attitudinal, behavioral, or conative—each request for help challenges the clinician to recognize what is relevant and organize this meaningfully. Understanding the person with their gamut of life’s experiences and influences, successes and failures, accomplishments and omissions, shame and secrets,

and health or illness is at the heart of being able to respond to the whole person as a unique individual within their culture, family, and social world.6 Clinicians respond to such complexity with organizational schemata that structure the phenomena into recognizable patterns and hierarchies. Training, skill, and experience are crucial here if order is to emerge from potential chaos and be channeled constructively toward improved coping and beneficial outcome. Nevertheless, health professionals need to suspend any preconceptions and listen intently, lest the real needs of the patient are ignored with an inherent inability to heal, even if the disease is being treated. During the final weeks and days of life, matters existential, relational, and spiritual come to the fore and may be more important ultimately than physical symptom management.7 How do clinicians organize patients’ concerns to aid comprehension and plan consequent intervention? While listening to the narrative of illness, themes are identified and clustered into groups. Common themes include: (1) loss, (2) emotional response, (3) meaning, and (4) coping. Loss is myriad in its presentations during the course of illness, and unless normalized as universal yet forever challenging, grief may not be well supported. When loss corresponds with expectations consonant with the life cycle, acceptance results readily; when illness is out of step with this natural order, distress, resentment, and profound grief develop easily. Identifying relevant emotions and any meaning attributed to illness is pertinent. Concepts of the inevitability of change or transitions associated with aging prove helpful, while adaptation as a response invokes some form of coping to optimize outcome and sustain quality of life. The biopsychosocial and existential/spiritual model is one framework for organizing common issues that present for 477

Textbook of Palliative Medicine and Supportive Care

478

TABLE 49.1  Biopsychosocial and Spiritual Orientation to Common Issues that may Arise in Counseling during Palliative Care Biological

Psychological

Social

Spiritual

Specific somatic symptoms, e.g., pain, fatigue, insomnia Reduced physical function, e.g., frailty, impairment, disability Altered bodily appearance, e.g., disfigurement Treatment processes, e.g., radiation, chemotherapy

Emotional responses, e.g., sadness, grief, anger, fear, low morale Adaptation, e.g., courage, acceptance, avoidance, rejection Sense of self, e.g., self-esteem, shame, stigma, loss of worth Decision-making, e.g., quality of life and treatment adherence Powerlessness, e.g., hopelessness, trapped, suicidality

Instrumental care, e.g., nursing, pharmacy Occupational and physical therapies, e.g., respite, aides Relational, e.g., marital, family, sexual, intimacy Financial and supportive, e.g., burden, withdrawal

Meaning of illness, e.g., dying, punishment, spiritual doubt Dignity of person, e.g., respect, valuing accomplishments Freedom and control, e.g., choice, mastery, being a burden Rituals, e.g., prayer, connection with the sacred

counseling during palliative care. Its value lies in its integration of the somatic with psychological, social, and spiritual concerns. Table 49.1 illustrates typical issues without seeking to be exhaustive in its coverage of potential themes.

What diagnoses potentially underpin these concerns? Sometimes therapists offer counseling about specific issues or focused requests like “what do I say to my children?” In these circumstances, direct exploration of options and role play will assist readily. Generally, however, the process of making a clinical diagnosis is pivotal to considering all of the therapeutic options available to ease distress and promote healing. The beauty of diagnosis is that it should trigger a comprehensive treatment plan, one based on experience, clinical wisdom, and, indeed, evidence of effectiveness. In this sense, no counseling should occur in palliative care without a competent, thorough clinical assessment leading to a thoughtful management plan. The clinician is thus always the professional. Moreover, just as each physical symptom should lead to an assessment, examination, differential diagnosis, and continued reevaluation of response to treatment, so too should each emotional theme generate its differential and continued exploration. Thus, is the sadness an expression of grief or depression? Is the fear grounded in reality or is it excessive because of coping style? Does a pattern of low self-esteem increase embarrassment or sense of stigma? Does the loss of meaning constitute demoralization or depression?8 Is concern about being a burden driven by altruism, independence, or shame at loss of control? Before considering what the applicable model of intervention is, these golden rules are vital: always take a careful history; examine the mental state; understand what has predisposed to, precipitated, or perpetuated such distress; and formulate why this person is ill in this manner and at this time.

Table 49.2 overviews the common clinical diagnoses that are suitable for counseling. In terms of psychiatric nosological systems, these fall into grief reactions, situational or adjustment disorders, anxiety and depression, existential concerns, and relational and V-code categories. Diagnostic and Statistical Manual of Mental Disorders, fifth edition, with more emphasis on the dimensional severity on any disorder, has not changed the basic diagnoses. Other common diagnoses such as delirium, dementia, psychoses, and a range of other organic states are not suitable for psychotherapy primarily, pharmacotherapy being the mainstay of treatment. For a number of conditions including anxiety and depressive disorders, combinations of psychotropic and psychotherapeutic treatment are indicated.

Indications for counseling Distress, formal psychiatric disorder, concern about coping, and lack of sufficient social supports are the common indications for counseling. Sometimes it can be as simple as unmet information needs, but in general, we try to distinguish those who can be supported by all members of the multidisciplinary care team from those who warrant referral for specialist counseling. The latter involves particularly clinicians trained in social work, psychology, or psychiatry. Risk factors for poorer coping include: 1. Factors in the person: Past history of depression or psychiatric disorder, cumulative life events, and high levels of perceived stress or poor coping. 2. Factors in the illness: Onset at a young age; delay in diagnosis; recent diagnosis with rapid disease progression; long, intensive treatments or complications of treatment; specific cancers—pancreatic, neuroendocrine, lymphomas.

TABLE 49.2  Common Psychiatric Diagnoses that Lead to Counseling Therapies Category

Examples

Adjustment disorder Anxiety disorder Depressive disorder Demoralization disorder Relational disorder Existential disorder Organic psychiatric disorder

Coping with intense grief, social withdrawal Panic attacks, nightmares, insomnia Anhedonia, unhappiness, lost interest Loss of meaning, loss of hope, suicidality Marital and family dysfunction, personality disorders, sexual dysfunction Spiritual despair, concern about being a burden, need to be in control, profound aloneness Delirium, medication side effects, alcohol and substance abuse, or withdrawal

Counseling in Palliative Care

479

3. Factors in the environment: Poor social supports, family dysfunction, socioeconomic deprivation, potential to leave young children behind. Whenever one or more of these factors are present, consideration of the benefits of supportive counseling proves worthwhile.9 Once an established psychiatric disorder exists, referral should be axiomatic. Because of the large research literature showing that psychiatric disorders are often missed,10 usually through normalization of grief, many institutions utilize a model of screening for distress11 to assist recognition of those in greater need of psychosocial care. A randomized controlled trial of computer-assisted screening and referral for intervention has demonstrated an ability to reduce depressive disorders in oncology patients.12 Many services today use a triage mechanism to refer patients with milder levels of distress to social workers and those with more severe distress to psychologists or psychiatrists.

Models of counseling A number of schools of psychotherapy exist, many developed originally for specific clinical circumstances, but generally these are applied eclectically by counselors so that aspects of these different models are combined to suit the clinical predicament of the patient or family. Table 49.3 summarizes the common models of psychotherapy. The following case example will illustrate how each psychotherapeutic model can be used. David and Alison had been married for 22 years and had three teenage children. Shortly after the eldest started university, Alison, who was aged 45, was diagnosed with metastatic ovarian cancer involving the peritoneum, with extensive intra-abdominal lymphadenopathy. Alison was working as a registered mental health nurse, while raising three children with David. These were her two great passions in life, family and service to the community. However, as the cancer progressed, Alison was increasingly fatigued and unable to engage in family life with the same energy and vigor of earlier years. She had significant abdominal pain and a recurrent bowel obstruction, which resulted in recurring hospitalization. Alison began to feel burdensome to her family, who would drop everything to be at her bedside. She felt guilt for taking her children away from their studies, and her husband from his work as an engineer, which TABLE 49.3  Models of Psychotherapy Targets of Therapy

Categories of Therapy

Individual

Psychoeducational Supportive expressive Grief therapy Mindfulness therapy Existential psychotherapy Cognitive behavioral therapy Interpersonal psychotherapy Psychodynamic therapies Narrative and dignity therapies Meaning-centered therapies CALM therapy Systemic therapies

Couple Group Family

Community

was essential income since she had stopped working. Alison was afraid that her children would remember her as a frail sick woman, and not as the vibrant, capable mother that she had always been. She was concerned that her care placed too great a demand on her family.

Psychoeducational interventions

Whether delivered individually to groups, or to families, the provision of information about the illness and its treatment is foundational and a counseling component of all clinical encounters. In their meta-analysis of 116 studies, Devine and Westlake13 proved that psychoeducational models have a large effect size, which should not be surprising, as the outcome measure in such studies is simply the acquisition of new knowledge. Studies of unmet needs have nevertheless identified information provision as a major concern of patients. The efficacy of psychoeducation improves when delivered by individuals with medical or nursing expertise.14 In Alison’s case, nursing education covered pain and other symptom management, the nature of her cancer and its treatment, the anticipated process of dying, and how David could optimize his role and coordinate care with other members of Alison’s family.

Supportive psychotherapy

Supporting a patient and family through cancer is best done by listening to the story of illness and its treatment, providing emotional support, exploring the meaning of the diagnosis and prognosis, conveying understanding, and building trust. The counselor employs a range of therapeutic techniques including questions that seek clarification and invite sharing of emotions; comments that affirm, reassure, encourage, or explain; and suggestions that guide, promote acceptance, and optimize support. This approach is the most generic form of counseling and its techniques are found in all other models of psychotherapy. Although cited in group work, the following goals are also pursued in individual supportive therapy: building bonds, expressing emotions about the illness and its impact on relationships, detoxifying death and dying, redefining life priorities, mobilizing supports, and improving coping and communication.15–17 Evidence for its effectiveness in advanced cancer is strongest for supportive-expressive group therapy (SEGT) where randomized controlled trials have demonstrated its ability to reduce emotional distress, anxiety, and depression.18 The unfairness of Alison’s illness occurring out of step with her expected life cycle was acknowledged, her grief at the many losses normalized, her courage praised and the family’s commitment to each other affirmed. Helping Alison and David to share their feelings and consider how best to support one another led to recognition of their greater closeness that this tragedy had brought. Accompaniment and commitment were key principles in sustaining continuity of care for them.

Grief therapy

Loss is found universally in the illness experience and with it comes grief. Thus, the model of counseling developed for the bereaved serves well also as a response to the cumulative experience of loss during any journey with advanced disease. The tasks involved include promoting the sharing of emotion, normalizing the sadness, educating about the pattern of distress (waves of

Textbook of Palliative Medicine and Supportive Care

480 emotionality) and time course of mourning, interpreting any displacement of anger, and encouraging adaptive coping responses. Care needs to be taken to avoid premature grief, as time spent grieving distracts from a focus on the living. Such counseling techniques should be applied by all clinicians working in palliative medicine. Counseling the bereaved also becomes an important dimension of comprehensive palliative care, those at high risk being identified through recognition of (1) personal vulnerability, such as past history of psychiatric disorder; (2) relational problems like dependence or ambivalence; (3) a death experienced as in some way shocking, unexpected, or traumatic; and (4) the presence of family dysfunction or perception of being unsupported or disenfranchised. Group work is especially helpful for the isolated.

Existential psychotherapy

Based on the challenges that arise from the very givens of our humanity, existential psychotherapy addresses concepts of selfawareness, freedom and autonomous choice, fundamental aloneness and our human need for relatedness, the meaning of life, and the inevitable reality of death.19 Existential distress is a dominant experience for patients diagnosed with cancer as it forces individuals to confront their mortality.20 The common sources of existential distress are summarized in Table 49.4 with suitable models of counseling for specific challenges. The counselor helps to define the particular existential challenge that each patient perceives and invites consideration of realistic ways of responding. Built upon processes of confrontation, reaction formation, and inviting choice about those aspects of life that should be most valued, and informed by the

TABLE 49.4  Adaptive and Maladaptive Responses to Existential Challenges and Relevant Counseling Nature of Existential Challenge

Features of Successful Adaptation

Form of Existential Distress Problematic

Common Symptoms Experienced

Related Psychiatric Disorders

Suitable Model of Therapy

Anxiety disorders, panic disorder, agoraphobia, generalized anxiety disorder, acute stress disorder, adjustment disorder with anxious mood Depressive disorders

Psychoeducational, cognitive behavioral therapy, existential psychotherapy, psychodynamic therapy Supportive psychotherapy, grief therapy, interpersonal psychotherapy Interpersonal psychotherapy, family-focused therapy, supportive group therapy Supportive psychotherapy, interpersonal psychotherapy, psychodynamic therapy Interpersonal psychotherapy, narrative and dignity-conserving therapies, meaningcentered therapies, existential therapy Narrative and dignity-conserving therapies, supportive psychotherapy, grief therapy Meaning-centered therapy, life narrative therapies, spiritual ritual

1. Death

Courageous awareness of and acceptance of death; saying goodbye

Death anxiety

Fear of the process of dying or the state of being dead; panic at somatic symptoms; distress at uncertainty

2. Loss

Sad at reality of loss yet resigned to the occurrence of illness

Complicated grief

Intense tearfulness, grief, and waves of emotionality, distress

3. Aloneness

Accompanied and supported by family and friends

Profound loneliness

Isolated, alienated, and sense of complete aloneness in life

Dysfunctional family, absence of social support, relationship problems

4. Freedom

Acceptance of frailty and reduced independence

Loss of control

Angst at loss of control; obsessional mastery; indecisive, nonadherent to treatments; fear of dependency

Phobic disorders, obsessive compulsive disorders, substance abuse disorders

5. Meaning

Sense of fulfillment

Demoralization

Pointlessness, hopelessness, futility, loss of role, desire to die

Demoralization syndrome, adjustment or depressive disorders with demoralization

6. Dignity

Sense of worth despite disfigurement or handicap

Worthlessness

Shame, horror, body image concerns, fear of being a burden

Adjustment disorders

7. Mystery

Reverence for the unknowable and sacred

Spiritual doubt and despair

Guilt, loss of faith, loss of connection with the transcendent

Adjustment, anxiety and depressive disorders

Counseling in Palliative Care narrative story of their life, patients are helped to live authentic and purposeful lives with a particular focus on living in the present moment.21,22 Recent end-of-life models of therapy (dignity- and meaning-centered) have developed from existential psychotherapy. In Alison’s case, questions were asked about the meaning of her relationship with David and her children. They explored the values they held in their life together as partners and parents. They focused on realistic priorities and family goals. David expressed the significant meaning he derived in being able to care for Alison after years where she had “taken care of” him. Open acknowledgment of the potential for death helped identify the preciousness of each moment. Grief was checked to the extent that it risked spoiling continued living. The random nature of Alison’s illness, which they had once felt to be so unfair, was contrasted with their spiritual wonder about life’s mysteries.

Cognitive behavioral therapy

Cognitive behavioral therapy (CBT) involves teaching the patient to make connections between emotional events or triggers, associated automatic thoughts or beliefs, and resultant feelings or behaviors. This model has been developed specifically for the cancer setting where thoughts are evaluated for how helpful or realistic they are.23 Cognitive reframing and disputing of negative automatic thoughts is used, taking a metacognitive stance when thoughts are not helpful.24 Existential themes are explored in parallel, examining guilt about prior lifestyle choices; checking feelings of burden, hopelessness, or helplessness; and countering perceptions of loss of control, anxiety about disfigurement, perceived rejection by friends, and fear of the dying process. Attention can be given to effective communication, problemsolving, and activity scheduling to optimize living.25 Mind reading and negative predictions were identified as some of the cognitive distortions being used and alternative explanations were suggested to Alison. As well, she was urged to clarify this with David, who was distressed to learn that she was feeling this way. David explained that being present for Alison and attentive to her needs was a privilege that enabled him to feel purposeful in a situation where he otherwise felt powerless. He reiterated to her that he was committed to their life together in sickness and in health, and that the grace he witnessed in her acceptance of each day, made him love and respect her more than ever.

Mindfulness-based interventions

Additional interventions teach mindfulness and build on older processes of relaxation training through progressive muscular relaxation, guided imagery, hypnosis, and meditation.26 Mindfulness has not only been developed to reduce stress, but also combined with cognitively oriented techniques to foster inner calm and sense of well-being.27 Massage therapy is also popular in community-based palliative care.

Psychodynamic psychotherapy, including Managing Cancer and Living Meaningfully (CALM) therapy

Patterns of prior coping and relationship difficulties may be revealed in the threat of loss, and recognition of such patterns in earlier life may increase understanding and aid resolution of conflicts.28 Making sense of transference and countertransference

481 reactions are useful processes to optimally support the dying patient with cancer. Projected feelings of helplessness may develop in therapists treating patients facing the terminal phase of illness. Understanding this as a countertransference response increases the therapist’s insight into what the patient is experiencing, guiding what the focus of therapeutic work might therefore be. Defenses such as denial and regression may, in fact, be adaptive and promote functioning, while death awareness can also coexist with a strong will to live in the patients with advanced cancer. Such defenses may serve to alleviate distress such as fear or helplessness, assuming they do not result in disruption of appropriate medical treatment or fulfillment of goals, including the organization of one’s final affairs. Derived from relational theory, attachment theory, and existential therapy, a brief 3- to 6-session individual psychotherapy, managing Cancer And Living Meaningfully (CALM), has been found to provide substantial benefit for patients with advanced cancer prior to end of life.29 Therapeutic elements of CALM include the supportive relationship, authenticity, modulation of affect, encouragement of reflective functioning, renegotiation of attachment security, joint creation of meaning, shifting frame and flexibility, and facing the limits and boundaries related to mortality, interpretation, and ultimately, termination. 30 In reminiscing about her childhood, Alison recalled how her mother was frequently unwell with rheumatoid arthritis, which resulted in significant pain flares and retreat. Her father, who worked in shipping, was a heavy drinker and went missing whenever Alison’s mother was unwell. As a result, Alison had to take care of her siblings and her mother. She felt abandoned by both parents and observed her father abandoning her mother in illness. Alison was afraid of being unwell lest this drive David away. When Alison asked her therapist if the sessions were too upsetting, comparison was drawn between her fears of being a burden to the therapist and to David, akin to how she feared her absent parents in her childhood. It dawned on Alison that her fear of David retreating from her care was based on her old pattern of relating and not something coming from David.

Life narrative, biography, and dignity-conserving therapies

The narrative account of the person’s life aims to generate an understanding of the patient’s reaction to illness from the perspective of their overall philosophy and approach to life. The therapist uses the coherent developmental story to promote a sense of accomplishment, fostering celebration and sense of fulfillment, while highlighting key roles, relationships, and any apparent meaning in the patients’ life. A shared consensus is sought about all that has been accomplished. Chochinov developed a model of dignity-conserving care for patients approaching death. Efforts to improve their self-worth and promote respect are at its core. A key goal is to promote hope, autonomy, and sense of control, while also addressing the spiritual concerns. Dignity therapy invites the patient to give a narrative account on tape of important aspects of their life that they would most want remembered. This biography is transcribed, edited, and given to the patient, as well as being a legacy for their family. Key questions include: how they want their families to remember them?; vital roles they have played within their family, job, and community; accomplishments they are most proud of; hopes and dreams for relatives and friends; words of advice to

482 pass along to others; things they want to say to family that have not been said before or that they want to say again; and words that might provide comfort to their family and friends. Although dignity therapy was not found to be better than client-centered care or standard palliative care in reducing overall distress, patients reported that it was helpful.31 Community volunteers have taken up this model as biographers, leaving the narrative as a legacy that families deeply appreciate.

Meaning-centered psychotherapy

Individual and group meaning-centered psychotherapies (IMCT and MCGT) have been developed that promote a sense of meaning and purpose, 32,33 adopting many principles from Viktor Frankl’s “logotherapy.” Patients are active members in their own treatment, sharing experiences that have helped promote a sense of meaning, peace, and purpose. Exercises are assigned as homework and reviewed at subsequent meetings. Sense of personal responsibility, attitudes, creative and experiential values, and the meaning they bring to life are explored. Alison identified the immense fulfillment and joy that David had brought into her life as a partner and co-parent, which she ascribed as her greatest achievement in life. She was grateful for the life they had built together, which had given her a sense of purpose and meaning. Alison expressed her sadness that she would not grow old with David, but told him that she hoped he would find someone after her death that he could build the next stage of his life with. David told Alison that he would continue to talk about her with the children, continue parenting them as they had done, and that he would tell future grandchildren about her so that her legacy lived on.

Systemic therapies

Whether focused on the marital, parental, or sibling systems, the family of origin, or current nuclear family, the mutual and reciprocal influence of one party upon another can be an important consideration therapeutically. Furthermore, insight into recurring patterns across generations helps families to vary these “scripts” and choose a new direction in their relationships. Family-focused grief therapy (FFGT) is one preventive model that targets at-risk families during palliative care and continues with the bereaved post death, aiming to optimize family functioning so that complicated grief and prolonged grief disorder are prevented. 34 Communication is enhanced in families who have struggled to talk about an approaching death. FFGT has much to offer families at risk in palliative care, its brief and focused approach delivering cost-effectiveness alongside continuity of care into bereavement. Similarly, when couples struggle to communicate and support one another, couple sessions can do much to open up communication and foster compassion and intimacy. 35 Alison and David were brought together with their siblings and their parents, the broader family rallying to support the couple and their children. Open communication about the cancer and its treatment ensured their grief was shared, hope fostered, and respite organized to protect David from exhaustion. As teamwork grew, each family’s sense of celebration of Alison’s life became apparent, and support was sustained for David and their children throughout the subsequent period of bereavement.

Textbook of Palliative Medicine and Supportive Care

Therapist and process issues On the one hand, all members of the multidisciplinary team make a contribution to psychosocial support. But when it comes to developing skill and expertise in the specific models of counseling described in this chapter, formal training is needed. Research confirms that patients respond better to brief interventions provided by well-trained and skilled therapists. The core elements of counseling comprise the relationship that is established, the explanatory model of intervention used, the procedure for promoting change, and the healing that in turn induces further benefit. A number of therapeutic factors are common to all models of intervention. Developing a strong working relationship, often termed a therapeutic alliance, with the patient and their caregivers is foundational. Other key factors include engaging in active listening, allowing patients to ventilate their feelings about their experience, validating their concerns, providing support, and building trust and respect. Exploration of prior losses, especially deaths in the family, and how members coped with their related grief is illuminating. For much of this counseling in palliative care, a delicate balance is needed between promoting hope and supporting grief, these two themes often evolving in parallel. The counselor provides a secure relationship, whose structure creates an experience in which “holding” and “containment” of distress are achieved. The therapist’s warmth, empathy, and unconditional regard help create this holding frame. Nevertheless, an emphasis still exists on appropriate restriction of therapist self-disclosure, here and now feelings being sensitively shared, while greater caution is exercised over one’s personal life. Disclosure of a gay orientation may be helpful to homosexual patients, but disclosure of personal cancer or illness experiences is generally unwise, the focus of the therapy being truly directed toward the patient. In the setting of medical illness, most counseling needs to be brief and focused for pragmatic reasons. Clinical judgments determine what is worthy of constructive focus and what should be wisely left as a long-term or irremediable pattern of behavior. Personality disorders would not be addressed at the individual therapy level, and entrenched family conflict might be respected as ultimately a difference of opinion best resolved by accepting distance between relatives. Selection of a model of therapy is usually eclectic and based on clinical experience, combining elements from several models in response to the prevailing symptoms or predicaments that the patient presents. Flexibility in number, frequency, and duration of sessions, location of appointments, and modality of treatment used are necessary parts of working with the palliative care population. Telephone support may substitute for direct patient care. Physical symptoms, side effects of treatments, and stage of illness all significantly impact on delivery of services and a change in medical status may necessitate a shift in therapeutic focus. An open flexible approach is best maintained throughout the course of treatment. The potential for psychopharmacological treatment is always considered alongside any counseling and its need monitored.

Effectiveness of counseling and limitations Several meta-analyses have examined the effectiveness of psychological interventions for the treatment of anxiety and depression in patients with cancer.4,5 The overall evidence for benefit is modest. 36 Research limitations were felt to include challenges related to issues of recruitment and attrition, data analyses, follow-up

Counseling in Palliative Care KEY LEARNING POINTS • High rates of distress exist among patients, caregivers, and family members during palliative care. • Counseling interventions have proven efficacy in relieving distress, anxiety, depression and in enhancing coping. • The training and experience of the therapist strongly influences the effectiveness of interventions. • Outcome is progressively improved by longer interventions. • Group interventions are at least as efficacious as individual therapies; family group counseling may be more cost-effective when applicable. • While psychoeducational, supportive, and grief therapies are the mainstay of psychotherapeutic approaches, interpersonal, narrative, and meaning-centered models also offer promise in ameliorating existential distress. assessments, confounding factors, and operationalization of outcomes. Group therapy is at least as effective as individual counseling, while length of treatment and experience of therapist are pertinent influences on outcome. These findings challenge palliative care services to hire appropriately skilled counselors. Finally, a caveat is needed about the risks of counseling. Just as pharmacotherapy can induce side effects, sometimes with deleterious consequences, similarly counseling can also cause harm. Research suggests that about 10% of counseling interventions generate untoward effects, such as worsening anxiety, depression, or marital and family conflict. This limitation calls for skill and experience derived from formal training in the models of intervention and in one of the basic psychosocial disciplines, so that therapists can identify any deterioration and introduce corrective strategies. When counseling is delivered by trained and experienced professionals, it has much to offer in ameliorating distress and suffering.

References









1. Mehnert A, Brähler E, Faller H, Härter M, Keller M, Schulz H, et al. Four-week prevalence of mental disorders in patients with cancer across major tumor entities. J Clin Oncol 2014;32:3540–3546. 2. Robinson S, Kissane, DW, Brooker, J, Burney, S. A systematic review of the demoralization syndrome in individuals with progressive disease and cancer: a decade of research. J Pain Symptom Manage 2015;49(3):595–610. 3. Dionne-Odom JN, Applebaum AJ, Ornstein KA, Azuero A, Warren PP, Taylor RA, et al. Participation and interest in support services among family caregivers of older adults with cancer. Psycho-Oncology 2018;27(3):969–976. 4. Faller H, Schuler M, Richard M, Heckl U, Weis J, Kuffner R. Effects of psycho-oncologic interventions on emotional distress and quality of life in adult patients with cancer: systematic review and meta-analysis. J Clin Oncol 2013;31:782–793. 5. Li M, Kennedy EB, Byrne N, Gerin-Lajoie C, Katz MR, Keshavarz H, et al. Systematic review and meta-analysis of collaborative care interventions for depression in patients with cancer. Psycho-Oncology 2017;26:573–587. 6. Cassell EJ. The Nature of Suffering and the Goals of Medicine. New York: Oxford University Press, 1991. 7. Kissane DW. The relief of existential suffering. Arch Intern Med 2012;172(19):1501–1505.

483















8. Bobevski I, Kissane DW, Vehling S, McKenzie D, Glaesmer H, Mehnert A. Latent class analysis differentiation of adjustment disorder and demoralization, more severe depressive-anxiety disorders, and somatic symptoms in a cohort of patients with cancer. PsychoOncology 2018;27(11);2623–2630. 9. Lederberg MS, Holland JC. Supportive psychotherapy in cancer care: an essential ingredient of all therapy. In: Watson M, Kissane DW, eds. Handbook of Psychotherapy in Cancer Care Chichester, U.K.: WileyBlackwell, 2011, 3–14. 10. Kissane DW. Unrecognised and untreated depression in cancer care. Lancet Psychiatry 2014;1(5):320–321. 11. Liu F, Huang J, Zhang L, Fan F, Chen J, Xia K, Liu Z. Screening for distress in patients with primary brain tumor using distress thermometer: a systematic review and meta-analysis. BMC Cancer 2018;18:124. 12. McLachlan SA, Allenby A, Matthews J, Wirth A, Kissane DW, Bishop M, Beresford J, Zalcberg J. Randomized trial of coordinated psychosocial interventions based on patient self-assessments versus standard care to improve the psychosocial functioning of patients with cancer. J Clin Oncol 2001;19:4117–4125. 13. Devine EC, Westlake SK. The effects of psychoeducational care provided to adults with cancer: meta-analysis of 116 studies. Oncol Nurs Forum 1995;22:1369–1381. 14. Zimmerman T, Heinrichs N, Baucom DH. “Does one size fit all?” Moderators in psychosocial interventions for breast cancer patients: a meta-analysis. Ann Behav Med 2007;34:225–239. 15. Goodwin P, Leszcz M, Ennis M, et al. The effect of group psychosocial support on survival in metastatic breast cancer. N Engl J Med 2001;345:1719–1726. 16. Kissane DW, Grabsch B, Clarke DM, et al. Supportive-expressive group therapy for women with metastatic breast cancer: survival and psychosocial outcome from a randomized controlled trial. Psycho-Oncology 2007;16:277–286. 17. Spiegel D, Butler L, Giese-Davis J, et al. Effects of supportive-expressive group therapy on survival of patients with metastatic breast cancer. Cancer 2007;110:1130–1138. 18. Kissane DW, Grabsch B, Clarke DM, et al. Supportive-expressive group therapy: the transformation of existential ambivalence into creative living while enhancing adherence to anti-cancer therapies. PsychoOncology 2004;13(11):755–768. 19. Yalom ID. Existential Psychotherapy. New York: Basic Books, 1980. 20. Kissane DW, Bloch S, Smith GC, et al. Cognitive-existential group psychotherapy for women with primary breast cancer: a randomized controlled trial. Psycho-Oncology 2003;12:532–546. 21. Lethborg C, Schofield P, Kissane DW. The advanced cancer patient experience of undertaking meaning and purpose (MaP) therapy. Palliat Support Care 2012;10(3):177–188. 22. Lethborg C, Kissane DW, Schofield P. Meaning and purpose (MAP) therapy I: therapeutic processes and themes in advanced cancer. Palliat Support Care 2019;17(1):13–20. 23. Kissane DW, Bloch S, Miach P, Smith GC, Seddon A, Keks N. Cognitive-Existential group therapy for patients with primary breast cancer—Techniques and themes. Psycho-Oncology 1997;6:25–33. 24. Moorey S, Greer S. Cognitive Behaviour Therapy for People with Cancer, 2nd edn. Oxford, U.K.: Oxford University Press, 2002. 25. Horne D, Watson M. Cognitive-behavioural therapies in cancer care. In: Watson M, Kissane DW, eds. Handbook of Psychotherapy in Cancer Care. Chichester, U.K.: Wiley-Blackwell, 2011, pp. 15–26. 26. Carlson L, Ursuliak Z, Goodey E, Angen M, Speca M. The effects of a mindfulness meditation-based stress reduction program on mood and symptoms of stress in cancer outpatients: 6-month follow-up. Support Care Cancer 2001;9:112–123. 27. Payne DK. Mindfulness interventions for cancer patient. In: Watson M, Kissane DW, eds. Handbook of Psychotherapy in Cancer Care. Chichester, U.K.: Wiley-Blackwell, 2011, pp. 39–47. 28. Kent LK, Blumenfield M. Psychodynamic psychiatry in the general medical setting. J Am Acad Psychoanal Dynamic Psychiatry 2011;39:41–62. 29. Nissim R, Freeman E, Lo C, Zimmerman C, Gagliese L, Rydall A, et al. Managing Cancer and Living Meaningfully (CALM): a qualitative study of a brief individual psychotherapy for individuals with advanced cancer. Palliat Med 2014;28:234–242. 30. Rodin G, Lo C, Rydall A, et al. Managing Cancer and Living Meaningfully (CALM): A randomized controlled trial of a psychological intervention for patients with advanced cancer. J Clin Oncol 2018;36(23):2422–2432.

484 31. Chochinov HM, Kristjanson L, Breitbart W, et al. Effect of dignity therapy on distress and end-of-life experience in terminally ill patients: a randomized controlled trial. Lancet Oncol 2011;12:753–762. 32. Breitbart W, Rosenfeld B, Pessin H, Applebaum A, Kulikowski J, Lichtenthal WG. Meaning-centered group psychotherapy: an effective intervention for improving psychological well-being in patients with advanced cancer. J Clin Oncol 2015;33:749–754. 33. Breitbart W, Pessin H, Rosenfeld B, et al. Individual meaning-centered psychotherapy for the treatment of psychological and existential distress: a randomized controlled trial in patients with advanced cancer. Cancer 2018;124(15):3231–3239.

Textbook of Palliative Medicine and Supportive Care 34. Kissane DW, Zaider TI, Li Y, et al. Randomized controlled trial of family therapy in advanced cancer continued into bereavement. J Clin Oncol 2016;34:1921–1927. 35. Zaider TI, Kissane DW. Couples therapy in advanced cancer: Using intimacy and meaning to reduce existential distress. In: Watson M, Kissane DW, eds. Handbook of Psychotherapy in Cancer Care. Chichester, U.K.: Wiley-Blackwell, 2011, pp. 161–173. 36. Okuyama T, Akechi T, Mackenzie L, Furukawa TA. Psychotherapy for depression among advanced, incurable cancer patients: a systematic review and meta-analysis. Cancer Treat Rev 2017;56:16–27.

50

HOPE IN END-OF-LIFE CARE

Cheryl L. Nekolaichuk The biggest pain to go through in the end… is the gradual drop-away of visitors. Hope my friends keep their promises. Promises about sitting with me and being with me when that time comes. A palliative care patient (May 29, 2012)

Contents Introduction....................................................................................................................................................................................................................... 485 Therapeutic value of hope in illness.............................................................................................................................................................................. 485 Nature of hope in palliative care.................................................................................................................................................................................... 486 Universality................................................................................................................................................................................................................... 486 Dimensionality............................................................................................................................................................................................................. 486 Intangibility.................................................................................................................................................................................................................. 486 Temporality.................................................................................................................................................................................................................. 486 Predictability................................................................................................................................................................................................................ 487 Value based................................................................................................................................................................................................................... 487 Reality based................................................................................................................................................................................................................. 487 Assessment of hope.......................................................................................................................................................................................................... 487 Hope-enhancing strategies and interventions............................................................................................................................................................ 488 Summary............................................................................................................................................................................................................................. 489 References........................................................................................................................................................................................................................... 489

Introduction The progressive, unpredictable nature of a terminal illness— marked by debilitating symptoms, body image distortions, and multiple losses—propels patients and their families onto a pathway of uncertainty, fear, and, for some, despair. Traditional roles may be reversed or erased, as patients feel marginalized from society. External messages of “There is no cure” become internal messages of “There is no hope,” as they wrestle with their own mortality. In a study involving advanced cancer patients, 48% of participants reported at least some sense of hopelessness.1 Despite these substantive challenges, patients at the end of life strive to maintain hope within their caring circles. In interviews with 120 terminally ill cancer patients, 99% of respondents rated having a sense of hope as a very important existential concern.2 Based on a review of research studies, Lin and Bauer-Wu3 identified living with meaning and hope as one of six essential themes of psychosocial spiritual well-being in patients with advanced cancer. In a qualitative study focusing on information needs, patients with advanced cancer identified the provision of hope and need for hopeful messages as one of the two most important concerns regarding information content.4 Health-care professionals equally emphasize the importance of hope in the delivery of palliative care. Numerous position papers and literature reviews highlight the need for intentionally incorporating hope within end-of-life care.5–11 Janssens et al.12 have further embedded the concept within a philosophy of care for palliative care, consisting of three realms—medical, psychosocial,

and spiritual—with hope as a central existential phenomenon within the spiritual realm. Despite these overwhelming endorsements, the systematic integration of hope within routine clinical practice remains relatively underdeveloped. Beginning with an overview of the therapeutic value of hope, this chapter will address the following questions for intentionally integrating hope within end-oflife care: • What is the nature of hope in palliative care? • How can we enhance our approaches for assessing hope in people who are terminally ill? • What types of hope-enhancing strategies and interventions would be most appropriate for this unique population?

Therapeutic value of hope in illness The therapeutic value of hope in chronic and life-threatening illnesses is well documented. Hope has been positively linked to effective coping,13–15 enhanced quality of life,16–18 spiritual wellbeing,19 and healing;20–22 inversely associated with depression23 and weakly associated with symptom burden.23 In contrast, hopelessness may be associated with low levels of perceived emotional support,24,25 depression,25,26 suicidal intent,27 desire for hastened death,28 and pain.28,29 Studies in terminally ill patients have revealed that hopelessness is a strong predictor of poorer healthrelated quality of life, 30 desire for hastened death, 31,32 will to live, 33 and suicidal intent. 34 485

486

Textbook of Palliative Medicine and Supportive Care

Although these findings are significant, some caution is warranted in making cross-study comparisons. Study samples were quite diverse and were not entirely limited to the terminal illness phase, including patients with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS)19,24,25 and cancer,13,16,31,32,34 depressed patients,21,22,26,27 patients with longterm disabilites,14,20 and older patients.17 The use of different measures to assess hope or hopelessness across studies further limits meaningful comparisons. Future research studies, focusing on relationships between hope, symptom expression, and positive health indicators, such as quality of life, well-being, and coping, need to specifically target the terminally ill, using consistent measurement approaches appropriate for this population.

• Predictability: The experience of hope may have both predictable and unpredictable components. • Value based: The value of hope appears to be embedded in personal experience. • Reality based: Hope appears to be connected with some sense of realism, although the viewpoints of reality remain unclear.

Nature of hope in palliative care What does hope mean to you as a health-care provider? What does hope mean to the patients for whom you provide care? In health care, the concept of hope has been closely linked with treatments and cures. 35–37 When hope for a cure is no longer viable, health-care professionals and patients may give up hope. Although the situation may be hopeless, there is always hope for the individual. 38 A key challenge is to understand the nature of hope in palliative care. A diversity of conceptual frameworks exist in the literature, with no consensus for a universal definition of hope. A critique of the hope literature revealed seven themes associated with these differing perspectives39 (see Figure 50.1), accompanied by the following assumptions: • Universality: Hope is both a universal and an intensely personal experience. • Dimensionality: Hope is a complex concept, ranging from unidimensional to multidimensional aspects of a person’s experience. • Intangibility: Hope has both tangible and intangible components, some of which may never be elucidated. • Temporality: Hope appears to imply some sense of temporality, although this may not necessarily be limited to a future orientation. It is also possible that some components of hope may not be bound by time.

These seven themes provide a cohesive framework for understanding the nature of hope in palliative care. Subsequent text provides a brief description of each of these themes, with corresponding reflective questions for interacting with patients in clinical practice.

Universality

Although hope is a universal human experience, it is also intensely unique. A number of qualitative studies, focusing on the terminally ill patient’s experience of hope, have been conducted in diverse settings, such as palliative home care,40–45 inpatients,45–50 outpatient clinics, 37,40,46,50–53 and nonmedical settings. 38,54–56 Samples varied, including patients with cancer,40–42,45,46,48,50 HIV/ AIDS, 38,54–56 amyotrophic lateral sclerosis (ALS), 57 end-stage renal disease, 51 chronic obstructive lung disease,45 and heart failure.45 In contrast, one study involved interviewing nurses about their perceptions of hope in palliative care patients with cancer.52 Another study integrated the triadic perspectives of patients, their “loved ones,” and physicians in a tertiary specialized cancer center.58 This theme gives rise to the following reflective question for use in the clinical setting: What is this person’s unique experience or personal story of hope?

Dimensionality

A diversity of conceptual frameworks for hope has emerged, ranging from unidimensional to multidimensional models. Of the many diverse frameworks, Dufault and Martocchio’s model, 59 qualitatively derived from a sample of older cancer and terminally ill patients, provides a useful initial framework for understanding hope in the terminally ill patients. Dufault and Martocchio proposed a multidimensional framework for hope, consisting of six dimensions: cognitive, affective, behavioral, affiliative, contextual, and temporal. Each of these dimensions may be impacted in different ways when a person is facing a terminal illness, resulting in the question, How has the challenge of facing a life-threatening illness impacted each of these dimensions for this person?

Intangibility

The experience of hope may have both tangible and intangible components. Dufault and Martocchio59 described these two types of hope as particularized and generalized hopes. Particularized hopes are hopes that are directed toward specific goals. For terminally ill patients, specific hopes may change over time,60,61 for example, shifting from hope for a cure to hope for symptom relief, a special time with family, or a peaceful death. In contrast, generalized hopes represent an intangible inner experience of hope that is not connected to any specific goal. This invisible part of hope may be difficult to articulate and is often experienced at a deep, spiritual level, leading to two questions for reflection: What specific hopes does this person have? What is this person’s general orientation to hope?

Temporality FIGURE 50.1  Thematic analysis of the concept of hope.

Although most definitions for hope include a future orientation, this may not always be appropriate for the terminally ill.5

Hope In End-of-life Care For some people, with strong faith beliefs, hope may be tied to a future beyond this life. For others, the experience of hope may be interwoven with past, present, and future experiences5,59,62,63; may be lived in the present16; or may transcend time. 59,64 It might be helpful to deemphasize the future component of hope, while reflecting on the question, How has this person’s hope(s) changed over time?

Predictability

The uncertainty of advancing disease raises fears in most patients who are terminally ill. Although frameworks do differ, some models have included uncertainty as an inherent part of the hope experience.52,65 Exploring personal fears, as well as focusing on predictable aspects of an individual’s life, helps buffer the uncertainties of progressive illness: What is in this person’s control? What is not in this person’s control?

Value based

Few could argue with the potential therapeutic benefits that hope offers to the dying. Not everyone, however, may value hope positively, particularly if they have been previously disappointed by hope. For example, patients who direct all their hopes toward finding a cure are often devastated when they are told that their condition is incurable. The challenge is to be able to help patients develop a broad hoping repertoire, including hopes beyond a cure,5 using the following reflective questions as a guide: To what extent does this person value hope? Is this a positive or negative experience? How, if at all, can this person develop a broader hoping repertoire?

Reality based

Often, people may concurrently hold two opposing hopes, such as hope for a cure and hope for a peaceful death. 39,66 This may be troubling for some professional caregivers and family members, who might view this as unrealistic or unhealthy denial. In contrast, Jevne and Nekolaichuk67 describe this phenomenon as a normal way for patients to prioritize their hopes: It is important to listen to the descriptive words that they [patients] attach to their hopes, acknowledging the range (and depth) of their hopes. One elderly patient who was forced to stop traveling due to a progression of his disease described his hope to travel as a “forlorn” hope. Another palliative patient who expressed a hope for peace in the world described that particular hope as a “big” hope. Yet another patient who hung onto a hope for a cure, despite being told that her cancer was incurable, suggested that it “may not be

487 a very realistic” hope, but that “miracles do happen.” For a patient who believed in life after death, her hope to be united with God was her “ultimate” hope. (p. 195) Professional caregivers need to normalize these apparently polarizing views, balancing the provision of honest truthful information with the maintenance of hope.66,68,69 In an interpretive synthesis of 31 articles focusing on health-care professionals’ views on hope of palliative care patients, Olsman et al.69 revealed three distinct perspectives: (a) hope as an expectation of being truthful (realistic), (b) hope as a coping mechanism (functional), and (c) hope as meaningful (narrative). The integration of all three perspectives can help health-care professionals work with polarizing viewpoints and improve their communication with patients, guided by the following question: How can health-care professionals provide honest truthful information while still maintaining a person’s hope?

Assessment of hope How can you tell how hopeful a person is? What do you need to know to understand a person’s experience of hope? Although a variety of hope assessment approaches have been developed in clinical practice,66 few have been developed specifically for palliative care.5,10,70 Given the frailty of this population, assessments need to be relatively brief, psychometrically sound in terms of quantitative measures, and closely linked with the development of hope-enhancing strategies and interventions. In some cases, the assessment itself may be a therapeutic intervention. The Herth Hope Index71 is a well-validated measure that has been used extensively in the palliative care population. Although psychometric findings are generally favorable across different cultures, in one validation study involving Swedish palliative patients, the authors cautioned against its use in Swedish clinical palliative settings, due to linguistic, conceptual, and cultural translation difficulties.72 Given the complexity of the hope experience, quantitative measures need to be combined with qualitative assessments. Olsman and colleagues73 developed a qualitative Hope Communication Tool (HCT), focusing on four concepts: hope, further exploration of hope, hopelessness/despair, and support, which they pilot tested with 14 health-care professionals. They concluded that the HCT is feasible for use in clinical practice, but requires further evaluation. Another example of a qualitative hope assessment framework for palliative care appears in Table 50.1.5

TABLE 50.1  A Hope Assessment Framework for Terminally Ill Patients Theme

Questions for the Health-Care Professional

Questions for the Patient

Personal spirit

What is meaningful in this person’s life? What is this person’s relationship with time? How might past, present, and future experiences influence this person’s experience of hope? What is this person’s tolerance for uncertainty?

What gives you meaning in your life? How has your hope changed over time? Tell me about a time in your past that has influenced your hope in some way How have you handled times of uncertainty in the past? What are you most afraid of? Without taking away your hope for a cure, what else might keep you going in the event that a cure is not possible? Who in your world cares about you? Whom do you care about?

Risk

Authentic caring

Source:

How can I enhance this person’s hope, beyond a hope for a cure? Who authentically cares about this person? How can I provide truthful information to this person, yet still remain hopeful?

Adapted from Nekolaichuk CL, Bruera E. J Palliat Care 1998;14:36.

Textbook of Palliative Medicine and Supportive Care

488 This framework is based on an empirically derived model of hope, consisting of three dimensions: personal spirit, risk, and authentic caring.74 Personal spirit is a predominant personal dimension, represented by a core theme of meaning. Risk, a situational dimension, is primarily represented by an underlying theme of uncertainty. Authentic caring, a relational dimension, is characterized by the complementary themes of credibility and caring. Thus, a person’s experience of hope may be associated with finding meaning in life, taking risks in spite of uncertainty, and developing caring, credible relationships.

Hope-enhancing strategies and interventions How do you enhance hope for someone who appears to have given up? How do you serve as a model of hope for your patients? There are many descriptions of hope-enhancing strategies and interventions for the terminally ill patients, based on literature reviews,75 research studies,8,60,76–80 theoretical perspectives,81 and clinical experience.82–84 In a systematic review of nursing literature, Holt85 identified 14 hope intervention themes, the 6 most common being positive relationships, patient self-worth, patient control, goal setting, use of distraction, and family support. Despite the interest in this area, there are very few hope-focused intervention studies, specifically targeted for the terminally ill population. Duggleby and colleagues have developed a Living with Hope Program (LWHP), which they evaluated in senior palliative home care patients.86 Using a mixed-method concurrent nested experimental design, patients in the LWHP arm had significantly higher hope (p = 0.005) and quality of life (p = 0.027) than those in the standard care comparison group. In a subsequent qualitative study with 13 patients with advanced cancer– caregiver dyads, Duggleby et al.87 identified four psychosocial processes by which the LWHP fosters positive hope outcomes: (a) reminiscing, (b) leaving a legacy, (c) positive appraisal, and (d) motivational processes. They have also pilot tested a parallel program for caregivers of family members with advanced cancer.88 Using a quasi-experimental design, Herth89 demonstrated the effectiveness of an eight-session hope-enhancing nursing intervention program in a convenience sample of patients with first recurrence of cancer. Patients in the treatment arm had significantly higher levels of hope and quality of life immediately after and at 3-, 6-, and 9-month post treatment than the comparison group. A follow-up evaluation of this intervention program was also conducted with the treatment group.90 Preliminary findings of the development of an interactive art installation (i.e.,

“Hope Tree”) in a hospice setting provide support for the use of the creative arts as an expression and promotion of hope among patients, family members, and hospice staff.91 However, further research with larger and more diverse sample sizes, as well as different palliative care settings, is needed. In contrast to targeted hope interventions, other studies involving advanced cancer patients have included hope or hopelessness as an outcome of specific therapeutic interventions, such as meaning-centered therapy,92 dignity therapy,93,94 forgiveness therapy,95 or life review,96 with mixed results. Further, DeMartini and colleagues97 explored the relationship between patients’ hopes and advanced cancer treatment. A range of treatment hopes were identified, consisting of eight hope categories: quality of life, life extension, tumor stabilization, remission, milestone, unqualified cure, control not otherwise specified, and cure tempered by realism. Others have demonstrated the effectiveness of hope-specific interventions in nonpalliative populations, such as homeless veterans98 and patients newly diagnosed with cancer.99 Based on a quasi-experimental design, Tollett and Thomas98 studied the effect of rational thought on levels of hope in a sample of 40 homeless veterans. Rustøen et al.99 conducted a quasi-experimental study to evaluate the effect of an eight-session hope-focused nursing intervention on hope and quality of life in patients newly diagnosed with cancer. In both of these studies, hope was significantly higher after the intervention than in the comparison groups. In a systematic review of interventions for the treatment of holistic suffering in cancer, Best and colleagues100 provided further support for three of the hope-focused interventions: Duggleby et al.’s LWHP,86 Herth’s hope-enhancing nursing intervention program for cancer recurrence, 89 and Rustøen et al.’s hope-focused nursing intervention for patients newly diagnosed with cancer.99 They concluded that these interventions showed promise in enhancing hope in patients at different stages of the cancer trajectory, including end of life, as well as impacting existential well-being. They also suggested, however, that further research is warranted to determine the extent to which the effectiveness of these interventions is sustained over time. An example of an integrated hope intervention framework for cancer patients appears in Table 50.2. This framework was derived from a thematic analysis of the literature, patient interviews, and clinical experiences. It consists of seven hope-enhancing themes: caring, communication, commitment, coping, creating, community, and celebrating. Within each theme, specific strategies for enhancing hope are proposed, some of which may be explicit while others may be implicit (see Jevne and Nekolaichuk67 for detailed descriptions of additional strategies). Although this

TABLE 50.2  The Seven Cs: A Hope Intervention Framework Theme

Questions for the Patient

Caring Communication Commitment Coping Creating Community Celebrating

Tell me about a time in your life when you experienced a moment of caring Tell me about what it is like to be ill. How has your hope changed since you have become ill? What would be one small thing that you might do on a regular basis to help strengthen your hope? What has helped you through difficult times in the past? If you were to create a “hope kit,” what things would you put in it? How is hope experienced in your community (culture)? If you were to plan a celebration of hope, what might you do?

Source:

Adapted from Jevne RF, Nekolaichuk CL. Threat and hope in coping with cancer for health care professionals. In: Jacoby R, Keinan G, eds. Between Stress and Hope: From a Disease-Centered to a Health-Centered Perspective. Westport, CT: Praeger Publishers, 2003, pp. 187–212.

Hope In End-of-life Care KEY LEARNING POINTS • Patients, health-care providers, and health researchers have all acknowledged the important role of hope in terminal illness. • Hope is an inherent part of being human. Although it is a universal human experience, it is also an intensely personal one. It is important to understand what hope means to each person suffering from a terminal illness. • Hope assessments and interventions are closely intertwined. Assessment is a continuous process and may be a type of intervention. Interventions are closely linked to the types of assessments that are conducted. • Although many assessment and intervention approaches for hope have been proposed, few have been developed for and validated in the terminally ill. • Systematic approaches for hope assessment and intervention need to be developed and integrated into routine clinical practice in end-of-life care.

framework was developed for cancer patients, many of these strategies could be applied to the terminally ill patients. Further research is needed to extend its use in this population. The use of explicit hope-enhancing interventions needs to be integrated with implicit approaches, in which hope is modeled by the professional caregiver’s hopeful presence and orientation.67 To better understand patients’ experiences of hope and develop appropriate interventions, professional caregivers need to have an awareness of their own perceptions and experiences of hope, which can impact their interactions with patients and families. A number of qualitative studies have focused on professional caregivers’ experiences of hope in palliative care, including registered nurses,101–103 physicians,103,104 and interdisciplinary team members.102,103 In a qualitative study of 14 community palliative care nurses, participants identified a main concern of “keeping their hope when faced with work life challenges and contrasting viewpoints (p. 281),” when their hopes varied from others.101 In another study focusing on palliative care professionals’ hope experiences, Olsman and colleagues103 identified four metaphors of hope—grip (safety), source (strength), tune (harmony), and vision (positive perspective)—which could be used to improve communication in palliative care. The importance of therapeutic presence is further supported by a study focusing on the development of an empirical model of therapeutic effectiveness, based on the perceptions of 78 psychosocial oncology clinicians.105 Although not specific to palliative care, many of the elements of this model of communication could be adapted for supporting patients and family members at end of life.

Summary You have to have hope. There isn’t anything if you haven’t got hope… Even if it’s a small percentage. You have to have it. A palliative care patient How might we create a space for hope in end-of-life care?

489 This chapter highlighted three specific challenges for intentionally integrating hope within clinical practice: • The need to understand the nature of hope at end of life • The need to develop brief, psychometrically sound measures and complementary qualitative assessment frameworks • The need to develop and evaluate specific hope-enhancing interventions for the terminally ill The concept of hope is a dynamic, yet enduring element of palliative care. The lack of well-developed assessment approaches and effective hope-enhancing interventions, targeted specifically for the terminally ill, has impeded progress in this area. Through collaborative efforts involving patients, family members, clinicians, and researchers, appropriate hope assessment frameworks and hope-focused interventions need to be developed that eventually may become part of routine end-of-life care.

References

1. Wilson KG, Graham IG, Viola RA, et al. Structured interview assessment of symptoms and concerns in palliative care. Can J Psychiatry 2004;49:350–357. 2. Greisinger AJ, Lorimor RJ, Aday LA, et al. Terminally ill cancer patients: their most important concerns. Cancer Pract 1997;5:147–154. 3. Lin H, Bauer-Wu SM. Psycho-spiritual well-being in patients with advanced cancer: an integrative review of the literature. J Adv Nurs 2003;44:69–80. 4. Kirk P, Kirk I, Kristjanson LJ. What do patients receiving palliative care for cancer and their families want to be told? A Canadian and Australian qualitative study. BMJ 2004;328:1343. 5. Nekolaichuk CL, Bruera E. On the nature of hope in palliative care. J Palliat Care 1998;14:36–42. 6. Bustamante JJ. Understanding hope. Persons in the process of dying. Int Forum Psychoanal 2001;10:49–55. 7. Duggleby W. Hope at the end of life. J Hosp Palliat Nurs 2001;3:51–64. 8. Herth KA, Cutcliffe JR. The concept of hope in nursing 3: hope and palliative care nursing. Br J Nurs 2002;11:977–983. 9. Sullivan MD. Hope and hopelessness at the end of life. Am J Geriatr Psychiatry 2003;11:393–405. 10. Parker-Oliver D. Redefining hope for the terminally ill. Am J Hosp Palliat Care 2002;19:115–120. 11. McClement SE, Chochinov HM. Hope in advanced cancer patients. Eur J Cancer 2008;44:1169–1174. 12. Janssens RM, Zylicz Z, Ten Have HA. Articulating the concept of palliative care: philosophical and theological perspectives. J Palliat Care 1999;15:38–44. 13. Herth KA. The relationship between level of hope and level of coping response and other variables in patients with cancer. Oncol Nurs Forum 1989;16:67–72. 14. Elliott TR, Witty TE, Herrick S et al. Negotiating reality after physical loss: hope, depression, and disability. J Pers Soc Psychol 1991;61:608–613. 15. Van Laarhoven HWM, Schilderman J, Bleijenberg G et al. Coping, quality of life, depression, and hopelessness in cancer patients in a curative and palliative, end-of-life care setting. Cancer Nurs 2011;34:302–314. 16. Post-White J, Ceronsky C, Kreitzer MJ et al. Hope, spirituality, sense of coherence, and quality of life in patients with cancer. Oncol Nurs Forum 1996;23:1571–1579. 17. Staats S. Quality of life and affect in older persons: hope, time frames, and training effects. Curr Psychol Res Rev 1991;10:21–30. 18. Pipe TB, Kelly A, LeBrun G et al. A prospective descriptive study exploring hope, spiritual well-being, and quality of life in hospitalized patients. MedSurg Nurs 2008;17:247–257. 19. Carson V, Soeken KL, Shanty J et al. Hope and spiritual well-being: essentials for living with AIDS. Perspect Psychiatr Care 1990;26:28–34. 20. Udelman HD, Udelman DL. Hope as a factor in remission of illness. Stress Med 1985;1:291–294. 21. Udelman DL, Udelman HD. A preliminary report on anti-depressant therapy and its effects on hope and immunity. Soc Sci Med 1985;20:1069–1072.

490 22. Udelman DL, Udelman HD. Affects, neurotransmitters, and immunocompetence. Stress Med 1991;7:159–162. 23. Davis M, Lagman R, Parala A, et al. Hope, symptoms, and palliative care: do symptoms influence hope? AJHPM 2017;34:223–232. 24. Zich J, Temoshok L. Perceptions of social support in men with AIDS and ARC: relationships with distress and hardiness. J Appl Soc Psychol 1987;17:193–215. 25. Rabkin JG, Williams JBW, Neugebauer R, et al. Maintenance of hope in HIV-spectrum homosexual men. Am J Psychiatry 1990;147:1322–1326. 26. Beck AT, Weissman A, Lester D, et al. The measurement of pessimism: the hopelessness scale. J Consult Clin Psychol 1974;42:861–865. 27. Beck AT, Steer RA, Kovacs M, et al. Hopelessness and eventual suicide: a 10-year prospective study of patients hospitalized with suicidal ideation. Am J Psychiatry 1985;142:559–563. 28. Arnold EM. Factors that influence consideration of hastening death among people with life-threatening illnesses. Health Soc Work 2004;29:17–26. 29. Hsu TH, Lu MS, Tsou TS, et al. The relationship of pain, uncertainty and hope in Taiwanese lung cancer patients. J Pain Symptom Manage 2003;26:835–842. 30. Mystakidou K, Tsilika E, Parpa E, et al. The relationship between quality of life and levels of hopelessness and depression in palliative care. Depress Anxiety 2008;25:730–736. 31. Breitbart W, Rosenfeld B, Pessin H, et al. Depression, hopelessness, and desire for hastened death in terminally ill patients with cancer. JAMA 2000;284:2907–2911. 32. Rodin G, Lo C, Mikulincer M, et al. Pathways to distress: the multiple determinants of depression, hopelessness, and the desire for hastened death in metastatic cancer patients. Soc Sci Med 2009;68:562–569. 33. Chochinov HM, Hack T, Hassard T, et al. Understanding the will to live in patients nearing death. Psychosomatics 2005;46:7–10. 34. Chochinov HM, Wilson KG, Enns M, et al. Depression, hopelessness, and suicidal ideation in the terminally ill. Psychosomatics 1998;39:366–370. 35. Perakyla A. Hope work in the care of seriously ill patients. Qual Health Res 1991;1:407–433. 36. Nuland SB. How We Die: Reflections on Life’s Final Chapter. New York: Alfred A Knopf, 1994. 37. Eliott J, Olver IN. Hope and hoping in the talk of dying cancer patients. Soc Sci Med 2007;64:138–149. 38. Hall BA. The struggle of the diagnosed terminally ill person to maintain hope. Nurs Sci Quart 1990;3:177–184. 39. Nekolaichuk CL. Diversity or divisiveness? A critical analysis on hope. In: Cutcliffe JRM, McKenna H, eds. Essential Concepts in Nursing. Oxford, U.K.: Elsevier, 2005, pp. 179–212. 40. Benzein E, Norberg A, Saveman BI. The meaning of the lived experience of hope in patients with cancer in palliative home care. Palliat Med 2001;15:117–126. 41. Appelin G, Bertero C. Patients’ experiences of palliative care in the home: a phenomenological study of a Swedish sample. Cancer Nurs 2004;27:65–70. 42. Olsson L, Östlund G, Strang P, et al. The glimmering embers: experiences of hope among cancer patients in palliative home care. Palliat Support Care 2011;9:43–54. 43. Duggleby W, Wright K. Transforming hope: how elderly palliative patients live with hope. CJNR 2005;37:70–84. 44. Duggleby W, Holtslander L, Steeves M, et al. Discursive meaning of hope for older persons with advanced cancer and their caregivers. Can J Aging 2010;29:361–367. 45. Olsman E, Leget C, Duggleby W, et al. A singing choir: understanding the dynamics of hope, hopelessness, and despair in palliative care patients. A longitudinal study. Palliat Support Care 2015;13:1643–1650. 46. Flemming K. The meaning of hope to palliative care cancer patients. Int J Palliat Nurs 1997;3:14–18. 47. Salander P, Bergenheim T, Henriksson R. The creation of protection and hope in patients with malignant brain tumors. Soc Sci Med 1996;42:985–996. 48. Mok E, Wai ML, Chan LN, et al. The meaning of hope from the perspective of Chinese advanced cancer patients in Hong Kong. Int J Palliat Nurs 2010;16:298–305. 49. Hong IWM, Ow R. Hope among terminally ill patients in Singapore: an exploratory study. Soc Work Health Care 2007;45:85–105. 50. Sachs E, Kolva E, Pessin H, et al. On sinking and swimming: the dialectic of hope, hopelessness, and acceptance in terminal cancer. AJHPM 2012;30:121–127.

Textbook of Palliative Medicine and Supportive Care 51. Weil CM. Exploring hope in patients with end stage renal disease on chronic hemodialysis. Nephrol Nurs J 2000;27:219–224. 52. Benzein E, Saveman BI. Nurses’ perception of hope in patients with cancer: a palliative care perspective. Cancer Nurs 1998;21:10–16. 53. Eliott J, Olver IN. Hope, life, and death: a qualitative analysis of dying cancer patients’ talk about hope. Death Stud 2009;33:609–638. 54. Kylma J, Vehvilainen-Julkunen K, Lahdevirta J. Hope, despair and hopelessness in living with HIV/AIDS: a grounded theory study. J Adv Nurs 2001;33:764–775. 55. Ezzy D. Illness narratives: time, hope and HIV. Soc Sci Med 2000;50:605–617. 56. Wong-Wylie G, Jevne RF. Patient hope: exploring the interactions between physicians and HIV seropositive individuals. Qual Health Res 1997;7:32–56. 57. Fanos JH, Gelinas DF, Foster RS, et al. Hope in palliative care: from narcissism to self-transcendence in amyotrophic lateral sclerosis. J Palliat Med 2008;11:470–475. 58. Daneault S, Lussier V, Mongeau S, et al. Ultimate journey of the terminally ill. Ways and pathways of hope. Can Family Phys 2016;62:648–656. 59. Dufault K, Martocchio BC. Hope: its spheres and dimensions. Nurs Clin North Am 1985;20:379–391. 60. Herth K. Fostering hope in terminally-ill people. J Adv Nurs 1990;15:1250–1259. 61. Reynolds MA. Hope in adults, ages 20–59, with advanced stage cancer. Palliat Support Care 2008;6:259–264. 62. Stephenson C. The concept of hope revisited for nursing. J Adv Nurs 1991;16:1456–1461. 63. Jevne RF, Nekolaichuk CL, Boman J. Experiments in Hope: Blending Art and Science with Service. Edmonton, Alberta, Canada: Hope Foundation of Alberta, 1999. 64. Yates P. Towards a reconceptualization of hope for patients with a diagnosis of cancer. J Adv Nurs 1993;18:701–706. 65. Farran CJ, Herth KA, Popovich JM. Hope and Hopelessness: Critical Clinical Constructs. Thousand Oaks, CA: Sage, 1995. 66. Clayton JM, Hancock K, Parker S, et al. Sustaining hope when communicating with terminally ill patients and their families: a systematic review. Psycho-Oncology 2008;17:641–659. 67. Jevne RF, Nekolaichuk CL. Threat and Hope in Coping with Cancer for Health Care Professionals. In: Jacoby R, Keinan G, eds. Between Stress and Hope: From a Disease-Centered to a Health-Centered Perspective. Westport, CT: Praeger Publishers, 2003, pp. 187–212. 68. Innes S, Payne S. Advanced cancer patients’ prognostic information preferences: a review. Palliat Med 2009;23:29–39. 69. Olsman E, Leget C, Onwuteaka-Philipsen B, et al. Should palliative care patients’ hope be truthful, helpful or valuable? An interpretive synthesis of literature describing healthcare professionals’ perspectives on hope of palliative care patients. Palliat Med 2014;28:59–70. 70. Nekolaichuk CL, Bruera E. Assessing hope at end-of-life: validation of an experience of hope scale in advanced cancer patients. Palliat Support Care 2004;2:243–253. 71. Herth K. Abbreviated instrument to measure hope: development and psychometric evaluation. J Adv Nurs 1992;17:1251–1259. 72. Benzein E, Berg A. The Swedish version of Herth Hope Index—An instrument for palliative care. Scand J Caring Sci 2003;17:409–415. 73. Olsman E, Leget C, Willems D. Palliative care professionals’ evaluations of the feasibility of a hope communication tool: a pilot study. Progress in Palliative Care 2015;23:321–325. 74. Nekolaichuk CL, Jevne RF, Maguire TO. Structuring the meaning of hope in health and illness. Soc Sci Med 1999;48:591–605. 75. MacLeod R, Carter H. Health professionals’ perception of hope: understanding its significance in the care of people who are dying. Mortality 1999;4:309–317. 76. Cutcliffe JR. How do nurses inspire and instil hope in terminally ill HIV patients? J Adv Nurs 1995;22:888–895. 77. Herth K. Contributions of humor as perceived by the terminally ill. Am J Hosp Care 1990;7:36–40. 78. Herth K. Engendering hope in the chronically and terminally ill: nursing interventions. Am J Hosp Palliat Care 1995;12:31–39. 79. Kennett CE. Participation in a creative arts project can foster hope in a hospice day centre. Palliat Med 2000;14:419–425. 80. Duggleby W, Wright K. Elderly palliative care cancer patients’ descriptions of hope-fostering strategies. IntJ Palliat Nurs 2004;10:352–359. 81. Gum A, Snyder CR. Coping with terminal illness: the role of hopeful thinking. J Palliat Med 2002;5:883–894.

Hope In End-of-life Care 82. Centers LC. Beyond denial and despair: ALS and our heroic potential for hope. J Palliat Care 2001;17:259–264. 83. Aldridge D. Spirituality, hope, and music therapy in palliative care. Arts Psychother 1995;22:103–109. 84. Jevne RF. It All Begins with Hope: Patients, Caregivers and the Bereaved Speak Out. San Diego, CA: LuraMedia, 1991. 85. Holt J. A systematic review of the congruence between people’s needs and nurses’ interventions for supporting hope. Online J Knowledge Synthesis Nurs 2001;8:10. 86. Duggleby WD, Degner L, Williams A, et al. Living with hope: initial evaluation of a psychosocial hope intervention for older palliative home care patients. J Pain Symptom Manage 2007;33:247–257. 87. Duggleby W, Cooper D, Nekolaichuk C, et al. The psychosocial experiences of older palliative patients while participating in a living with hope program. Palliat Support Care 2016;14:672–679. 88. Duggleby W, Wright K, Williams A, et al. Developing a living with hope program for caregivers of family members with advanced cancer. J Palliat Care 2007;23:24–31. 89. Herth K. Enhancing hope in people with a first recurrence of cancer. J Adv Nurs 2000;32:1431–1441. 90. Herth K. Development and implementation of a hope intervention program. Oncol Nurs Forum 2001;28:1009–1017. 91. Collins A, Bhathal D, Field T, et al. Hope tree: an interactive art installation to facilitate the expression of hope in a hospice setting. AJHPM 2018;35:1273–1279. 92. Breitbart W, Rosenfeld B, Gibson C, et al. Meaning-centered group psychotherapy for patients with advanced cancer: a pilot randomized controlled trial. Psycho-Oncology 2010;19:21–28. 93. Chochinov HM, Kristjanson L, Breitbart W, et al. Effect of dignity therapy on distress and end-of-life experience in terminally ill patients: a randomised controlled trial. Lancet Oncol 2011;12:753–762. 94. Hall S, Goddard C, Opio D. A novel approach to enhancing hope in patients with advanced cancer: a randomized phase II trial of dignity therapy. BMJ Support Palliat Care 2011;1:315–321.

491 95. Hansen MJ, Enright RD, Baskin TW, et al. A palliative care intervention in forgiveness therapy for elderly terminally ill cancer patients. J Palliat Care 2009;25:51–60. 96. Ando M, Morito T, Akechi T, et al. Efficacy of short-term life-review interviews on the spiritual well-being of terminally ill cancer patients. J Pain Symptom Manage 2010;39:993–1002. 97. DeMartini J, Fenton JJ, Epstein R, et al. Patients’ hopes for advanced cancer treatment. J Pain Symptom Manage 2019;57:57–63. 98. Tollett JH, Thomas SP. A theory-based nursing intervention to instill hope in homeless veterans. Adv Nurs Sci 1995;18:76–90. 99. Rustøen T, Wiklund I, Hanestad BR, et al. Nursing intervention to increase hope and quality of life in newly diagnosed cancer patients. Cancer Nurs 1998;21:235–245. 100. Best M, Aldridge L, Butow P, et al. Treatment of holistic suffering in cancer: a systematic literature review. Palliat Med 2015;29:885–898. 101. Penz K, Duggleby W. Harmonizing hope: a grounded theory study of the experience of hope of registered nurses who provide palliative care in community settings. Palliat Support Care 2011;8:281–294. 102. Nierop-van Baalen C, Grypdonck M, van Hecke A, et al. Health professionals dealing with hope in palliative patients with cancer, an explorative qualitative research. Eur J Cancer Care 2019;28:e12889. 103. Olsman E, Duggleby W, Nekolaichuk C, et al. Improving communication on hope in palliative care. A qualitative study of palliative care professionals’ metaphors of hope: grip, source, tune, and vision. J Pain Symptom Manage 2014;48:831–838. 104. Wolf A, Garlid CF, Hyrkas K. Physicians’ perceptions of hope and how hope informs interactions with patients: a qualitative, exploratory study. AJHPM 2018;35:993–999. 105. Chochinov H, McClement SE, Hack TF, et al. Health care provider communication. An empirical model of therapeutic effectiveness. Cancer 2013;119:1706–1713.

51

DEHYDRATION AND REHYDRATION

Robin L. Fainsinger

Contents Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������493 Scenario 1����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������493 Scenario 2����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������493 Scenario 1����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������493 Scenario 2����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������494 What is dehydration?�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������494 Hydration controversy�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������495 Hydration research�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������496 Biochemical findings and hydration status������������������������������������������������������������������������������������������������������������������������������������������������������������496 Biochemical findings/hydration status and clinical symptoms�������������������������������������������������������������������������������������������������������������������������496 Ethical, social, and cultural considerations������������������������������������������������������������������������������������������������������������������������������������������������������������������497 Alternative hydration techniques����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������498 Nasogastric tubes and gastrostomy�������������������������������������������������������������������������������������������������������������������������������������������������������������������������498 Hypodermoclysis���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������498 Proctoclysis�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������498 Conclusion��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������498 References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������499

Introduction There are many facets to the often-complicated and controversial topic of dehydration and rehydration of palliative care populations. The ongoing divergent opinion is well illustrated by the following statements: Research is limited but suggests that artificial hydration in imminently dying patients influences neither survival nor symptom control.1 The best available evidence suggests that hydration of advanced cancer patients plays an important role in maintaining cognitive function and is therefore an important factor in the prevention and reversal of delirium in this population.2 Superimposed on these conflicting medical comments are other complex issues: Terminal dehydration is a controversial topic, weighted heavily with historic symbolism, and strong religious, societal, and cultural conflicts. 3 Some of these issues can be illustrated with the following examples.

Scenario 1

A 70-year-old woman living in an isolated rural community in southern Africa develops increasing abdominal discomfort. She has been active and in good health, although she has lost approximately 3 kg of weight over the last 2 months. She develops severe nausea and vomiting and inability to maintain an adequate oral

intake. The family’s access to transportation that would enable them to travel to the nearest hospital 10 km away is limited. Her extended family nurses her at home, and after a few days, she is able to resume a reasonable oral intake, her strength improves, and she resumes her role with household maintenance and care of her grandchildren.

Scenario 2

A 70-year-old woman living in a wealthy country with universal health care develops increasing abdominal discomfort. She has been active and in good health, although she notes that she has lost approximately 3 kg of weight over the last few months. Extensive diagnostic imaging and subsequent liver biopsy confirm pancreatic cancer with liver metastases. She develops severe nausea and vomiting and presents to the emergency department of her local hospital with clinical evidence of dehydration. She is rehydrated with intravenous fluids and admitted for investigation. No evidence of bowel obstruction is found on diagnostic imaging. The patient improves, resumes a reasonable oral intake, and is discharged home.

Scenario 1

Over the course of the next few weeks, the woman again develops increasing abdominal pain, poor appetite and loss of weight, and intermittent nausea and vomiting. She is fortunate that a mobile health clinic has now started to visit her isolated community on a monthly basis. The nurse practitioner doing the examination notes that the patient looks cachectic and has an enlarged, tender liver. She suspects that the patient is dying from an unknown gastrointestinal primary with extensive intra-abdominal metastatic disease. The family and patient are provided with an explanation of the suspected diagnosis and prognosis. The clinic is able to 493

Textbook of Palliative Medicine and Supportive Care

494 provide a free prescription of morphine liquid and an explanation of dietary supplements they could use to prevent constipation. The nurse practitioner is aware of the options for hydration supplementation such as intravenous, hypodermoclysis, and rectal hydration. However, for a variety of reasons, including economic and the increased burden this would place on the family caregivers, all of these options are rejected. Instead, the family is given suggestions to assist the patient to continue to drink as long as this is comfortable for her, as well as some suggestions to provide mouth care. The nurse practitioner wishes the patient and family well and indicates that they should return for a follow-up visit when the mobile clinic is back in their community. The nonverbal communication in the room indicates that all of them understand that the nurse practitioner does not really expect to see them for a follow-up visit.

Scenario 2

Over the next few weeks, increasing abdominal pain requires escalating morphine doses to achieve good control. The patient expresses a preference to remain at home as she deteriorates. However, the patient and her husband indicate to the family physician that their religious beliefs are that everything possible should be done to maintain life for as long as possible. Intermittent nausea and vomiting result in the oral morphine being changed to the subcutaneous route, and increasing abdominal pain requires increasing the morphine dose to 100 mg subcutaneously per day. The family physician discusses the option of parenteral hydration. Hypodermoclysis at 1 L overnight is instituted. A daughter and son now arrive to assist and support their father in caring for their mother. The son has worked as a hospice nurse and questions the value of ongoing hydration at this point. The daughter is a nephrologist who believes that hydration is necessary to maintain normal renal function and avoid the accumulation of morphine metabolites that may cause side effects. The patient and her husband have had extensive discussions over the years with their family physician who has a good understanding of how their spirituality affects their decision-making. Although respecting their children’s opinions, the couple relies heavily on their family physician to provide information and direction on appropriate management. These scenarios highlight some of the complexity that surrounds this widely debated and controversial topic. At the center of the discussion, irrespective of the setting and circumstances, is the desire to keep patients as comfortable as possible while avoiding unnecessary management or procedures. However, there is no doubt that the definition of “unnecessary” will have great international variation. Clinicians with the responsibility to make these decisions will need to sort through expressions of opinion, information on pathophysiology and biochemical changes, research looking at a variety of outcomes, differing family and cultural expectations, and consensus statements. This diverse information then has to be individually applied to the specific trajectory and circumstances of patients and their families.

What is dehydration? As has been pointed out in past reviews, use of the term dehydration in considering this issue is often inaccurate.2,4 Fluid deficit is the state of water loss with or without electrolytes, which includes the subtypes of volume depletion and dehydration. Dehydration should be understood as total body water deficit that

FIGURE 51.1  Types of fluid deficit. is predominantly intracellular and associated with hypernatremia. Volume depletion implies a deficit in the intravascular fluid volume and can be isotonic, hyponatremic, or hypernatremic (Figure 51.1). A variety of factors can be associated with fluid deficits (Table 51.1). Any of these etiologies for fluid deficit can occur at any stage of a palliative care illness and multiple possible mechanisms can occur simultaneously. The assessment of risk or presence of fluid deficits is based on a variety of factors that can be determined by history, physical examination, and laboratory findings. The history is of obvious value in determining the possible risk factors listed in Table 51.1. There are sometimes practical difficulties in estimating the accuracy of fluid intake estimates and potential fluid loss through urine and fecal incontinence. Symptoms of fluid deficit can include behavior and cognitive changes, fatigue, thirst, nausea, and dry mouth. The classic signs of fluid deficit include dry mouth, reduced skin turgor, postural hypotension, tachycardia, reduced jugular venous pressure, sunken eyes, and reduced sweating. However, all of these problems need to be interpreted with caution as they can be associated with other causes present in aging, cachexia, advanced cancer, and side effects due to commonly used medications. Laboratory evaluation can provide some helpful information in evaluating fluid deficits but will obviously depend on the setting of care and whether such investigations are acceptable to the patient, family, and health-care team. The common findings present in volume-depleted patients include elevated levels of urea, creatinine, plasma proteins, hematocrit, and sodium. It is worth noting that in a systematic review attempted to clarify the physical diagnosis of hypovolemia in adults, 5 the authors concluded that in patients with vomiting, diarrhea, or decreased oral intake, few findings, with the exception of serum electrolytes, urea, and creatinine values, have proven value. TABLE 51.1  Factors Associated with Fluid Deficits Decreased Intake

Increased Fluid Loss

Asthenia Anorexia Coma Delirium

Bowel resection Diarrhea Diuretics Diabetes mellitus/ insipidus Fistulas Fever/sweating Hypercalcemia Vomiting

Dementia Depression Dysphagia Nausea

Dehydration and Rehydration

495

Hydration controversy There is no controversy that palliative care populations should be encouraged to maintain an adequate oral intake to prevent fluid deficit. However, there are many literature reports illustrating opposing viewpoints on the use of supplemental parenteral hydration. These have been considered from both clinical and ethical viewpoints.6–16 Historical reviews on this topic have referenced a similar collection of clinical anecdotes and opinions. The arguments for and against hydrating palliative care populations are summarized in Box 51.1.11,12 It would appear that the arguments for initiating or maintaining parenteral hydration in palliative care populations originate from the standard medical approach to fluid deficits. Thus, it would be reasonable to expect that most patients dying in hospitals will have an intravenous line unless they have undergone rapid deterioration or unanticipated demise. This was originally demonstrated by a Canadian report17 where 73 of 106 cancer patients dying in a tertiary care hospital were noted to have intravenous fluids administered. A retrospective study on the use of artificial hydration in an acute care hospital in England1 noted that of 111 patients, 65% were hydrated during the last week of life and 46% were being hydrated at the time of death. The mean rate of parenteral hydration was 2000 mL/day. The results suggested that artificial hydration is no longer necessarily considered routine hospital practice for dying patients in this setting. In order to clarify the routine practice of physicians involved in end-of-life care in Edmonton, Canada, the routine management of parenteral hydration for patients dying in a palliative care unit and acute care hospital while receiving or not receiving consult advice from the palliative care program was reported.18 A retrospective chart review of 50 consecutive patients dying at each of the three sites was included. The majority of patients (66–98%) at all sites received hydration during the last week of life. However,

the volume of hydration was noted to be significantly lower in the palliative care unit site. A survey questionnaire of Japanese physicians attempted to clarify attitudes toward terminal dehydration. Results revealed that physicians with more positive attitudes toward intravenous hydration were less involved in end-of-life care and more likely to regard fluid as a necessary physiological requirement, consider it a minimum standard of care, and believe that this was beneficial for palliating symptoms.19 A Canadian study distributed a questionnaire to 18 palliative care physicians in major Canadian centers in an attempt to clarify the routine practice of physicians involved in end-of-life care.20 Results demonstrated a wide range of practice. Physicians estimated that they ordered parenteral hydration in a median of 6–10% of patients (range 0–100%). The routes of parenteral hydration were intravenous hydration, with a median of 30% (range 0–100%), and hypodermoclysis, with a median of 70% (range 0–100%). The estimated average volume range per 24 hours was between 200 and 2400 mL. A survey of 238 palliative care physicians in Latin America reported that 60% prescribed parenteral hydration to 40–100% of their patients in the last weeks of life. These results differ from traditional hospice philosophy, and the report concludes that clinical perceptions of benefit drive practice to prescribe or withhold parenteral hydration based on individualized treatment decisions.21 It is easy to imagine the problems inflicted on advanced palliative care populations by a policy of maintaining intravenous hydration with volumes in excess of 3 L/day. Under this circumstance, complications such as increased respiratory and gastrointestinal symptom distress can be anticipated. The literature reports against parenteral hydration would suggest that some health-care professionals looking after palliative care populations have reacted to overuse of intravenous fluids and concluded that no parenteral hydration is the preferred approach. This has been reinforced by anecdotal literature reports noting that many

BOX 51.1  HYDRATION IN PALLIATIVE CARE Arguments against parenteral hydration: • • • • • • • •

Symptom distress is not experienced by comatose patients. Dying is prolonged by parenteral fluids. There is less urine and thus less problem with incontinence and catheter use. Decreased gastrointestinal fluid associated with dehydration results in less nausea and vomiting. Decreased respiratory secretions will result in less cough and pulmonary edema. The severity of edema and ascites is decreased. Dehydration can act as a natural anesthetic for the central nervous system. Parenteral hydration is uncomfortable and limits patient mobility.

For parenteral hydration: • • • •

Parenteral hydration assists in making dying patients more comfortable. There is no evidence that parenteral hydration prolongs life. Fluid deficits can cause restlessness, confusion, and neuromuscular irritability. Oral hydration is provided to dying patients complaining of thirst, and therefore, parenteral hydration should be an option. • Emphasis on the poor quality of life of palliative care populations detracts from efforts to improve comfort and life quality. • Parenteral hydration is considered a minimum standard of care. • Withholding parenteral fluid from palliative care populations may result in withholding therapies to other compromised patient groups.

Textbook of Palliative Medicine and Supportive Care

496 palliative care patients appear to die comfortably without parenteral hydration. Nevertheless, a review of the literature indicates that these reports are mostly based on unsubstantiated data.12 There are other issues worth considering11,12,22–25: • Fluid deficit as a cause of confusion and restlessness in non-terminally ill patients is well recognized. The problems of delirium and agitation have been well reported in palliative care populations.2 • Reduced intravascular volume and glomerular filtration rate caused by fluid deficits are well accepted as a cause of prerenal failure.2,4 Opioid metabolite accumulation in the presence of renal failure, resulting in confusion, myoclonus, and seizures, has been well documented. Reports with regard to agitated delirium and terminal restlessness have frequently appeared in the palliative care literature. Discussion of these problems has generally been centered on the need for pharmacological management, which often includes sedation.26–28 Ventafridda et al.29 reported 9% of patients requiring sedation for agitated delirium in a study of unendurable symptoms experienced by patients with cancer during their last days of life. This prompted a report by our group30 that agitated delirium was the most frequent problem requiring sedation in the last week of life in 10% of our patients. A later report noted that the severity of agitated delirium requiring sedation had decreased to 3% in our palliative care unit. 31 We speculated that this resulted due to a change in our practice to include more frequent use of hypodermoclysis for hydration, switching opioids earlier when toxicity developed, and the use of less sedating treatments such as haloperidol for delirium, decreasing the prevalence and difficulty of managing agitated delirium in this setting. 32 Reports in the palliative care literature have noted a range of options for the pharmacological management of symptoms associated with agitated delirium, including the use of intravenous propofol. 33–35 A retrospective chart review of 76 consecutive patients dying at St. Luke’s Hospice in Cape Town, South Africa, found that 29% of patients required sedation for agitated delirium. Although none of these patients were treated with parenteral hydration, patients requiring sedation were noted to require significantly higher doses of opioids during a longer admission. 36 Further reports on the use of sedation have suggested that agitated delirium appears to be less problematic in a number of different settings in Edmonton, 37 where parenteral hydration is more common practice,18 compared with requirements for sedation in a number of other international settings. 38 As a result, it has been suggested that dehydration could be a reversible component of agitated delirium, which may be ignored by an approach that focuses on a sedative pharmacological solution to this apparently common and certainly distressing situation. 39 Thus, it may be illogical for a patient to receive medications for agitated delirium, myoclonus, and seizures, if in some circumstances these problems could be prevented or corrected by the use of parenteral hydration.

Hydration research Research into the use of hydration in palliative care settings has focused on three dimensions40: • The association between biochemical findings and hydration status

TABLE 51.2  Comparison of Biochemical Findings in Patients Taking Oral Fluids (Sips) 47 and those Receiving Hypodermoclysis48 Fainsinger et al.48

Urea (mmol/L) Creatinine

Ellershaw et al.47

Mean

Normal Range

Mean

Normal Range

8.8 101

3.2–8.2 62–133

15.5 177

2.5–6.5 60–120 (μmol/L)

• The association between biochemical findings and clinical symptoms • The association between hydration status and clinical symptoms

Biochemical findings and hydration status

There is no controversy that dehydration is a cause of renal failure.41–43 However, while parenteral hydration is accepted standard management in many settings, the impact of fluid deficit and rehydration on the renal function and electrolyte balance of palliative care populations is still questioned.10,44–47 Ellershaw et al.48 undertook a biochemical investigation in 82 patients with advanced cancer. The patients were taking oral sips of fluid and were no longer able to tolerate oral medication. Our group49 reported biochemical investigation of 100 consecutive patients, 69 of whom received hypodermoclysis at an average volume of 1203 ± 505 mL/day. A comparison of these two reports50 has been published (Table 51.2). Morita et al.51 published further results on the biochemistry of terminally ill cancer patients and concluded that relatively small amounts of parenteral hydration may result in less abnormal biochemistry, particularly with regard to renal function.

Biochemical findings/hydration status and clinical symptoms

Much of the early literature on this issue was based on anecdotal opposing viewpoints and case reports.52,53 However, subsequent reports attempted to study this issue more carefully. Burge46 reported a cross-sectional survey studying the quantitative assessment of the dehydration experience in patients with advanced cancer. The study concluded that parenteral hydration on the basis of fluid intake and laboratory measures were not helpful if the aim was to reduce thirst. McCann et al.54 studied 48 consecutive patients with regard to symptom prevalence and management of hunger and thirst in terminally ill patients not receiving parenteral hydration. Symptoms of hunger, thirst, and dry mouth were apparently well managed with oral sips and mouth care. Ellershaw et al.48 investigated the relationship between symptoms and dehydration in 82 patients not provided with parenteral hydration. No significant association was demonstrated between the level of hydration and respiratory tract secretions, thirst, and dry mouth. However, they did acknowledge that the effect of renal failure and possible consequences of agitation and confusion were not assessed. Musgrave et al.55 studied the effect of intravenous fluids on a group of patients with advanced cancer dying in a hospital oncology unit. No relationship was demonstrated between level of thirst, intravenous fluids, and biochemical parameters. A subsequent study56 also failed to demonstrate any relation between intravenous fluids, fluid balance, and the prevalence of crepitations, ascites, and leg edema. A retrospective

Dehydration and Rehydration chart review of 117 and 162 patients admitted to a palliative care unit in 1988–1989 and 1991–1992 assessed the impact of a change in practice with regard to management of dehydration and cognitive impairment.57 The authors concluded that the data suggested that routine cognitive assessment, opioid rotation, and hydration may reduce the frequency of agitated confusion in terminally ill cancer patients. Although hydration may have had a role, it was not possible to determine the relative contribution. A partial replication of this study considered the role of hydration and an incomplete opioid substitution on the prevalence of agitated delirium.58 No significant decrease in the occurrence of agitated delirium was noted. Ashby et al.59 measured plasma concentrations of morphine and metabolites in 36 hospice patients. They concluded that morphine metabolites may be a causal aggravating factor in nausea and vomiting and cognitive impairment in palliative care patients with significant renal impairment. Lawlor et al.60 completed prospective serial assessments of 113 patients with advanced cancer in a delirium study. Univariate analysis demonstrated reversibility associated with psychoactive medications and dehydration. They concluded that although delirium is multifactorial, hydration using hypodermoclysis may be one of the potential useful measures to consider. Bruera et al. published the first randomized, controlled, double-blind study of parenteral hydration in terminally ill cancer patients. This was a multicenter study where patients with clinical and biochemical evidence of dehydration and history of an oral intake of less than 1 L of fluid per day were randomly assigned to receive 1000 mL (treatment group) or 100 mL (placebo group) of normal saline over 4 hours for 2 days. The outcome measures were patient- and investigator-rated symptoms of fatigue, sedation, myoclonus, hallucinations, and a global sense of well-being. A significant improvement in sedation and myoclonus scores was noted in the hydration treatment group.61 A follow-up study using similar methodology and 6 hospices in the Houston area included 129 patients randomly assigned to hydration or placebo and found no significant differences. The authors concluded that in this population, hydration of 1000 mL/day does not improve symptoms, quality of life, or survival compared with placebo. They did comment that further research in other patient populations such as delirium associated with dehydration and opioid toxicity should be explored in future studies.62 Fritzon et al.A completed an observational study of symptoms and parenteral fluid administered in the last week of life and suggested an association with higher volumes and increased documentation of dyspnea. A review by Burge63 concluded that there is little clinical evidence to guide patients, families, and clinicians in treatment decisions regarding fluid intake during the terminal phase of life. A subsequent systematic review by Viola et al.64 summarized existing evidence regarding fluid status effects and fluid therapy. Six studies were selected for inclusion and the authors concluded that given the study limitations, it was impossible to draw firm conclusions regarding clinical care. A Cochrane review (updated in 2014) concluded that there was insufficient quality research for practice recommendations in the use of alternative hydration assistance for palliative care patients.65

Ethical, social, and cultural considerations There are other important issues to consider with regard to the use of parenteral hydration.66 Patient and family attitudes, level of comfort with the situation, and education and health-care

497 workers’ attitudes, level of education, and biases in presentation all influence the decision-making process. Unfortunately, artificial nutrition and hydration are often considered as the same issue in ethical and clinical discussion papers. This causes unnecessary confusion, as the arguments and rationale for providing nutritional calories via artificial means as opposed to hydration should be considered independently. Morita et al.67 studied patients’ and family members’ perceptions about rehydration to identify factors contributing to decision-making. The survey included 121 Japanese hospice patients with insufficient oral intake. Patient performance status, fluid retention symptoms, denial, physician recommendations, patients’ and family members’ beliefs with regard to hydration effect on patient distress, and family anxiety about withholding rehydration were significantly associated with decision-making. The main determinants for rehydration were the patient performance status, fluid retention symptoms, denial, and care receiver’s beliefs about the effects of rehydration on patient distress. A Canadian study68 identified issues of importance to family caregivers with regard to administering parenteral hydration to patients with advanced cancer. Factors influencing caregivers included symptom distress issues, ethical and emotional considerations, information exchanged between health professionals and families, and culture. Perceived benefits of artificial hydration were central to the ethical, emotional, and cultural considerations involved in caregivers’ decision-making. An article presenting the values of the Jewish faith with regard to terminal dehydration69 illustrates the difficulty of applying cultural and ethnic research and opinion. Letters in response varied from describing this as an “excellent article” 70 to “extremely offensive in its references to Jewish people.” 71 Malia et al. noted that artificial hydration in palliative care is a controversial practice in the United Kingdom and applied Q methodology to identify issues of most concern to patients in influencing decisions. The importance of considering the different views patients bring to their decision-making and the need to involve them in making unbiased informed treatment choices are nicely demonstrated in this novel research study.72 Cohen et al. used phenomenological interviews with patients and caregivers in home hospice care in the United States to understand how they viewed parenteral hydration. Findings differed from traditional hospice beliefs in that this was described by some participants as enhancing comfort, dignity, and quality of life.73 Gent et al. (B) completed a literature review on attitudes and knowledge of patients, families, health-care personnels and the general public toward assisted hydration in dying patients and identified three core themes: symbolic value; beliefs and misconceptions; and cultural, ethical, and legal ideas. It has been proposed that terminal dehydration or voluntary cessation of drinking may provide an alternative to physicianassisted suicide. Miller and Meier74 suggested that terminal dehydration accompanied by standard palliative care management offers patients a way to escape agonizing, incurable conditions that they consider to be worse than death, without requiring transformation of the law and medical ethics. Quill et al.75 suggested that voluntary cessation of “eating and drinking are clinical options that may be acceptable to a patient and physician and do not require fundamental changes in the law.” Craig76 argued passionately that a blanket policy of no hydration, as initially endorsed in a national guideline end-of-life care pathway in the United Kingdom, was ethically indefensible. Her primary concern was that the value of hydration is

Textbook of Palliative Medicine and Supportive Care

498 underestimated and could increase deaths associated with palliative sedation. Craig77 has devoted a book to this issue, in which she stated, “My personal role in the hydration debate has been to highlight the ethical, legal and medical dangers of a regime of sedation without hydration in the dying and draw attention to the plight of dissenting relatives.”

Alternative hydration techniques There is universal agreement that the best and most convenient route to correct fluid deficits is increasing or improving oral intake. However, when this is impossible or inadequate, there are some circumstances where parenteral hydration may be of benefit. It is often not well understood that we are not necessarily all seeing patients in the same trajectory of illness. Clinical circumstances evolve78 and a physically independent and cognitively intact patient at an early stage of a palliative illness is likely to be viewed very differently to the same patient a number of months later who is now cognitively impaired and physically dependent. However, if a decision is made to use parenteral hydration, there are considerations with regard to the type of fluid, volume, and route of administration. There is no doubt that intravenous hydration is the route of choice in acute care institutions. It has obvious disadvantages such as difficulty finding venous access, pain, infection, limitations to mobility, and displaced lines, particularly with confused patients. Nevertheless, it should be noted that a report from an Italian palliative care program stated that 82% of palliative care patients will have an intravenous line and receive a range of 1–1.5 L of fluid per day.79 In addition, they stated that although hypodermoclysis has been suggested as an alternative, experience suggests that it is not less stressful for palliative care patients and that the intravenous route is preferred.

Nasogastric tubes and gastrostomy

Nasogastric tubes are generally uncomfortable for patients and prolonged use, particularly in palliative care populations, and should be avoided where possible.80,81 Percutaneous gastrostomies are commonly used with head and neck or esophageal cancer patients with increasing dysphagia who may benefit from nutrition as well as hydration.82 As patients deteriorate, there is a need to review the goals of care with regard to enteral nutrition. However, difficulty with discontinuing management and ease of access can result in ongoing enteral nutrition and hydration in circumstances where this might not otherwise have been instituted.

Hypodermoclysis

The safety of hypodermoclysis has been well documented and reported in noncancer patients.83,84 There have also been studies in palliative care patients demonstrating the ease of administration and minimal toxicity.49,85,86 The procedure is simple and associated with minimal pain. A butterfly needle is inserted subcutaneously and attached to a fluid line that can run via gravity or an infusion pump. It requires minimal training for insertion and surveillance, and family caregivers can be trained to supervise this management in the home with minimal burden, equipment, or technical support (C*). There is evidence of increasing acceptance of hypodermoclysis in the acute care setting.18 It is generally recommended that solutions with some electrolytes are used, as nonelectrolyte solutions have been reported to draw fluid into the interstitial space.11,12,87 Initial recommendation suggested rates of infusion limited to a

maximum of 100–120 mL/hour; however, patients can tolerate boluses up to 500 mL/hour.88 The use of hypodermoclysis has been assisted by adding hyaluronidase to promote absorption in a dose ranging from 150 to 750 units/L. Initially, smaller volumes of hyaluronidase were demonstrated to be just as effective.88 However, a shortage of hyaluronidase led to clinical experience and anecdotal reports suggesting good absorption of hypodermoclysis without hyaluronidase. This resulted in a report of 24 consecutive patients receiving hypodermoclysis without hyaluronidase.89 Hydration was maintained for a mean 12 ± 9 days, with an infusion varying in range between 20 and 300 mL/hour. Three patients were demonstrated to tolerate twice daily boluses of 500 mL over 1 hour. The average infusion site duration was 3.3 ± 3.6 days. These results and the increasing difficulty obtaining hyaluronidase have resulted in the ongoing clinical observation that most patients tolerate hypodermoclysis without requiring the addition of hyaluronidase. This is now standard practice in our setting with rates up to 80 mL/hour well tolerated by most patients. However, recombinant human hyaluronidase use has been reported in clinical studies and may have a future role in improving the absorption of subcutaneously administered fluids.90

Proctoclysis

As noted, intravenous hydration can be uncomfortable, expensive, and difficult to maintain in the home, while even hypodermoclysis can be expensive and too complicated in some settings. The potential advantage of the rectal administration of fluid, particularly in resource-limited developing countries, prompted a trial of rectal hydration in terminally ill cancer patients.91 Proctoclysis was offered to 17 adult patients with a fluid deficit where resources were inadequate for the use of hypodermoclysis. Tap water was used and the rectal infusion was increased from 100 mL to a maximum of 400 mL/hour, unless fluid leakage occurred before the maximum volume was achieved. The mean daily volume, hourly rate, and duration were reported as 1035 ± 150 mL/day, 224 ± 58 mL/hour, and 14 ± 8 days, respectively. Rectal hydration was noted to be well tolerated with minimal side effects in the majority of patients. A follow-up report92 included 78 advanced cancer patients receiving rectal hydration. Volumes infused, patient tolerance, and side effects were similar to the earlier report, confirming that this is a safe, effective, and low-cost technique for rehydration in terminally ill palliative care populations.

Conclusion Reconsider the varying circumstances and sociocultural circumstances of the two patients described in the introduction to this chapter. Discussion of management of these two patients, the manner in which information should be presented to them, literature interpretation as reviewed earlier, and the biases of healthcare providers and the circumstances in which we work will have significant implications on how we consider the issue of fluid deficit and rehydration. We can perhaps achieve consensus that dehydration is a cause of renal failure and that hypodermoclysis is a safe and effective way of providing rehydration. There may be agreement that rehydration of palliative care populations may result in better biochemical parameters for some patients. There is certainly much evidence to recommend that if terminally ill patients are not rehydrated, medications such as opioids should be gradually decreased to avoid accumulation and unnecessary

Dehydration and Rehydration KEY LEARNING POINTS • Hydration in palliative care is a controversial topic with divergent opinions. • Fluid deficits can cause confusion and renal failure. • Hydration research is inconclusive in guiding clinical care. • Hypodermoclysis is an excellent alternative for rehydration in palliative care populations. • Diverse clinical and sociocultural circumstances need to be considered. • Evidence recommends that if terminally ill patients are not rehydrated, medications should be decreased to avoid accumulation and side effects. • Rehydration may be helpful in some individual situations. • Patient and family preferences need to be understood and incorporated into the treatment plan. side effects. There is likely to be consensus that the major clinical issue is to consider whether rehydration will cause benefit or harm to palliative care patients unable to sustain adequate oral intake. The need to consider individual circumstances and predictions of life expectancy in evaluating the potential benefits of rehydration is a recurring theme.2,11,93 Although starting from different perspectives, there is some consensus10,39,64 that: • Available data are inadequate for final conclusions on this issue. • Careful individual assessment of the relevance of fluid deficit to each clinical situation is essential. • Further carefully designed research trials are requi red. 61,62

References

1. Soden K, Hoy A, Hoy W, et al. Artificial hydration during the last week of life in patients dying in district general hospital. Palliat Med 2002;16:542–543. 2. Lawlor P. Delirium and dehydration: some fluid for thought? Support Care Cancer 2002;10:445–454. 3. Huffman JL, Dunn GP. The paradox of hydration in advanced terminal illness. J Am Coll Surg 2002;194:835–839. 4. Sarhill N, Walsh D, Nelson K, Davis M. Evaluation and treatment of cancer related fluid deficits: volume depletion and dehydration. Support Care Cancer 2001;9:408–419. 5. McGee S, Abernethy WB, Simel DI. Is this patient hypovolemic? J Am Med Assoc 1999;281:1022–1029. 6. Craig GM. On withholding nutrition and hydration in the terminally ill: has palliative medicine gone too far? J Med Ethics 1994;20:139–143. 7. Ashby M, Stoffell B. Artificial hydration and alimentation at the end of life: a reply to Craig. J Med Ethics 1995;21:135–140. 8. Dicks B. Rehydration or dehydration? Support Care Cancer 1994;2:88–90. 9. Dunlop RJ, Ellershaw JE, Baines MJ, et al. On withholding nutrition and hydration in the terminally ill: Has palliative medicine gone too far? A reply. J Med Ethics 1995;21:141–143. 10. Dunphy K, Finlay I, Rathbone G, et al. Rehydration in palliative and terminal care: if not–Why not? Palliat Med 1995;9:221–228. 11. Fainsinger RL, Bruera E. The management of dehydration in terminally ill patients. J Palliat Care 1994;10:55–59.

499 12. Fainsinger RL, Bruera E. Hypodermoclysis for symptom control vs the Edmonton injector. J Palliat Care 1991;7:5–8. 13. Meares CJ. Terminal dehydration. A review. Am J Hospice Palliat Care 1994;11:10–14. 14. Slomka J. What do apple pie and motherhood have to do with feeding tubes and caring for the patient? Arch Intern Med 1995;155:1258–1263. 15. Smith SA. Patient induced dehydration: can it ever be therapeutic? Oncol Nurs Forum 1995;22:1487–1491. 16. Wilkes E. On withholding nutrition and hydration in the terminally ill: has palliative medicine gone too far? A commentary. J Med Ethics 1994;20:144–145. 17. Burge FI, King DB, Wilson D. Intravenous fluids and the hospitalized dying: a medical last rite? Can Fam Physician 1990; 883–886. 18. Lanuke K, Fainsinger RL, de Moissac D. Hydration management at the end of life. J Palliat Med 2004;7:257–263. 19. Morita T, Shima Y, Adachi I. Attitudes of Japanese physicians towards terminal dehydration: a nationwide study. J Clin Oncol 2002;20:4699–4704. 20. Lanuke K, Fainsinger RL. Hydration management in palliative care settings: a survey of experts. J Palliat Care 2004;19:278–279. 21. Torres-Vigil I, Mendoza TR, Alonso-Babarro A, et al. Practice patterns and perceptions about parenteral hydration in the last weeks of life: a survey of palliative care physicians in Latin America. J Pain Symptom Manage 2012;43:47–58. 22. Fainsinger RL, Bruera E, Watanabe S. Rehydration in palliative care. Palliat Med 1996;10:165–166. 23. Fainsinger RL. Deshydratation et soins palliatifs. In: Roy DJ, Rapin C, eds. Les annales de soins palliatifs. Vol. 3. Montreal, Quebec, Canada: Centre de Bioethique. Institut de Recherches Cliniques de Montreal, 1995; pp. 171–180. 24. Fainsinger RL. Nutrition and hydration for the terminally ill. J Am Med Assoc 1995;273:1736. 25. MacDonald SM, Fainsinger RL. Symptom control: the problem areas. Palliat Med 1994;8:167–168. 26. Burke AL, Diamond PL, Hulbert J. Terminal restlessness: its management and the role of midazolam. Med J Aust 1999;155:485–487. 27. Back IN. Terminal restlessness in patients with advanced malignant disease. Palliat Med 1992;6:293–298. 28. Lichter I, Hunt E. The last 48 hours of life. J Palliat Care 1990;6:7–15. 29. Ventafridda V, Ripamonti C, De Conno F, et al. Symptom prevalence and control during cancer patients last days of life. J Palliat Care 1990;6:7–11. 30. Fainsinger RL, Bruera E, Miller MJ, et al. Symptom control during the last week of life on a palliative care unit. J Palliat Care 1991;7:5–11. 31. Fainsinger RL, MacEacheron T, Miller MJ, et al. The use of hypodermoclysis for rehydration in terminally ill cancer patients. J Palliat Care 1992;8:70. 32. Fainsinger RL, Tapper M, Bruera E. A perspective on the management of delirium in the terminally ill. J Palliat Care 1993;9:4–8. 33. Mercadante S, De Conno F, Ripamonti C. Propofol in terminal care. J Pain Symptom Manage 1995;10:639–642. 34. Moyle J. Use of propofol in palliative medicine. J Pain Symptom Manage 1995;10:643–646. 35. Hosker MG, Bennett MI. Delirium and agitation at the end of life. BMJ 2016;353;i3085 36. Fainsinger RL, Landman W, Hoskings M, Bruera E. Sedation for uncontrolled symptoms in a South African hospice. J Pain Symptom Manage 1998;16:145–152. 37. Fainsinger RL, deMoissac D, Mancini I, Oneschuk D. Sedation for delirium and other symptoms in terminally ill patients in Edmonton. J Palliat Care 2000;16:5–10. 38. Fainsinger RL, Waller A, Bercovici M et al. A multi-centre international study of sedation for uncontrolled symptoms in terminally ill patients. Palliat Med 2000;14:257–265. 39. Fainsinger RL, Bruera E. When to treat dehydration in a terminally ill patient? Support Care Cancer 1997;5:205–211. 40. Morita T, Ichiki T, Tsunoda J, et al. Three dimensions of the rehydration: dehydration problem in a palliative care setting. J Palliat Care 1999;15:60–61. 41. Badr K, Ichikawa I. Prerenal failure: a deleterious shift from renal compensation to decompensation. N Engl J Med 1988;319:623–629. 42. Brady HR, Singer GG. Acute renal failure. Lancet 1995;346:1533–1540. 43. Weinberg A, Minakar KL. Dehydration. Evaluation and management in older adults. J Am Med Assoc 1995;274:1552–1556. 44. Waller A. Letter to the Editor. Am J Hospice Palliat Care 1995;7:5–6. 45. Oliver D. Terminal dehydration [letter]. Lancet 1994;ii:631.

500 46. Burge FI. Dehydration symptoms of palliative care cancer patients. J Pain Symptom Manage 1993;8:454–464. 47. Waller A, Hershkowitz M, Adunsky A. The effect of intravenous fluid infusion on blood and urine parameters of hydration and on the state of consciousness in terminal cancer patients. Am J Hospice Palliat Care 1994;11:22–27. 48. Ellershaw JE, Sutcliffe JM, Saunders CM. Dehydration and the dying patient. J Pain Symptom Manage 1995;10:192–197. 49. Fainsinger RL, MacEacheron T, Miller MJ, et al. The use of hypodermoclysis for rehydration in terminally ill cancer patients. J Pain Symptom Manage 1994;9:298–302. 50. Fainsinger RL. Biochemical dehydration in terminally ill cancer patients. J Palliat Care 1999;15:59–61. 51. Morita T, Ichika T, Tsunoda J, et al. Biochemical dehydration and fluid retention symptoms in terminally ill cancer patients whose death is impending. J Palliat Care 1998;14:60–62. 52. Andrews M, Bell ER, Smith SA, et al. Dehydration in terminally ill patients. Is it appropriate palliative care? Postgrad Med 1993;93:201–208. 53. Yan E, Bruera E. Parenteral hydration of terminally ill cancer patients. J Palliat Care 1991;7:40–43. 54. McCann RM, Hall WJ, Groth-Juncker A. Comfort care for the terminally ill patients. The appropriate use nutrition and hydration. J Am Med Assoc 1994;272:1263–1266. 55. Musgrave CF, Bartle N, Opstad J. The sensation of thirst in dying patients receiving IV hydration. J Palliat Care 1995;11:17–21. 56. Musgrave CF. Fluid retention and intravenous hydration in the dying. Palliat Med 1996;10:53. 57. Bruera E, Franco JJ, Maltoni M, et al. Changing pattern of agitated impaired mental status in patients with advanced cancer: association with cognitive monitoring, hydration, and opioid rotation. J Pain Symptom Manage 1995;10:287–291. 58. Morita T, Tei U, Ionoue S. Agitated terminal delirium and association with partial opioid substitution and hydration. J Palliat Med 2003;6:557–563. 59. Ashby M, Fleming B, Wood M, et al. Plasma morphine and glucuronide (M3G & M6G), concentrations in hospice in-patients. J Pain Symptom Manage 1997;14:157–167. 60. Lawlor PG, Gagnon B, Mancini IL, et al. Occurrence, causes, and outcome of delirium in patients with advanced cancer. Arch Intern Med 2000;160:786–794. 61. Bruera E, Sala R, Rico MA, et al. Effects of parenteral hydration in terminally ill cancer patients: a preliminary study. J Clin Oncol 2005;23(10):2366–2371. 62. Bruera E, Hui D, Dalal S, et al. Parenteral hydration in patients with advanced cancer: a multicenter, double blind, placebo controlled randomized trail. J Clin Oncol 2013;31(1):111–118. 63. Burge FI. Dehydration and provision of fluids in palliative care. What is the evidence? Can Fam Physician 1996;42:2383–2388. 64. Viola RA, Wells GA, Peterson J. The effects of fluid status and fluid therapy on the dying: a systematic review. J Pallia Care 1997;13:41–52. 65. Good P, Richard R, Syrmis W, et al. Medically assisted hydration for adult palliative care patients. Cochrane Database of Syst Rev 2014;4:CD006273. 66. Baumrucker S. Science, hospice, and terminal dehydration. Am J Hosp Palliat Care 1999;16:502–503. 67. Morita T, Tsunoda J, Inoue S, et al. Perceptions and decision making on rehydration of terminally ill cancer patients and family members. Am J Hosp Palliat Care 1999;16:509–516. 68. Parkash R, Burge F. The family’s perspective on issues of hydration in terminal care. J Palliat Care 1997;13:23–27. 69. Bodell J, Weng MA. The Jewish patient in terminal dehydration: a hospice ethical dilemma. Am J Hosp Palliat Care 2000;17:185–188. 70. Schur TG. Life and afterlife in Jewish tradition. Am J Hosp Palliat Care 2000;17:296–297. 71. Rothstein JM. Out of context? Am J Hosp Palliat Care 2000;17:297. 72. Malia C, Bennett MI. What influences patients’ decisions on artificial hydration at the end of life? A Q-methodology study. J Pain Symptom Manage 2011;42(2):192–201.

Textbook of Palliative Medicine and Supportive Care 73. Cohen MZ, Torres-Vigil I, Burbach BE, et al. The meaning of parenteral hydration to family caregivers and patients with advanced cancer receiving hospice care. J Pain Symptom Manage 2012;43:855–865. 74. Miller FG, Meier DE. Voluntary death: a comparison of terminal dehydration and physician-assisted suicide. Ann Intern Med 1998;128:559–562. 75. Quill TE, Meier DE, Block SD, et al. The debate over physicianassisted suicide: empirical data and conversant views. Ann Intern Med 1998;128:552–558. 76. Craig G. Palliative care in overdrive: patients in danger. Am J Hosp Palliat Care 2008;25(2):155–160. 77. Craig G. Challenging Medical Ethics 1: No Water—No Life: Hydration in the Dying. Cheshire, UK: Fairway Folio (Christian Publishing Services), 2004. 78. Fainsinger R. Dehydration. In: MacDonald N. ed. Palliative Medicine: A Case-Based Manual. New York: Oxford University Press, 1998. pp. 91–99. 79. Mercadante S, Villari P, Ferrera P. A model of acute symptom control unit: Pain relief and palliative unit of La Maddalena Cancer Centre. Support Care Cancer 2003;11:114–119. 80. Fainsinger RL, Spachynski K, Hanson J, et al. Symptom control in terminally ill patients with malignant bowel obstruction. J Pain Symptom Manage 1994;9:12–18. 81. Ripamonti C, Mercadante S, Groff L, et al. Role of octreotide, scopolamine butylbromide and hydration in symptom control of patients with inoperable bowel obstruction and nasogastric tubes: A prospective randomized trial. J Pain Symptom Manage 2000;19:23–24. 82. Steiner N, Bruera E. Methods of hydration in palliative care patients. J Palliat Care 1998;14:6–13. 83. Constans T, Dutertre J, Froge E. Hypodermoclysis in dehydrated elderly patients: local effects with and without hyaluronidase. J Palliat Care 1991;7:10–12. 84. Molloy DJ, Cunje A. Hypodermoclysis and the care of old adults. An old solution for new problems? Can Fam Physician 1992;38:2038–2043. 85. Hays H. Hypodermoclysis for symptom control in terminal cancer. Can Fam Physician 1985;31:1253–1256. 86. Bruera E, Legris M, Keuhn N, Miller MJ. Hypodermoclysis for the administration of fluids and narcotic analgesics in patients with advanced cancer. J Pain Symptom Manage 1990;5:218–220. 87. Turner T, Cassano A. Subcutaneous dextrose for rehydration of elderly patients: an evidence based review. BioMed Central Geriatr 2004;4:2. 88. Bruera E, de Stoutz ND, Fainsinger RL, et al. Comparison of two different concentrations of hyaluronidase in patients receiving one hour infusions of hypodermoclysis. J Pain Symptom Manage 1995;10:505–509. 89. Centeno C, Bruera E. Subcutaneous hydration with no hyaluronidase in patients with advanced cancer. J Pain Symptom Manage 1999;17:305–306. 90. Pirrello R, Ting Chen C, Thomas SH. Initial experiences with subcutaneous recombinant human hyaluronidase. J Palliat Med 2007;10(4):861–864. 91. Bruera E, Schoeller T, Pruvost M. Proctoclysis for hydration of terminal cancer patients. Lancet 1994;344:1699. 92. Bruera E, Pruvost M, Schoeller T. Proctoclysis for hydration of terminally ill cancer patients. J Pain Symptom Manage 1998;15:216–219. 93. Dalal S, Del Fabbro E, Bruera E. Is there a role for hydration at the endof-life? Curr Opin Support Palliat Care 2009;3:72–78. A. Fritzson A, Tavelin B, Axelsson B. Association between parenteral fluids and symptoms in hospital end-of-life care: an observational study of 280 patients. BMJ Support Palliat Care 2015;5:160–168. B. Gen, MJ, Fradsham S, Whyte GM, et al. What influences attitudes towards clinically assisted dehydration in the care of dying patients? A review of the literature. BMJ Support Palliat Care 2015;5:223–231. C. Vidal M, Hui D, Williams J, et al. A prospective study of hypodermoclysis performed by caregivers in the home setting. J Pain Symptom Manage 2016;52:570–574

52

FEVER, SWEATS, AND HOT FLASHES

Ahsan Azhar and Shalini Dalal

Contents Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������501 Fever�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������501 Pathophysiology of fever��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������501 Etiology of fever (Box 52.1)���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������502 Infections����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������502 Paraneoplastic fever����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������502 Transfusion-associated fever������������������������������������������������������������������������������������������������������������������������������������������������������������������������������503 Drug fever���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������503 Evaluation of fever�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������503 Interventions for fever������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������503 Goals of care�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������503 Nonspecific interventions������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������504 Primary interventions directed at the etiology of fever���������������������������������������������������������������������������������������������������������������������������������504 Fever versus hyperthermia����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������505 Sweats����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������506 Hot flashes��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������507 Pathophysiology����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������507 Assessment and treatment of hot flashes���������������������������������������������������������������������������������������������������������������������������������������������������������������507 Hormone replacement therapy��������������������������������������������������������������������������������������������������������������������������������������������������������������������������508 Nonhormonal agents��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������508 Other nonhormonal agents���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������509 Complementary and alternative medicine approaches���������������������������������������������������������������������������������������������������������������������������������509 References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������509

Introduction Fever, sweats, and hot flashes are commonly encountered in the terminally ill and cancer patients. These may sometimes be associated with considerable morbidity and mortality. Although infection remains the most common etiology of fever in patients, irrespective of whether they are receiving chemotherapy or not, fever is commonly seen in patients in the absence of infection as well. Fever is also one of the most common symptoms experienced by elderly people at the end of life.1,2 Similarly, hot flashes are reported by the majority of menopausal women and, in some women, can be a major source of distress.3,4 Less well recognized is the impact of hot flashes on individuals with cancer, particularly women with a history of breast cancer and men with prostate cancer. In women with a history of breast cancer, approximately two-thirds experience hot flashes.5,6 Optimal management of fevers, chills, sweats, and hot flashes is therefore of vital consideration in symptom management. As detailed in this chapter, it is contingent on meticulous patient assessment, on ascertaining the likely etiology, if possible, and on the implementation of appropriate treatment interventions befitting the patient-determined goals of care.

Fever Fever, as defined in Stedman’s Medical Dictionary, is a “complex physiologic response to disease mediated by pyrogenic cytokines and characterized by a rise in core temperature, generation of

acute phase reactants, and activation of immune systems.” 7 More commonly, fever is defined as the elevation of core body temperature above normal. Normal average adult core body temperature is 37°C (98.6°F) and displays a circadian rhythm with body temperatures being the lowest in the predawn hours, at 36.1°C (97°F) or lower, and rising to 37.4°C (99.3°F) or higher in the afternoon. In oncology practice, a single reading of temperature of more than 38.3°C (101°F) or three readings (each taken at least an hour apart) of temperatures more than 38°C (100.4°F) is considered significant.

Pathophysiology of fever

Much like other fundamental aspects of human biology, core body temperature is closely regulated by intricate control mechanisms, involving a complex interplay of autonomic, endocrine, and behavioral responses. Integral to this process is the hypothalamus, which functions much like a thermostat, balancing heat production with heat loss. Fever is considered a hallmark of immune system activation, resulting in a regulated rise in body temperature. The regulation of this phenomenon is accomplished by the actions of two types of endogenous immunoregulatory proteins called cytokines, some functioning as pyrogens and others as antipyretics. This is described later and illustrated in Figure 52.1. A number of exogenous substances, often referred to as exogenous pyrogens, have been found to be capable of evoking fever in animal models.8 Of these, lipopolysaccharide (LPS), a cell wall product derived from Gram-negative bacteria, has been the most 501

502

Textbook of Palliative Medicine and Supportive Care cyclooxygenase (COX)-2, and subsequently stimulate the production of prostaglandins of the E series.20,21 These prostaglandins activate thermoregulatory neurons of the anterior hypothalamic area to elevate body temperature.22 Peripherally produced cytokines can also communicate with the brain indirectly in several ways, including the stimulation of terminal fibers of the autonomic nervous system.23,24 Norepinephrine is the principal neurotransmitter, although several others such as acetylcholine, endorphins, enkephalins, substance P, somatostatin, and vasoactive intestinal polypeptide (VIP) have also been implicated.25

Etiology of fever (Box 52.1) Infections

Nearly two-thirds cases of fever in patients with prolonged neutropenia may be attributed to infections, 26 a major cause of morbidity in patients with cancer. Fever in a cancer patient should be considered indicative of infection unless proven otherwise, with appropriate assessments being instituted in a timely fashion. Febrile neutropenic patients (absolute neutrophil count ≤ 500/mm 3) represent an absolute emergency. In patients with advanced Alzheimer’s disease, physical consequences of the progression of dementia predispose them to infection and fever, especially to aspiration pneumonia, urinary tract infections, 27−30 and decubiti.

Paraneoplastic fever

FIGURE 52.1  Pathophysiology of fever. IL, interleukin; TNF, tumor necrosis factor; IFN, interferon; PGE, prostaglandin E; NSAID, nonsteroidal anti-inflammatory drug. extensively studied. Exogenous pyrogens induce the production of proinflammatory cytokines, such as interleukin (IL)-1b and IL-6 (Castleman’s disease, pheochromocytoma, and renal cell carcinoma), interferon α (INFα), and tumor necrosis factor (TNF), like in Hodgkin’s disease, which act as humoral mediators influencing brain structures involved in resetting the hypothalamic set-point.9 Cytokines are thought to exert their effect on the brain via direct and indirect mechanisms.10–13 Peripherally produced cytokines reach the central nervous system (CNS) directly by crossing the leaky areas in the blood–brain barrier via circumventricular vascular organs, which are networks of enlarged capillaries surrounding the hypothalamic regulatory centers.14,15 In disease states such as bacterial infections, the blood–brain barrier can be compromised further, leading to an influx of cytokines from the periphery. This can account for several of the neurological manifestations associated with sickness behavior, including fever.16,17 Cytokines are also produced locally within the CNS,11 and may account for the hyperpyrexia of CNS hemorrhage. Among the cytokines measurable in the blood plasma during LPS-induced fever, circulating levels of IL-6 have shown the best correlation with fever.18,19 Although not fully understood, it is proposed that cytokines stimulate the central production of the inducible enzyme

Fever may be a common presentation for some malignancies and their progression may parallel the occurrence of fevers. Although Hodgkin’s disease has classically been associated with Pel– Epstein fevers (recurring periods of fever lasting for 3–10 days at a time), several other malignancies are also associated with paraneoplastic fevers and include acute leukemias, lymphomas, renal cell carcinomas, bone sarcomas, adrenal carcinomas, and pheochromocytomas. Solid tumors such as breast, lung, and colon cancer are less often associated with paraneoplastic fevers. However, the presence of liver metastasis from these tumors may result in fever. In addition, any solid tumor causing obstruction can result in fever. Malignancy is often found during the workup of patients presenting with fever of unknown origin. While earlier reports found an incidence of 20%, a later study reported malignancy as the cause of fever in 15% of patients. 31 In patients with cancer presenting with fever of unknown origin, paraneoplastic fever was found to be the most common etiology. 32 Although the exact mechanism of tumor-associated fever is unclear, it is thought to involve inflammatory cytokines such as TNFα, IL-1, and IL-6,

BOX 52.1  ETIOLOGY OF FEVER IN CANCER PATIENTS • Blood transfusion reaction • CNS metastasis • Drug-associated etiologies (e.g., cytotoxic agents, antibiotics, IFN) • Infections • Radiation-induced fevers (e.g., radiation pneumonitis) • Thrombosis • Tumor (paraneoplastic fever)

Fever, Sweats, and Hot Flashes

503

which are produced either by host macrophages in response to the tumor or by the tumor itself. 33,34

malignant syndrome [NMS]) and antidepressants (serotonin syndrome).60 See fever versus hyperthermia in the following. Withdrawal from opioids can also present in similar manner.

Transfusion-associated fever

Evaluation of fever

Febrile and allergic nonhemolytic transfusion reactions (NHTRs) are the most common adverse effects of blood transfusions. 35,36 These reactions are generally not life threatening, but they are expensive in their management, evaluation, and associated blood product wastage. The true incidence of febrile NHTRs (FNHTRs) is not well established in patients with cancer. In a large retrospective study, the incidence of side effects following transfusion of 100,000 units of packed red blood cells to more than 25,000 cancer patients over a 4-year period was found to be at 0.3% (of these, 51.3% were FNHTRs, 36.7% were allergic urticarial reactions, and 17% were hemolytic reactions). 37 This is comparable to other studies where the incidence has ranged from 0.2 to 0.7%. 38,39 The occurrence of fever is usually caused by the presence of antibodies to antigens on the donor’s white blood cells. Its prevention by using leukodepleted blood components was demonstrated more than two decades ago.40−42 Some studies have shown a correlation with storage time of platelets and the release of cytokines as another reason for the occurrence of FNHTRs.43−45 Infection may also be a source of fever in patients receiving blood transfusions.46−48 The prevalence of bacteria is estimated to be about 0.04−2%, depending on the type of components, the number and age of the evaluated components, and the detection methods used. It is estimated that 1 in each 1000/2000 units of platelet concentrates (obtained from whole blood or apheresis) is contaminated with bacteria.49−52 The incidence of bacterial contamination in red cell concentrates is much lower and almost zero for fresh frozen plasma and cryoprecipitate.

Drug fever

Drug-associated fever is usually a diagnosis of exclusion, except for some drugs such as biological response modifiers, amphotericin B, and bleomycin, where the occurrence of fever may be predictable. Other drugs commonly implicated as a cause of fever include antibiotics, cardiovascular drugs, anticonvulsants, cytotoxic agents, and growth factors. In one retrospective study of 148 episodes of drug fever, antimicrobials were found to be the most common offending agents (31%).53 Cytotoxic agents accounted for 11 episodes (7.4%). In a retrospective chart review of 50 patients who had received at least 100 mg of amphotericin B for at least 3 days, the incidence of fever and chills was 34 and 56%, with rates of 2.6 and 3.5 mean episodes per patient per treatment course, respectively.54 INF therapy is associated with acute “flu-like” syndrome consisting of fever, chills, fatigue, myalgias, arthralgia, and headaches, with some variation according to type of IFN, route of administration, schedule, dose, and age of patient.55 The administration of growth factors is also associated with fever, being more common following granulocyte macrophage colony-stimulating factor (GM-CSF) administration than granulocyte colony-stimulating factor (G-CSF) administration. Bleomycin-associated fever occurs in 20−50% of patients and is more common when it is administered intravenously. Fever is also associated with other cytotoxic agents such as cisplatin, streptozocin, 5-fluorouracil, and therapy with monoclonal antibodies.56−59 In addition to antibiotics, common drugs in palliative care setting which can mimic rise in body temperature include antipsychotics (neuroleptic

Assessment of fever requires a careful study of history, medication review, and a thorough physical examination to include all major body systems. Patients should undergo meticulous evaluation of the skin and all body orifices, including mouth, ears, nose, throat, urethra, vagina, rectum, venipuncture sites, biopsy site, skin folds (i.e., breast, axilla, abdomen, and groin), and interdigital spaces. In nearly two-thirds of neutropenic patients, the initial evaluation may not identify a focus of infection. 33 This may relate in part to the high frequency of empirical treatment with broadspectrum antibiotics, which may make it harder to determine the site of infection. Careful physical examinations should be repeated at least daily in patients with neutropenia, even after the initiation of empirical antibiotics. It must be remembered that immunocompromised patients may be vulnerable to more than one infection and that different organisms may emerge during a single febrile episode.

Interventions for fever Goals of care

The presence of fever may be associated with potential metabolic consequences including dehydration, increased oxygen consumption, and metabolic rate,61,62 which may be especially pronounced in debilitated terminally ill patients. If prolonged, fevers may be associated with increased nutritional demands and debilitating fatigue. Although fever may be beneficial for enhancing host defense,63,64 other factors such as the patient’s comfort and physiological responses also deserve consideration. Suppression of fever may help alleviate uncomfortable, constitutional symptoms of fatigue, myalgias, diaphoresis, and chills. In addition to constitutional symptoms, focal findings related to the etiology of fever may also contribute to symptom burden. For example, abscess formation is often associated with pain, while uncomfortable dyspnea and cough can be related to pneumonia. The specific interventions used for fever management are determined by the underlying etiology, together with patient-determined goals of care. Workup of fever can lead to unnecessary and prolonged hospitalization as well as additional costs for patients near the end of their life, resulting in significant suffering.65 Patients with advanced cancer may opt not to treat the underlying etiology of fever and seek only nonspecific palliative measures. For patients who can communicate, it may be beneficial to be certain that if the fever is uncomfortable, and whether curing the fever is more uncomfortable than the fever itself for the patient. Although empiric, there is no compelling reason to think that treatment of fever actually reduces suffering for dying, unresponsive patients.66 Individuals seeking comfort-oriented care exclusively may decline parenteral antibiotic treatment of pneumonia to avoid hospitalization and remain at home. For others, treating the underlying etiology of fever with more aggressive interventions, such as surgical drainage of a painful abscess, will offer symptom palliation and potentially contribute to improvement in quality of life and even life prolongation. Aggressive treatment of infection does not improve survival rates among persons with severe dementia and has been associated with accelerated progression of the severity of dementia.67 Antibiotics and other aggressive measures are often associated with numerous deleterious outcomes, including renal failure and ototoxicity, allergic or

504 drug reactions, rash, diarrhea, blood dyscrasias, antibiotic resistance, use of intravenous lines and mechanical restraints, prolonged time to death, and increased costs.68,69

Nonspecific interventions

During febrile episodes, increasing fluid intake, removing excess clothing and linens, tepid water bathing or sponging, and use of antipyretics may offer relief. In the very sick, administration of fluids intravenously or subcutaneously may be warranted. Other comfort measures include the application of lubricant to dried lips and keeping mucous membranes moist with ice chips. Convective cooling via increasing air circulation by fans or using an airflow blanket may be effective in reducing temperatures and improving patient comfort.70 Ensure that clothes and bed linens are dry and changed as needed. Again, patient preferences must always be given priority. Noisy and labor-intensive measures that may distract family and other caregivers from more meaningful interactions at the death-bed should be avoided. Education and reassurance is of paramount importance in such situations.66 Antipyretic agents such as acetaminophen, aspirin, or nonsteroidal anti-inflammatory drugs (NSAIDS) act by lowering the elevated thermal set-point by the inhibition of enzyme COX. Although these agents are commonly administered to hospitalized patients to enhance patient comfort,71 no studies have been done in the cancer population with fever, and carefully controlled efficacy studies have not quantified the degree to which the antipyretics therapy enhances the comfort of febrile patients in other populations. Although theoretically, patients with pulmonary and cardiovascular disorders may benefit from antipyretic therapy by minimizing the impact of increased metabolic demands, the risk versus benefit of this approach has not been determined. Similarly, antipyretic therapy has not been demonstrated to prevent febrile seizures in children.72 Several studies have confirmed that increasing the dose of acetaminophen from moderate dosage (10 mg/kg every 4 hours, maximum 5 doses/day) to relatively higher dosage (15−20 mg/kg every 4 hours, maximum 5 doses/day) in children failed to reduce the rate of recurrence of febrile seizures.73 Fever control may be enhanced by combining physical methods with antipyretics. In children, a randomized placebo-controlled trial of sponging with ice water, isopropyl alcohol, or tepid water (with or without acetaminophen) demonstrated that all combinations enhanced fever control, but comfort was greatest in children receiving placebo or sponging, followed by those who received acetaminophen combined with tepid water sponging.74 Discomfort was found to be greatest when sponging with ice water or isopropyl alcohol with or without concomitant administration. Like acetaminophen, aspirin may be effective in reducing fever, but should be used with caution in patients with or at risk of thrombocytopenia due to its antiplatelet effects. In children, aspirin use is contraindicated due to the risk of Reye syndrome with fever related to certain viral etiologies, including varicella and influenza.75 NSAIDs should also be used cautiously in the cancer population, as they inhibit platelet function and may also cause gastrointestinal hemorrhage and adversely affect renal function.

Primary interventions directed at the etiology of fever Infections Patients should be instructed to seek medical help if a fever develops when the neutrophil count is low or declining. In febrile

Textbook of Palliative Medicine and Supportive Care neutropenic patients, broad-spectrum antibiotics should be initiated immediately even before culture results are available,76 as mortality rate is 70% for patients not receiving antibiotics within 48 hours.77 Initial antibiotic use is guided by the knowledge of the treating institution’s antimicrobial spectrum and antibiotic resistance pattern, as well as the suspected cause. Although there is general consensus that empirical therapy is appropriate, there is no consensus as to which antibiotics or combinations of antibiotics should be used. The Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guidelines Panel recommends empirical antibiotics based on the patient’s clinical condition and risk for complications, and determination of the need of vancomycin in the initial regimen.78 These four protocols are depicted in Table 52.1. Treatment regimens are further modified by the duration of fever and individual patient risk factors such as the presence of central lines or other artificial devices, history of steroid use, and history of injection drug use. After a specific pathogen is isolated, antibiotic therapy is then changed to provide optimal therapeutic response. The single most important determinant of successful discontinuation of antibiotics is the neutrophil count. If infection is not identified after 3 days of treatment, if the neutrophil count is >500 cells/mm3 for 2 consecutive days, and if the patient is afebrile for >48 hours, antibiotic therapy may be discontinued. For neutropenic hosts with persistent or recurrent fevers after 1 week of broad-spectrum antibiotic therapy, the addition of an antifungal agent is recommended, as continued granulocytopenia is usually associated with the development of nonbacterial opportunistic infections, particularly candidiasis and aspergillosis.79 Acyclovir is the drug of choice in the treatment of herpes simplex or varicella zoster viral infection. Ganciclovir has activity against cytomegalovirus (CMV). Both agents can be used prophylactically in the management of patients at high risk for these infections. Foscarnet is useful in the treatment of CMV and acyclovir-resistant herpes simplex virus. Various investigators have developed models predicting risk groups of febrile neutropenia, with implications for management strategies. Therapeutic options under evaluation include early hospital discharge, home intravenous antibiotic therapy, and oral antibiotic regimens. Due to rapid changes in the field, the reader is directed to specialized sources for specific management recommendations of febrile neutropenia.

Paraneoplastic fever

The best management for paraneoplastic fevers is the treatment of the underlying neoplasm with definitive antineoplastic therapy. If not possible, NSAIDs have been considered as the mainstay of treatment,66 with naproxen being the most extensively studied. However, indomethacin and diclofenac have also been found to be effective.80 Several studies have suggested that neoplastic fevers are more responsive to NSAIDs than infectious fevers, leading to advocacy of the “naproxen test” to differentiate between neoplastic and nonneoplastic fevers.65,81,82 However, this approach has not been validated.83 Thalidomide, an immunomodulatory agent, has been shown to have modulatory and/or suppressive effects on several cytokines such as TNFα, IL-1, and IL-6,84,85 all involved in paraneoplastic fever and which, theoretically, may have a role in the treatment of cancer patients with fever and sweats.86 Despite reports of its antipyretic and antidiaphoretic activity,87,88 this agent has not been formally tested in clinical studies with cancer patients for fever or sweat control. Strategies, using the IL-1

Fever, Sweats, and Hot Flashes

505

TABLE 52.1 Empiric Antibiotic Regimens for Unexplained Neutropenic Fever in the Cancer Population Regimen

Route

Antibiotic Selection

1

Oral

Ciprofloxacin plus amoxicillin-clavulanate

2

Intravenous

Choose one: cefepime, ceftazidime, imipenem, or meropenem

3

Intravenous

4

Intravenous

Aminoglycoside plus antipseudomonal penicillin or ceftazidime or carbapenem Vancomycin plus antibiotics from regimens 2 or 3 above

Source:

Comments • For use in select adult patients • Patients mostly in remission and at low risk for serious life-threatening infections • Can be used on an outpatient basis if ready access to care, no signs of focal infection and no signs or symptoms suggestive of systemic infection other than fever • Mono drug choice is as effective as multiple drug combinations for uncomplicated neutropenic patients • Monitor closely for poor response, emergence of secondary infection(s) and drug resistance • Advantages include potential synergistic effects against some Gram-negative bacilli • Potential minimal emergence of drug-resistant strains during treatment • Restrict to • Institutions with high prevalence of infections with penicillin-resistant Gram-positive bacteria • Suspected catheter-related cellulitis or bacteremia • Gram-positive bacteremia • Evidence of septic shock

Data from Milner LV. Butcher K. Transfusion 1978 July–August;18(4): 493.

receptor antagonist model, have been explored in paraneoplastic fever aimed at blocking IL-6 signaling pathways.13

Transfusion-associated fever

Many institutions have moved toward leukoreduced transfusions in an effort to decrease incidence of FNHTRs, and several countries have even restricted the manufacture and transfusion of blood products to prestorage leukodepleted blood components only. A retrospective analysis conducted at Johns Hopkins Hospital examined the frequency of transfusion reactions associated with the transfusion of red blood cells (RBCs), between July 1994 and December 2001. 89 The study directly compared two time periods before and after the initiative toward leukoreduction. In the initial period (July– December 1994) before the initiative to move toward leukoreduction, 96% of RBC inventory was non-leukoreduced. In the study period after leukoreduction (July–December 2001) 99.5% of RBC inventory was leukoreduced. When comparing these two time periods, the incidence of FNHTRs decreased from 0.37 to 0.19% (p = 0.0008). The trend over the entire 7.5-year study period confirmed the decrease in FNHTRs as the percentage of leukoreduced RBCs increased. The incidence of allergic NHTRs remained unchanged. The decreased incidence of FNHTRs with leukoreduction has been found in other studies as well.90−93 Common clinical practice prior to blood product transfusions includes premedication with acetaminophen/ diphenhydramine with or without steroids. The use of erythropoietin for cancer-related anemia may decrease the need of blood transfusions and may be used for cancer-related anemia. The risks versus benefits, including cost, of such prophylactic

treatments to avoid or delay transfusions needs to be carefully reviewed as they are not devoid of side effects, including reduction in survival.94−97

Drug fever

Drug-associated fever responds to cessation of the offending agent, when possible. Response to fever and related symptoms, with biological response modifier administration, is type-, route-, dose-, and schedule-dependent. These factors may sometimes be altered for fever control without compromising with efficacy. Liposomal amphotericin B is as effective as conventional amphotericin B for empirical antifungal therapy in patients with fever and neutropenia, but is associated with decreased toxicity, including occurrence of fever and chills.98 Caspofungin has also shown promising responses.79 Fever may also be attenuated by the use of acetaminophen, NSAIDs, with or without steroid, premedication. It is common clinical practice to administer meperidine to attenuate severe chills associated with a febrile reaction, although empirical data confirming its efficacy are not available. Index of suspicion should be kept higher when using multiple antidepressants or antipsychotics and while rotating or suddenly stopping opioids or any drugs of abuse when patient gets admitted (withdrawal).

Fever versus hyperthermia

Although in the vast majority of patients, an elevated body temperature usually represents a fever, there are instances where elevated temperatures could be secondary to hyperthermia. These include heat stroke syndromes, certain metabolic diseases (hyperthyroidism), and drugs that interfere with

506 thermoregulation. With fever, thermoregulatory mechanisms remain intact, but the hypothalamic thermal set-point is raised by exposure to endogenous pyrogens,99 leading to behavioral and physiological responses to elevate body temperature. In contrast, during hyperthermia, the setting of the thermoregulatory center remains unchanged66 at normothermic levels, while body temperature increases in an uncontrolled fashion and overrides the ability to lose heat. Hyperthermia thus results from overwhelming of the peripheral heat-dissipating mechanisms by disease, drugs, or from excessive heat, be it external or internal.100 Atropine may increase endogenous heat production by interfering with thermoregulation: It blocks sweating and vasodilation, thereby raising core temperature. Hyperthermia also occurs with NMS, an idiosyncratic reaction to drugs that block the dopamine receptor. Haloperidol and chlorpromazine, which are conventional antipsychotic agents, can be the common offenders.101,102 Atypical antipsychotic medications, including clozapine, risperidone, olanzapine, and quetiapine, have also been associated with NMS.103,104 There are also case reports of other medications causing NMS, including venlafaxine, promethazine, and metoclopramide.105,106 NMS typically occurs within several days of the initiation of treatment, while dosages and serum concentration of these medications are usually within the therapeutic range. The probability of developing NMS is directly related to the antidopaminergic potency of the neuroleptic agent. In addition, specific polymorphisms of the dopamine D2 receptor may predispose some patients to NMS.107 Use of multiple antidepressants can present with serotonin syndrome. 60 Great care should be taken not to predispose a patient to withdrawal of opioids or sudden stoppage of a drug of abuse, especially immediately after the patient gets admitted. It is important to make the distinction between fever and hyperthermia, since management approaches to these distinct syndromes differ. There is no rapid way to differentiate elevated core temperature due to fever from hyperthermia, and a diagnosis of hyperthermia is often made because of a preceding history of heat exposure or use of certain drugs that interfere with normal thermoregulation. On physical examination, the skin is hot but dry in heat stroke syndromes and in patients taking drugs that block sweating. Antipyretic agents act by lowering the elevated thermal setpoint and are used in the treatment of fever, but are ineffective in hyperthermia, where the thermal set-point is normal. In hyperthermia, drugs that interfere with vasoconstriction, such as phenothiazines and those that block muscle contractions or shivering, are useful. However, these are not true antipyretics as they can reduce body temperature independently of hypothalamic control. Shivering may be suppressed with intravenous benzodiazepines such as diazepam or lorazepam. Chlorpromazine intravenously (25–50 mg) may also be used for this purpose if NMS is not suspected. In patients diagnosed with hyperthermia, physical cooling should be started immediately with techniques such as removing bedclothes, sponging the patient with tepid water, and using bed fans. More rapid reductions in body temperature can be achieved by sponging the patient with alcohol or by using hypothermic mattresses or ice packs. Immersion in ice water is the most effective means of physical cooling, but it should be reserved for true hyperthermic emergencies, such as heat stroke. In true emergencies, treatment may also include the intravenous or intraperitoneal administration of

Textbook of Palliative Medicine and Supportive Care cool fluid, gastric lavage or enemas with ice water, and even extracorporeal circulation. No matter what technique is used, the body temperature must always be monitored closely to avoid hypothermia.

Sweats In patients with advanced disease or those receiving palliative care, the prevalence of sweating (hyperhidrosis) ranges from 14 to 28%, is frequently nocturnal (nocturnal diaphoresis or night sweats), and is moderate to severe in intensity.108−111 Although night sweats have been defined as drenching sweats that require the patient to change bedclothes, this definition may not describe the majority of patients who complain of the symptom. Sweating is a feature unique to humans (and apes) in which skin loses heat through evaporation and it helps in regulating body temperatures when exposed to hot environment. Patients with inherited disorder of anhidrotic ectodermal hypoplasia as well as infants and frail elderly fail to sweat sufficiently to maintain cooler body temperatures.111 In the literature, night sweats have also been associated with a variety of medical problems including malignancies (e.g., lymphomas), some infections including tuberculosis, autoimmune diseases, and drugs. Common malignancies associated with night sweats include lymphomas, leukemia, renal

BOX 52.2  ETIOLOGY OF NIGHT SWEATS Malignancy • • • •

Castleman’s disease Leukemia Lymphoma Renal cell carcinoma

Infections • • • • • • •

Endocarditis Fungal infections Human immunodeficiency virus Infectious mononucleosis Lung abscess Mycobacterium avium complex Tuberculosis

Others • • • • • • •

Anxiety Chronic fatigue syndrome Diabetes insipidus Gastroesophageal reflux disease Granulomatous disease Obstructive sleep apnea Rheumatologic diseases

Endocrine • Acromegaly • Diabetes insipidus

Fever, Sweats, and Hot Flashes • Diabetes mellitus (nocturnal hypoglycemia) • Endocrine tumors (pheochromocytoma, carcinoid tumor) • Hyperthyroidism (thyrotoxicosis) • Orchiectomy • Perimenopausal and postmenopausal women Drugs • • • • • •

Antihypertensives Antipyretics: salicylates, acetaminophen Drugs of abuse: alcohol, heroin Leuprolide Niacin Opioids: morphine, diamorphine, methadone, butorphanol • Phenothiazines • Selective estrogen receptor modulator drugs (SERMs): tamoxifen and raloxifene • Selective serotonin receptor inhibitors cell carcinoma, and Castleman’s disease. The classic presentation of tuberculosis includes fever, weight loss, and night sweats. AIDS-related infections might also cause night sweats, including Mycobacterium avium complex (MAC) infection and CMV syndromes. The differential diagnosis for night sweats is broad, and Box 52.2 lists some of these conditions. Patients presenting with night sweats warrant a detailed evaluation including history and physical examination aimed at revealing associated symptoms to help narrow down the broad differential diagnosis and guide further workup. Compensatory hyperhidrosis can usually occur in normal sweat-producing skin areas in response to anhidrosis in other areas of skin. The prevalence of sweats and their impact on quality of life in the cancer population is not well established and requires further description. Clinically, hot flashes are often seen in association with sweats. By far this is the most common cause of sweats encountered in clinical medicine, experienced by the majority of perimenopausal and postmenopausal women, and hence, this topic is being covered in detail later.

Hot flashes Hot flashes, experienced by three-quarters of menopausal women, are described as a sudden onset of an uncomfortable sensation of intense heat, accompanied by skin flushing, warmth, and sweating, usually of the chest and face.4 Hot flashes typically last for 2–4 minutes and are often accompanied by palpitations and anxiety, and may be triggered by emotional stress, anxiety, alcohol, and certain foods.112 Factors associated with a greater risk of hot flashes are listed in Box 52.3.113–116 Approximately two-thirds of women with history of breast cancer experience hot flashes.5 In postmenopausal women with a history of breast cancer, predictors of hot flash severity include higher body mass index, a high school education or less, younger age at diagnosis, and tamoxifen use (SERM).117,118 For patients starting tamoxifen, hot flashes typically increase in the first 2–3 months, followed by a plateau and then gradual dissipation.119 In men treated with androgen ablation for locally advanced or metastatic prostate cancer, 50–88% experience hot

507 BOX 52.3  FACTORS ASSOCIATED WITH HOT FLASHES Abrupt menopause • • • •

Chemotherapy Drugs Radiation Surgery

Cancer type • Breast • Prostate Early menopause Ethnicity • African women • Western women Lack of exercise High body mass index Low education Low estrogen levels Low socioeconomic status Smokers

flashes.120,121 Patients with other cancers are also affected with hot flashes; however, data on this is limited. The rapid menopause associated with cancer treatments does not allow for a gradual adjustment of falling estrogen levels, and this may explain why hot flashes resulting from cancer treatment tend to be more profound.

Pathophysiology

The prevailing hypothesis relates the development of hot flashes to lowering of estrogen levels leading to complex neuroendocrine mechanisms, including alterations in the level of hypothalamic neurotransmitters, which resets the thermostat to a lower level with a narrower range, as compared with those who do not experience hot flashes.122,123 A small rise in core body temperature has been found to occur 15 minutes prior to hot flashes in 60% of hot flash episodes.124 This subtle elevation in core body temperature stimulates mechanisms of heat dissipation, resulting in cutaneous vasodilation and sweating, the two central components of the hot flash syndrome. Two most recognized neurotransmitters involved in hypothalamic thermoregulatory processes are norepinephrine and serotonin. Catecholestrogens (estrogenic metabolites) abundant in the hypothalamus stimulate the production of β-endorphins. Both catecholestrogens and endorphins inhibit the production of hypothalamic norepinephrine. Loss of this negative feedback in low estrogenic states results in rise of norepinephrine levels and an upregulation of certain hypothalamic serotonin receptors responsible for resetting of the thermostat.125 Norepinephrine is believed to be responsible for the rise in core temperature prior to onset of hot flashes.124 In men, it is uncertain if low testosterone levels or decline in estrogen levels or both are responsible for development of the hot flash syndrome.

Textbook of Palliative Medicine and Supportive Care

508 BOX 52.4  TREATMENT INTERVENTIONS FOR HOT FLASHES IN PATIENTS WITH CANCER

Progestational agents

Hormonal agents • Androgens • Estrogens • Progestational agents Nonhormonal agents • • • • • •

α-Adrenergic agents Antidepressants β-Blockers Gabapentin Veralipride Vitamin E

Complementary approaches

was associated with an increased risk of breast cancer, including lobular, ductal, and estrogen and progesterone receptor positive tumors.

and

alternative

medicine

(CAM)

• Herbal medications • Acupuncture • Behavioral interventions

Assessment and treatment of hot flashes

Hot flashes should be routinely assessed as a component of systematic symptom surveys, and if present, a careful assessment of hot flash frequency, intensity, duration, potential triggers, and impact on quality of life is advised in order to construct an individualized treatment plan. Patient self-report diaries with hot flash frequency, intensity, possible trigger factors, and associated distress can be helpful to clinicians to formulate treatment recommendations.126 Hot flash score is determined by multiplying the daily frequency of hot flashes by their average severity. Box 52.4 lists the possible options for management of hot flashes.

Hormone replacement therapy Estrogen

Estrogen replacement is effective for treatment of hot flashes in 80–90% of patients, regardless of underlying etiology.127,128,129,130 However, some women have absolute or relative contraindications to hormone replacement therapy (HRT), and others are reluctant to take hormones due to perceived risks and side effects. The Women’s Health Initiative Study evaluated the risks and benefits of estrogen plus progestin therapy in healthy postmenopausal women.131 The estrogen plus progestin arm was stopped prematurely in women with an intact uterus at a mean follow-up of 5.2 years due to detection of a 1.26 times increased breast cancer risk (95% CI 1.00–1.59). Observed benefits of HRT on hip fractures and colon cancer risk were far outweighed by increased risks of venous thromboembolic disease, breast cancer, stroke, and coronary artery disease. Another population-based, case-control study of 975 postmenopausal women diagnosed with breast cancer supports an increased risk of breast cancer with combined HRT.132 In this cohort, HRT use

Progestational agents have comparable efficacy to estrogens for hot flash reduction. Agents studied include megestrol acetate and transdermal progesterone, and the long-acting intramuscular preparation, depo-medroxyprogesterone acetate (DMPA).133,134,135 Despite benefit of amelioration of hot flashes, there is ongoing debate about safety of progesterone in patients with breast, uterine, or prostate cancer. In men with prostate cancer, several investigators have reported a decline in prostate-specific antigen levels after withdrawal of megestrol acetate, raising concerns that its use may be harmful in this population.136–138 Risk associated with progestin use in women with a history of breast cancer is unknown at this time, as is its effect on the outcome of tamoxifen treatment. Some data have suggested that progestational agents may increase epithelial cell proliferation, an undesirable effect in breast cancer.139,140 There is also some evidence of antitumor activity in breast cancer.141

Tibolone

Tibolone, a synthetic steroid compound with combined estrogenic, progestogenic, and androgenic properties, has been reported to reduce hot flashes.142,143 One study of postmenopausal women receiving tamoxifen after surgery for breast cancer found a significant reduction in the severity of hot flashes with tibolone compared with placebo (rated as 0.4 vs. 0.2, respectively, p = 0.031) but no change in the daily number of hot flashes with either tibolone or placebo (p = 0.219).144 Tibolone is not available in the United States.

Nonhormonal agents

Nonhormonal agents are gaining popularity as therapy for hot flash reduction due to the heightened concerns about the risks of using HRT. These include pharmacotherapies as well as complementary and alternative medicinal approaches.

Antidepressants

Several large placebo-controlled, randomized trials have shown the beneficial effects of antidepressants from the selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SSNRIs) class in hot flash management. In the Mayo Clinic study, breast cancer survivors and menopausal women experiencing hot flashes were assigned to receive one of three different dose levels of venlafaxine (37.5, 75, and 150 mg daily), or placebo for 4 weeks.145 A dose-related diminution in average hot flashes scores from baseline was noted (27% in the placebo subjects vs. 37, 61, and 61% for the three venlafaxine groups, respectively). Similar beneficial results have been found in studies with paroxetine and fluoxetine.146,147 Preliminary studies with other newer antidepressants, including citalopram and mirtazapine, have also shown good results in standard starting doses.148,149 Of note, many of the SSRIs can inhibit the cytochrome P450 enzyme system involved in the hepatic metabolism of tamoxifen, a drug commonly used in the treatment of breast cancer. In a prospective study, coadministration of paroxetine with tamoxifen was shown to result in decreased concentrations

Fever, Sweats, and Hot Flashes

509

of 4-hydroxy-N-desmethyl-tamoxifen, an active tamoxifen metabolite (also known as endoxifen).150 Women with the wildtype CYP2D6 genotype demonstrated greater decreases in endoxifen levels than those with a variant genotype (p = 0.03). Given the widespread use of SSRIs for the treatment of mood disorders and hot flashes, the interactions of SSRIs with tamoxifen merit further study.

KEY LEARNING POINTS • Fever, chills, and hot flashes are frequently encountered in palliative care patients. • Fever in patients with cancer should be considered indicative of infection, unless proven otherwise. Neutropenic fever is a medical emergency. • Fever may be associated with potential metabolic consequences including dehydration and fatigue, which may be especially pronounced in debilitated terminally ill patients. • Paraneoplastic and drug fevers should be considered in the differential diagnosis of fever. • Cytokines are implicated in the etiology of fever secondary to infections and paraneoplastic fevers. • Both fever and hyperthermia result in the elevation of core body temperatures but differ in their pathophysiology and management. Many palliative care patients are on drugs that have the potential to cause hyperthermia. • Patients should be assessed for night sweats and hot flashes. • Hot flashes are widely prevalent in some cancers (breast, prostate) and postmenopausal women and may be associated with significant distress. • Many nonhormonal therapies are available for consideration for hot flash management.

Other nonhormonal agents

Several other agents have been found to be useful in hot flash management. In a placebo-controlled, randomized study of 59 postmenopausal women, gabapentin was more effective than placebo in reducing hot flash frequency (45 vs. 29%, respectively) and hot flash composite score (54 vs. 31%, respectively).151,152 Gabapentin appears to decrease hot flashes in men to similar degree as in women.153 Clonidine, a central acting α2-adrenergic receptor agonist, has been shown to have modest benefits in hot flash reduction in several studies in healthy postmenopausal women, breast cancer survivors on tamoxifen, and men with prostate cancer, but with significant dose-related side effects,154,155 especially dry mouth, constipation, and sleeping problems. The North Central Cancer Treatment Group (NCCTG), in a randomized, placebo-controlled crossover trial of vitamin E in women with a history of breast cancer, found a minor decrease with treatment, with a mean reduction of one flash/day, without adverse effects.156 This reduction is unlikely to be of meaningful clinical benefit. Bellergal, a combination of belladonna and phenobarbital, was widely used in the past for hot flash management. Although several reports favor its use over placebo,157 this therapy cannot be recommended in view of the risk of phenobarbital dependence and dose-dependent anticholinergic side effects of belladonna, including dry mouth, constipation, blurry vision, and dizziness.

Complementary and alternative medicine approaches

Eighty percent of women in the 45–60-year age groups have reported the use of nonprescription therapies for the management of menopausal symptoms.158 Often perceived to be safer than HRT, CAM may provide users with a sense of personal control over their healthcare. Soy phytoestrogens are weak estrogens found in plant foods, and while dietary supplementation with natural soy products appears to be a benign intervention, long-term effects are not known. Two randomized, placebo-controlled studies show no clinical benefit of soy over placebo for hot flash management.159,160 Breast cancer risk in the general population and risk of recurrence in breast cancer survivors has not yet been clarified, nor has its effect on hormonally mediated antitumor therapies, such as tamoxifen and the aromatase inhibitors. Black cohosh (Cimicifuga racemosa) is approved in Germany for the treatment of hot flashes. The anecdotal clinical and observational experience suggests black cohosh may be 25–30% more effective than placebo for menopausal symptoms, including hot flashes.161 In a randomized, double-blind, placebo-controlled study on breast cancer survivors in the United States, however, efficacy of black cohosh was not significantly different from placebo.162 The high prevalence of tamoxifen use in study participants may have confounded study results. Red clover, which contains isoflavones (phytoestrogens) and dong quai (Angelica

sinensis, “female ginseng”), have not been found to be beneficial in the management of hot flashes. Acupuncture has been suggested as a remedy for hot flashes. In a randomized controlled study, Wyon et al. compared the efficacy of electro-acupuncture with oral estradiol treatment and superficial needle insertion on hot flash reduction in 45 postmenopausal women.163 They found that electro-acupuncture decreased the number of hot flashes significantly over time, but not to the same extent as the estrogen treatment. No significant difference in effect was found between electro-acupuncture and the superficial needle insertion. In a small pilot study of prostate cancer patients who underwent castration therapy, a substantial decrease (70% reduction) in hot flash symptoms was noted at 10 weeks, with a sustained reduction of 50% at 3 months.164 Further studies are warranted to determine efficacy and potential mechanisms of action of acupuncture as a modality of therapy for the treatment of hot flashes. Behavioral methods may play a role in hot flash management. Studied methods include relaxation response training165 and paced respirations.166 These may be used as primary alternatives for patients who do not want to take medications or as an adjunct for individuals who achieve suboptimal relief with other interventions. The beneficial effects may be related to the decreased adrenergic tone mediated by relaxation techniques. Exercise would similarly be beneficial.167,168

References

1. Seah ST, Low JA, Chan YH. Symptoms and care of dying elderly patients in an acute hospital. Singapore Med J 2005 May;46(5):210–214.

510













2. Hall P, Schroder C, Weaver L. The last 48 hours of life in long term care: a focused chart audit. J Am Geriatr Soc 2002 March;50(3):501–506. 3. McKinlay SM, Jefferys M. The menopausal syndrome. Br J Prev Soc Med 1974 May;28(2):108–115. 4. Feldman BM, Voda A, Gronseth E. The prevalence of hot flash and associated variables among perimenopausal women. Res Nurs Health 1985 September;8(3):261–268. 5. Couzi RJ, Helzlsouer KJ, Fetting JH. Prevalence of menopausal symptoms among women with a history of breast cancer and attitudes toward estrogen replacement therapy. J Clin Oncol 1995 November;13(11):2737–2744. 6. Carpenter JS, Andrykowski MA, Cordova M, Cunningham L, Studts J, McGrath P, et al. Hot flashes in postmenopausal women treated for breast carcinoma: prevalence, severity, correlates, management, and relation to quality of life. Cancer 1998 May 1;82(9):1682–1691. 7. Stedman TL. Stedman’s Medical Dictionary, 28th edn. Philadelphia, PA: Lippincott Williams & Wilkins, 2006. 8. Kluger MJ. Fever: role of pyrogens and cryogens. Physiol Rev 1991 January;71(1):93–127. 9. Saper CB. Neurobiological basis of fever. Ann N Y Acad Sci 1998 September 29;856:90–94. 10. Besedovsky HO, del Rey A, Klusman I, Furukawa H, Monge Arditi G, Kabiersch A. Cytokines as modulators of the hypothalamus-pituitaryadrenal axis. J Steroid Biochem Mol Biol 1991;40(4–6):613–618. 11. Breder CD, Dinarello CA, Saper CB. Interleukin-1 immunoreactive innervation of the human hypothalamus. Science 1988 April 15;240(4850):321–324. 12. Sternberg EM. Neural-immune interactions in health and disease. J Clin Invest 1997 December 1;100(11):2641–2647. 13. Dalal S, Zhukovsky DS. Pathophysiology and management of fever. J Support Oncol 2006 January;4(1):9–16. 14. Stitt JT. Evidence for the involvement of the organum vasculosum laminae terminalis in the febrile response of rabbits and rats. J Physiol 1985 November;368:501–511. 15. Banks WA, Ortiz L, Plotkin SR, Kastin AJ. Human interleukin (IL) 1 alpha, murine IL-1 alpha and murine IL-1 beta are transported from blood to brain in the mouse by a shared saturable mechanism. J Pharmacol Exp Ther 1991 December;259(3):988–996. 16. Elmquist JK, Scammell TE, Saper CB. Mechanisms of CNS response to systemic immune challenge: the febrile response. Trends Neurosci 1997 December;20(12):565–570. 17. Plata-Salaman CR. Immunoregulators in the nervous system. Neurosci Biobehav Rev Summer 1991;15(2):185–215. 18. Roth J, Conn CA, Kluger MJ, Zeisberger E. Kinetics of systemic and intrahypothalamic IL-6 and tumor necrosis factor during endotoxin fever in guinea pigs. Am J Physiol 1993 September;265(3 Part 2): R653–R658. 19. LeMay LG, Vander AJ, Kluger MJ. Role of interleukin 6 in fever in rats. Am J Physiol 1990 March;258(3 Part 2):R798–R803. 20. Elmquist JK, Breder CD, Sherin JE, Scammell TE, Hickey WF, Dewitt D, et al. Intravenous lipopolysaccharide induces cyclooxygenase 2-like immunoreactivity in rat brain perivascular microglia and meningeal macrophages. J Comp Neurol 1997 May 5;381(2):119–129. 21. Li S, Ballou LR, Morham SG, Blatteis CM. Cyclooxygenase-2 mediates the febrile response of mice to interleukin-1beta. Brain Res 2001 August;910(1–2):163–173. 22. Rivest S, Lacroix S, Vallieres L, Nadeau S, Zhang J, Laflamme N. How the blood talks to the brain parenchyma and the paraventricular nucleus of the hypothalamus during systemic inflammatory and infectious stimuli. Proc Soc Exp Biol Med 2000 January;223(1):22–38. 23. Blatteis CM, Sehic E. Fever: how may Circulating cyrogens signal the brain? Physiology 1997;12(1):1–9. 24. Li S, Sehic E, Wang Y, Ungar AL, Blatteis CM. Relation between complement and the febrile response of guinea pigs to systemic endotoxin. Am J Physiol 1999 December;277(6 Part 2):R1635–R1645. 25. Vizi ES. Receptor-mediated local fine-tuning by noradrenergic innervation of neuroendocrine and immune systems. Ann N Y Acad Sci 1998 June 30;851:388–396. 26. Pizzo PA, Robichaud KJ, Wesley R, Commers JR. Fever in the pediatric and young adult patient with cancer. A prospective study of 1001 episodes. Medicine (Baltimore) 1982 May;61(3):153–165. 27. Fabiszewski KJ, Volicer B, Volicer L. Effect of antibiotic treatment on outcome of fevers in institutionalized Alzheimer patients. JAMA 1990 June 20;263(23):3168–3172.

Textbook of Palliative Medicine and Supportive Care 28. Volicer L, Seltzer B, Rheaume Y, Karner J, Glennon M, Riley ME, et al. Eating difficulties in patients with probable dementia of the Alzheimer type. J Geriatr Psychiatry Neurol 1989 October–December;2(4):188–195. 29. Parulkar BG, Barrett DM, Volicer L, Seltzer B, Rheaume Y, Karner J, et al. Urinary incontinence in adults. Surg Clin North Am 1988;68(5):945–963. 30. Lipsky BA. Urinary tract infections in men. Epidemiology, pathophysiology, diagnosis, and treatment. Ann Intern Med 1989 January 15;110(2):138–150. 31. Vanderschueren S, Knockaert D, Adriaenssens T, Demey W, Durnez A, Blockmans D, et al. From prolonged febrile illness to fever of unknown origin: the challenge continues. Arch Intern Med 2003 May 12;163(9):1033–1041. 32. Chang JC. How to differentiate neoplastic fever from infectious fever in patients with cancer: usefulness of the naproxen test. Heart Lung 1987 March;16(2):122–127. 33. Young L. Fever and Septicemia. In: Rubin R, Young L, eds. Clinical Approach to Infection in the Compromised Host, 2nd edn. New York: Plenum Medical Book Co., 1995, pp. 75–114. 34. Dinarello CA, Wolff SM. Molecular basis of fever in humans. Am J Med 1982 May;72(5):799–819. 35. Kasprisin DO, Yogore MG, Salmassi S, Bolf EC. Blood compounds and transfusion reactions. Plasma Therapy Transfus Technol 1981;2(1):25–29. 36. Milner LV, Butcher K. Transfusion reactions reported after transfusions of red blood cells and of whole blood. Transfusion 1978 July–August;18(4):493–495. 37. Huh YO, Lichtiger B. Transfusion reactions in patients with cancer. Am J Clin Pathol 1987 February;87(2):253–257. 38. Climent-Peris C, Velez-Rosario R. Immediate transfusion reactions. P R Health Sci J 2001 September;20(3):229–235. 39. Decary F, Ferner P, Giavedoni L, Hartman A, Howie R, Kalovsky E, et al. An investigation of nonhemolytic transfusion reactions. Vox Sang 1984;46(5):277–285. 40. Goldfinger D, Lowe C. Prevention of adverse reactions to blood transfusion by the administration of saline-washed red blood cells. Transfusion 1981 May–June;21(3):277–280. 41. Schned AR, Silver H. The use of microaggregate filtration in the prevention of febrile transfusion reactions. Transfusion 1981 November–December;21(6):675–681. 42. Wenz B. Microaggregate blood filtration and the febrile transfusion reaction. A comparative study. Transfusion 1983 March–April;23(2):95–98. 43. Hogman CF. Adverse effects: bacterial contamination(including shelf life). A brief review of bacterial contamination of blood components. Vox Sang 1996;70(S3):78–82. 44. Morel P, Deschaseaux M, Bertrand X, Naegelen C, Talon D. Transfusion-transmitted bacterial infection: residual risk and perspectives of prevention. Transfus Clin Biol 2003 June;10(3):192–200. 45. Blajchman MA, Goldman M. Bacterial contamination of platelet concentrates: incidence, significance, and prevention. Semin Hematol 2001 October;38(4 Suppl 11):20–26. 46. Andreu G, Morel P, Forestier F, Debeir J, Rebibo D, Janvier G, et al. Hemovigilance network in France: organization and analysis of immediate transfusion incident reports from 1994 to 1998. Transfusion 2002 October;42(10):1356–1364. 47. Stainsby D, Jones H, Asher D, Atterbury C, Boncinelli A, Brant L, et al. Serious hazards of transfusion: a decade of hemovigilance in the UK. Transfus Med Rev 2006 October;20(4):273–282. 48. Ness P, Braine H, King K, Barrasso C, Kickler T, Fuller A, et al. Singledonor platelets reduce the risk of septic platelet transfusion reactions. Transfusion 2001 July;41(7):857–861. 49. Blajchman MA, Ali AM. Bacteria in the blood supply: an overlooked issue in transfusion medicine. In: Nance ST ed. Blood Safety: Current Challenges. Bethesda, Maryland: American Association of Blood Banks, 1992, p. xvi, 232 p. 50. Yomtovian R, Lazarus HM, Goodnough LT, Hirschler NV, Morrissey AM, Jacobs MR. A prospective microbiologic surveillance program to detect and prevent the transfusion of bacterially contaminated platelets. Transfusion 1993 November-December;33(11):902–909. 51. Soeterboek AM, Welle FH, Marcelis JH, van der Loop CM. Sterility testing of blood products in 1994/1995 by three cooperating blood banks in The Netherlands. Vox Sang 1997;72(1):61–62. 52. Leiby DA, Kerr KL, Campos JM, Dodd RY. A retrospective analysis of microbial contaminants in outdated random-donor platelets from multiple sites. Transfusion 1997 March;37(3):259–263.

Fever, Sweats, and Hot Flashes 53. Mackowiak PA, LeMaistre CF. Drug fever: a critical appraisal of conventional concepts. An analysis of 51 episodes in two Dallas hospitals and 97 episodes reported in the English literature. Ann Intern Med 1987 May;106(5):728–733. 54. Clements JS, Jr., Peacock JE, Jr. Amphotericin B revisited: reassessment of toxicity. Am J Med 1990 May;88(5N):22N–27N. 55. Quesada JR, Talpaz M, Rios A, Kurzrock R, Gutterman JU. Clinical toxicity of interferons in cancer patients: a review. J Clin Oncol 1986 February;4(2):234–243. 56. Ashford RF, McLachlan A, Nelson I, Mughal T, Pickering D. Pyrexia after cisplatin. Lancet 1980 September 27;2(8196):691–692. 57. Shah KA, Greenwald E, Levin J, Rosen N, Zumoff B. Streptozocininduced eosinophilia and fever: a case report. Cancer Treat Rep 1982 June;66(6):1449–1451. 58. Boye J, Elter T, Engert A. An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab. Ann Oncol 2003 April;14(4):520–535. 59. Ishii E, Hara T, Mizuno Y, Ueda K. Vincristine-induced fever in children with leukemia and lymphoma. Cancer 1988 February 15,;61(4):660–662. 60. Perry PJ, Wilborn CA. Serotonin syndrome vs neuroleptic malignant syndrome: a contrast of causes, diagnoses, and management. Ann Clin Psychiatry 2012 May;24(2):155–162. 61. Styrt B, Sugarman B. Antipyresis and fever. Arch Intern Med 1990 Aug ust;150(8):1589–1597. 62. Horvath SM, Spurr GB, Hutt BK, Hamilton LH. Metabolic cost of shivering. J Appl Physiol 1956 May;8(6):595–602. 63. Kluger MJ. Is fever beneficial? Yale J Biol Med 1986 March-April; 59(2):89–95. 64. Mackowiak PA. Fever: blessing or curse? A unifying hypothesis. Ann Intern Med 1994 June 15;120(12):1037–1040. 65. Alsirafy SA, El Mesidy SM, Abou-Elela EN, Elfaramawy YI. Naproxen test for neoplastic fever may reduce suffering. J Palliat Med 2011 May;14(5):665–667. 66. Strickland M, Stovsky E. Fever near the end of life #256. J Palliat Med 2012 August;15(8):947–948. 67. Hurley AC, Volicer BJ, Volicer L. Effect of fever-management strategy on the progression of dementia of the Alzheimer type. Alzheimer Dis Assoc Disord Spring 1996;10(1):5–10. 68. Ahronheim JC, Morrison RS, Baskin SA, Morris J, Meier DE. Treatment of the dying in the acute care hospital. Advanced dementia and metastatic cancer. Arch Intern Med 1996 October 14,;156(18):2094–2100. 69. Hurley AC, Mahoney M, Volicer L. Comfort Care in End-Stage Dementia: What to Do After Deciding to Do No More? In: Olson E, Chichin ER, Libow LS, eds. Springer Series on Ethics, Law, and Aging: Controversies in Ethics in Long-Term Care. New York: Springer Pub. Co., 1995, p. xxvii, 155 p. 70. Creechan T, Vollman K, Kravutske ME. Cooling by convection vs cooling by conduction for treatment of fever in critically ill adults. Am J Crit Care 2001 January;10(1):52–59. 71. Isaacs SN, Axelrod PI, Lorber B. Antipyretic orders in a university hospital. Am J Med 1990 January;88(1):31–35. 72. Rosman N. Febrile Convulsions. In: Mackowiak PA, ed. Fever: Basic Mechanisms and Management, 2nd edn. Philadelphia, PA: LippincottRaven Publishers, 1997, p. xvii, 506 p. 73. Schnaiderman D, Lahat E, Sheefer T, Aladjem M. Antipyretic effectiveness of acetaminophen in febrile seizures: ongoing prophylaxis versus sporadic usage. Eur J Pediatr 1993 September;152(9):747–749. 74. Steele RW, Tanaka PT, Lara RP, Bass JW. Evaluation of sponging and of oral antipyretic therapy to reduce fever. J Pediatr 1970 November;77(5):824–829. 75. Forsyth BW, Horwitz RI, Acampora D, Shapiro ED, Viscoli CM, Feinstein AR, et al. New epidemiologic evidence confirming that bias does not explain the aspirin/Reye’s syndrome association. JAMA 1989 May 5;261(17):2517–2524. 76. Pizzo PA. Management of fever in patients with cancer and treatmentinduced neutropenia. N Engl J Med 1993 May 6;328(18):1323–1332. 77. Pizzo PA. Evaluation of fever in the patient with cancer. Eur J Cancer Clin Oncol 1989;25(Suppl 2):S9–S16. 78. Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002 March 15;34(6):730–751. 79. Walsh TJ, Teppler H, Donowitz GR, Maertens JA, Baden LR, Dmoszynska A, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med 2004 September 30;351(14):1391–1402.

511 80. Tsavaris N, Zinelis A, Karabelis A, Beldecos D, Bacojanis C, Milonacis N, et al. A randomized trial of the effect of three non-steroid antiinflammatory agents in ameliorating cancer-induced fever. J Intern Med 1990 November;228(5):451–455. 81. Chang JC, Gross HM. Utility of naproxen in the differential diagnosis of fever of undetermined origin in patients with cancer. Am J Med 1984 April;76(4):597–603. 82. Chang JC. NSAID test to distinguish between infectious and neoplastic fever in cancer patients. Postgrad Med 1988 December;84(8):71–72. 83 Vanderschueren S, Knockaert DC, Peetermans WE, Bobbaers HJ. Lack of value of the naproxen test in the differential diagnosis of prolonged febrile illnesses. Am J Med 2003 November;115(7):572–575. 84. Sampaio EP, Sarno EN, Galilly R, Cohn ZA, Kaplan G. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 1991 March 1;173(3):699–703. 85. Sampaio EP, Kaplan G, Miranda A, Nery JA, Miguel CP, Viana SM, et al. The influence of thalidomide on the clinical and immunologic manifestation of erythema nodosum leprosum. J Infect Dis 1993 Aug ust;168(2):408–414. 86. Peuckmann V, Fisch M, Bruera E. Potential novel uses of thalidomide: focus on palliative care. Drugs 2000 August;60(2):273–292. 87. Calder K, Bruera E. Thalidomide for night sweats in patients with advanced cancer. Palliat Med 2000 January;14(1):77–78. 88. Iyer CG, Languillon J, Ramanujam K, Tarabini-Castellani G, De las Aguas JT, Bechelli LM, et al. WHO co-ordinated short-term double-blind trial with thalidomide in the treatment of acute lepra reactions in male lepromatous patients. Bull World Health Organ 1971;45(6):719–732. 89. King KE, Shirey RS, Thoman SK, Bensen-Kennedy D, Tanz WS, Ness PM. Universal leukoreduction decreases the incidence of febrile nonhemolytic transfusion reactions to RBCs. Transfusion 2004 January;44(1):25–29. 90. Pruss A, Kalus U, Radtke H, Koscielny J, Baumann-Baretti B, Balzer D, et al. Universal leukodepletion of blood components results in a significant reduction of febrile non-hemolytic but not allergic transfusion reactions. Transfus Apher Sci 2004 February;30(1):41–46. 91. Heddle NM, Klama LN, Griffith L, Roberts R, Shukla G, Kelton JG. A prospective study to identify the risk factors associated with acute reactions to platelet and red cell transfusions. Transfusion 1993 October;33(10):794–797. 92. Dzik S. Prestorage leukocyte reduction of cellular blood components. Transfus Sci 1994 June;15(2):131–139. 93. Heddle NM. Febrile nonhemolytic transfusion reactions to platelets. Curr Opin Hematol 1995 November;2(6):478–483. 94. FDA. Procrit Label; Epogen label. FDA; 2007; Warning label. Available from: http://www.accessdata.fda.gov/drugsatfda_docslabel/ 2007/103234s5122lbl.pdf. 95. Steinbrook R. Erythropoietin, the FDA, and oncology. N Engl J Med 2007 June 14;356(24):2448–2451. 96. Martinsson U, Lundstrom S. The use of blood transfusions and erythropoietin-stimulating agents in Swedish palliative care. Support Care Cancer 2009 February;17(2):199–203. 97. Oster HS, Neumann D, Hoffman M, Mittelman M. Erythropoietin: the swinging pendulum. LeukRes 2012 August;36(8):939–944. 98. Walsh TJ, Finberg RW, Arndt C, Hiemenz J, Schwartz C, Bodensteiner D, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National institute of allergy and infectious diseases mycoses study group. N Engl J Med 1999 March;340(10):764–771. 99. Dinarello CA, Cannon JG, Wolff SM. New concepts on the pathogenesis of fever. Rev Infect Dis 1988 January-February;10(1):168–189. 100. Goodman E, Knochel J. Heat stroke and other forms of hyperthermia. In: Mackowiak PA, ed. Fever: Basic Mechanisms and Management. New York: Raven Press, 1991, p. xvi, 366 p. 101. Bhanushali MJ, Tuite PJ. The evaluation and management of patients with neuroleptic malignant syndrome. Neurol Clin 2004 May;22(2):389–411. 102. Hadad E, Weinbroum AA, Ben-Abraham R. Drug-induced hyperthermia and muscle rigidity: a practical approach. Eur J Emerg Med 2003 June;10(2):149–154. 103. Farver DK. Neuroleptic malignant syndrome induced by atypical antipsychotics. Expert Opin Drug Saf 2003 January;2(1):21–35. 104. Kogoj A, Velikonja I. Olanzapine induced neuroleptic malignant syndrome–a case review. Hum Psychopharmacol 2003 June;18(4):301–309. 105. Nimmagadda SR, Ryan DH, Atkin SL. Neuroleptic malignant syndrome after venlafaxine. Lancet 2000 January 22;355(9200):289–290.

512 106. Chan-Tack KM. Neuroleptic malignant syndrome due to promethazine. South Med J 1999 October;92(10):1017–1018. 107. Mihara K, Kondo T, Suzuki A, Yasui-Furukori N, Ono S, Sano A, et al. Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome. Am J Med Genet B Neuropsychiatr Genet 2003 February;117B(1):57–60. 108. Lichter I, Hunt E. The last 48 hours of life. J Palliat Care Winter 1990;6(4):7–15. 109. Quigley CS, Baines M. Descriptive epidemiology of sweating in a hospice population. J Palliat Care Spring 1997;13(1):22–26. 110. Ventafridda V, De Conno F, Ripamonti C, Gamba A, Tamburini M. Quality-of-life assessment during a palliative care programme. Ann Oncol 1990 November;1(6):415–420. 111. Hanks GWC. Oxford Textbook of Palliative Medicine, 4th edn. Oxford, New York: Oxford University Press, 2010. 112. Kronenberg F. Hot flashes: phenomenology, quality of life, and search for treatment options. Exp Gerontol 1994 May-August; 29(3–4):319–336. 113. Erlik Y, Meldrum DR, Judd HL. Estrogen levels in postmenopausal women with hot flashes. Obstet Gynecol 1982 April;59(4):403–407. 114. Chiechi LM, Ferreri R, Granieri M, Bianco G, Berardesca C, Loizzi P. Climacteric syndrome and body-weight. Clin Exp Obstet Gynecol 1997;24(3):163–166. 115. Gold EB, Sternfeld B, Kelsey JL, Brown C, Mouton C, Reame N, et al. Relation of demographic and lifestyle factors to symptoms in a multiracial/ethnic population of women 40-55 years of age. Am J Epidemiol 2000 September 1;152(5):463–473. 116. Fuh JL, Wang SJ, Lu SR, Juang KD, Chiu LM. The Kinmen womenhealth investigation (KIWI): a menopausal study of a population aged 40-54. Maturitas 2001 August 25;39(2):117–124. 117. Kronenberg F. Hot flashes: epidemiology and physiology. Ann N Y Acad Sci 1990;592:52–86; discussion 123–133. 118. Hoskin PJ, Ashley S, Yarnold JR. Weight gain after primary surgery for breast cancer–Effect of tamoxifen. Breast Cancer Res Treat 1992;22(2):129–132. 119 Loprinzi CL, Zahasky KM, Sloan JA, Novotny PJ, Quella SK. Tamoxifeninduced hot flashes. Clin Breast Cancer 2000 April;1(1):52–56. 120. Buchholz NP, Mattarelli G, Buchholz MM. Post-orchiectomy hot flushes. Eur Urol 1994;26(2):120–122. 121. Schow DA, Renfer LG, Rozanski TA, Thompson IM. Prevalence of hot flushes during and after neoadjuvant hormonal therapy for localized prostate cancer. South Med J 1998 September;91(9):855–857. 122. Freedman RR, Krell W. Reduced thermoregulatory null zone in postmenopausal women with hot flashes. Am J Obstet Gynecol 1999 July;181(1):66–70. 123. Rosenberg J, Larsen SH. Hypothesis: pathogenesis of postmenopausal hot flush. Med Hypotheses 1991 August;35(4):349–350. 124. Freedman RR, Norton D, Woodward S, Cornelissen G. Core body temperature and circadian rhythm of hot flashes in menopausal women. J Clin Endocrinol Metab 1995 August;80(8):2354–2358. 125. Berendsen HH. The role of serotonin in hot flushes. Maturitas 2000 October 31;36(3):155–164. 126. Carpenter JS. The hot flash related daily interference scale: a tool for assessing the impact of hot flashes on quality of life following breast cancer. J Pain Symptom Manage 2001 December;22(6):979–989. 127. Notelovitz M, Lenihan JP, McDermott M, Kerber IJ, Nanavati N, Arce J. Initial 17beta-estradiol dose for treating vasomotor symptoms. Obstet Gynecol 2000 May;95(5):726–731. 128. Miller JI, Ahmann FR. Treatment of castration-induced menopausal symptoms with low dose diethylstilbestrol in men with advanced prostate cancer. Urology 1992 December;40(6):499–502. 129. Smith JA, Jr. A prospective comparison of treatments for symptomatic hot flushes following endocrine therapy for carcinoma of the prostate. J Urol 1994 July;152(1):132–134. 130. Gerber GS, Zagaja GP, Ray PS, Rukstalis DB. Transdermal estrogen in the treatment of hot flushes in men with prostate cancer. Urology 2000 January;55(1):97–101. 131. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women’s health initiative randomized controlled trial. JAMA 2002 July 17;288(3):321–333.

Textbook of Palliative Medicine and Supportive Care 132. Li CI, Malone KE, Porter PL, Weiss NS, Tang MT, Cushing-Haugen KL, et al. Relationship between long durations and different regimens of hormone therapy and risk of breast cancer. JAMA 2003 June 25;289(24):3254–3263. 133. Loprinzi CL, Michalak JC, Quella SK, O’Fallon JR, Hatfield AK, Nelimark RA, et al. Megestrol acetate for the prevention of hot flashes. N Engl J Med 1994 August 11;331(6):347–352. 134. Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol 1999 August;94(2):225–228. 135. Lobo RA, McCormick W, Singer F, Roy S. Depo-medroxyprogesterone acetate compared with conjugated estrogens for the treatment of postmenopausal women. Obstet Gynecol 1984 January;63(1):1–5. 136. Dawson NA, McLeod DG. Dramatic prostate specific antigen decrease in response to discontinuation of megestrol acetate in advanced prostate cancer: expansion of the antiandrogen withdrawal syndrome. J Urol 1995 June;153(6):1946–1947. 137. Wehbe TW, Stein BS, Akerley WL. Prostate-specific antigen response to withdrawal of megestrol acetate in a patient with hormone-refractory prostate cancer. Mayo Clin Proc 1997 October;72(10):932–934. 138. Burch PA, Loprinzi CL.Prostate-specific antigen decline after withdrawal of low-dosemegestrol acetate. J Clin Oncol 1999 March;17(3):1087–1088. 139. Hofseth LJ, Raafat AM, Osuch JR, Pathak DR, Slomski CA, Haslam SZ. Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast. J Clin Endocrinol Metab 1999 December;84(12):4559–4565. 140. Isaksson E, Sahlin L, Soderqvist G, von Schoultz E, Masironi B, Wickman M, et al. Expression of sex steroid receptors and IGF-1 mRNA in breast tissue—effects of hormonal treatment. J Steroid Biochem Mol Biol 1999 September-October;70(4-6):257–262. 141. Dixon AR, Jackson L, Chan S, Haybittle J, Blamey RW. A randomised trial of second-line hormone vs single agent chemotherapy in tamoxifen resistant advanced breast cancer. Br J Cancer 1992 August;66(2):402–404. 142. Egarter C, Huber J, Leikermoser R, Haidbauer R, Pusch H, Fischl F, et al. Tibolone versus conjugated estrogens and sequential progestogen in the treatment of climacteric complaints. Maturitas 1996 February;23(1):55–62. 143. Ginsburg J, Prelevic G, Butler D, Okolo S. Clinical experience with tibolone (Livial) over 8 years. Maturitas 1995 January;21(1):71–76. 144. Kroiss R, Fentiman IS, Helmond FA, Rymer J, Foidart JM, Bundred N, et al. The effect of tibolone in postmenopausal women receiving tamoxifen after surgery for breast cancer: a randomised, doubleblind, placebo-controlled trial. BJOG 2005 February;112(2):228–233. 145. Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, LaVasseur BI, Barton DL, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 2000 December 16;356(9247):2059–2063. 146. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA 2003 June 4;289(21):2827–2834. 147. Loprinzi CL, Sloan JA, Perez EA, Quella SK, Stella PJ, Mailliard JA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 2002 March 15;20(6):1578–1583. 148. Barton DL, Loprinzi CL, Novotny P, Shanafelt T, Sloan J, WahnerRoedler D, et al. Pilot evaluation of citalopram for the relief of hot flashes. J Support Oncol 2003 May-June;1(1):47–51. 149. Perez DG, Loprinzi CL, Barton DL, Pockaj BA, Sloan J, Novotny PJ, et al. Pilot evaluation of mirtazapine for the treatment of hot flashes. J Support Oncol 2004 January-February;2(1):50–56. 150. Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 2003 December 3;95(23):1758–1764. 151. Guttuso T, Jr., Kurlan R, McDermott MP, Kieburtz K. Gabapentin’s effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol 2003 February;101(2):337–345.

Fever, Sweats, and Hot Flashes 152. Pandya KJ, Morrow GR, Roscoe JA, Zhao H, Hickok JT, Pajon E, et al. Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial. Lancet 2005 September 3–9;366(9488):818–824. 153. Loprinzi CL, Dueck AC, Khoyratty BS, Barton DL, Jafar S, Rowland KM, Jr., et al. A phase III randomized, double-blind, placebo-controlled trial of gabapentin in the management of hot flashes in men (N00CB). Ann Oncol 2009 March;20(3):542–549. 154. Loprinzi CL, Goldberg RM, O’Fallon JR, Quella SK, Miser AW, Mynderse LA, et al. Transdermal clonidine for ameliorating postorchiectomy hot flashes. J Urol 1994 March;151(3):634–636. 155. Pandya KJ, Raubertas RF, Flynn PJ, Hynes HE, Rosenbluth RJ, Kirshner JJ, et al. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a university of Rochester cancer center community clinical oncology program study. Ann Intern Med 2000 May 16;132(10):788–793. 156. Barton DL, Loprinzi CL, Quella SK, Sloan JA, Veeder MH, Egner JR, et al. Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. J Clin Oncol 1998 February;16(2):495–500. 157. Bergmans MG, Merkus JM, Corbey RS, Schellekens LA, Ubachs JM. Effect of Bellergal Retard on climacteric complaints: a double-blind, placebo-controlled study. Maturitas 1987 November;9(3):227–234. 158. Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, Van Rompay M, et al. Trends in alternative medicine use in the United States, 19901997: results of a follow-up national survey. JAMA 1998 November 11;280(18):1569–1575. 159. Quella SK, Loprinzi CL, Barton DL, Knost JA, Sloan JA, LaVasseur BI, et al. Evaluation of soy phytoestrogens for the treatment of hot flashes in breast cancer survivors: a north central cancer treatment group trial. J Clin Oncol 2000 March;18(5):1068–1074.

513 160. Van Patten CL, Olivotto IA, Chambers GK, Gelmon KA, Hislop TG, Templeton E, et al. Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: a randomized, controlled clinical trial. J Clin Oncol 2002 March 15;20(6):1449–1455. 161. Taylor M. Botanicals: medicines and menopause. Clin Obstet Gynecol 2001 December;44(4):853–863. 162. Jacobson JS, Troxel AB, Evans J, Klaus L, Vahdat L, Kinne D, et al. Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol 2001 May 15;19(10):2739–2745. 163. Wyon Y, Wijma K, Nedstrand E, Hammar M. A comparison of acupuncture and oral estradiol treatment of vasomotor symptoms in postmenopausal women. Climacteric 2004 June;7(2):153–164. 164. Hammar M, Frisk J, Grimas O, Hook M, Spetz AC, Wyon Y. Acupuncture treatment of vasomotor symptoms in men with prostatic carcinoma: a pilot study. J Urol 1999 March;161(3):853–856. 165. Irvin JH, Domar AD, Clark C, Zuttermeister PC, Friedman R. The effects of relaxation response training on menopausal symptoms. J Psychosom Obstet Gynaecol 1996 December;17(4):202–207. 166. Freedman RR, Woodward S. Behavioral treatment of menopausal hot flushes: evaluation by ambulatory monitoring. Am J Obstet Gynecol 1992 August;167(2):436–439. 167. Morrow PK, Mattair DN, Hortobagyi GN. Hot flashes: a review of pathophysiology and treatment modalities. Oncologist. [Rev] 2011;16(11):1658–1664. 168. Luoto R, Moilanen J, Heinonen R, Mikkola T, Raitanen J, Tomas E, et al. Effect of aerobic training on hot flushes and quality of life—a randomized controlled trial. Ann Med [Randomized Controlled Trial Research Support, Non-U.S. Gov’t]. 2012 September;44(6):616–626.

53

PRURITUS

Michael Tang, Katie Taylor, and Andrew Thorns

Contents Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������515 Classification and pathogenesis of pruritus�����������������������������������������������������������������������������������������������������������������������������������������������������������������515 Neural pathways����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������515 Central and peripheral mediators����������������������������������������������������������������������������������������������������������������������������������������������������������������������������516 Scratch���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������516 Complications of pruritus�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������516 Assessment of the pruritic patient���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������516 Measuring itch�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������516 Causes of pruritus in advanced disease������������������������������������������������������������������������������������������������������������������������������������������������������������������������516 Management of pruritus��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������517 General management techniques����������������������������������������������������������������������������������������������������������������������������������������������������������������������������517 Topical agents��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������517 Systemic agents������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������517 Specific management strategies�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������518 Cancer-specific pruritus��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������518 Opioid-induced pruritus��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������518 Cholestasis��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������519 Chronic renal failure���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������520 HIV/AIDS���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������520 Central lesions and multiple sclerosis���������������������������������������������������������������������������������������������������������������������������������������������������������������520 Summary�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������521 References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������521

Introduction

Neural pathways

Pruritus is defined as “an unpleasant sensation that provokes the desire to scratch.” It has a prevalence of 27% in common tumor sites,1 and in cholestasis, up to 80% of patients may complain of itch.2 Severe cases cause distress and can be difficult to treat. This chapter will summarize the pathogenesis, causes, and effects of pruritus and will discuss possible treatment options.

The neurons responsible for the sensation of itch are a subset of the large population of polymodal C-nociceptors. They are situated close to the dermal–epidermal junction and comprise about 20% of the C-fiber population in the skin. The sensation of itch is closely linked to that of pain, and for many years, it was thought that both were transmitted identically. Both are unpleasant sensory experiences; however, pain sensation results in a reflex withdrawal, whereas itch results in a scratch reflex. C fibers that are associated with itch are anatomically identical to those that mediate pain, but there are some important functional differences. The itch C fibers are insensitive to mechanical stimuli and are more sensitive to histamine than those responsible for the sensation of pain.4 Conduction is 50% slower than for those fibers transmitting pain, and the receptor field is three times larger and more superficial than that associated with pain.5 The neural impulse passes via the C fibers to the ipsilateral dorsal root ganglia, and from there to the opposite anterolateral spinothalamic tract, onto the posterolateral ventral thalamic nucleus and through the internal capsule to the somatosensory cortex of the postcentral gyrus. There is a substantial coactivation of the motor areas of the brain which supports the clinical observation that itch is linked to scratching. There does not appear to be a distinct “itch center.”6

Classification and pathogenesis of pruritus The pathogenesis of itch is complex and has not been fully elucidated. Both central and peripheral mechanisms are involved, and a number of mediators are being studied to generate future treatment options. The duration of symptoms can also be used to classify pruritus with an acute pruritus indicating a duration of less than 6 weeks or chronic pruritus indicating a duration of longer than 6 weeks.EE The International Forum for the Study of Itch (IFSI) has proposed a system which classifies pruritus into three groups: pruritus on diseased skin, pruritus on skin without disease, and pruritus presenting with secondary scratch lesions.EE There are also six categories proposed which include the following: dermatologic, systemic, neurologic, psychogenic, mixed, and other.EE The category defined as “other” denotes an undetermined origin.EE

515

Textbook of Palliative Medicine and Supportive Care

516 The sensation of itch can originate at several points on the neural pathway. Activation of the C fibers in the skin/mucous membranes will trigger itch. This type of pruritus is mediated by histamine and therefore generally responsive to treatment with H1 antihistamines. In the chronic setting, this response diminishes, presumably secondary to desensitization at a central level. Itch can originate at any point along the afferent pathway. This may occur with neural damage locally (e.g., postherpetic neuralgia) or centrally (e.g., a space-occupying lesion).7,8 This neuropathic itch is not usually H1 antihistamine responsive. Pruritus may also result from the accumulation of toxins (endogenous or exogenous) in the spinal cord or brain. This type of pruritus is histamine independent. The sensation of itch can be magnified by psychological factors such as stress or anxiety or reduced by training and distraction. It appears that the central inhibitory circuits can be altered, thereby affecting the threshold for detecting pruritogenic stimuli.

Central and peripheral mediators

There are many substances known to be involved in the mediation of itch. Histamine is perhaps the best known of these. It is released from mast cells in response to pruritogenic stimuli and acts on the H1 receptors of the C fibers in the skin, causing the characteristic wheal and flare reaction specific to histaminemediated pruritus. Prostaglandins E2 and H2 potentiate pruritus via other mediators including histamine,9 and, in the case of prostaglandin E2, directly also.10 Substance P is synthesized in the cell bodies of C fibers and can directly induce itch as well as modulate the sensation. The release of substance P can be stimulated by tryptase from activated mast cells and neutrophils, and this may increase itch. Other neuropeptides, vasoactive intestinal polypeptide (VIP), and calcitonin gene-related protein (CGRP) are found in the free nerve endings and have been implicated in the mediation of itch. An intradermal injection of acetylcholine causes itch in atopic subjects, but pain in nonatopic subjects,11 which may explain why some atopic subjects experience itch when sweating. Opioids are thought to mediate itch at several points in the pathway. Peripherally, opioids cause mast cell degranulation and histamine release, but it is at a spinal level that the role of opioids appears most interesting. They modulate secondary transmission of the itch sensation by stimulating inhibitory signals to afferent neurons. Centrally, opioids have been shown to trigger itch in the laboratory setting by direct action on the floor of the fourth ventricle. Serotonin induces itch by two mechanisms: indirectly by release of histamine from dermal mast cells, and centrally via a mechanism, which may involve opioid neurotransmitters. Both opioid and serotonin receptors appear to alter the central inhibitory circuits, and therefore adjust the itch threshold. More detailed reviews on the basic mechanisms of itch are available.•12

Scratch Scratch is the natural response to itch. In evolutional terms, it is likely to have originated when most pruritogens were parasites or insects and served to remove the superficial layers of skin which harbor these.•13 Itch is linked to the motor response of scratching via a spinal reflex and can be inhibited by cortical centers. Scratching stimulates A fibers adjacent to those conducting itch and the A fibers in turn synapse with inhibitory interneurons, subsequently causing inhibition of C fibers and a reduced

sensation of itch. Scratching provides relief for several minutes; it has been postulated that this occurs due to temporary disruption of the circuits in the relay synapses of the spinal cord which otherwise reinforce the itch sensation.

Complications of pruritus The commonest complication is excoriation that can result in secondary infection. The effects of lack of sleep, social unacceptability, and interference with daily functioning should not be overlooked. One study found depressive symptoms in one-third of patients with generalized pruritus.14 The power of suggestion can result in itch and learned behavior can quickly develop. The resultant itch-scratch cycle can be hard to break.

Assessment of the pruritic patient Routine assessment involves careful history and examination, particularly noting whether the itch is generalized or localized, and with careful attention to drug history, exacerbating factors, and previous medical history. Examination should involve a detailed description of the site and nature of any skin lesions and ideally photographic records. A general first-line evaluation may include complete blood count with differential, which can help evaluate for malignancies, anemias or elevations in eosinophil counts, erythrocyte sedimentation rate, creatinine/blood urea nitrogen to evaluate for renal dysfunction, and liver profiles to evaluate for liver dysfunction if clinically indicated. Biopsy of any suspicious lesions should be discussed with a dermatologist or dermo-oncologist prior to proceeding.

Measuring itch The subjective nature of this symptom makes it notoriously difficult to quantify. Two validated questionnaires have been developed which attempt to assess the qualitative, temporal, and spatial characteristics of itch, based on the long and short forms of the McGill Pain Questionnaire.6 Monitoring systems have been developed which provide quantitative data independent of hand/arm movement, and these provide the most reliable assessment method to date.15

Causes of pruritus in advanced disease Table 53.1 summarizes the causes of pruritus that may be relevant in patients with advanced disease. These can be divided into general causes of pruritus and those specifically related to disease. In either case, pruritus may be localized or generalized. Senile itch is defined as a chronic itch with no determined etiology in a person aged 65 years or older.FF The majority have xerosis and skin atrophy; in others the cause is unknown. It is best treated with general measures (see the following text) and the application of emollient creams. Pruritus can be iatrogenic, and the following drugs are common culprits: opioids, aspirin, etretinate, amphetamines, and drugs that can cause cholestasis such as erythromycin, hormonal treatment, and phenothiazines. Iron deficiency with or without anemia can cause pruritus16 and responds to iron replacement. Pruritus occurs in up to 11% of patients with thyrotoxicosis, particularly long-term untreated Grave’s disease and less commonly in hypothyroidism. Other common causes of pruritus are discussed in the management section.

Pruritus

517

TABLE 53.1  Causes of Pruritus Localized

Generalized

Dry skin (xerosis) Infestation, e.g., scabies Insect bites

Primary skin diseases Metabolic disorders: hypothyroidism and hyperthyroidism, carcinoid syndrome: diabetes mellitus and insipidus Renal disorders: renal failure with uremia Liver disorders: cholestasis Infection: HIV, syphilis Hematological disorders: polycythemia vera, iron deficiency anemia Neurological disorders: cerebrovascular accident multiple sclerosis, brain abscess/tumors, drug-induced (see text), senile pruritus, aquagenic, and psychogenic

Candida Eczema Contact dermatitis Bullous pemphigoid

Dermatitis herpetiformis Urticaria

Cancer-specific pruritus Melanomatosis Mycosis fungoides Carcinoma in situ: vulval, anal Paraneoplastic syndrome: prostatic, rectal/colonic, cervical carcinomas; glioblastoma Metastatic infiltration of skin

Chronic lymphocytic leukemia Hodgkin’s and non-Hodgkin’s lymphoma Mycosis fungoides Cutaneous T cell lymphoma Multiple myeloma

Paraneoplastic syndrome: breast, colonic, lung, stomach carcinomas and others

Management of pruritus Removal of causative agents (e.g., drugs) and appropriate investigation and treatment of underlying disease are essential firstline measures in the treatment of pruritus. Management can be divided into general and pharmaceutical measures suitable for all causes, and pharmacological measures that are more causespecific. With any intervention for pruritus, a strong placebo response is common. Evidence for the use of different systemic agents in the treatment of pruritus is limited. In the context of advanced disease, there are few useful trials, and the use of many agents remains historical or originates from case reports. This is not to say that these agents are not helpful, just that the evidence either confirming or refuting their use is, thus far, unavailable.

General management techniques

These measures are widely accepted as essential, although the evidence for their efficacy is largely anecdotal. Exacerbating factors such as heat, dehydration, anxiety, and boredom should be avoided. Particular attention should be paid to measures that keep the skin well hydrated and avoid sweating. Patients should wear light clothes, use fans to maintain a passage of air, take tepid baths or shower avoiding hot water, and use emulsifying ointment or aqueous cream instead of soap. Skin hydration should be maintained with regular use of emollients. Alcohol and spicy foods may worsen the itch.

Patients should be advised to gently rub the skin rather than scratching it, and to keep nails short and wear cotton gloves at night to limit the damage to the skin. Sweating may exacerbate itch; the general measures described earlier may help reduce sweating; otherwise, an antimuscarinic agent may be required. Exposure to ultraviolet (UV) B light may help in cholestatic-, uremic-, and acquired-immune–deficiency-syndrome (AIDS)related pruritus. Although the nontoxic nature of this treatment makes it an attractive alternative, it may not be a suitable treatment for a very sick patient. The antipruritic effect is thought to be due to a reduction in the vitamin A content of the skin, inhibition of the release of histamine, and inhibition of dermal mast cell proliferation.17,18 Sedatives such as benzodiazepines do not relieve itch but may help improve associated anxiety and insomnia.19 Behavioral treatments and hypnotherapy may help ease associated psychological issues and break the cycle of itching and scratching.20 Transcutaneous electronic nerve stimulation (TENS) and acupuncture have been successful in case reports.21,22

Topical agents

Topical agents generally provide some relief but may be inconvenient to apply in generalized pruritus, and are probably best reserved for localized symptoms. A number of topical agents have been suggested such as: zinc oxide, calamine, glycerin, and salicylates, but their mechanisms are not understood and their effectiveness is unproved. One double-blind, controlled trial of crotamiton (Eurax®) showed it to be ineffective.23 Polidocanol bath oil has been shown to reduce itch in uremia, 24 and 3% polidocanol/5% urea cream has been shown to reduce itch in psoriasis.25 Corticosteroid creams may help localized areas of inflamed skin but are not generally indicated for chronic use.26 Local anesthetic creams can be helpful but may cause skin sensitization. Lidocaine is the least likely to have this effect, but systemic absorption prevents its use over large areas or for prolonged periods. Another anesthetic cream, parmoxine 1% lotion, used twice a day to a localized area in patients with uremic pruritus was shown superior to placebo in a small randomized control trial.R Topical counterirritants such as menthol 0.25–2% or camphor 1–3% may be useful. Capsaicin 0.025% acts by depleting substance P in C fibers on repeated application thus reducing pain and itch. It needs to be applied four times a day and has shown benefit in uremic pruritus.27 Application can cause an initial burning sensation that prohibits widespread application and decreases compliance; for these reasons, it is best reserved for localized pruritus. Strontium nitrate cream is an effective antipruritic which may act by selectively blocking C fiber transmission.28 Tacrolimus 0.03% ointment has shown some effect in localized pruritus in renal impairment,29 as has topical gamma linolenic acid. 30 Doxepin, a tricyclic antidepressant with potent antihistaminic action now produced in a topical form, has been shown to be effective in atopic dermatitis and chronic urticaria. The topical form has been shown to be less effective than the systemic form. 31 Its place in other causes of pruritus has not been established. Topical diphenhydramine preparations have been shown to have a toxicity associated with them that has been described in literature due to inconsistent absorption patterns. S

Systemic agents

Choice of systemic agents remains based on limited evidence and theories of action. While the number of placebo-controlled trials

518 has increased clarifying some treatment choices, there are little comparative data to indicate one treatment’s effectiveness over another. Antihistamines are active at either the H1 or H2 receptor. H1 receptor antagonists are often used as the first choice for any form of generalized pruritus; however, there is little evidence for their use other than in urticaria or allergy. The more sedative agents, such as chlorphenamine, are believed to be more effective either because of a more potent central action or because the sedation itself helps to improve the insomnia caused by the itch. H2 antihistamines, such as cimetidine, have been shown to be beneficial in the pruritus associated with lymphoproliferative disorders (see the following text). Doxepin, which acts at H1 and H2 receptors, is effective in atopic dermatitis, as discussed earlier. The 5-hydroxytryptamine 3 (5-HT3) receptor antagonists showed initial promising results in relieving itch from a number of causes. 32,33 However, there are some subsequent studies in which the initial promising results have not been replicated. 34–37 The serotonin selective reuptake inhibitor (SSRI) paroxetine is helpful in paraneoplastic pruritus, but the effect may only be temporary, lasting about 6 weeks, 38 and may also be associated with initial nausea and vomiting. Paroxetine and fluvoxamine (also an SSRI) have shown a beneficial effect in chronic pruritus of unknown origin. 39 Another SSRI, sertraline, has some effects in cholestatic pruritus.40 Mirtazapine is a norepinephrine and specific serotonin antidepressant, and its actions include blocking H1, 5-HT2, and 5-HT3 receptors. It has been shown to be a helpful antipruritic agent in cholestasis, uremia, and lymphoma.41 Opioid antagonists and kappa-receptor agonists are receiving increasing attention. In some case reports, naltrexone, an opioid receptor antagonist, was shown to reduce pruritus in patients with non-Hodgkin’s lymphoma and mycosis fungoides.KK,LL Butorphanol was shown to also help reduce pruritus in one patient with non-Hodgkin’s lymphoma.MM,NN Gabapentinoids, such as gabapentin and pregabalin, appear effective in uremic pruritus along with pruritus due to hematologic diseases and paraneoplastic syndromes.GG,HH The mechanism of action is thought to be due to central inhibition of the perception of pruritus along with inhibition of serotonergic pathways and supraspinal neurons.II,JJ.

Specific management strategies Cancer-specific pruritus

Pruritus can be associated with almost any malignancy, complicating the disease in different ways: for example, as a consequence of direct tumor growth, secondary to cholestasis, or as a complication of treatment.42 Pruritus is commonly associated with hematological malignancies. Pruritus occurs in about 50% of patients with polycythemia rubra vera, in almost 100% of patients with cutaneous T-cell lymphoma, and in 30% of patients with Hodgkin’s disease being more common in the nodular sclerosing subtype with mediastinal mass.43 Its presence may precede overt disease by up to 5 years.44 In pruritus secondary to polycythemia vera, the use of diseasemodifying therapy often reduces pruritus and should be considered first45; aspirin, paroxetine, and cimetidine have been shown to be helpful.46,47,48 In Hodgkin’s disease, cimetidine49 and topical 5% sodium cromoglycate50 have been reported as helpful. Corticosteroids have been used historically and are felt to be effective, but evidence is lacking. Although cimetidine is an H2 receptor antagonist, its action is not thought to have a direct antihistaminic effect as it

Textbook of Palliative Medicine and Supportive Care has little effect on itching caused by histamine, but it is thought to be related to its inhibitory action on CYP2D6 liver enzymes that are involved in the synthesis of endogenous opioids and possibly other pruritogens.51 Mycosis fungoides often presents in the early stages with pruritic dermatitis that may precede cutaneous lesions by up to 10 years.52 Tumor-modifying treatments are effective in reducing pruritus, and mycosis fungoides cells are very radiosensitive. Neurokinin-1 receptor antagonists have also been shown to provide relief in pruritus in patients with cutaneous T-cell lymphoma.Z,AA Although the exact mechanism is not well understood, thalidomide, which is an immunomodulatory agent, has been shown to improve refractory pruritus in those with cutaneous T-cell lymphoma and Hodgkin’s lymphoma.BB,CC,DD Other options suggested in lymphoma are mirtazepine41 or kappa opioid agonists.54 In solid tumors, generalized pruritus may be part of a paraneoplastic syndrome in association with lung, colon, breast, stomach, and prostate primary sites. Localized pruritus can result from gliomas and carcinomas of the cervix, anus and rectum, sigmoid colon, vulva, and prostate, which may manifest with pruritus in the related anatomical areas sometimes as the presenting symptom. Itch in Hodgkin’s disease may appear some years before the tumor is identifiable. However, research has shown that patients with generalized pruritus followed up for 6 years did not have a higher overall incidence of malignancy and that follow-up screening was not warranted.55 Paroxetine, an SSRI antidepressant, has been shown to relieve itch in a case series of advanced cancer patients with paraneoplastic itch and in a randomized controlled trial for severe nondermatological pruritus. Its action is probably due to downregulation of 5-HT3 receptors, but side effects (nausea, vomiting, and sedation) may limit its use. 38,56 A small study showed that gabapentin was effective and safe in the treatment of interleukin (IL)-2-induced pruritus for patients undergoing this therapy for metastatic renal cell carcinoma and malignant melanoma.57

Opioid-induced pruritus

Opioids provide good pain control for the majority of patients, and are used frequently in advanced disease. Itch is a well-recognized side effect of opioids although the exact etiology is currently unknown. Pruritus occurs in about 1% of patients on opioids delivered subcutaneously, orally, or intravenously, and up to 90% of patients receiving neuroaxial opioids. Experience suggests that pruritus tends to be generalized in patients on nonspinal opioids; although in children, it is more common in the facial area, particularly the nose. In neuroaxial delivery, the pruritus spreads upward from the level of injection, is commonly maximal in the face, and may be limited to the nose.58 Postulated mechanisms include a direct central effect, 59 including serotonin release60 and a peripheral effect.61 With regards to the peripheral effect, opioids seem to have two ways in which they exert their effect: through a direct vasodilator effect on vessels and through histamine release.OO,PP,QQ There is data to suggest that certain opioids may have a histamine-independent mechanism of action and only involve μ-receptors including fentanyl, oxymorphone, and tramadol.OO,PP,QQ Another postulated mechanism involves a more indirect role in that the activation of μ-receptors reduces pain signaling and therefore can increase pruritic signaling.D,E Although it is suggested that itch is more

Pruritus common with the naturally occurring opioids, the effect is not limited to one class of drug with previous reports of itch with morphine,62,63 fentanyl,64 and oxycodone.65 Opioid antagonists are useful in reducing pruritus but may reverse the analgesic effect,66 making them an unhelpful choice of treatment for most patients with advanced disease. In addition to this, only 2 of 13 studies that were included in a meta-analysis involving naloxone for the treatment of opioid-induced pruritus, among other side effects of opioids, included patients with cancer pain.U There is evidence that using an agonist-antagonist drug, such as nalbuphine or pentazocine,67 can reduce pruritus without compromising analgesic effect.68 Methylnaltrexone, a selective peripheral opioid receptor antagonist, decreases several side effects of opioids including pruritus.69,70,71 Opioid rotation, in particular changing to hydromorphone, may be a more practical and effective solution.63 Ondansetron, among other 5-HT3 receptor antagonists, may also be useful in opioid-induced itch mainly via the neuroaxial route72 at traditional antiemetic doses.V–Y Mirtazepine and gabapentin used prophylactically before neuroaxial opioids appear to decrease the frequency of itch.73,74 Antihistamines may be only of partial benefit given that the mechanism of action for many opioids for causing a peripherally induced pruritus involves more than just histamine release.OO,PP,QQ

Cholestasis

Cholestasis may occur in the general population as a result of gallstones, drugs, or intrahepatic disease, as well as obstruction from primary or secondary tumors involving the biliary tree. Pruritus is a common sequela of cholestasis, starting on the palmar and planter surfaces and becoming more generalized. Accumulation of bile salts has long been suspected as an etiological factor, and although it may have a role to play, the evidence for a central mechanism related to increased opioidergic tone and activation of itch centers in the brain is gathering pace. 3 Bile salts also may play a role in peripheral causes of pruritus as they have been shown to cause mast cell degranulation in vitro.A A second mechanism that has been reported involves the increased level of endogenous opioids in patients with cholestasis.B,C Treatment of cholestatic pruritus with the opioid antagonists naltrexone, naloxone, and nalmefene follows this body of evidence and is successful.75,76,77,78 It is interesting to note that opioid withdrawal effects were noted even in opioid-naive patients with cholestatic pruritus; this may be an effect of high levels of endogenous opioids. Pain may also

FIGURE 53.1  Management of cholestatic pruritus.

519 be a complication of using opioid antagonists for symptom control.79 These side effects may be avoided by titrating an infusion of naloxone to establish an effective dose before switching to an oral form.80 The most effective method of relieving pruritus secondary to cholestasis is to relieve the obstruction. This may be possible by treating the underlying disease with surgery or chemotherapy or high-dose dexamethasone, though the initial treatment of choice is a biliary stent, even in the terminally ill. Cholestyramine binds bile salts in the gut and has traditionally been used for the treatment of cholestatic pruritus, although evidence for benefit is limited to one small, open-label study completed more than 40 years ago.81 As a result of this mechanism of action, it is ineffective in complete biliary obstruction. Although often quoted as the first step in management ladders, its use is limited in palliative care, because it is unpalatable and relatively large quantities must be consumed for effect, although it is helpful to mix it with fruit juice. Charcoal has been used along the same therapeutic line, with similar success and similar acceptability problems. Rifampicin has been shown to reduce pruritus in cholestasis.82 The mechanism is not clear, but it is thought to interrupt the enterohepatic circulation of bile acids and therefore reduce the impact of bile acids on the metabolic processes of the liver. The presence of severe idiosyncratic side effects in one study requires liver transaminases to be monitored and may limit its use.83 Sertraline showed benefit in a small randomized double-blind study.40 Gabapentin showed no benefit in cholestatic pruritus in a double-blind placebo-controlled trial.84 Antihistamines are unlikely to be helpful. Treatment with 5-HT3 antagonists was supported by early evidence, but recent robust trials have found little or no benefit. 32,34,35,85 The 17-α alkyl androgens have also been used historically with some effect. The action is not fully understood, but the 17-α alkyl androgens are directly toxic to hepatocytes and may limit the capacity of the liver’s enkephalin production.86 Care should be taken when considering long-term use of 17-α alkyl androgens in patients with years to live as they have the potential to cause masculinization in women and occasional serious liver impairment. Their use in practice has been largely superseded by opioid antagonists and other agents. Other experimental options have also been explored including: albumin dialysis with molecular absorbent recirculating system,F UV B phototherapy,G partial biliary diversion,H and plasmapheresis.I Please see Figure 53.1 for suggested management strategy.

520 Chronic renal failure

Renal failure may occur as a primary disorder or secondary to a cancer. It is chronic renal failure that is likely to be associated with pruritus. Pruritus may be generalized or limited to the back and the forearm at the site of the arteriovenous shunt.88 There have been several risk factors associated to pruritus in patients with chronic renal failure and they include the following: inadequate dialysis,J hyperparathyroidism,K high calcium/phosphorus product,L and elevated serum magnesium and aluminum concentrations.M,N The pathogenesis of pruritus in this setting has not been fully defined but is thought to be multifactorial. The skin of these patients is atrophic and dry,89 cytokine production in the skin and IL-1 may cause the release of pruritogens. Mast cells are more numerous in patients with pruritic uremia.90 Although plasma histamine levels have been shown to be highly increased in this group of patients, antihistamines per se are ineffectual in improving the pruritus.91 Pruritus is reportedly more common in uremic patients receiving dialysis than those who are not, although a recent report of symptoms in patients with stage 5 chronic kidney disease managed without dialysis revealed that more than 80% reported itch in the month before death.92 High-permeability hemodialysis has been shown to be more effective in relieving itch than conventional hemodialysis.93 Literature involving the management of uremic pruritus is limited. Initial therapy typically involves optimizing dialysis,O treatment of hyperparathyroidism,P and regular use of emollients and topical agents.Q Pruritus is local in 70% of patients, and for these patients, capsaicin cream can be effective and practical.26 For generalized pruritus resistant to the above measures, there appears to be a role for the antiepileptic drugs gabapentin and pregabalin in uremic patients receiving hemodialysis.94,95,96 The doses studied are similar to those commonly used to treat neuropathic pain. The efficacy of opioid antagonists is under dispute: opioid antagonists have been found to be effective by some researchers,97 and not by others. 33 A novel kappa-receptor agonist, nalfurafine

Textbook of Palliative Medicine and Supportive Care hydrochloride, improved both itch and sleep disturbance in endstage renal failure.98,99 Ondansetron has been used to treat uremic pruritus, but the evidence for success is conflicting. 36,100 There is some good evidence of thalidomide having an antipruritic effect in uremia.101 Postulated mechanisms for its antipruritic effect include reduction of tumor necrosis factor synthesis by monocytes, anti-inflammatory action, and interference with cytokine production. It has also been shown to be effective in the pruritus of various primary skin conditions, senile pruritus, and primary biliary cirrhosis.102 UV B phototherapy is established therapy for uremic itch. Its use in palliative care may be limited by the delay of 1–2 months before having an effect.18 Other treatments that are being studied for the uremic patients having dialysis include oral cromolyn sodium103 and topical 1% pramoxine.104 Please see Figure 53.2 for a suggested management strategy.

HIV/AIDS

There are many causes of pruritus in HIV-positive patients,106 and itch can be the first symptom of disease even in the absence of apparent skin lesions. Pruritus in HIV may be related to cytokine-induced prostaglandin-2 synthesis, and increased plasma cytokine levels are not uncommon in patients with HIV.107,108 Localized pruritus may occur with peripheral neuropathy.6 There is a subset of HIV patients who may also experience refractory pruritus that is thought to be due to overactivation of humoral immunity. These patients often have recurrent urticarial papules and infrequent pustules with hypereosinophilia.T Treatment should relate to the specific cause, but in the absence of an obvious cause, indometacin (25 mg) three times daily may be helpful. 3 Exposure to UV B light has been shown to be effective.109

Central lesions and multiple sclerosis

Historically, pruritus in this group of patients has been treated effectively with antiepileptic drugs such as carbamazepine.

FIGURE 53.2  Suggested management strategy of uremic pruritus based on current literature regarding common management practices.O,RR,SS,TT,UU,V V

Pruritus

521

Gabapentin may be a better-tolerated choice and does not interfere with other medications by inducing liver enzymes.110 Nonsteroidal anti-inflammatory drugs such as ibuprofen may also be helpful.111

Summary Pruritus can be a troublesome symptom in patients with advanced disease and may have a substantial effect on quality of life despite the apparent trivial nature of the symptom relative to a life-limiting diagnosis. Careful history and examination may reveal an easily reversible cause; where this is not the case, symptomatic intervention may be helpful. First and foremost, management should include patient education and lifestyle changes to recognize and avoid triggering factors, and to include important general measures for maximal skin hydration in daily routine. Besides these measures, investigation and treatment of the underlying cause, where possible, is helpful. Topical or systemic medication, appropriate to the cause, should be used when required. The relatively limited etiological understanding of pruritus has hindered logical management, but there is now a more comprehensive body of evidence slowly but surely being created. Development of further useful interventions depends on continued investigation of the complex mechanisms by which pruritus is created, and more detailed evaluation of currently available interventions.

References

KEY LEARNING POINTS • Pruritus may be directly related to advanced disease (e.g., cancer, multiple sclerosis), indirectly related (e.g., cholestasis, uremia), or associated with the treatment of advanced disease. • Pruritus may significantly impact sleep, social acceptance, and daily functioning, and has been shown to be associated with depression. • Initial management should include patient education and lifestyle changes to encourage identification and avoidance of triggering factors. • The use of emollients to keep the skin continually hydrated cannot be overemphasized and must continue on a long-term basis. In addition, a large number of other topical agents are available and there is a reasonable evidence base supporting their use. • Diagnosis of the underlying cause of pruritus is important and treatment of underlying disease, in many cases, resolves the pruritus. • If topical measures and lifestyle changes are not adequate, systemic treatment may be necessary and this chapter provides some evidence-based suggestions for first-, second-, and third-line treatments based on etiology. • The historical use of histamine antagonists in the treatment of all pruritus has now been modified by the growing evidence base in this area, and these drugs are now only recommended for use in the treatment of urticaria, allergy, and lymphoproliferative pruritus.



1. Portenoy RK, Thaler HT, Kornblith AB, et al. Symptom prevalence, characteristics and distress in a cancer population. Qual Life Res 1994;3:183–189. 2. Connolly CS, Kantor GR, Menduke H. Hepatobiliary pruritus: What are effective treatments? J Am Acad Dermatol 1995;33:801–805. 3. Twycross R, Greaves MW, Handwerker H, et al. Itch: Scratching more than the surface. Q J Med. 2003;96:7–26 4. Schelmz M, Michael K, Weidner C, et al. Which nerve fibres mediate the axon reflex flare in human skin? Neuroreport 2000;11:645–648. 5. Schmelz M, Schmidt R, Bickel A, et al. Specific C-receptors for itch in human skin. J Neurosci 1997;17:8003–8008. 6. Yosipovitch G, Greaves M, Schmelz M. Itch. Lancet 2003;361:690–694. 7. Oaklander AL, Cohen SP, Raju SV. Intractable postherpetic itch and cutaneous deafferentation after facial shingles. Pain 2002;96:9–12. 8. King CA, Huff FJ, Jorizzo JL. Unilateral neurogenic pruritus: Paroxysmal itching associated with central nervous system lesions. Ann Intern Med 1982;97:222–223. 9. Greaves MW, McDonald-Gibson W. Itch: The role of prostaglandins. Br Med J 1973;22:608–609. 10. Woodward DF, Nieves AL, Hawley SB, et al. The pruritogenic and inflammatory effects of prostanoids in the conjunctiva. J Ocul Pharmacol Ther 1995;11:339–347. 11. Vogelsang M, Heyer G, Hornstein OP. Acetylcholine induces different cutaneous sensations in atopic and non-atopic subjects. Acta Derm Venereol 1995;75:434–436. 12. Potenzieri C, Undem BJ. Basic mechanisms of itch. Clin Exp Allergy 2011;42:8–19. 13. Krajnik M, Zylicz Z. Understanding pruritus in systemic disease. J Pain Symptom Manage 2001;21:151–168. 14. Sheehan-Dare RA, Henderson MJ, Cotterill JA. Anxiety and depression in patients with chronic urticaria and generalised pruritus. Br J Dermatol 1990;123:769–774. 15. Molenaar HAJ, Oosting J, Jones EA. Improved device for measuring scratching activity in patients with pruritus. Med Biol Eng Comput 1998;36:220–224. 16. Vickers CF. Iron deficiency pruritus. JAMA 1977;238:129. 17. Szeptietowski JC, Morita A, Tsuji T. Ultraviolet B induces mast cell apoptosis: A hypothetical mechanism of ultraviolet B treatment for uraemic pruritus. Med Hypotheses 2002;58:167–170. 18. Gilchrest BA, Rowe JW, Brown RS, et al. Relief of uraemic pruritus with ultraviolet phototherapy. N Engl Med J 1977;297:136–138. 19. Ebata T, Izumi H, Aizawa H, et al. Effects of nitrazepam on nocturnal scratching in adults with atopic dermatitis: A double blind placebocontrolled crossover study. Br J Dermatol 1998;138:631–634. 20. Pittelkow MR, Loprinzi CL. Pruritus and sweating. In: Doyle D, Hanks GWC, MacDonald N, eds. Oxford Textbook of Palliative Medicine, 2nd edn. New York: Oxford University Press, 1998, p. 633. 21. Monk BE. Transcutaneous electronic nerve stimulation in the treatment of generalised pruritus. Clin Exp Dermatol 1993;18:67–68. 22. Bjorna H, Kaada B. Successful treatment of itching and atopic eczema by transcutaneous nerve stimulation. Acupunct Electrother Res 1987;12:101–112. 23. Smith EB, King CA, Baker MD. Crotamiton and pruritus. Int J Dermatol 1984;23:684–685. 24. Wasik F, Szeptietowski JC, Szeptietowski T, Weyde W. Relief of uraemic pruritus after balneological therapy with a bath oil containing polidocanol. An open clinical study. J Dermatol Treat 1996;7:231–233. 25. Freitag G, Hoppner T. Results of a postmarketing drug monitoring survey with a polidocanol-urea preparation for dry itching skin. Curr Med Res Opin 1997;13:529–537. 26. Rhiner M, Slatkin NE. Pruritus, Fever and sweats. In: Ferrell BR, Coyle N, eds. Textbook of Palliative Nursing. New York: Oxford University Press, 2006, pp. 345–361. 27. Breneman DL, Cardone JS, Blumsack RF, et al. Topical capsaicin for treatment of haemodialysis related pruritus. J Am Acad Dermatol 1992;26:91–94. 28. Zhai H, Hannon W, Hahn GS, Harper RA, et al. Strontium nitrate decreased histamine induced itch magnitude and duration in man. Dermatology 2000;200:244–246. 29. Kuypers SR, Claes K, Evenepoel P, et al. A prospective proof of concept study of the efficacy of tacrolimus ointment on uraemic pruritus (UP) in patients on chronic dialysis therapy. Nephrol. Dial. Transplant 2004;19(7):1895–1901.

522 30. Chen YC, Chiu WT, Wu MS. Therapeutic effect of topical gammalinolenic acid on refractory uremic pruritus. Am JKidneyDis 2006:48(1):69–76. 31. Smith PF, Corelli RL. Doxepin in the management of pruritus associated with allergic cutaneous reactions. Ann Pharmacother 1997;31:633–635. 32. Jones EA, Bergasa NV. Evolving concepts of the pathogenesis and treatment of the pruritus of cholestasis. Can J Gastroenterol 2000;14:33–40. 33. Kirschner D, Nagel W, Gugeler N, et al. Naltrexone does not relieve uremic pruritus: Results of a randomised, double blind, placebo-controlled study. J Am Soc Nephrol 2000;11:514–519. 34. Muller C, Pongratz S, Pidlich J, et al. Treatment of pruritus in chronic liver disease with the 5HT3 antagonist ondansetron: A randomised, placebo-controlled double-blind cross over trial. Eur J Gasterenterol Hepatol 1998;10:865–870. 35. O’Donohue JW, Haigh C, Williams R. Ondansetron in the treatment of pruritus of cholestasis: A randomised controlled trial. Gastroenterology 1997;112:A1349. 36. Murphy M, Reaich D, Pai P, et al. A randomised, placebo-controlled, double blind trial of ondansetron in renal itch. Br J Dermatol. 2001;145(Suppl 59):20–21. 37. Reich A, Szepietowski JC. Opioid induced pruritus: An update. Clin Exp Dermatol 2009;35:2–6. 38. Zylicz Z, Smits C, Krajnik M. Paroxetine for pruritus in advanced cancer. J Pain Symptom Manage 1998;16:121–124. 39. Stander S, Bockenholt B, Schurmeyer-Horst F, et al. Treatment of chronic pruritus with the selective serotonin re-uptake inhibitors paroxetine and fluvoxamine: Results of an open-labelled, two-arm proofof-concept study. Acta Dermato-Venerologica 2009;89:45–51. 40. Mayo MJ, Handem I, Saldana S, et al. Sertraline as a first-line treatment for cholestatic pruritus. Hepatology 2007;45:666–674. 41. Davis MP, Frandsen JL, Walsh D, et al. Mirtazapine for pruritus. J Pain Symptom Manage 2003;25:288–291. 42. Zylicz Z. Neuropathic pruritus. In: Zylicz Z, Twycross R, Jones EA. Pruritus in Advanced Disease. Oxford, U.K.: Oxford University Press, 2004. 43. Lober CW. Should the patient with generalized malignancy be evaluated for malignancy? J Am Acad Dermatol 1988;19:350–352. 44. Goldman BD, Koh HK. Pruritus and malignancy. In: Bernhard JD, ed. Itch Mechanisms and Management of Pruritus. New York: McGrawHill, 1994, pp. 299–319. 45. Terrifi A. Polycythaemia vera: A comprehensive review and clinical recommendations. Mayo Clin Proc 2003;78:174–194. 46. Jackson N, Burt D, Crocker J, Boughton B. Skin mast cells in polycythameia vera: Relationship to pathogenesis and treatment of pruritus. Br J Dermatol 1987;116:21–29. 47. Terrifi A, Fonseca R. Selective serotonin reuptake inhibitors are effective in the treatment of polycythaemia vera associated pruritus. Blood 2002;99:26–27. 48. Weick JK, Dinovan PB, Najean Y, et al. The use of cimetidine for the treatment of pruritus in polycythaemia rubra vera. Arch Intern Med 1982;142:241–242. 49. Aymard JP, Lederlin P, Witz F, et al. Cimetidine for pruritus in Hodgkin’s Disease. Br J Med 1980;280:151–152. 50. Leven A, Naysmith A, Pickens S, et al. Sodium cromoglycate and Hodgkin’s disease. Br J Med 1977;2:896. 51. Martinez C, Albet C, Agundez JA, et al. Comparative in vitro and in vivo inhibition of cytochrome p450, CYP1A2, CYP2D6 and CYP3A by H2 receptor antagonists. Clin Pharmacol Ther 1999;65:369–376. 52. Pujol RN, Gallardo F, Llistosella E, et al. Invisible mycosis fungiodes: A diagnostic challenge. J Am Acad Dermatol 2002;47(2 Suppl):S168–S171. 53. Wang H, Yosipovitch G. New insights into the pathophysiology and treatment of chronic itch in patients with end stage renal disease, chronic liver disease and lymphoma. Int J Dermatol 2010;49:1–11. 54. Paul R, Jansen C. Itch and malignancy prognosis in generalised pruritus: A 6 year follow-up of 125 patients. J Am Acad Dermatol 1987;16:1179–1182. 55. Zylicz Z, Krajnik M, van Sorge A, Constantini M. Paroxetine in the treatment of severe non-dermatological pruritus: A randomised controlled trial. J Pain Symptom Manage 2003;26:1105–1112. 56. Lee SH, Baig M, Rusciano V, Dutcher JP. Novel management of pruritus in patients treated with IL-2 for metastatic renal cell carcinoma and malignant melanoma. J Immunother 2010;33(9):1010–1013.

Textbook of Palliative Medicine and Supportive Care 57. Ballantyne JC, Loach AB, Carr DB. Itching after epidural and spinal opiates. Pain 1988;33:149–160. 58. Stoelting RK. Pharmacology and physiology. In: Capan LM, Miller SM, Turndorf H, eds. Anaesthetics Practice, 2nd edn. Philadelphia, PA: Lippincott, 1991. 59. Etches RC. Complications of acute pain management. Anaesth Clin North Am. 1992;10:417–433. 60. Larijani G, Goldberg ME, Rogers KH. Treatment of opioid induced pruritus with ondansetron: Report of four patients. Pharmacotherapy 1996;16:958–960. 61. Chaplan S, Duncan SR, Brodsky JB, Brose WG. Morphine and hydromorphone epidural analgesia. Anaesthesiology 1992;77:1090–1094. 62. Katcher J, Walsh D. Opioid induced itching: Morphine sulfate and hydromorphone hydrochloride. J Pain Symptom Manage 1999;17:70–72. 63. Davies GG, From R. A blinded study using nalbuphine for prevention of pruritus induced by epidural fentanyl. Anaesthesiology 1988;69:763–765. 64. Glare P, Walsh TD. Dose ranging study of oxycodone for chronic pain in advanced cancer. J Clin Oncol 1993;11:973–978. 65. Wang JJ, Ho ST, Tzeng JI. Comparison of intravenous nalbuphine infusion versus naloxone in the prevention of epidural morphine related side effects. Reg Anesth Pain Med 1998;23:479–484. 66. Tamdee D, Charuluxananan S, Punjasawadwong Y, et al. A randomized controlled trial of pentazocine versus ondansetron for the treatment of intrathecal morphine-induced pruritus in patients undergoing cesarean delivery. Anesth Analg 2009;109(5):1606–1611. 67. Cohen SE, Ratner EF, Kreitzman TR, et al. Nalbuphine is better than naloxone for treatment of side effects after epidural morphine. Anesth Analg 1992;75:747–752. 68. Friedman JD, Dello Buono FA. Opioid antagonists in the treatment of opioid-induced constipation and pruritus. Ann Pharmacother 2001;35:85–91. 69. Yuan CS, Foss JF, O’Connor M, et al. Efficacy of orally administered methylnaltrexone in decreasing subjective effects after intravenous morphine. Drug Alcohol Depend 1998;52:161–165. 70. Yuan C, Israel RJ. Methylnaltrexone, a novel peripheral opioid receptor antagonist for the treatment of opioid side effects. Expert Opin Investig Drugs 2006;15:541–552. 71. Borgeat A, Stirnemann HR. Ondansetron is effective to treat spinal or epidural morphine-induced pruritus. Anaesthesiology 1999;90:432–436. 72. Sheen MJ, Ho ST, Lee CH, Tsung YC, Chang FL, Huang ST. Prophylactic mirtazapine reduces intrathecal morphine-induced pruritus. Br J Anaesth 2008;101(5):711–715. 73. Sheen MJ, Ho ST, Lee CH, Tsung YC, Chang FL. Preoperative gabapentin prevents intrathecal morphine-induced pruritus after orthopedic surgery. Anesth Analg 2008;106(6):1868–1872. 74. Wolfhagen FH, Sternieri E, Hop WC, et al. Oral naltrexone treat ment for cholestatic pruritus: A double blind placebo controlled study. Gastroenterology 1997;113:1264–1269. 75. Bergasa NV, Talbot TL, Alling DW, et al. A controlled trial of naloxone infusions for the pruritus of chronic cholestasis. Gastroenterology 1992;102:544–549. 76. Bergasa NV, Talbot TL, Alling DW, et al. Oral nalmefene therapy reduces scratching activity due to pruritus of cholestasis: A controlled study. J Am Acad Dermatol 1999;41:431–434. 77. Mansour-Ghanaei F, Taheri A, Froutan H, et al. Effect of oral naltrexone on pruritus in cholestatic patients. World J Gastroenterol 2006;12(7):1125–1128. 78. McRae CA, Prince MI, Hudson M, et al. Pain as a complication of opiate antagonists for symptom control in cholestasis. Gastroenterology 2003;125:591–596. 79. Jones EA, Neuberger J, Bergasa NV. Opiate antagonist therapy for the pruritus of cholestasis: The avoidance of opioid withdrawallike reactions. Quart J Med 2002;95:547–552. 80. Datta DV, Sherlock S. Cholestyramine for long-term relief of the pruritus complicating intrahepatic cholestasis. Gastroenterology 1966;50:323–332. 81. Ghent C, Curruthers S. Treatment of pruritus in primary biliary cirrhosis with rifampicin. Results of a double-blind randomised crossover trial. Gasterenterology 1988;94:488–493. 82. Prince MI, Burt AD, Jones DE. Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis. Gut 2002;50:436–439.

Pruritus 83. Bergasa NV, McGee M, Ginsburg IH, et al. Gabapentin in patients with the pruritus of cholestasis: A double blind, randomized, placebo controlled trial. Hepatology 2006;44:1317–1323. 84. Jones EA, Molenaar HA, Oosting J. Ondansetron and pruritus in chronic liver disease: A double blind controlled study. Hepatogastroenterology 2007;54(76):1196–1199. 85. Bergasa NV, Sabol SL, Yound WS, et al. Cholestasis is associated with preproenkephalin mRNA expression in the adult rat liver. Am J Physiol 1995;268:G346–G354. 86. Szepietowski JC. Selected elements of the pathogenesis of pruritus in haemodialysis patients: My own study. Med Sci Monitor 1996;2:343–347. 87. Young AW, Sweeney EW, David DS, et al. Dermatologic evaluation of pruritus in patients on hemodialysis. N Y State J Med 1973;73:2670–2674. 88. Matsumoto M, Ichimaru K, Horie A. Pruritus and mast cell proliferation of the skin in end stage renal failure. Clin Nephrol 1985;20:285–288. 89. Szepietowski JC, Schwartz RA. Uremic pruritus. In: Demis J, ed. Clinical Dermatology, 26th edn. New York: Lippincott, Williams & Wilkins, 1999, Unit 29–2B. 90. Murtagh FE, Addington-Hall J, Edmonds P, et al. Symptoms in the month before death for stage 5 chronic kidney disease patients managed without dialysis. J Pain Symptom Manage 2010;40(3):342–352. 91. Chen ZJ, Goa G, Tang WX, et al. A randomised controlled trial of high permeability haemodialysis against conventional haemodialysis in the treatment of uremic pruritus. Clin Exp Dermatol 2009;34(6):679–683. 92. Aperis G, Paliorus C, Zerovos A, et al. The use of pregabalin in the treatment of uraemic pruritus in haemodialysis patients. J Rena Care 2010;36(4):180–185. 93. Vila T, Gommer J, Scates AC. Role of gabapentin in the treatment of uremic pruritus. Ann Pharmacother 2008;42(7):1080–1084. 94. Gunal AI, Ozalp G, Yoldas TK, et al. Gabapentin therapy for pruritus in haemodialysis patients: A randomized, placebo-controlled, doubleblind trial. Nephrol Dial Transplant 2004;19(12):3137–3139. 95. Peer G, Kivity S, Agami O, et al. Randomised crossover trial of naltrexone in uraemic pruritus. Lancet 1996;348:1552–1554. 96. Wikstrom B, Gellert R, Ladefoged SD, et al. Kappa-opioid system in uremic pruritus: Multicenter, randomised, double-blind, placebo-controlled studies. J Am Soc Nephrology 2005;16(12):3742–3747. 97. Kumagai H, Ebata T, Takamori K, et al. Effect of a novel kappa-receptor agonist, nalfurafine hydrochloride, on severe itch in 337 haemodialysis patients: A phase III, randomised, double-blind, placebo-controlled study. Neph Dialysis Transplantation 2010;25(4):1251–1257. 98. Balaskas EV, Bamihas HI, Karamouzis M, et al. Histamine and serotonin in uremic pruritus: Effect of ondansetron in CAPD-pruritic patients. Nephron 1998;78:395–402. 99. Silva SR, Viana PC, Lugon NV, et al. Thalidomide for the treatment of uraemic pruritus: A crossover randomised double-blind trial. Nephron 1994;67:270–273. 100. Daly BM, Shuster S. Antipruritic action of thalidomide. Acta Dermatol Venereol 2000;80:24–25. 101. Vessal G, Sagheb MM, Shilian S, et al. Effect of oral cromolyn sodium on CKD-associated pruritus and serum tryptase level: A double-blind placebo-controlled study. Nephrol Dial Transplant 2010;25(5):1541–1547. 102. Young TA, Patel TS, Camacho F, et al. A pramoxine-based anti-itch lotion is more effective than a control lotion for the treatment of uremic pruritus in adult hemodialysis patients. J Dermatol Treat 2009;20(2):76–81. 103. Cockerall CJ. The itches of HIV infection and AIDS. In: Bernhard J, ed. Itch: Mechanisms and Management of Pruritus. New York: McGrawHill, 1994, pp. 347–365. 104. Smith CJ, Skelton HG, Yeager J, et al. Pruritus in HIV-1 disease: Therapy with drugs which may modulate the pattern of immune dysregulation. Dermatology 1997;195:353–358. 105. Breur-McHam JN, Marshall GD, Lewis DE, Duvic M. Distinct serum cytokines in AIDS related skin diseases. Viral Immunol 1998;11:215–220. 106. Lim HW, Vallurupalli S, Meola T, Soter NA. UVB phototherapy is an effective treatment for pruitus in patients infected with HIV. J Am Acad Dermatol 1997;37:414–417. 107. Jones EA, ed. Pruritus in Advanced Disease. Oxford, U.K.: Oxford University Press, 2004, pp. 117–131. 108. Khan OA. Treatment of paroxysmal symptoms in multiple sclerosis with ibuprofen. Neurology 1994;44:571–572.

523













A. Quist RG, Ton-Nu HT, Lillienau J, Hofmann AF, Barrett KE. Activation of mast cells by bile acids. Gastroenterology 1991;101:446–456. B. Oude Elferink RP, Kremer AE, Martens JJ, Beuers UH. The molecular mechanism of cholestatic pruritus. Dig Dis 2011;29:66–71. C. Spivey JR, Jorgensen RA, Gores GJ, Lindor KD. Methionine enkephalin concentrations correlate with stage of disease but not pruritus in patients with primary biliary cirrhosis. Am J Gastroenterol 1994;89:2028–2032. D. Bergasa NV, Schmitt JM, Talbot TL, Alling DW, Swain MG, Turner ML, Jenkins JB, Jones EA. Open-label trial of oral nalmefene therapy for the pruritus of cholestasis. Hepatology 1998;27:679–684. E. Bergasa NV, Alling DW, Talbot TL, Wells MC, Jones EA. Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study. J Am Acad Dermatol 1999;41:431–434. F. Parés A, Cisneros L, Salmerón JM, Caballería L, Mas A, Torras A, Rodés J. Extracorporeal albumin dialysis: a procedure for prolonged relief of intractable pruritus in patients with primary biliary cirrhosis. Am J Gastroenterol 2004;99:1105–1110. G. Decock S, Roelandts R, Steenbergen WV, Laleman W, Cassiman D, Verslype C, Fevery J, Pelt JV, Nevens F. Cholestasis-induced pruritus treated with ultraviolet B phototherapy: an observational case series study. J Hepatol 2012;57:637–641. H. van der Woerd WL, Houwen RH, van de Graaf SF. Current and future therapies for inherited cholestatic liver diseases. World J Gastroenterol 2017;23:763–775. I. Alallam A, Barth D, Heathcote EJ. Role of plasmapheresis in the treatment of severe pruritus in pregnant patients with primary biliary cirrhosis: case reports. Can J Gastroenterol 2008;22:505–507. J. Narita I, Alchi B, Omori K, et al. Etiology and prognostic significance of severe uremic pruritus in chronic hemodialysis patients. Kidney Int 2006;69:1626. K. Massry SG, Popovtzer MM, Coburn JW, et al. Intractable pruritus as a manifestation of secondary hyperparathyroidism in uremia. Disappearance of itching after subtotal parathyroidectomy. N Engl J Med 1968;279:697. L. Duque MI, Thevarajah S, Chan YH, et al. Uremic pruritus is associated with higher kt/V and serum calcium concentration. Clin Nephrol 2006;66:184. M. Friga V, Linos A, Linos DA. Is aluminum toxicity responsible for uremic pruritus in chronic hemodialysis patients? Nephron 1997;75:48. N. Navarro-González JF, Mora-Fernández C, García-Pérez J. Clinical implications of disordered magnesium homeostasis in chronic renal failure and dialysis. Semin Dial 2009;22:37. O. Hiroshige K, Kabashima N, Takasugi M, Kuroiwa A. Optimal dialysis improves uremic pruritus. Am J Kidney Dis 1995;25:413. P. Chou FF, Ho JC, Huang SC, Sheen-Chen SM. A study on pruritus after parathyroidectomy for secondary hyperparathyroidism. J Am Coll Surg 2000;190:65. Q. Balaskas E, Szepietowski JC, Bessis D, et al. Randomized, doubleblind study with glycerol and paraffin in uremic xerosis. Clin J Am Soc Nephrol 2011;6:748. R. Young TA, Patel TS, Camacho F, et al. A pramoxine-based anti-itch lotion is more effective than a control lotion for the treatment of uremic pruritus in adult hemodialysis patients. J Dermatolog Treat 2009;20:76. S. Reilly JF, Weisse M. Topically induced diphenhydramine toxicity. J Emergency Med 1990;8:59–61. T. Milazzo F, Piconi S, Trabattoni D, et al. Intractable pruritus in HIV infection: Immunologic characterization. Allergy 1999;54:266. U. He F, Jiang Y, Li L. The effect of naloxone treatment on opioid-induced side effects: A meta-analysis of randomized and controlled trails. Medicine (Baltimore) 2016;95:e4729. V. Borgeat A, Stirnemann HR. Ondansetron is effective to treat spinal or epidural morphine-induced pruritus. Anesthesiology 1999;90:432. W. Charuluxananan S, Somboonviboon W, Kyokong O, Nimcharoendee K. Ondansetron for treatment of intrathecal morphine-induced pruritus after cesarean delivery. Reg Anesth Pain Med 2000;25:535. X. Iatrou CA, Dragoumanis CK, Vogiatzaki TD, et al. Prophylactic intravenous ondansetron and dolasetron in intrathecal morphine-induced pruritus: a randomized, double-blinded, placebo-controlled study. Anesth Analg 2005;101:1516. Y. George RB, Allen TK, Habib AS. Serotonin receptor antagonists for the prevention and treatment of pruritus, nausea, and vomiting in women undergoing cesarean delivery with intrathecal morphine: a systematic review and meta-analysis. Anesth Analg 2009;109:174.

524



Z. Booken N, Heck M, Nicolay JP, et al. Oral aprepitant in the therapy of refractory pruritus in erythrodermic cutaneous T-cell lymphoma. Br J Dermatol 2011;164:665. AA. Duval A, Dubertret L. Aprepitant as an antipruritic agent? N Engl J Med 2009;361:1415. BB. Brightman L, Demierre MF. Thalidomide in mycosis fungoides. J Am Acad Dermatol 2005;52:1100. CC. Gonçalves F. Thalidomide for the control of severe paraneoplastic pruritus associated with Hodgkin’s disease. Am J Hosp Palliat Care 2010;27:486. DD. Haslett PA, Corral LG, Albert M, Kaplan G. Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in the CD8+ subset. J Exp Med 1998;187:1885. EE. Ständer S, Weisshaar E, Mettang T, et al. Clinical classification of itch: A position paper of the International Forum for the Study of Itch. Acta Derm Venereol 2007;87:291. FF. Ward JR, Bernhard JD. Willan’s itch and other causes of pruritus in the elderly. Int J Dermatol 2005;44:267–273. GG. Rowe B, Yosipovitch G. Paraneoplastic itch management. Curr Probl Dermatol 2016;50:149. HH. Serrano L, Martinez-Escala ME, Zhou XA, Guitart J. Pruritus in cutaneous T-cell lymphoma and its management. Dermatol Clin 2018;36:245. II. Demierre MF, Taverna J. Mirtazapine and gabapentin for reducing pruritus in cutaneous T-cell lymphoma. J Am Acad Dermatol 2006;55:543. JJ. Namaka M. et al. Major A treatment algorithm for neuropathic pain Clin Ther 2004;26: 951–979. KK. Metze D, Reimann S, Beissert S, Luger T. Efficacy and safety of naltrexone, an oral opiate receptor antagonist, in the treatment of

Textbook of Palliative Medicine and Supportive Care pruritus in internal and dermatological diseases. J Am Acad Dermatol 1999;41:533. LL. Ingber S, Cohen PD. Successful treatment of refractory aquagenic pruritus with naltrexone. J Cutan Med Surg 2005;9:215. MM. Dawn AG, Yosipovitch G. Butorphanol for treatment of intractable pruritus. J Am Acad Dermatol 2006;54:527. NN. Phan NQ, Lotts T, Antal A, et al. Systemic kappa opioid receptor agonists in the treatment of chronic pruritus: a literature review. Acta Derm Venereol 2012;92:555. OO. Levy JH, Brister NW, Shearin A, et al. Wheal and flare responses to opioids in humans. Anesthesiology 1989;70:756. PP. Rosow CE, Moss J, Philbin DM, Savarese JJ. Histamine release during morphine and fentanyl anesthesia. Anesthesiology 1982;56:93. QQ. Barth H, Giertz H, Schmal A, Lorenz W. Anaphylactoid reactions and histamine release do not occur after application of the opioid tramadol. Agents Actions 1987;20:310. RR. Metz M, Ständer S. Chronic pruritus–pathogenesis, clinical aspects and treatment. J Eur Acad Dermatol Venereol 2010;24:1249. SS. Morton CA, Lafferty M, Hau C, et al. Pruritus and skin hydration during dialysis. Nephrol Dial Transplant 1996;11:2031. TT. Mahmudpour M, Roozbeh J, Raiss Jalali GA, et al. Therapeutic effect of Montelukast for treatment of uremic pruritus in hemodialysis patients. Iran J Kidney Dis 2017;11:50. UU. Gunal AI, Ozalp G, Yoldas TK, et al. Gabapentin therapy for pruritus in haemodialysis patients: a randomized, placebo-controlled, doubleblind trial. Nephrol Dial Transplant 2004;19:3137. VV. Chan KY, Li CW, Wong H, et al. Use of sertraline for antihistaminerefractory uremic pruritus in renal palliative care patients. J Palliat Med 2013;16:966.

54

INFECTIONS IN PALLIATIVE CARE

Rudolph M. Navari

Contents Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������525 Incidence and type of infections������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������525 Evaluation of fever������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������526 Treatment with antimicrobials���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������527 Symptom control���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������528 Patient survival������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������528 Guidelines for antibiotic use�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������528 References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������529

Introduction Patients receiving palliative care are at high risk for infections as a result of their underlying disease, poor nutritional state, and/or a direct suppression of the hematological system due to chemotherapy or radiation treatments, viral infections, or use of corticosteroids.1 An infectious complication may occur due to an alteration in the phagocytic, cellular, or humoral immunity; an alteration or breach of skin or mucosal defense barriers; indwelling catheters; or a splenectomy. A high index of suspicion, an awareness of the possibility of unusual infectious agents, consideration of the empirical institution of antimicrobials, and constant surveillance of the hematological status of the patients are necessary to optimally manage infections in this patient population. In addition to the high risk of infections, patients in palliative care also experience a high incidence of and a wide variety of infections.1–5 Several retrospective studies have shown that a large number of patients receiving hospice or palliative care are treated with antibiotics for suspected or documented infections.6–13 The benefits and burdens of the use of antimicrobials in this patient population are topics of much discussion. 3,5,10,14 Prospective studies have suggested that symptom control may be the main objective of the decision to use antimicrobials to treat clinically suspected or documented infections in patients receiving palliative or hospice care.2,3,5,15,16 The use of symptom control as the main determinant of whether to use antimicrobials in any given clinical situation is markedly affected, however, by the uncertainty of predicting which patients will achieve symptom relief and which patients will experience only the additional burdens of treatment. Determining whether fever is due to infection, tumor, or other causes, and deciding which symptoms from suspected infections might respond to various antimicrobial interventions can be difficult clinical judgments, particularly in a patient population that has multiple active medical problems and where the goal of treatment is symptom control. These are crucial issues in patients receiving palliative care, in that studies have shown that incurably ill patients often receive nonpalliative interventions at the end of life.1,17 This chapter will discuss the incidence and the type of infections seen in various palliative care clinical settings and the

judicious use of antimicrobials in such settings. It will also suggest the use of symptom control as a major criterion for treatment. The chapter concludes by suggesting guidelines for the approach to infections in palliative care.

Incidence and type of infections Patients who are receiving palliative care or hospice care have a high frequency of infections due to the underlying disease, the use of indwelling urinary catheters and vascular access devices, and the generally poor functional status of the patients characterized by impaired cognition and immobility. There have been a number of reports on the use of antimicrobials in patients receiving hospice and palliative care.1–3,5–7,9,15,16 In a recent review of infections in palliative care, Macedo et al.1 suggested that patients and family should be involved in the discussion regarding how to best treat their infections. They suggested that symptomatic control was the main indication for the use of antimicrobials such as the antimicrobial treatment of urinary tract infections. Antimicrobials improve symptoms in a large majority of patients with urinary tract infections but are much less successful in respiratory and skin infections; however, bacteremia is very poorly controlled by these. They emphasized that in all situations, the decision on starting an antimicrobial therapy should depend on the predictable prognosis of survival and the course of the illness, as the expected survival time of the patient should be long enough to finish the course and profit from the antibiotics. Vallard et al.2 described the use of anticancer and non-anticancer treatments in cancer patients in palliative care units. Data from 1,091 cancer patients hospitalized in palliative care units were prospectively collected in 2010–2011, through a multicenter, observational cohort. The median overall survival after admittance in the palliative care units was 15 days. Specific anticancer treatments were systematically stopped in the first 24 hours in palliative care units, but 25.7% of patients were treated with antibiotics and oral or systemic antifungal drugs were prescribed in 21% of the patients. Infection symptoms independently predicted continuous prescription of antimicrobials. These prescriptions remained commonplace in terminally ill palliative cancer patients, although their benefit was questionable. Antibiotic and 525

526 antifungal agents were continuously prescribed until death with questionable therapeutic benefit. Vitetta et al.6 performed a retrospective chart review on the prevalence of infections in 102 patients (92% with terminal malignant illness) who died after admission to a tertiary care inpatient palliative care unit. Thirty-seven patients were diagnosed with 42 infections. The urinary tract, respiratory tract, blood, skin and subcutaneous tissues, and eyes were the most common sites of infection. Escherichia coli was the most common infectious organism. Of the 37 patients, 35 were treated with antibiotics and symptom improvement was noted in half of the treated patients; 2 of 37 patients were not treated with antibiotics due to survival limited to the day of admission. Dagli et al.7 reported on 113 patients in a palliative care unit during 2016–2017 in a retrospective study which showed that nosocomial infections were observed in 74.3% of patients and 92.0% were treated with antibiotics. The mean duration of antibiotic use was 23.1 days; the use of antibiotics increased the length of stay, increased the costs, and was not related to mortality. The authors suggested that antibiotic use for aggressive treatment of infections in palliative care is not consistent with the philosophy of palliative care. Oneschuk et al.9 retrospectively examined the frequency and types of antibiotics prescribed in the last week of life in three palliative care settings: acute care hospital, tertiary palliative care unit, and hospice inpatient unit. Of the 50 patients in each setting, 29 (58%) in the acute care hospital, 26 (52%) in the palliative care unit, and 11 (22%) in the inpatient hospice unit received antibiotics in the last week of life. The types of infection, the specific organisms, and symptom response were not reported. Clayton et al.15 prospectively studied all patients receiving parenteral antibiotics in a palliative care unit. Of the 913 consecutive admissions over a 13-month period, 41 patients received 43 courses of parenteral antibiotics. The most common sites of infection were urinary tract (37%), lower respiratory tract (26%), and soft tissue/skin (16%). The predominant organisms were not reported, and the use of antibiotics was considered “helpful” in 27 of the 43 antibiotics courses (62%). In a retrospective review of 138 patients in a palliative care unit, Al-Shaqi et al.13 reported that 63% of patients were receiving antimicrobials during the last week of life. In another retrospective review, Chun et al.12 reported that 70 of 131 patients receiving palliative care consultation were treated with antimicrobials. Fifty-four of the 70 patients received empiric therapy, primarily for presumed respiratory and urinary tract infections. The effectiveness of the control of symptoms with antimicrobials was not reported in either of these reports. Lam et al.11 retrospectively reviewed 87 patients enrolled in a palliative care service over a period of 6 months. Of 120 episodes of infection in 70 patients, 117 were treated with antimicrobials. The most frequent sites of infection were chest (52.5%), urinary tract (29.2%), and skin/wound (5%), and dyspnea was associated with a poor prognosis in patients with advanced cancer. White et al. 3 studied 255 patients with advanced cancer at the time they entered a community-based outpatient hospice and palliative care program. Antimicrobial options were discussed with patients at the time of the initiation of hospice care. Seventynine percent of patients chose no use of antimicrobials or symptomatic use only. The use and effectiveness of antimicrobials was prospectively documented during the palliative care period. One hundred and seventeen patients had a total of 129 infections with the most common sites being urinary tract, respiratory

Textbook of Palliative Medicine and Supportive Care tract, mouth/pharynx, and skin/subcutaneous tissues. The most common organisms in this patient population were E. coli, Staphylococcus aureus, Enterococcus spp., and Klebsiella pneumoniae. Seventy-seven patients received antimicrobials, and the use of antimicrobials controlled the symptoms in the majority of the urinary tract infections, but these were less effective in controlling symptoms of the other sites of infection. Survival was not affected by the patients’ choice of whether to use antimicrobials, the prevalence of infections, or the actual use of antimicrobials. Oh et al.10 retrospectively reviewed 141 terminal-stage cancer patients who were hospitalized for symptom control. One hundred and nineteen patients received antibiotics for a clinically suspected infection. Symptomatic improvement in infectionrelated symptoms was achieved in 18 patients (15.1%) with no improvement in 66 patients (55.4%). Reinbolt et al.5 prospectively followed 623 outpatient hospice patients with advanced cancer who were treated with antimicrobials for a clinically suspected infection. A complete or partial response of infection-related symptoms was observed in 79% of 265 patients with urinary tract infections, 43% of 221 patients with respiratory tract infections, 46% of 63 patients with oral cavity infections, 41% of 59 patients with skin or subcutaneous infections, and 0 of 25 patients with bacteremia. There was no difference in survival of patients with a diagnosed infection compared to those without an infection and no difference in survival of patients who received antimicrobials compared to those who did not receive antimicrobials. Thai et al.18 reported on 441 hospitalized advanced cancer patients referred to a palliative care consult service over a 12-month period. Sixteen percent had an episode of sepsis and 23.4% had organ-related infections; 89.7% of these received antibiotics. Sepsis and/or organ-related infection reduced overall survival, but a favorable antibiotic response was associated with an increase in survival. These studies, carried out in a wide variety of palliative care settings, have suggested that 20–65% of patients receiving palliative care have at least one or more infections which are considered for antimicrobial treatment. The most common clinical conditions are urinary tract infections, upper and lower respiratory tract infections, skin and subcutaneous tissues infections, and a fewer number of patients also suffer bacteremia. The most common organisms responsible for infection are E. coli, Staphylococcus spp., Enterococcus, and K. pneumoniae. Most patients are treated with antimicrobials when an infection is suspected, with varying responses.

Evaluation of fever In patients with advanced cancer, fever is common and it may or may not have an infectious etiology. It must be noted that fever may be the only manifestation of an infection in an immunocompromised patient, and there is no pattern of fever that can be used to definitively rule out an infectious etiology. Fever may also be modified by the use of specific medications such as corticosteroids or nonsteroidal anti-inflammatory agents. In patients with advanced or terminal cancer, fever must be evaluated in terms of the underlying disease, the specific risk for a local or systemic infection, the urgency for empirical antimicrobial therapy, the presence or absence of neutropenia, and any signs or symptoms which may suggest a site of infection. Attention should be directed to the most common sites of infection such as the oral cavity, lungs, perirectal area, urinary tract,

Infections in Palliative Care

527

skin, and soft tissues. In most patients with fever and neutropenia, the initial evaluation does not identify a site of infection. Depending on the status of the patient at the time of the fever, an initial evaluation may include, in addition to the history and physical examination, a hematological profile, cultures of nose and throat tissue, urine, blood, stool, and cerebrospinal fluid, and radiological evaluation of the chest and sinuses. Whether or not antimicrobials are initiated at the time of the initial fever, patients should be carefully reevaluated at least every 24 hours. It must be remembered that in patients with profound and prolonged neutropenia, multiple sites of infection and multiple infectious organisms may be present. The approach to fever in patients receiving palliative care should be similar to that outlined above, with symptom control as the primary goal that should be accomplished through a minimum of interventions. Chen et al.8 retrospectively studied 535 admissions to a hospice and palliative care unit and identified 93 fever episodes, of which 79 episodes were treated with antibiotics. Although the use of antibiotics appeared to decrease fever-related discomfort, it was not clear that quality of life was improved.

Treatment with antimicrobials Studies suggest that antimicrobials are initiated in the overwhelming majority (70–90%) of patients receiving palliative care when they have fever or a suspected or documented infection.1,8 The response rate to antibiotics appears to vary with symptom improvement in the majority of urinary tract infections, but there was symptom improvement in less than half of patients with infections of other organ systems.1–3,5,10,16 The decision-making process for the use of antimicrobials in patients receiving palliative care is highly complex. In most situations, the approach should be individualized for each patient based on the desires of the patient, the goal to control symptoms, and quality–of-life issues. Issues to be considered include the potential benefit of the use of antimicrobials compared to the potential toxicities that may result from the extent of the investigation of a suspected infection, the number of diagnostic tests to be employed, and the means to be employed to treat a suspected or documented infection. It may be appropriate to treat a fever with an antipyretic alone in a patient whose death is imminent rather than proceed with an extensive laboratory workup and

the initiation of antimicrobials. Alternatively, the pain resulting from a urinary tract infection or a symptomatic, localized skin or soft-tissue infection may be treated more successfully with both antibiotics and pain medications. For patients receiving hospice care at home or in an institution, such as a hospital palliative care unit or a chronic care facility, consideration should be given to initiating oral or parenteral antibiotics based on only clinical indications without the use of laboratory or imaging criteria. Mobilization of the patients for diagnostic interventions may lead to significant discomfort. Table 54.1 suggests an approach to the management of common infections in patients receiving palliative care. Patients with uncomplicated urinary tract infections or cystitis can be effectively and inexpensively treated with a 3-day course of oral trimethoprim-sulfamethoxazole or a fluoroquinolone.19 Acute uncomplicated pyelonephritis can often be managed with a 7-day course of an oral fluoroquinolone.20 For community-acquired bacterial pneumonia, an oral macrolide (erythromycin, azithromycin, or clarithromycin), doxycycline, or a fluoroquinolone with good anti-pneumococcal activity (levofloxacin, gatifloxacin, or moxifloxacin) is recommended.21 An antipneumococcal fluoroquinolone may be added to cover Legionella, Mycoplasma, and Chlamydia. For the management of skin- and soft-tissue infections, a first- or second-generation cephalosporin or a macrolide is recommended.22 Vancomycin may be added if there is minimal or no response. Issues that patients, families, and physicians consider when making decisions concerning the use of a respirator, cardiac resuscitation, dialysis, etc. should, in general, also apply to the use of antimicrobials. Antimicrobial use in patients receiving palliative care may be a part of symptomatic care, may or may not result in prolongation of life, and/or may be associated with symptom-producing interventions such as laboratory testing, venous access, and direct antimicrobial toxicities. The goal of antimicrobial therapy in palliative care is symptom control, in contrast to the goal of decreased morbidity and mortality in acute medical or surgical situations. White et al. 3 reported that when antimicrobial options were discussed with 255 advanced cancer patients at the time of admission to a hospice program, 79.2% chose either no antimicrobials or symptomatic use only. In a survey of patients concerning the use of antibiotics in a palliative care unit,

TABLE 54.1  Management of Common Infections in Patients Receiving Palliative Care Infection

Signs/symptoms

Antimicrobial(s)

Diagnostica

Urinary tract

Dysuria, fever, frequency, pain

Oral

Fever, mucositis, odynophagia, pain

Oral trimethoprim sulfamethoxazole or fluoroquinolones Fluconazole, nystatin

Respiratory tract

Cough, dyspnea, fever, sputum production

Urine analysis, culture and sensitivity Mouth swab for culture and sensitivity, endoscopy Sputum culture, chest X-ray, bronchoscopy

Skin/subcutaneous

Fever, pain, skin rash/discoloration

Bacteremia

Fever, disorientation, hypotension, tachycardia

a

Oral macrolides (erythromycin, azithromycin, clarithromycin), doxycycline, fluoroquinolones (levofloxacin, gatifloxacin, moxifloxacin) Cephalexin, macrolides Cefotaxime or ceftriaxone

Skin culture and sensitivity, blood cultures Blood cultures

The decision to use any diagnostic intervention should be evaluated in terms of potential benefit to the patient in symptom control versus the potential toxicities of the diagnostic interventions.

Textbook of Palliative Medicine and Supportive Care

528 Stiel et al.4 reported that 286 (63.8%) of 448 patients received antibiotic therapy. Eighty-eight patients had ongoing treatment withdrawn for various reasons, and the outcome of treatment was rated poor in 20%. The initiation of therapy was often decided by physicians only, whereas withdrawing therapy demanded more involvement of other team members. The involvement of patients and family members is essential in the decision to use antibiotics in patients receiving palliative care.

Symptom control There has been much discussion in the literature about the use of symptom control as criterion for use of antimicrobials in patients receiving palliative care. However, there have been only a few studies to evaluate the effects of antimicrobials on the symptoms associated with infections in patients with advanced cancer. Bruera 23 reported a marked improvement in pain with the use of antimicrobials for seven patients with infected, ulcerated head and neck neoplasms. Green et al. 24 described improved symptom control with the use of antibiotics in two patients with advanced cancer. One patient had severe respiratory distress from pneumonia and one patient had sepsis-induced delirium. In a retrospective study of 102 patients admitted to a tertiarycare palliative care unit, Vitetta et al.6 reported on antibioticinduced symptom control in 36 patients. Antibiotic-associated positive symptom response was seen in 8 of 17 patients with urinary tract infections, 3 of 9 patients with respiratory tract infections, 1 of 5 patients with subcutaneous skin infections, and 1 of 5 patients with bacteremia. Clayton et al.15 reported that the use of parenteral antibiotics was “helpful” (overall condition improved or symptoms and/or signs of infection improved) in 27 of 43 infections in 41 patients in an inpatient palliative care unit. Antibiotic response was seen in 14 of 16 patients with urinary tract infections, 6 of 11 patients with lower respiratory tract infections, 2 of 2 patients with purulent terminal respiratory secretions, 5 of 7 patients with soft-tissue/wound infections, and 0 of 7 patients with other suspected infections. The types of infections and the response rates followed a similar pattern to that found in the study by Vitetta et al.6, with a somewhat higher response rate possibly due to the use of parenteral rather than oral antibiotics. Mirhosseini et al.16 prospectively evaluated the effect of antibiotic treatment on infection-related symptoms in patients with advanced cancer using a questionnaire given to the patients. In 26 patients on a tertiary palliative care unit with 31 episodes of infection, patients reported a statistically significant improvement only in dysuria. Physician assessment revealed a statistically significant improvement only in cough. In a prospective study of antibiotic choices by patients with advanced cancer receiving outpatient hospice care by White et al. 3, antibiotic-associated positive symptom response was seen in 25 of 30 patients with urinary tract infections, 10 of 26 patients with respiratory tract infections, 4 of 9 patients with mouth/pharyngeal infections, 4 of 9 patients with subcutaneous skin infections, and 0 of 3 patients with bacteremia. In a large prospective study of 1,731 advanced cancer patients receiving outpatient hospice care, a complete or partial response of infection-related symptoms was observed in 79% of 265 patients with urinary tract infections, 43% of 221 patients with respiratory tract infections, 46% of 63 patients with oral cavity infections, 41% of 59 patients with skin or subcutaneous infections, and 0 of 25 patients with bacteremia.5

The types of infections and the responses recorded appear similar in the above studies, despite major differences in the types of palliative care settings. In these studies, it appeared that the majority of the organisms cultured were sensitive to the antimicrobials used, suggesting that the lack of symptom response in some patients may have been due to comorbid conditions such as an immunocompromised state, malnutrition, the failure of host barriers, decreased level of consciousness or immobility, or the presence of a neoplasm in the symptomatic organ. Regardless of the reason for the lack of symptom response, it is essential that treating clinicians use symptom control as the major criterion for antibiotic use and be aware of the limitations of the use of antimicrobials in this patient population in a palliative care modality.

Patient survival Although symptomatic care, and not survival, is the main issue in palliative and hospice care, survival may be an issue for some patients, families, and health-care professionals. Survival was not affected by the patients’ choice of whether to use antimicrobials, the prevalence of infections, or the actual use of antimicrobials in the study by White et al. 3 Similarly, in the large study by Reinbolt et al., 5 survival was not affected by the presence of infection or the use of antimicrobials. Antimicrobial use did not affect survival in patients severely affected with Alzheimer’s disease who were treated for fever.25 In a retrospective study of inpatient hospice patients, a high early mortality followed antibiotic administration.14 However, Vitetta et al.6 and Chen et al.8 showed that terminally ill hospice patients with documented infections treated with antibiotics had a longer median survival. A favorable antibiotic response did increase survival in hospitalized advanced cancer patients with sepsis or organ-related infection.18 The effect of the use of antimicrobials on survival is important information for patients entering hospice care. This information might strongly influence their choice of whether to use antimicrobials.

Guidelines for antibiotic use Based on the data generated in the current and previous studies, we suggest the following guidelines for the use of antimicrobials in patients with advanced cancer receiving hospice/ palliative care: • On entry into hospice/palliative care, discussions should be held with the patient and family members on their wishes regarding the treatment of infections, just as is done for cardiopulmonary resuscitation, use of a respirator, blood transfusions, etc. • Strong consideration should be given to symptom control as the major indication for the use of antimicrobials for the treatment of infections. In a previous study, 3 79% of patients chose either no antimicrobials or symptomatic use only. • Prospective studies3,5,16 and retrospective studies6,10 suggest that antimicrobial treatment of urinary tract infections improves symptoms in majority of patients, but antimicrobial treatment of respiratory tract infections, mucositis, and skin infections is much less successful in symptom control. Sepsis/bacteremia is poorly controlled by antimicrobials in this patient population. 3,5,16

Infections in Palliative Care KEY LEARNING POINTS

529

• Patients in palliative care settings experience high incidence of infections. • The most common sites of infection in patients receiving palliative care are the urinary tract, respiratory tract, skin and subcutaneous tissues, mouth, and blood. The most common pathogens are E. coli, Staphylococcus spp., Enterococcus, and K. pneumoniae. • Although the use of antimicrobials improves symptoms in the majority of patients with urinary tract infections, symptom control is less successful with antimicrobial use in infections of the respiratory tract, mouth/pharynx, skin/subcutaneous tissue, or blood. • Physicians should be aware of the limitations of the use of antimicrobials in patients receiving palliative care. • Strong consideration should be given to the use of symptom control as the major indication for the use of antimicrobials for the treatment of infections. • Antimicrobial use has not been shown to significantly affect patients’ survival and this information is very valuable to physicians, patients, and caregivers when making decisions about the use of antimicrobials. • Each patient’s specific situation and condition in the palliative care setting must be evaluated in the decision to employ antimicrobials for a suspected or documented infection. • Overall survival appears to be unaffected by antimicrobial use;3,5 there may be some survival benefit in patients with sepsis or organ-related infections, if the infection is sensitive to the employed antimicrobial.18 • Patients and families should be informed of the effects of antimicrobials on symptom control of various infections and on overall survival. • Each patient’s specific situation and condition must be evaluated in the decision to employ antimicrobials for a suspected or documented infection.

References

1. Macedo F, Nunes C, Ladeira K, et al. Antimicrobial therapy in palliative care: an overview. Support Care Cancer 2018;26:1361–1367. 2. Vallard A, Morisson S, Tinquaut F, et al. Drug management in endof-life hospitalized palliative care cancer patients: the RHESO cohort study. Oncology 2019. DOI: 10.1159/000500783.





3. White PH, Kuhlenschmidt HL, Vancura BG, Navari RM. Antimicrobial use in patients with advanced cancer receiving hospice care. J Pain Symptom Manage 2003;25:438–443. 4. Stiel S, Krumm N, Pestinger M, et al. Antibiotics in palliative medicine – results from a prospective epidemiological investigation from the HOPE survey. Support Care Cancer 2012;20:325–333. 5. Reinbolt RE, Shenk AM, White PH, Navari RM. Symptomatic treatment of infections in patients with advanced cancer receiving hospice care. J Pain Symptom Manage 2005;30:175–182. 6. Vitetta L, Kenner D, Sali A. Bacterial infections in terminally ill hospice patients. J Pain Symptom Manage 2000;20:326–334. 7. Dagli O, Tasdemir E, Ulutasdemir N. Palliative care infections and antibiotic cost: a vicious circle. Aging Male 2019. DOI: 10.1080/13685538. 8. Chen L, Chou Y, Hsu P, et al. Antibiotic prescription for fever episodes in hospice patients. Support Care Cancer 2002;10:538–541. 9. Oneschuk D, Fainsinger R, Demoissac D. Antibiotic use in the last week of life in three different palliative care settings. J Palliat Care 2002;18:25–28. 10. Oh DY, Kim JH, Kim DW, et al. Antibiotic use during the last days of life in cancer patients. Eur J Cancer Care 2006;15:74–79. 11. Lam PT, Chan KS, Tse CY, Leung MW. Retrospective analysis of antibiotic use and survival in advanced cancer patients with infections. J Pain Symptom Manage 2005;30:536–543. 12. Chun ED, Rodgers PE, Vitale CA, et al. Antimicrobial use among patients receiving palliative care consultation. Am J Hospice Palliat Med 2010;27:262–265. 13. Al-Shaqi MA, Alami AH, Al-Zahrani AS, et al. The pattern of antimicrobial use for palliative care in-patients during the last week of life. Am J Hospice Palliat Med 2012;29:60–63. 14. Brabin E, Allsopp L. How effective are parenteral antibiotics in hospice patients? Eur J Palliat Care 2008;15:115–117. 15. Clayton J, Fardell B, Hutton-Potts J, et al. Parenteral antibiotics in a palliative care unit: prospective analysis of current practice. Palliat Med 2003;17:44–48. 16. Mirhosseini M, Oneschuk D, Hunter B, et al. The role of antibiotics in the management of infection-related symptoms in advanced cancer patients. J Palliat Care 2006;22:69–74. 17. Ahronheim JC, Morrison S, Baskin SA, et al. Treatment of the dying in the acute care hospital. Arch Intern Med 1996;156:2094–2100. 18. Thai V, Lau F, Wolch G, et al. Impact of infections on the survival of hospitalized advanced cancer patients. J Pain Symptom Manage 2012;43:549–557. 19. Nicolle LE, Bradley SF, Colgan R, et al. Infectious Disease Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Inf Dis 2005;40:643–654. 20. Hooton TM, Bradley SF, Cardena DD, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infections in adults. Clin Inf Dis 2010;50:625–663. 21. Mandell LA, Wundernik RC, Anzueto A, et al. Infectious Disease Society of America/American Thoracic Society Consensus Guidelines on the management of community-acquired pneumonia in adults. Clin Inf Dis 2007;44:S27–S72. 22. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Inf Dis 2005;41:1373–1406. 23. Bruera E. Intractable pain in patients with advanced head and neck tumors: a possible role of local infection. Cancer Treat Rep 1986;70:691–692. 24. Green K, Webster H, Watanabe S, Fainsinger R. Case report: management of nosocomial respiratory tract infections in terminally ill cancer patients. J Palliat Care 1994;10:31–34. 25. Fabiszewski KJ, Volicer B, Volicer L. Effect of antibiotic treatment on outcome of fevers in institutionalized Alzheimer patients. JAMA 1990;263:3168–3172.

55

PEDIATRIC PALLIATIVE WOUND CARE: THE UNIQUE ANATOMY AND PHYSIOLOGY OF NEONATAL SKIN

Ann Marie Nie and Joyce M. Black

Contents Reducing pressure injury�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������531 Use of prophylactic dressings�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������532 Reducing pressure injury from medical devices���������������������������������������������������������������������������������������������������������������������������������������������������������533 Extracorporeal membrane oxygenation�����������������������������������������������������������������������������������������������������������������������������������������������������������������������533 Reducing medical adhesive-related skin injury����������������������������������������������������������������������������������������������������������������������������������������������������������533 Reducing extravasation injury����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������533 Pediatric traumatic wounds��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������534 Surgical site infection�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������535 Wounds commonly seen at end of life��������������������������������������������������������������������������������������������������������������������������������������������������������������������������535 Extruding cancers��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������535 Dressings�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������535 Symptom management����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������535 Conclusion��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������536 References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������536 Preterm neonates have an increased vulnerability of skin injuries and intolerance to external sources of skin injury due to the nature of the underdeveloped skin structures. The stratum corneum is thin in preterm neonates, having only 2–3 layers of cells, compared with 10–20 layers of cells in full-term infants and adults. In neonates less than 24 weeks of gestational age, there may be virtually no stratum corneum. Stratum corneum is thought to mature by 30–32 weeks of gestational age. In preterm neonates, the papillary dermis underlying the dermoepidermal junction is edematous; collagen fibrils are smaller than those of the full-term newborn or adult; and there are fewer anchoring points with wide spaces between them. The weak adherence of epidermis to dermis increases risk for skin injury.1 The undeveloped stratum corneum is also less able to control evaporative heat and transepidermal water loss (TEWL). The resulting dehydrated skin lacks the protective moisture and becomes more predisposed to skin injuries. Less collagen and fewer elastic fibers in the dermis can result in edema. Like adults, edema affects skin turgor or elasticity and reduces blood flow, resulting in ischemic injury.2–4 The mature skin’s acid mantle (pH 4.5–6) serves as a protection against some microorganisms. Skin barrier function is altered when the pH shifts from acidic to neutral, resulting in increase in the total number of bacteria on skin surface or conditions such as inflammatory dermatoses (“diaper dermatitis”). Prior to birth and for the first few weeks of life, the skin is more alkaline. Several mechanisms may play a role in alkaline skin pH at birth— the most relevant could be the exposure to the alkaline amniotic fluid during the preborn life. This alkaline skin influences

the growth of skin bacterial flora, increasing the risk for dermal inflammation.2–4 Anatomical variations increase the risk for pressure injury in children. Pediatric cartilage, muscle, and fat-tissue structures are softer than those of adults, making newborns and young children more susceptible to deformation-type pressure injuries of the nasal structures (Figure 55.1). In addition, children are at risk for pressure injury on body areas that differ from adults, such as the occiput (Figure 55.2) because the head of a child is proportionally larger and lacks adipose tissue. Older children develop pressure injuries in locations such as the sacrum, heels, and coccyx (Figure 55.3A and Figure 55.3B). The clinical implications that stem from the variances in anatomy and physiology increase the risk of skin injury in young children. Injury can occur from exposure to pressure, shear, burns, and chemicals. In addition, immature skin has a high permeability to topical agents. Topical products can cause toxicity due to systemic absorption.

Reducing pressure injury Pressure injuries unfortunately do occur in children. One of the largest sample of data (N = 39,984) was published from the National Database of Nursing Quality Indicators and reported that 30.2% of hospitalized children were considered at risk for pressure injury.5 The incidence of pressure injuries was 1.14%.6 Bundled prevention programs have been shown to reduce pressure injury incidence in children.7–9 The skin care bundles often include using an appropriate support surface, frequent turning and repositioning, moisture and incontinence management,

531

532

Textbook of Palliative Medicine and Supportive Care

FIGURE 55.3A  Coccygeal pressure injury in a teen; these pressure injuries occur in sites common to adults. FIGURE 55.1  Continuous positive airway pressure exerting pressure on the columella. appropriate nutrition, and nursing staff education. Nurse support was provided by skin champions on the units and advanced practice nurses. Support surfaces need to envelop the patient to redistribute the pressure and provide a low-friction interface to reduce shear. However, manufacturers do not recommend the use of low airloss support surfaces in children weighing < 70 Kg as the lower weight is not enough to allow for envelopment into the surface. The clinician also needs to consider frequent movements, risk for misplaced tubes and lines, and physical growth during the hospital stay. The most common pressure redistribution products and research behind these products are geared toward the adult population. These products and their supporting research are limited for the pediatric group. Computer simulation indicates that air cell-based mattresses protect against increased soft-tissue deformation around a misplaced tube compared to a foam mattress for the newborn intensive care unit and pediatric intensive care unit populations.10

FIGURE 55.2  Occipital pressure injury.

Critically ill children are at risk for immobility pressure injury and should be positioned using fluidized positioners. These can be used to cradle the whole body, support back of the head, elevate heels off the bed, and for assistance in lateral positioning of the coccyx. These positioners retain their shape after molding to the child or device. The preterm infant is held in a position that mimics how the body would have been in the womb, assisting development and preventing pressure injury.

Use of prophylactic dressings The occiput is the most common pressure injury site in children. Its location is not surprising, because younger child’s head is larger and heavier than the head of older child or adult. Children at risk for occipital pressure injury are often sedated and intubated (which may limit the ability of the head to be turned) on complex therapies or vasopressive medications.11 Fluidized positioners float the occiput when the head cannot be easily turned. Caution is needed to protect the ears from pressure when the head is turned to the side.

FIGURE 55.3B  Coccygeal pressure injury following debridement.

Pediatric Palliative Wound Care: The Unique Anatomy and Physiology of Neonatal Skin

Reducing pressure injury from medical devices In 2003, Curley and colleagues published the first prospective data on medical device ulcers in children between the ages of 21 days and 8 years. The overall incidence of ulceration was 27%, with 8% of children ulcerating due to medical devices. The oxygen saturation probe, nasal continuous positive airway pressure (CPAP) mask, bilevel positive airway pressure mask, tracheostomy and endotracheal tubes were the most common devices (74%) responsible for ulceration.12 Medical devices remain the most common cause for pressure injuries in neonates and children. The causes of the injury vary from poorly fitted devices, not having sizes for all ages, to overly tight securement of the device. Logically, different devices create different sources of pressure. The tracheostomy pressure stems from the trach plate, phalange, and the securement straps. In endotracheal tubes, the tube itself can cause a pressure injury on the lip, mouth, and/or columella. The securement device can injure the face or head (depending on how it is secured). Injury extends beyond pressure injury to the skin and soft–tissue injury; tight fitting nasal prongs can lead to nasal vestibular stenosis or columellar necrosis.13 Over time, this process can lead to ulceration, bacterial colonization, and then secondary healing with granulation tissue formation leading to disruption of nasal patency. Protecting the premature infant from pressure damage is imperative. Frequent skin assessments, focused examinations of the face, using the correct prong size, providing adequate humidification, and using skin barriers and silicone foams are methods to assist in prevention. Proper positioning of the oxygen delivery device can reduce pressure on the soft tissue. Endotracheal tubes should be moved in the mouth on each shift if not more often; tracheostomy ties should be padded. Pressure from the phalange can be reduced with foam dressings.14 Soft silicone dressing have been used under trach plates and phalange for pressure injury prevention. These dressing are also used to protect the columella and philtrum from pressure from CPAP masks and nasal prongs.15 Electroencephalogram (EEG) electrodes create a unique risk for injury. The wounds created resemble medical device pressure injury because they are the shape of the electrode. Mietzsch examined the problem of EEG electrode wounds in critically ill neonates and found that silver/silver chloride-plated electrodes, when exposed to external heat sources, can cause burns, resembling pressure injury.16 Furthermore, the securement device often increases the pressure of the leads on the scalp. The Neurodiagnostic Society recommends that if a dressing is used to assist in securing the leads, then stretchable, breathable gauze should be used that can easily fit two fingers under the dressing.17

Extracorporeal membrane oxygenation Indications for the use of extracorporeal membrane oxygenation (ECMO) in the critically ill child is an expanding field. As experience grows with ECMO, patients who were previously considered absolute contraindications are now being considered relative contraindications.18,19 Due to the risk of decannulation, many professionals limit the movement of the patient on ECMO, which leads to pressure injury of the occiput, buttocks, and heels, depending on the age of the patient and body size. Preventive foam dressings should be applied to the high-risk areas and the head should

533

be cradled in a positioner that supports the cannulas in the large vessels in the neck. The duration of ECMO has also increased; the average run time in neonates with congenital heart disease is 259 hours.18 Given the high rate of morbidity with EMCO in older patients, including muscle weakness, pressure ulcers and other events, there is a more concentrated effort to reduce sedation and move the patient both in bed and out of bed.20

Reducing medical adhesiverelated skin injury The fragility of the skin and the increased pressure injury risk is even more concerning when the skin is damaged. Medical adhesive-related skin injury (MARSI) is chemical or mechanical injury to the skin from dressings or tape.21 MARSI is a prevalent problem in pediatrics, with a rate of 37.15% (range 23.53–54.17%).22 In fact, 10–15% of neonates leave the intensive care unit with scars.22 In addition, products that promote adhesion (e.g., tincture of benzoin) may result in increased epidermal stripping because of the very strong bond between a product and the skin. In babies, transparent film has a stronger bond to the epidermis than the bond of epidermis to the dermis.22 Not only is skin injury an issue, the removal of adhesive materials, can increase TEWL levels in the neonate. The open skin can compound the toxicity of agents or further exacerbate skin damage.21 Hydrocolloids, polyurethane foams, and transparent films are also adhesive and injure the skin. Great care should be taken by clinicians when removing these products or applying products with known strong adhesive properties (e.g., cloth tape, transparent films). Gentle dressings or adhesives (e.g., tapes) with silicone are generally recommended. Routine use of petroleum-based products or products with zinc oxide are preferred and recommended for dermatitis as well as “crusting” techniques using stoma powder in combination with a skin ointment barrier. Caustic effluent from a percutaneous endoscopic gastrostomy tube may require the use of a foam dressing for protection and absorption.

Reducing extravasation injury Extravasation injury is damage to surrounding skin and soft tissue from the leakage of vesicant fluid from a vein. These injuries are most common in neonates and children due to the fragility and small caliber of veins. Children are at high risk of infiltration and extravasation of intravenous (IV) fluids and medications because of limited ability to communicate early signs of pain, movement of arms and legs, and fragility of veins. Infiltration is reported to occur in 5.5 cases per 1,000 patient days; extravasation is slightly less common at 4.4 cases per 1,000 patient days.23 Skin damage caused by vesicant fluid collection leads to vessel obstruction and possible ischemia.24 Skin damage can be blistering of skin or extensive with compartment syndrome with skin necrosis (see Box 55.1). With deeper structure involvement, surgical debridement and grafting is needed. The severity of extravasation injury can be described in stages (see Figure 55.4). Treatment of extravasation lacks empirical evidence. Saline flush of the site and hyaluronidase injections into the extravasation site are common treatment. This enzyme breaks down the hyaluronic acid bond between tissue cells. The extravasated medication can then disperse into larger area of capillary beds, thereby reducing edema and decreasing the risk of damage to the tissue and skin. The medication is normally given within 1 hour

Textbook of Palliative Medicine and Supportive Care

534 BOX 55.1  EXTRAVASATION SEVERITY SCALE Stage 1: painful IV site, no edema or redness at the site; flushes without difficulty Stage 2: painful IV site, slight edema, redness, no blanching, brisk capillary refill below infiltration site, good pulses below infiltration site Stage 3: painful IV site, marked edema, blanching, cool to touch, brisk capillary refill below infiltration site, good pulses below infiltration site Stage 4: painful IV site, very marked edema, blanching, cool to touch, capillary refill of more than 4 seconds, decreased or absent pulses, skin breakdown or necrosis of the injury in 4–5 injections around the site of damage. There is not standard time frame for administration.25 Treatment of the wounded skin is dependent on the severity of the damage. Moist wound healing should be followed for treatment options. Due to the risk for significant injury, prevention is the key. While it is standard nursing procedure to assess a peripheral IV site every hour, this can be challenging when a parent or caregiver requests that a child not be disturbed during the night hours. To prevent these types of injuries, the hourly assessment should be adhered to. Parents should be made aware of the need to prevent harm and offered assurance that care will be taken so as to not wake the child.

FIGURE 55.4  Eleven month old with intravenous site extravasation with compartment syndrome.

Pediatric traumatic wounds Traumatic injury is the leading cause of mortality and morbidity in children. Serious wounds in children include burns, fractures, abdominal and head trauma. Not all traumatic wounds require surgical management (e.g., splenic and liver trauma)26; however, penetrating injuries (e.g., gunshot, stab) are becoming increasingly common and often require exploratory surgery. The resulting wound is often left open to reduce the risk of abdominal compartment syndrome27 (see Figure 55.5). Burns are also common forms of injury among children. Tragically, almost one-quarter of burn injuries occur in children.28 In a study of 2,273 pediatric burn patients, scald burns were the most common (71.1%, n = 1,617), with 53% attributable to hot liquids related to cooking, including coffee or tea. In the teenage group, flame burns were the dominant cause (53.8%; see Figure 55.6). Mortality of burn injury was 0.9%.28 Some of these burn cases are due to child abuse; estimates indicate that as high as 40% of all burns in children are due to abuse by the parents or caregiver. 30 The traditional classification of burns (first, second, third degree) has been replaced by a classification system that reflects the need for surgical therapy. Burns are currently grouped as superficial, superficial partial-thickness, deep partialthickness, full-thickness, and fourth-degree burns (See Box 55.2). Initial care of the burn patient includes preventing hypovolemic shock, reducing pain, and determining the extent of the burn. Total body surface area (TBSA) calculation is important to guide resuscitation, prognosis, and disposition. The larger the TBSA burn, the higher the rate of death, infection, and need for multiple operations to close the wounds. Sepsis is generally preventable with prompt resuscitation and early excision of burned tissues. Prophylactic oral or topical antibiotics are not indicated. Nutritional support is crucial due to the hypermetabolic state. 31 Debridement of loose tissue and blisters can be performed simply with use of a topical anesthetic solution. Silver sulfadiazine (SSD) remains the traditional treatment for burn topical care despite dwindling outcomes. A systematic review of the literature to assess nonsilver versus SSD in pediatric burns reported that wounds treated with nonsilver dressings healed more rapidly, required less dressing changes, and had shorter length of stay than those using SSD for treatment. The nonsilver dressings

FIGURE 55.5  Traumatic abdominal wound.

Pediatric Palliative Wound Care: The Unique Anatomy and Physiology of Neonatal Skin

FIGURE 55.6  Partial-thickness burn in a 9 week old from a heating pad. caused less pain and SSD did not prove to be a better prevention measure for infection. Dressings that showed better efficacy include hydrogels, silicone nonadherence dressing, and silicone dressings with impregnated silver. 32

Surgical site infection Risk factors for surgical site infection have been well studied in adult patients; however, similar work in pediatric population is not as well studied. Surgical site infection occurs in 0.25–6% of children following cardiothoracic surgery. A case-matched review found no identifiable risk factors for infection following open heart surgery. In contrast, a systemic review found that timing and type of preoperative antibiotics, use of implanted products for repair, delayed recovery and more complex spinal problems (such as a combination of neurological and orthopedic) were more likely to develop infections. 33,34

Wounds commonly seen at end of life Extruding cancers

There are several forms of soft-tissue cancers in children. While there has been a dramatic improvement in survival of children and adolescents suffering with these tumors, not all are curable.

BOX 55.2  BURN CLASSIFICATION Superficial: epidermis involvement Partial thickness: epidermis and varying degrees of dermis involvement Superficial partial thickness and indeterminatethicknessDeep partial thickness– deeper dermis involvement Full thickness: dermis involvement Fourth degree: subcutaneous tissue with involvement of fascia, muscle, tendon, and bone

535

FIGURE 55.7  A 7.5 month old with extruding angiosarcoma. Rhabdomyosarcoma, a tumor of striated muscle, is the most common soft-tissue sarcoma in children aged 0–14 years and accounts for 50% of tumors in this age group. Ewing’s sarcoma family of tumors includes bone and soft-tissue tumors that are often characterized by a specific translocation between chromosome 11 and 22. Soft-tissue sarcoma is estimated to be about 8% of cancers diagnosed in adolescents. 35 Angiosarcoma is a rare tumor of blood vessels and little is known about its pathogenesis (See Figure 55.7). When these tumors extrude through the skin, wound care is needed to reduce the distress from the tumor.

Dressings

The ideal dressing should protect the wound from exposure to the environment, thereby reducing the risk of infection and irritation, provide a humidified and warm local wound environment to promote healing, absorb drainage from the wound bed and translocate it to the surface of the dressing. In addition, cultural and religious preferences should be observed. Some cultures and religions forbid the use of animal products (most commonly bovine and porcine sources), and therefore dressings which contain animal product should be avoided. Hydrocolloid dressings can contain porcine-derived gelatin. 36 Removal of a dressing should be as pain free as possible. Silicone lined layer foam dressings are preferred due to the absorptive capacity and pain-free removal. 37 If the child is mentally able to provide input, the clinician should do his/her best to meet the psychosocial needs of the child, including finding a dressing capable of being hidden by clothing and one that the child will tolerate and leave alone. When wound healing is not the goal, the dressings should be highly absorptive to reduce the number of dressing changes. Furthermore, there should be no need to “look at the wound” daily because, in theory, no change will be made in the care based on the wound’s condition.

Symptom management

The most common symptoms from the wound and its drainage include odor, pain, and wet clothing from drainage. Drainage from the inflammation in the wound is best controlled with highly absorptive dressings, such as foams and alginates. There should be no effort to examine the wound, except to change dressings when they are saturated. Dressings with a 5- to 7-day wear time should be used. 38

Textbook of Palliative Medicine and Supportive Care

536 Odor is from the invasion of the wound with bacteria; frank infection may be present. Depending on the timing of infection and condition of the patient, some patients and families will want it treated, others will not. Sharp debridement to debulk the necrotic tissue and reduce the odor is important to offer as an option. The debridement should not extend to bleeding tissues, because bleeding is more difficult to control and, of course, leads to great concern by the patient. If bleeding is encountered, use pressure to control it. For wounds that will not be debrided, ground metronidazole placed directly into the wound bed will reduce the number of anaerobic organisms and the odor from them. The odor from frank necrosis (gangrene) is very difficult to control, so it is best to stay ahead of necrotic tissue. Maggots can also be used to debride the wound; the benefit of maggots is that they quickly digest necrotic material but do not enter the viable wound tissue, so bleeding is not a concern. Maggots can be distasteful but can be placed into polymer bags, so they do not have to be seen. Some patients will report a tingling from the maggots, but often do not find it bothersome. Medical honey dressings have been used in children’s wounds, with good acceptance by the patient and care provider. The honey is a debriding agent through its hypertonic state and an antiseptic. 39 Many studies have been done on patients with wounds using medical-grade (Manuka) honey with positive results. A full review is beyond the scope of this chapter.40 Pain in the wound should be aggressively managed. Follow the preferences of the patient and family to achieve comfort. Pressure injuries do occur at end of life; they likely develop from a combination of efforts to allow the family time to be with the patient rather than provide bedside care and a reduction in perfusion of tissue. Adults and elders are said to have “skin failure” or “terminal ulcers”; this terminology does not appear in pediatric cases.

Conclusion Adult-based wound care practices provide a rudimentary foundation for neonatal and pediatric wound care but do not negate the need for developmentally specific evidence-based guidelines. Most of the currently available guidelines and information are based on adult research. However, given the wide variation in percutaneous toxicity potential and developmental and integumentary maturity spanning from the very-low-birth-weight premature infant through adolescence, clinicians desperately need age-appropriate, safe, and effective products, educational tools, and research-based guidelines so as to deliver safe and effective wound care practice.

References

1. Oranges T, Dini V, Romanelli M. Skin physiology of the neonate and infant: clinical implications. Adv Wound Care 2015;4(10):587–595. 2. Visscher MO, Adam R, Brink S, Odio M. Newborn infant skin: physiology, development, and care. Clin Dermatol 2015 May-June;33(3):271–280. 3. Taieb A. Skin barrier in the neonate. Pediatr Dermatol 2018 March;35 Suppl 1:s5–s9. 4. Fluhr JW, Darlenski R, Taieb A, et al. Functional skin adaptation in infancy - almost complete but not fully competent. Exp Dermatol 2010;19(6):483–492. 5. Razmus I, Bergquist-Beringer S. Pressure ulcer risk and prevention practices in pediatric patients: a secondary analysis of data from the National Database of Nursing Quality Indicators®. Ostomy Wound Manage 2017 January;63(2):28–32.















6. Razmus I, Bergquist-Beringer S. Pressure injury prevalence and the rate of hospital-acquired pressure injury among pediatric patients in acute care. J Wound Ostomy Continence Nurs 2017 March/ April;44(2):110–117. 7. Frank G, Walsh KE, Wooton S, Bost J, Dong W, Keller L, et al. Impact of a pressure injury prevention bundle in the solutions for Patient Safety Network. Pediatr Qual Saf 2017 February 16;2(2):e013. 8. Singh CD, Anderson C, White E, Shoqirat N. The impact of pediatric pressure injury prevention bundle on pediatric pressure injury rates: a secondary analysis. J Wound Ostomy Continence Nurs 2018;45(3):209–212. 9. Cummins KA, Watters R, Leming-Lee T. Reducing pressure injuries in the pediatric intensive care unit. Nurs Clin North Am 2019 March;54(1):127–140. 10. Levy A, Kopplin K, Gefen A. Adjustability and adaptability are critical characteristics of pediatric support surfaces. Adv Wound Care 2015;4(10):615–622. 11. Manning M, Gauvreau K, Curley MAQ. Factors associated with occipital pressure ulcers in hospitalized infants and children. Am Assoc Crit Nurses 2015;24(4):342–348. 12. Curley MA, Quigley SM, Lin M. Pressure ulcers in pediatric intensive care: incidence and associated factors. Pediatr Crit Care Med 2003;4(3):284–290. 13. Maruccia M, Fanelli B, Ruggier M. Necrosis of the columella associated with nasal continuous positive airway pressure in a preterm infant. Int Wound J 2012;11(3):335–336. 14. Black J, Kalowes P. Medical device related pressure ulcers. Chronic Wound Care Manage Res 2016;3:91–99. 15. Visscher M, King A, Nie AM, et al. A quality improvement collaborative project to reduce pressure ulcers in PICS. Pediatrics 2013;131(6):e1950–e1960. 16. Mietzsch U, Cooper K, Harris M. Successful reduction in electroderelated pressure ulcers during EEG monitoring in critically ill neonates. Adv Neonatal Care 2019;19(4):262–274. 17. Neurodiagnostic Society. ASET position statement: skin safety during EEG procedures: a guideline to improving outcome. 2016. https:// www.aset.org/i4a/pages/index.cfm?pageid=4134 (Accessed August 27, 2019). 18. Jenks C, Raman L, Dalton H. Pediatric extracorporeal membrane oxygenation. Crit Care Clin, 2017;33(4):825–841. 19. Fletcher K, Chapman R, Keene S. An overview of medical ECMO for neonates. Semin Perinatol 2018;42:68–79. 20. Raman L, Dalton H. A year in review 2015: extracorporeal membrane oxygenation. Resp Care 2016;61(7):986–991. 21. McNichol L, Lund C, Rosen T, Gray M. Medical adhesives and patient safety: state of the science: consensus statements for the assessment, prevention and treatment of adhesive-related skin injury. J Wound Ostomy Continence Nurs 2013;40(4):365–380. 22. Wang D, Xu H, Chen S, Low X, Tan K, Xu J. Medical adhesive-related skin injuries and associated risk factors in pediatric intensive care unit. Adv Skin Wound Care 2019;32(4):176–182. 23. Boyer V. Medical adhesive-related skin injury and chemical injury in a preterm neonate. Wound Manage Prev 2019;65(2):8–12. 24. Özalp Gerçeker G, Kahraman A, Yardimci F, et al. Infiltration and extravasation in pediatric patients: A prevalence study in a children’s hospital. J Vasc Access 2018 May;19(3):266–271. 25. Beall V, Hall B, Mulholland J, Gephart S. Neonatal extravasation, overview and algorithm for evidence-based treatment. Newborn Infant Nurs Rev 2013;13(4):189–195. 26. Lynch T, Kilgar K, Shibli A. Pediatric abdominal trauma. Current Pedi Rev 2018;14:59–63. 27. Thabet FC, Ejike JC. Intra-abdominal hypertension and abdominal compartment syndrome in pediatrics. A review. J Crit Care 2017 October;41:275–282. 28. National Burn Association Fact Sheet, 2018. 29. Lee CJ, Mahendraraj K, Houng A, Marano M, Petrone S, Lee R, et al. Pediatric burns: a single institution retrospective review of incidence, etiology, and outcomes in 2273 burn patients (1995–2013). J Burn Care Res 2016 November/December;37(6):e579–e585. 30. Rosado N, Charleston E, Gregg M, Lorenz D. Characteristics of accidental versus abusive pediatric burn injuries in an urban burn center over a 14-year period. J Burn Care Res 2019 June 21;40(4):437–443. 31. Strobel A, Fey R. Emergency care of pediatric burns. Emerg Med Clin North Am 2018;36:441–458.

Pediatric Palliative Wound Care: The Unique Anatomy and Physiology of Neonatal Skin 32. Rashaan ZM, Krijnen P, Klamer RR, Schipper IB, Dekkers OM, Breederveld RS. Nonsilver treatment vs. silver sulfadiazine in treatment of partial thickness burn wounds in children: a systematic review and meta-analysis. Wound Repair Regen 2014 July-August;22(4):473–482. 33. Subramanyam R, Schaffzin J, Cudilo E, Roa M. Varughese A. Systemic review of risk factors for surgical site infection in pediatric scoliosis surgery. Spine J 2015;15:1422–1431. 34. Sochet A, Cartron A, Nyhan A, Spaeder M, Song X, Brown A, et al. Surgical site infection after pediatric cardiothoracic surgery: impact on hospital cost and length of stay. Congenital Heart Surg 2017;8(1):7–12. 35. Papworth KE, Arroyo VM, Styring E, Zaikova O, Melin BS, Lupo PJ. Soft-tissue sarcoma in adolescents and young adults compared with older adults: a report among 5000 patients from the Scandinavian Sarcoma Group Central Register. Cancer 2019;125(20):3595–3602.

537

36. Rodger D, Blackshaw B. Using animal-derived constituents in anesthesia and surgery: the case for disclosing to patients. BMC Medical Ethics; 2019;20(14):1–9. 37. Baharestani M. An overview of neonatal and pediatric wound care knowledge and considerations. Ostomy Wound Manage 2007;53(6):34–55. 38. Hotaling, P, Black J. Pressure injury at end of life. Wounds Inter 2018;9(1):18–21. 39. Amaya R. Little patients, big outcomes: the role of Medihoney® in pediatric wound care. Ostomy Wound Manag 2014;60(8):8–10. 40. Minden-Birkenmaier BA, Bowlin GL. Honey-based templates in wound healing and tissue engineering. Bioengineering (Basel) 2018 June;5(2):46.

56

MOUTH CARE

Flavio Fusco

Contents Introduction and prevalence...........................................................................................................................................................................................539 Infections.............................................................................................................................................................................................................................539 Fungal infections..........................................................................................................................................................................................................539 Treatment of oral fungal infections............................................................................................................................................................................... 540 Viral infections............................................................................................................................................................................................................. 540 Treatment of oral viral infections.................................................................................................................................................................................. 540 Xerostomia......................................................................................................................................................................................................................... 540 Management of xerostomia............................................................................................................................................................................................ 541 Chemotherapy-/radiation-induced stomatitis............................................................................................................................................................ 541 Management of chemotherapy-/radiation-induced stomatitis............................................................................................................................... 542 Altered taste sensations................................................................................................................................................................................................... 542 Management of altered taste sensations...................................................................................................................................................................... 542 Oral lesions in HIV/AIDS patients................................................................................................................................................................................ 543 Management of oral lesions in patients with HIV/AIDS.......................................................................................................................................... 543 Osteonecrosis of the jaw.................................................................................................................................................................................................. 543 Management of osteonecrosis of the jaws................................................................................................................................................................... 543 Oral health in frail elderly with dementia.................................................................................................................................................................... 544 References........................................................................................................................................................................................................................... 544

Introduction and prevalence

Infections

In a palliative care patient, oral cavity represents a true “target organ.” The mouth plays a fundamental role in many aspects of life: nutrition; hydration; phonation; speech articulation processes; relational and communication activities; and emotional, affective, and sexual relations.1 Several studies have shown that oral complications and abnormalities of the oral microflora can be found in significant numbers of terminally ill cancer patients, affecting their quality of life. A total of 77 of 99 patients recruited from 2 Norway palliative care units reported dry mouth, 67% reported mouth pain, and problems with food intake were referred by 56%.2 Sweeney and Bagg 3 studied the prevalence of oral signs and symptoms among a group of 70 terminally ill cancer patients: 68 patients (97%) complained of oral dryness during the day, and 59 patients (84%) complained of oral dryness at night. Oral soreness was reported by 22 patients (31%). Forty-six patients (66%) had difficulty talking, and 36 (51%) reported difficulty eating. Oral mucosal abnormalities were detected in 45 patients (65%), most commonly erythema (20%), coated tongue (20%), atrophic glossitis (17%), angular cheilitis (11%), and pseudomembranous candidiasis (9%). This problem reaches a dramatic evidence in frail population living in poor-resourced settings: a study of 95 children referred for palliative care in Malawi showed that 51% of them had mouth sores and 40% had oral candidiasis.4 This chapter describes the major and more frequent oral problems experienced by patients with advanced cancer followed in palliative care programs. Aspects of their management will also be discussed.

Fungal and viral infections frequently develop in patients with advanced cancer.

Fungal infections

The most common oral infection is oral candidiasis: high levels of Candida have been reported among terminally ill patients, with correspondingly high levels of mucosal disease. 5,6 Debilitated patients, such as those receiving antibiotics, steroids, and cytotoxic therapies, are particularly susceptible to oral candidiasis. Other general factors, such as diabetes mellitus, or predisposing local factors (e.g., poor denture hygiene, presence of xerostomia) are also important in the pathogenesis of oral candidiasis. There are more than 150 species of Candida, but only 10–15 of them are regarded as important pathogens for humans. Candida albicans is one of these candidal species, which is found in the oral cavity and responsible for most oral candidal infections. The pseudomembranous form (thrush) is a classic clinical feature, characterized by creamy white, curd-like patches on the tongue and other oral mucosal surfaces. The patches can be removed by scraping and leave a raw, bleeding, and painful surface. Beside the classic lesion, other manifestations include: • Acute atrophic candidiasis or “antibiotic-related stomatitis”: This is a nonspecific atrophy of the tongue, associated with burning sensation, dysphagia, and mouth pain. • Chronic atrophic candidiasis (erythematous candidiasis) or “denture sore mouth”: This is a chronic inflammatory reaction and epithelial thinning under the dental plates. Dysgeusia is usually present. 539

Textbook of Palliative Medicine and Supportive Care

540 • Angular cheilitis: This is an inflammatory reaction at the corners of the mouth (not due exclusively to Candida but to mixed infection with Staphylococcus aureus or, less frequently, beta-hemolytic Streptococci). Bleeding may be sometimes present. • Candida leukoplakia (hyperplasic candidiasis): In this, the lesions are firm, adherent plaques involving the cheek, lips, and tongue. Symptoms are usually absent. The diagnosis can be made by the clinical appearance of the lesion, by scraping (using either a potassium hydroxide smear or a Gram stain to show masses of hyphae, pseudohyphae, and yeast forms). Other simple methods are swabs, imprint cultures, or culture of oral rinses.

Treatment of oral fungal infections Specific antifungal treatment may be provided either topically and systemically. Nystatin in the form of suspension (100,000 units/mL, 4–6 mL every 6 h), pastilles, or tablets (100,000 units) is a traditional local treatment. Duration of treatment is usually 10–14 days, but some patients need to continue the treatment for at least 2 weeks after clinical resolution. Miconazole gel is useful for the management of angular cheilitis; it has a weak activity against grampositive cocci as well as yeasts.7 Clotrimazole lozenges (10 mg 5 times a day) are effective and well tolerated in the treatment of oropharyngeal candidiasis forms.8 Ketoconazole is available in a number of oral and topical forms. The slow therapeutic response, variable absorption, and frequent adverse effects (anorexia, nausea, vomiting, and liver toxicity) all make it a poor choice in patients with advanced cancer. Fluconazole is a triazole with established therapeutic efficacy in candidal infections. It is both an oral and parenteral fungistatic agent that inhibits ergosterol synthesis in yeasts. Fluconazole, 50–100 mg once daily, is one of the most effective treatments of oropharyngeal candidiasis; daily doses of 100–200 mg are recommended for esophageal candidiasis. Extensive clinical studies have demonstrated fluconazole’s remarkable efficacy, favorable pharmacokinetics, and reassuring safety profile, all of which have contributed to its widespread use.9,10 Itraconazole, structural similar to ketoconazole, has a broader spectrum of action, and it is available in parenteral and oral formulations. To obtain the highest plasma concentration, the tablet is given with food and acidic drinks, whereas the solution is taken in the fasted state. The most common triazoles-related adverse effects are doserelated nausea, abdominal discomfort, and diarrhea, but symptoms rarely necessitate stopping therapy.11 Ketoconazole and itraconazole may seriously interact with some of the substrates of CYP3A4. In a double-blind, randomized, three-phase crossover study, Varhe et al.12 reported that ketoconazole and itraconazole seriously affect the pharmacokinetics of triazolam and increase the intensity and duration of its effects with potentially hazardous consequences. Azoles have also been implicated in fatal interactions with antihistamines (polymorphic ventricular tachycardia). Caution should be used when fluconazole and methadone are administrated concurrently.13,14 Several studies have showed an emerging high prevalence of non-C. albicans yeasts and azole resistance in the oral flora of patients with advanced cancer: Bagg et al.15 examined the oral mycological flora of 207 patients receiving palliative care. A total of 194 yeasts were isolated, of which 95 (49%) were C. albicans.

There was a high prevalence of C. glabrata (47 isolates), of which 34 (72%) were resistant to both fluconazole and itraconazole. Other non-C. albicans species, such as C. parapsilosis, C. kruseii, and, more recently, C. dubliniensis, are less susceptible than C. albicans to fluconazole.16 In the last years, the echinocandins (caspofungin, micafungin, and anidulafungin) have shown fungicidal activity against most Candida spp., including strains that are fluconazole-resistant.17 Posaconazole, a new oral broad-spectrum triazole agent, is active against many species resistant to fluconazole and itraconazole. It is administered as oral suspension, with a favorable toxicity profile, and appears to be a promising addition in the antifungal armamentarium.18

Viral infections

Herpes simplex virus (HSV-1) is the commonest cause of viral infection of the oral mucosa. Herpes viruses are characterized by their ability to establish and maintain latent infections, which can get reactivated. Several stimuli, such as radiotherapy or chemotherapy, can trigger the reactivation of herpes viruses. Small vesicles usually appear on the pharyngeal and oral mucosa; these rapidly ulcerate and increase in number, often involving the soft palate, buccal mucosa, tongue, and floor of the mouth. Anorexia, fever, mouth pain, and dysphagia may be present. The disease generally runs its course over 10–14 days.

Treatment of oral viral infections Acyclovir triphosphate is available as a topical 5% ointment, an intravenous form, and an oral form. In the immunocompromised patients, acyclovir is useful as both treatment and suppression of recurrent mucocutaneous HSV lesions.19 Penciclovir, a novel acyclic nucleoside analogue, has demonstrated efficacy against HSV types 1 and 2 and seems to have a pharmacological advantage due to a prolonged half-life of its active form in HSVinfected cells.20,21 Al-Waili22 carried out an interesting, small, prospective, randomized trial that compared topical application of honey with acyclovir cream in patients with recurrent episodes of labial and genital herpes simplex lesions. For labial herpes, the mean duration of attacks, occurrence of crust, healing time, and pain duration were significantly lower when treated with honey when compared with acyclovir treatment (p < 0.05).

Xerostomia Xerostomia, defined as the subjective feeling of oral dryness, is one of the five most common symptoms affecting patients with advanced cancer, with a reported prevalence between 30% and 97%.1,23,24 Indeed, despite the high prevalence of this distressing symptom—which may contribute to mouth pain and oral infections—there has been relatively little research into this “orphan topic in supportive care.”25 There are many general causes of xerostomia (Box 56.1), but drug therapies are probably the most important, via a number of different mechanisms: the direct effects include interference with the nerve supply to the salivary glands (e.g., antidepressants), or with the productive capacity of salivary glands (e.g., diuretics, opioids). The indirect effects include imbalance with the normal stimuli to the secretion of saliva.26 The effects of xerostomia on patient’s symptoms are numerous: the absence of protective effect of saliva on the oral mucosa is a

Mouth Care BOX 56.1  MAIN CAUSES OF XEROSTOMIA IN PATIENTS WITH ADVANCED CANCER Related to Cancer Itself • Head and neck cancer • Obstruction/compression/destruction of the salivary glands Related to Dehydration • • • • •

Anorexia, poor fluid intake Diarrhea, vomiting Hemorrhage Fever Oxygen supply

Related to Treatment • Radiotherapy • Oral and jaw surgery • Drug therapy: Anticholinergics, antihistamines; antihypertensive/diuretics; opioid analgesics; nonsteroidal anti-inflammatory drugs (NSAIDs); corticosteroids; proton pump inhibitors Related to Concurrent Disorders • • • • •

Sjögren syndrome Diabetes (mellitus and insipidus) Sarcoidosis Thyroid dysfunctions Anxiety/depression states

facilitating factor of exogenous bacterial colonization and infections and the loss of lubrification makes swallowing and chewing difficult and painful. Another feature of xerostomia is taste alteration with a subsequent loss of appetite. The sensation of burning, soreness, and dryness sensations may have a considerable effect on speech, with subsequent fall in mood state and relational abilities. Saliva also plays an important role in preventing the loss of tooth substance by its antimicrobial, buffering, and cleansing activities: thus, dental caries and dental erosions are often seen in terminally ill patients. 3,24

Management of xerostomia The primary management of xerostomia involves treatment of underlying cause. A recent, cross-sectional study of 135 patients with advanced progressive diseases underlined the importance to take a detailed assessment, highlighting the functional impact on day-to-day activities such as talking, dysphagia, and sleep.27 Discontinuation or substitution of regimens of xerostomic drugs may sometimes be possible. Patients with ill-fitting dentures can be advised to see their dentist: relining of dentures can improve their fit and function and help to lessen oral pain and dryness caused by the lack of support for dentures. Dentate patients should receive preventive or dietary advice, as well as treatment of any caries present.

541 Current therapy for chronic xerostomia involves the use of salivary substitutes or salivary stimulants. Pilocarpine is a muscarinic agonist, although it does have some effect on the beta-adrenergic receptors in the salivary and sweat glands. There have been a number of double-blind, randomized controlled studies that have shown that pilocarpine is an effective treatment for radiation and drug-induced xerostomia. Davies et al.,28 in a multicenter, crossover study, compared a mucin-based artificial saliva with oral formulation of pilocarpine hydrochloride in 70 patients with advanced disease and xerostomia. The pilocarpine formulation was found to be more effective than artificial saliva, but it was found to be associated with more side effects, such as sweating, lacrimation, and dizziness. Extreme caution in the use of pilocarpine is important due to reported side effects of glaucoma, cardiac disturbances, and sweating. For this reason, other studies explored the possibility to use other saliva stimulants. Davies29 carried out a prospective, randomized, open, crossover study comparing a mucin-based artificial saliva with a low-tack, sugar-free chewing gum in the management of xerostomia in 43 patients with advanced cancer. Chewing gum is a saliva stimulant. It produces an increase in salivary flow due to a combination of stimulation of chemo- and mechanoreceptors. In this study, both artificial saliva and chewing gum were effective in the management of xerostomia, but 61% of the patients preferred the chewing gum to the artificial saliva. The use of chewing gum may be limited by the presence of jaw and oral discomfort, headache, and swallowing difficulties. A variety of saliva substitutes are now commercially available. The substitutes contain different synthetic polymers as thickening agents, for example, carboxymethylcellulose, polyacrylic acid, and xanthan gum, but conflicting results have been repor ted.1,3,24,30 Recent developments—still in the experimental stage— include bioactive salivary substitutes and mouthwashes containing antimicrobial peptides to protect the oral tissues against microbial colonization and to suppress and to cure mucosal and gingival inflammation. 30 A randomized, controlled trial of standard fractionated radiation with or without amifostine 200 mg/m2, before each fraction of radiation, was conducted in 315 patients with head and neck (H&N) cancer. Amifostine administration was associated with a reduced incidence of grade ≥ 2 xerostomia over 2 years of follow-up (p = 0.002), an increase in the proportion of patients with meaningful (>0.1 g) unstimulated saliva production at 24 months (p = 0.011), and reduced mouth dryness scores on a patient benefit questionnaire at 24 months (p < 0.001). 31 A recent, systematic review was carried out by a task force of the Multinational Association of Supportive Care in Cancer (MASCC) and International Society of Oral Oncology (ISOO) to assess the literature for management strategies and economic impact of salivary gland hypofunction and xerostomia induced by cancer therapies and to determine the quality of evidencebased management recommendations. There was evidence that salivary gland hypofunction and xerostomia induced by cancer therapies can be prevented or symptoms be minimized with intensity-modulated radiation therapy (RT), amifostine, muscarinic agonist stimulation, oral mucosal lubricants, acupuncture, and submandibular gland transfer. 32

Chemotherapy-/radiation-induced stomatitis The oral mucosa is frequently damaged during chemotherapy/ radiotherapy in patients with cancer, leading to a high incidence of oral and esophageal mucositis. Patients with mucositis often

Textbook of Palliative Medicine and Supportive Care

542 experience considerable pain and discomfort. The incidence of oral mucositis (OM) ranges from 15% to 40% in patients receiving stomatotoxic chemotherapy or radiotherapy, raising to 80% in patients with H&N cancer. 33 Raber-Durlacher et al. 34 reported a retrospective analysis of the incidence and the severity of chemotherapy-associated OM in 150 patients with various solid tumors. Eighty-seven episodes of mucositis occurred in 47 (31%) patients. Twenty-six patients each experienced only 1 episode, whereas 21 patients had up to 8 episodes of mucositis. Multivariate analysis identified the administration of paclitaxel, doxorubicin, or etoposide as an independent risk factor (adjusted rate ratio 8.06, 7.35, and 6.70, respectively), whereas low body mass was associated with a slightly increased risk (adjusted rate ratio 0.92). Other anticancer drugs, such as alkylating agents, vinca alkaloids, antimetabolites, and antitumor antibiotics, are especially liable to cause stomatitis, and it is important to carefully consider their use in patients with advanced cancer. 35 Both chemotherapy and radiotherapy interfere with cellular mitosis and reduce the regenerative property of the oral mucosa. A poor nutritional status further interferes with mucosal regeneration; oral infections can exacerbate the mucositis and may lead to systemic infections. If the patient develops both severe mucositis and thrombocytopenia, oral bleeding may occur and this may be difficult to treat. Direct stomatotoxicity usually is seen 5–7 days after the start of chemotherapy or radiotherapy; in non-immunocompromised patient, oral lesion heals within 2–3 weeks. The most common sites include the buccal, labial, and soft palate mucosa, as well as the floor of the mouth and the ventral surface of the tongue. 35 In recent years, development of biological targeted therapies and immune checkpoints inhibitors has redefined the treatment of many cancers but has brought a new spectrum of toxicities, including stomatitis, migratory glossitis, hyperkeratotic lesions, lichenoid reactions, and osteonecrosis of the jaw. These oral adverse events also appear to be less symptomatic than chemotherapy-induced mucositis but may require dose adjustments. Oral lesions can be clinically quite specific, and systematic examination of the oral mucosa is recommended as part of the monitoring regimen of patients treated with these drugs. Physicians should be aware of these induced mucosal changes; early recognition and appropriate management are essential in order to preserve better patients’ quality of life. 36

Management of chemotherapy-/ radiation-induced stomatitis A recent systematic review of basic oral care for the management of OM in cancer patients was conducted by the Mucositis Study Group of the MASCC/ISOO to update the clinical practice guidelines for the use of basic oral care interventions for the prevention and/or treatment of OM in cancer patients. The panel suggests that the implementation of multi-agent combination oral care protocols is beneficial for the prevention of OM during chemotherapy, H&N RT, and hematopoietic stem-cell transplantation (Level of Evidence III). The panel suggests that chlorhexidine not be used to prevent OM in patients undergoing H&N RT (Level of Evidence III).37 A Cochrane Review was conducted in 2006 to evaluate the effectiveness of prophylactic agents for OM in patients receiving treatment, compared to other interventions, placebo, or no treatment. It included 5217 randomized patients. Of the 29 interventions included in trials, 10 showed some evidence of benefit. Only

amifostine, antibiotic paste or pastille, hydrolytic enzymes, and ice cubes showed a significant difference when compared with placebo or no treatment in more than one trial. Benzydamine, calcium phosphate, honey, oral care protocols, povidone, and zinc sulfate showed some benefit in only one trial. 38 Topical anesthetics, mixtures (also called cocktails), and mucosal coating agents have been used despite the lack of experimental evidence supporting their efficacy. In the last 5 years, palifermin, a recombinant humanized keratinocyte growth factor, has demonstrated an ability to decrease the incidence and duration of mucositis in randomized, placebocontrolled studies and in systematic reviews. The drug seems to be generally well tolerated, but most patients experienced thickening of oral mucosa, flushing, and dysgeusia. 39,40 Biswal et al.41 carried out the first prospective, randomized trial to evaluate the effect of pure natural honey with radiationinduced mucositis. Forty patients undergoing radiotherapy to the head and neck region received topical application of the honey along with radiotherapy or radiotherapy alone. A significant reduction in the symptomatic grade 3–4 mucositis (radiation/ toxicity oncology grading system) was found in the honey group in respect to controls (p = 0.0005). Another recent Egyptian study tried to evaluate the effect of topical application of honey and a mixture of honey, olive oil-propolis extract, and beeswax (HOPE) in the treatment of OM in 90 pediatric patients with acute lymphoblastic leukemia and OM grades 2 and 3. Generally, in both grades of mucositis, honey produced faster healing than either HOPE or controls (p < 0.05).42 The potential analgesic effect of topical morphine, prepared with taste supplements, in treating persistent mucosal pain in palliative care patients, has been explored in two studies. In one study, mouth rinses with morphine were superior to topical lidocaine in treating pain due to chemotherapy-associated mucositis.43 In another, randomized, double-blind study, an oral application of 2/1000 morphine solution in patients suffering from radiotherapy- and/or chemotherapy-induced OM showed a pain alleviation 1 h after mouthwash. Duration of pain relief was 123.7 (standard deviation ±98.2) minutes for morphine mouthwash.44

Altered taste sensations A reduction (hypogeusia), distortion (dysgeusia), or absence (ageusia) of normal taste sensation is common in patients with cancer and can be the result of the disease itself and/or its treatment (drug therapy, chemotherapy, radiotherapy). Between 25% and 50% of patients with cancer are reported to experience taste changes. A recent longitudinal, observational study showed that the prevalence of taste alterations in patients receiving chemotherapy was alarmingly high (69.9%). Patients receiving irinotecan courses reported significantly more taste alterations than patients in other treatment groups.45 Taste alterations often start at the beginning of chemotherapy and may persist for weeks or even months beyond its termination.46 Typically, patients appeared to have difficulty in differentiating sour and bitter tastes, which are affected more than salty and sweet tastes. Women appeared to report greater changes in taste than men.1,47,48 Zinc deficiency has been linked with abnormalities in taste sensation.

Management of altered taste sensations Nonpharmacological treatment includes mouth care, dental hygiene improvement, the withdrawal of drugs that can induce

Mouth Care the symptoms, and dietary advice. The urea content in the diet can be reduced by eating white meats and eggs. This masks the bitter taste of food. Food should be eaten cold or at room temperature. Ripamonti et al.,49 in a randomized, double-blind, placebo-controlled trial, described the beneficial effects of oral zinc sulfate tablets (45 mg 3 times a day) in 18 patients with cancer receiving external radiotherapy (ERT) to the head and neck region. One month after ERT was terminated, the patients receiving zinc sulfate had a quicker recovery of taste acuity than those receiving placebo. A recent, randomized, double-blind, placebo-controlled, pilot trial described the impact of delta-9-tetrahydrocannabinol (THC) on taste and smell (chemosensory) perception in 46 adults with advanced cancer. Compared with placebo, THC-treated patients reported improved (p = 0.026) and enhanced (p < 0.001) chemosensory perception and food “tasted better” (p = 0.04).50

Oral lesions in HIV/AIDS patients Oral candidiasis, hairy leukoplakia, Kaposi sarcoma, necrotizing ulcerative gingivitis, linear gingival erythema, necrotizing ulcerative periodontitis, and oral non-Hodgkin lymphoma are strongly associated with human immunodeficiency virus (HIV) infection and may be present in up to 80% of people with acquired immune deficiency syndrome (AIDS).51 These lesions parallel the decline in number of CD4 cells and an increase in viral load. Cross-sectional studies have associated low CD4 lymphocyte count with the presence of oral Kaposi sarcoma, non-Hodgkin lymphoma, and necrotizing ulcerative periodontitis. 52 Highly active antiretroviral therapy (HAART) has altered the prevalence and incidence of oral mucosal lesions of HIV infection. Although oral candidiasis appears to be the infection more significantly decreased after the introduction of HAART, recent reports show a variation in the prevalence of oral mucosal lesions in different population groups. A cross-sectional estimation of the prevalence of oral mucosal lesions was carried out in 101 HIVinfected ethnic Chinese in Hong Kong. The prevalence of oral mucosal lesions was more common in patients who were classified at baseline as Centers for Disease Control (CDC) C3 category than CDC A2, A3, B2, and B3 (p < 0.05). An overall prevalence of 1.98% was observed for oral Kaposi sarcoma.53 Another study, aimed to determine the therapeutic effects of HAART on the clinical presentations of HIV-related oral lesions in 142 Nigerian adults recruited into the HAART program of an AIDS referral center, showed that parotid gland enlargement, melanotic hyperpigmentation, and Kaposi sarcoma were more persistent and had slower response to HAART.54 HAART may predispose to human papilloma virus infection and potentially increase the risk of later oral squamous cell carcinoma.55,56 Regimens based on protease inhibitors may also have adverse effects including oral problems such as paresthesia, taste disturbances, and xerostomia and may interact with a number of drugs used in oral health care.57

Management of oral lesions in patients with HIV/AIDS The greater majority of HIV/AIDS-affected people reside today in the developing world and do not have affordable access to HAART and/or conventional antifungal therapy (clotrimazole, fluconazole, and itraconazole). For this reason, some less expensive and more readily available alternatives are being tested: in Malawi, gentian violet was found to be as effective as nystatine

543 for the management of oral candidiasis; topical chlorhexidine, in a pilot study, also showed promise in the prevention of oral candidiasis in HIV-infected children; the essential oral oil solution of Melaleuca alternifolia (tea tree oil) has been successfully used to treat fluconazole-refractory oropharyngeal candidiasis in AIDS patients.51,58,59 In poor-resourced limited settings, thalidomide may be a cheap palliative therapy for mucocutaneous pediatric Kaposi sarcoma.51

Osteonecrosis of the jaw Osteonecrosis of the jaw has been shown to be associated with the use of pamidronate and zoledronic acid, two bisphosphonates that inhibit bone resorption and thus bone renewal by suppressing the recruitment and activity of osteoclasts. People at risk include those with multiple myeloma and cancer metastatic to bone who are receiving intravenous bisphosphonates. The risk of developing complication appears to increase with the time of use of the medication.60,51 The predilection for mandibular molar and premolar regions and the infectious conditions that often precede the onset of osteonecrosis support recent pathogenesis theories stating that local inflammation and associated pH changes may trigger the release and activation of nitrogen-containing bisphosphonates, ultimately resulting in necrosis.62 Bamias et al.63 studied the incidence, characteristics, and risk factors for the development of osteonecrosis of the jaw among 252 patients with advanced cancer. The incidence increased with time to exposure from 1.5% among patients treated for 4–12 months to 7.7% in those treated for 37–48 months. The cumulative hazard was significantly higher with zoledronic acid compared with pamidronate alone or pamidronate and zoledronic acid sequentially (p < 0.001). In addition, some authors have reported a few cases of osteonecrosis of the jaw in patients taking oral doses of alendronate to treat osteoporosis or osteopenia.64,65 Comorbid factors may play a role, such as the presence of diabetes mellitus, the degree of immunosuppression, and the use of other medications (chemotherapeutic agents, corticosteroids). Other drug-related risk factors include the use of antiangiogenic agents such as thalidomide and bortezomib in patients with multiple myeloma.66 Local comorbid factors include oral health status, presence of infection, and the history of radiation therapy. A survey conducted by the International Myeloma Foundation, in 1203 patients receiving intravenous bisphosphonate therapy for the treatment of myeloma or breast cancer, showed that 81% of the patients with myeloma and 69% of the patients with breast cancer who developed osteonecrosis had underlying dental disease, such as infection, or had a dental extraction, as compared with 33% of the patients who did not develop osteonecrosis.61 The most common initial complaint is the sudden presence of intraoral discomfort and the presence of roughness that may traumatize the oral soft tissues surrounding the area of necrotic bone. The classic clinical features are a growing, painful, and unilateral swelling with jaw pain and difficulty in chewing and brushing teeth.67 The mandible and maxilla, with or without oroantral fistulae, are the main areas affected by osteonecrosis.

Management of osteonecrosis of the jaws The treatment in patients receiving oral or intravenous bisphosphonate therapy is principally preventive in nature.60 Ruggiero et al.,64 in a case series of 63 patients, reported that despite several

Textbook of Palliative Medicine and Supportive Care

544 BOX 56.2  BISPHOSPHONATEASSOCIATED OSTEONECROSIS OF THE JAW: PREVENTIVE MEASURES

KEY LEARNING POINTS • Oral disturbances are frequently experienced by patients with advanced cancer. • The most common problems are xerostomia, fungal infections, therapy-related mucositis, and taste disturbances. • Azoles resistance may become a clinical problem in the treatment of oral fungal infections. • Improving dental and oral hygiene, good fluid intake, ice chips, and dietary advice are the mainstay of nonpharmacological prophylaxis and treatment of xerostomia, mucositis, and taste alterations in palliative care patients. • Honey can be a cheaper and worldwide available choice for treating herpes simplex lesions and radiation-induced mucositis. • In poor-resourced limited settings, mouth care for people with AIDS is a basic clinical strategy. • Bisphosphonate-related osteonecrosis of the jaw is a challenging problem in palliative care: prevention of the osteonecrosis is the best approach to management of this complication. • Mouth care in advanced dementia elderly people is a challenge for palliative care teams in the next future.

• Clinical dental examination: Comprehensive extraoral and intraoral examination; full-mouth radiographic series plus panoramic radiograph; evaluation of third molars • Removal of abscessed and nonrestorable teeth • Restore periodontal health status (pocket elimination, plaque reduction) • Caries control, elimination of defective restorations • Oral hygiene and self-care education • Functional rehabilitation of salvageable dentition (endodontic therapy) • Properly fitting dentures • Scheduled periodic follow-up visits

treatment modalities, such as minor debridement, major surgical sequestrectomies, partial or complete maxillectomies, and hyperbaric oxygen therapies, no healing occurred in any of the patients treated. For this reason, preventive measures prior to the initiation of intravenous bisphosphonate therapy are of paramount importance, with the dentist and oncologist working collaboratively. In an observational, longitudinal, noncontrolled study of 43 consecutive patients treated with zoledronate who underwent tooth extractions, the removal of the alveolar bone after the tooth extractions (alveolectomy) and correct antimicrobial prophylaxis (antibiotics and mouthwash) could reduce the risk of occurrence of osteonecrosis.62 Box 56.2 summarizes the potential preventive measures in osteonecrosis of the jaw. There is no scientific evidence to support the discontinuation of bisphosphonate therapy to promote healing of necrotic osseous tissues in the oral cavity.60 Systemic antibiotic therapy to control secondary infection and pain may be beneficial and should be administered whenever active infection is present. Antibiotics that have been found useful for osteonecrosis include penicillin or amoxicillin and, in the presence of penicillin-related allergy, clindamycin or erytromycin ethylsuccinate. A 0.12% chlorohexidine antiseptic mouthwash, or minocycline hydrochloride, can be useful for periodontal pockets.69,70

Oral health in frail elderly with dementia Caring for patients with advanced dementia will be a most important challenge in the next future of palliatrive care with an expected 115 million people with dementia by 2050: almost half of them experience daily pain. 37 Orofacial pain in this population is common and may be caused by teeth or their supporting tissues, the muscles and joints of the masticatory system, or other non-odontogenic tissues but can be difficult to detect and is often undertreated.71,72 A cross-sectional observational study was carried out in 2 UK hospitals to identify orofacial pain, in 101 participants with dementia, admitted to acute medical wards using a specific tool, the Orofacial Pain Scale in Non-Verbal Individuals (OPS-NVI) Orofacial pain, assessed with the OPS-NVI, was present in 11.9%

(95% confidence interval (CI) 5.9, 18.8) of participants at rest and 21.9% (95% CI 14.6, 31.3) while chewing. Brush frequency, indication of chewing quality, consistency of the food, presence of extra-oral abnormalities, person who performed mouth care, and oral hygiene in dentate participants were significant predictors for the presence of orofacial pain. This study highlights that dry mouth in patients with advanced disease can have a significant negative impact on the day-today ability to talk, eat, and taste and can interfere with nasal passages, lips, throat, swallowing, and sleep.73 Unfortunately, current available evidence in literature on orofacial pain and mouth care in this frail population is insufficient and has produced variable findings. This emphasizes the urgent need for further research in this area.

References



1. De Conno F, Sbanotto A, Ripamonti C, Ventafridda V. Mouth care. In: Doyle D, Hanks G, Cherny N, Calman K, eds. Oxford Textbook of Palliative Medicine, 3rd edn. Oxford, UK: Oxford University Press, 2004. 2. Wilberg P, Hjermstad MJ, Ottesen S, Herlofson BB. Oral health is an important issue in end-of-life cancer care. Support Care Cancer 2012;20(12):3115–3322. 3. Sweeney MP, Bagg J. The mouth and palliative care. Am J Hosp Palliat Care 2000;17(2):118–124. 4. Lavy V. Presenting symptoms and signs in children referred for palliative care in Malawi. Palliat Med 2007;21(4):333–339. 5. Finlay IG. Oral symptoms and candida in the terminally ill. Br Med J 1986;292:592–593. 6. Davies AN, Brailsford SR, Beighton D, Shorthose K, Stevens VC. Oral candidosis in community-based patients with advanced cancer. J Pain Symptom Manage 2008;35(5):508–514. 7. Roed-Petersen B. Miconazole in the treatment of oral candidosis. Int J Oral Surg 1978;7:558–563.

Mouth Care









8. Meunier F, Paesmans M, Autier P. Value of antifungal prophylaxis with antifungal drugs against oropharingeal candidiasis in cancer patients. Eur J Cancer 1994;30:196–199. 9. Meunier F. Fluconazole treatment of fungal infections in the immunocompromized host. Semin Oncol 1990;17(S6):19–23. 10. Goodman JL, Winston DJ, Greenfield RA, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992;326:845–851. 11. Perfect JR, Lindsay MH, Drew RH. Adverse drug reactions to systemic antifungals. Drug Safety 1992;7:323–363. 12. Varhe A, Olkkola KT, Neuvonen PJ. Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994;56:601–607. 13. Cobb MN, Desai J, Brown LS Jr, Zannikos PN, Rainey PM. The effect of fluconazole on the clinical pharmacokinetics of methadone. Clin Pharmacol Ther 1998;63:655–662. 14. Tarumi Y, Pereira J, Watanabe S. Methadone and fluconazole: respiratory depression by drug interaction. J Pain Symptom Manage 2002;23(2):148–153. 15. Bagg J, Sweenwy MP, Lewis MAO, et al. High prevalence of non-albicans yeasts and detection of anti-fungal resistance in the oral flora of patients with advanced cancer. Palliat Med 2003;17:477–481. 16. Davies A, Brailsford S, Broadley K, Beighton D. Resistance amongst yeasts isolated from the oral cavities of patients with advanced cancer. Palliat Med 2002;16:527–531. 17. Sucher AJ, Chahine EB, Balcer HE Echinocandins: the newest class of antifungals. Ann Pharmacother 2009;43:1647–1657. 18. Rachwalski EJ, Wieczorkiewicz JT, Scheetz MH. Posaconazole: an oral triazole with an extended spectrum of activity. Ann Pharmacother 2008;42(10):1429–1438. 19. Rooney JF, Straus SE, Manix ML, et al. Oral acyclovir to suppress frequently recurrent herpes labialis: a double-blind, placebo controlled trial. Ann Intern Med 1993;118:268–272. 20. Schmid-Wendtner MH, Korting HC. Penciclovir cream improved topical treatment for herpes simplex infection. Skin Pharmacol Physiol 2004;17:214–218. 21. Raborn GW, Martel AY, Lassonde M, et al. Effective treatment of herpes simplex labialis with penciclovir cream: combined results from two trials. J Am Dent Assoc 2002;133:303–309. 22. Al-Waili NS. Topical honey application vs. acyclovir for the treatment of recurrent herpes simplex lesions. Med Sci Monit 2004;10:MT94–MT98. 23. Ventafridda V, De Conno F, Ripamonti C, Gamba A, Tamburini M. Quality-of-life assessment during a palliative care program. Ann Oncol 1990;1:415–420. 24. Sweeney MP, Bagg J, Baxter WP, Aitchinson TC. Oral disease in terminally ill cancer patients with xerostomia. Oral Oncol 1998;34:123–126. 25. Senn HJ. Orphan topics in supportive care: how about xerostomia? Support Care Cancer 1997;5:261–262. 26. Davies AN, Broadley K, Beighton D. Xerostomia in patients with advanced cancer. J Pain Symptom Manage 2001;22:820–825. 27. Fleming M, Craigs CL, Bennet MI. Palliative care assessment of dry mouth: what matters most to patients with advanced diseases? Supp Care Cancer 2019. Online first https://doi.org/10.1007/ s00520-019-04908-9.28(3):1121-1129. 28. Davies AN, Daniels C, Pugh R, Sharma K. A comparison of artificial saliva and pilocarpine in the management of xerostomia in patients with advanced cancer. Palliat Med 1998;12:105–111. 29. Davies AN. A comparison of artificial saliva and chewing gum in the management of xerostomia in patients with advanced cancer. Palliat Med 2000;14:197–203. 30. Vissink A, Burlage FR, Spijkervet FK, Veerman EC, Nieuw Amerongen NV. Prevention and treatment of salivary gland hypofunction related to head and neck radiation therapy and chemotherapy. Support Cancer Ther 2004;1:111–118. 31. Wasserman TH, Brizel DM, Henke M, et al. Influence of intravenous amifostine on xerostomia, tumour control, and survival after radiotherapy for head-and-neck cancer: 2-year follow-up of a prospective, randomised, phase III trial. Int J Radiat Oncol Biol Phys 2005;63:985–990. 32. Jensen SB, Pedersen AM, Vissink A, et al. A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact. Support Care Cancer 2010;18:1061–1079.

545 33. Trotti A, Bellm LA, Epstein JB, et al. Mucositis incidence, severity and associates outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiother Oncol 2003;66:253–262. 34. Raber-Durlacher JE, Weijl NI, Abu Saris M, de Koning B, Zwinderman AH, Osanto S. Oral mucositis in patients treated with chemotherapy for solid tumours: a retrospective analysis of 150 cases. Support Care Cancer 2000;8:366–371. 35. Pico JL, Avila-Garavito A, Naccache P. Mucositis: its occurrence, consequences, and treatment in the oncology setting. Oncologist 1998;3:446–451. 36. Vigarios E, Epstein JB, Sibaud V, Oral mucosal changes induced by anticancer targeted therapies and immune checkpoint inhibitors. Supp Care Cancer 2017;25(5):1713–1739. 37. Hong CHL, Gueiros LA, Fulton JS, et al. (On behalf of the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO). Systematic review of basic oral care for the management of oral mucositis in cancer patients and clinical practice guidelines. Supp Care Cancer 2019;27:3949–3967. 38. Worthington HV, Clarkson JE, Eden OB. Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database of Systematic Reviews 2006;2:CD000978. 39. McDonnell AM, Lenz KL. Palifermin: role in the prevention of chemotherapy- and radiation-induced mucositis Ann Pharmacother 2007;41:86–94. 40. Le QT, Kim HE, Schneider CJ, Muraközy G. Palifermin reduces severe mucositis in definitive chemoradiotherapy of locally advanced head and neck cancer: a randomized, placebo-controlled study. J Clin Oncol 2011;29:2808–2814. 41. Biswal BM, Zakaria A, Ahmad NM. Topical application of honey in the management of radiation mucositis: a preliminary study. Support Care Cancer 2003;11:242–248. 42. Abdulrhman M, Samir El Barbary N, Ahmed Amin D, Saeid Ebrahim R. Honey and a mixture of honey, beeswax, and olive oilpropolis extract in treatment of chemotherapy-induced oral mucositis: a randomized controlled pilot study. Pediatr Hematol Oncol 2012;29:285–292. 43. Cerchietti LC, Navigante AH, Korte MW, et al. Potential utility of peripheral analgesic properties of morphine in stomatitis-related pain: a pilot study. Pain 2003;105:265–273. 44. Vayne-Bossert P, Escher M, deVautibault CG, et al. Effect of topical morphine (mouthwash) on oral pain due to chemotherapy- and/or radiotherapy-induced mucositis: a randomized double-blinded study. J Palliat Med 2010;13:125–128. 45. Zabernigg A, Gamper EA, Giesinger JM, et al. Taste alterations in cancer patients receiving chemotherapy: a neglected side effect? Oncologist 2010;15:913–920. 46. Bernhardson BM, Tishelman C, Rutqvist LE. Self-reported taste and smell changes during cancer chemotherapy. Support Care Cancer 2008;16:275–283. 47. Twycross RG, Lack SA, eds. Taste change. In: Control of Alimentary Symptoms in Far Advanced Cancer. Edinburgh, Scotland: Churchill Livingstone, 1986, vol. 4, pp. 57–65. 48. Ripamonti C, Fulfaro F. Taste disturbance. In: Davies A, Finlay I, eds. Oral Care in Advanced Disease. Oxford, New York: Oxford University Press 2004, pp. 115–124. 49. Ripamonti C, Zecca E, Brunelli C, et al. A randomised, controlled clinical trial to evaluate the effects of zinc sulfate on cancer patients with taste alterations caused by head and neck irradiation. Cancer 1998;82:1938–1945. 50. Brisbois TD, deKock IH, Watanabe SM, et al. Delta-9tetrahydrocannabinol may palliate altered chemosensory perception in cancer patients: results of a randomized, double-blind, placebocontrolled pilot trial. Ann Oncol 2011;22:2086–2093. 51. Coogan MM, Greensoan J, Challacombe SJ. Oral lesions in infection with human immunodeficiency virus. Bull World Health Org 2005;83:700–706. 52. Glick M, Muzyka BC, Lurie D, Salkin M. Oral manifestation associated with HIV-related disease as markers for immune suppression and AIDS. Oral Surg Oral Med Oral Pathol 1994;77:344–349. 53. Perera M, Tsang PC, Samaranayake L, Lee MP, Li P. Prevalence of oral mucosal lesions in adults undergoing highly active antiretroviral therapy in Hong Kong. J Investig Clin Dent May 10, 2012. doi: 10.1111/j.2041–1626.2012.00124.x.3(3): 208-214.

546 54. Taiwo OO, Hassan Z. The impact of Highly Active Antiretroviral Therapy (HAART) on the clinical features of HIV-related oral lesions in Nigeria. AIDS Res Ther 2010;25:7–19. 55. Ramirez-Amador V, Esquivel-Pedraza L, Sierra-Madero J, AnayaSaavedra G, Gonzalez-Ramirez I, Ponce-de-Leon S. The changing clinical spectrum of human immunodeficiency virus (HIV)-related oral lesions in 1,000 consecutive patients: a twelve-year study in referral center in Mexico. Medicine 2003;82:39–50. 56. Frezzini C, Leao JC, Porter S. Current trends of HIV disease of the mouth. J Oral Pathol Med 2005;34:513–531. 57. Porter SR, Scully C. HIV topic update: protease inhibitor therapy and oral health care. Oral Dis 1998;4:159–163. 58. Barasch A, Safford MM, Dapkute-Marcus I, Fine DH. Efficacy of chlorhexidine gluconate rinse for treatment and prevention of oral candidiasis in HIV-infected children: a pilot study. Oral Surg, Oral Med, Oral Pathol, Oral Radiol Endod 2004;97:204–207. 59. Vazquez JA, Zawawi AA. Efficacy of alcohol-based and alcohol-free melaleuca oral solution for the treatment of fluconazole-refractory oropharyngeal candidiasis in patients with AIDS. HIV Clinical Trials 2002;3:379–385. 60. Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Woo SB. Managing the care of patients with bisphosphonates-associated osteonecrosis: an American Academy of Oral Medicine position paper. J Am DentAssoc 2005;136:1658–1668. 61. Durie BGM, Katz M, Crowley J. Osteonecrosis of the jaw and bisphosphonates. N Eng J Med 2005;353:99–100. 62. Otto S, Schreyer C, Hafner S, Mast G, Ehrenfeld M, Stürzenbaum S, Pautke C. Bisphosphonate-related osteonecrosis of the jaws— Characteristics, risk factors, clinical features, localization and impact on oncological treatment J Craniomaxillofac Surg 2012;40:303–309. 63. Bamias A, Kastritis E, Bamia C, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 2005;23:8580–8587.

Textbook of Palliative Medicine and Supportive Care 64. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaw associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62:527–534. 65. Purcell PM, Boyd IW. Bisphosphonates and osteonecrosis of the jaw. Med J Aust 2005;182:417–418. 66. Clerc D, Fermand JP, Mariette X. Treatment of multiple myeloma. Joint Bone Spine 2003;70:173–186. 67. Sanna G, Zampino MG, Pelosi G, Nolè F, Goldhirsch A. Jaw vascular bone necrosis associated with long-term use of bisphosphonates. Ann Oncol 2005;16:1207–1213. 68. Ferlito S, Puzzo S, Liardo C. Preventive protocol for tooth extractions in patients treated with zoledronate: a case series. J Oral Maxillofac Surg 2011;69:e1–e4. 69. Migliorati CA, Schubert MM, Peterson DE, Seneda LM. Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: an emerging oral complication of supportive cancer therapy. Cancer 2005;104:83–93. 70. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 2005;63:1567–1575. 71. van Kooten J, Delwel S, Binnekade TT, et al. Pain in dementia: prevalence and associated factors: protocol of a multidisciplinary study. BMC Geriatrics. 2015;15:29. 72. Lobbezoo F, Weijenberg RA, Scherder EJ. Topical review: orofacial pain in dementia patients. A diagnostic challenge. J Orofac Pain. 2011;25(1):6–14. 73. van de Rij MLJ, Weijenbeg RAF, Feast AR, Vickerstaff V, Lobbezoo F, Sampson EL. Oral health and orofacial pain in people with dementia admitted to acute hospital wards: observational cohort study. BMC Geriatrics 2018;18:121–129.

57

FISTULAS

Maurizio Lucchesi, Fabio Fulfaro, Raffaele Giusti, and Carla Ida Ripamonti

Contents Fistulas................................................................................................................................................................................................................................. 547 General principles of treatment..................................................................................................................................................................................... 547 Gastrointestinal fistulas................................................................................................................................................................................................... 547 Esophageal fistulas...................................................................................................................................................................................................... 547 Gastric and duodenal fistulas................................................................................................................................................................................... 548 Pancreatic fistulas........................................................................................................................................................................................................ 548 Small bowel and colonic fistulas.............................................................................................................................................................................. 549 Head and neck fistulas..................................................................................................................................................................................................... 549 Bronchopleural fistulas.................................................................................................................................................................................................... 549 Genitourinary fistulas.......................................................................................................................................................................................................550 Conclusions.........................................................................................................................................................................................................................550 References............................................................................................................................................................................................................................550

Fistulas A fistula is an abnormal communication between two internal organs (internal fistula) or between the skin and an internal organ (external fistula).1 Fistulas may be classified according to the amount of the output: low output (500 mL/day).2 Fistulas may be single or multiple. 3 In oncological patients, the most frequent causes of fistulas are related to cancer (local progression of the disease and/or local relapse) and/ or treatments (surgery, radiotherapy, chemotherapy, antiangiogenic biological therapy, locoregional liver tumor ablation, photodynamics, endoscopy, and invasive diagnostic procedures) or both4–16 (Table 57.1). The onset of a fistula produces various complications: infection (sepsis), electrolyte imbalance, dehydration, malnutrition, cutaneous lesions, bleeding, delay in oncological treatments, and psychosocial problems. Sepsis is the most frequent cause of death in patients with fistulas.17 Nutritional status as well as a condition of impaired tissue vascularity may be predisposing factors18,19 (Table 57.2).

TABLE 57.1  Causes of Fistulas in Cancer Patients Causes correlated to treatments

Causes correlated to cancer Mixed causes (correlated to treatments and to cancer)

Surgery Radiotherapy Chemotherapy Photodynamics Endoscopy Invasive diagnostic procedure Tumoral local progression locoregional relapse of the disease

TABLE 57.2  Frequent Complications Induced by the Fistulas Infection → sepsis Hydro-electrolytic losses Malnutrition Skin lesions Hemorrhages Delay in oncological treatments Psychosocial problems

General principles of treatment Prior to planning a treatment, it is important to define the objectives to be achieved. In advanced cancer patients, treatment will be conservative, whereas for a patient with a longer survival expectancy, a more invasive treatment may be performed. Table 57.3 shows the possible conservative20–22 and nonconservative treatments.23,24

Gastrointestinal fistulas Gastrointestinal fistulas may be classified as external (enterocutaneous fistulas) and internal (communication between hollow organs), or according to the anatomical site of onset such as esophageal, gastric and duodenal, pancreatic, enteric, and colonic.18

Esophageal fistulas

Esophageal fistulas may be classified as esophagorespiratory (particularly esophagotrachealis) and esophagocardiovascular. As far as the first ones are concerned, most of them are due to esophageal carcinoma (75%) and lung cancer (16%).25,26 Literature cites some rare cases due to Hodgkin’s disease.27 The patient’s symptoms may be dysphagia, coughing, aspiration, suffocation, and fever.

547

548 TABLE 57.3  General Management of Fistulas Conservative treatment • Skin care and local disinfection • Pouching of secretions (particularly gastric and pancreatic) • Control of odor, delicate fistula areas, and use of antibiotics against anaerobic bacteria (metronidazole) • Control of local itching and pain • Control of infections (specific antibiotic treatment, care in the use of corticosteroids, Radiotherapy RT, and chemotherapy) • Control of nutrition and electrolytes (particularly in high-output fistulas) and eventual TPN and antisecretory treatments (scopolamine, octreotide) • Treatment of site-related symptoms (antiemetic, antispastic, antihemorrhagic, antisecretory, use of vasopressin for urinary incontinence, use of urinary catheters) • Control of psychological conditions (distortion of body image, isolation, social discomfort) Nonconservative treatment • Surgical resection of fistula • Surgical repair with corrective procedures or with myocutaneous flaps • Colonic and/or urinary diversion • Endoscopic treatments with metallic stents

Whenever the patient’s clinical condition allows it, surgery may be performed28 with an eventual gastrostomy and/or jejunostomy (including newly drainage tubeless bypass surgery approach), the use of metallic stents,29–32 and/or palliative radiotherapy. Regarding self-expandable metal stent, stricture of the upper esophagus and shorter stent patency are independent predictors of initial clinical failure. Moreover, initial clinical failure is an independent predictor of shorter survival. 33 Chemotherapy is indicated particularly in the presence of lymphomas. Stents are used also for palliation of other symptoms or issues, such as dysphagia. In these cases, plastic stent, conventional stent, and fully covered self-expandable metal stents were better treatments in terms of lower risk of fistula formation. 34 From a prognostic point of view, patients with esophago-respiratory fistula are at high risk of developing lung abscesses, empyema, and pneumonia ab ingestis.28 Esophagocardiovascular fistulas are very rare in cancer patients and also include the aortoesophageal fistula, which is mainly caused by the rupture of a thoracic aneurysm into the esophagus, and the esophagocardiac fistula.4,28

Gastric and duodenal fistulas

More than 90% of gastric and duodenal fistulas are a consequence of surgery in those areas. 35 Postoperative fistulas are frequently due to an “anastomotic leak” and abscess formation. Cancers of the transverse colon, stomach, and duodenum are more prone to fistulization. Other rare causes are lymphomas and the placing of pumps for chemotherapy infusion in the gastroduodenal artery.10 While external fistulas are easily diagnosed, internal fistulas that can cause diarrhea and nutritional deficit are less detectable. Generally, internal fistulas diagnosis occurs between the fifth and tenth postoperative day. Main fistulas-related complications are sepsis, abdominal abscess, wound infection, pneumonia, and intra-abdominal bleeding. 36

Textbook of Palliative Medicine and Supportive Care Most postoperative gastrointestinal fistulas heal spontaneously within 4–5 weeks. Factors associated with poor healing or delayed healing include multiple fistulous tracts, malnutrition, acute infection or sepsis, level of serum transferrin (unfavorable 6 weeks (PPI < 2.0); prognostic factors included are PPS, oral intake, edema, dyspnea at rest, and delirium (Table 74.4). Some studies comparing different prognostic scores in advanced cancer patients have been conducted. Stiel et al. assessed PPI and PaP, 35 concluding that both scores yielded similar results, with a better performance in predicting poor prognosis. Tavares et al. reported that PPS alone was less accurate than PaP or PPI, the former slightly more accurate than the latter, but both showing problems in the intermediate prognosis group.76 Maltoni et al. recently published the results from a prospective multicenter study that compared four prognostic scores described in palliative care literature (PaP, D-PaP, PPS, and PPI). All scores showed a statistically significant predictive capacity, and log-rank tests were highly significant (p < 0.0001). PaP and its modified version showed a better performance with an accuracy at 30 days of 88.0% for PaP score and 79.6% for D-PaP compared to 72.3% for PPI and 55 days). Two separate prognostic models were created, the (PiPS-A), for patients without blood results and the (PiPS-B), for patients with blood results. The resulting PiPS algorithms produce an estimate of survival that was shown to be clinically meaningful and that can be compared to clinicians’ evaluation.83

Prognosis in noncancer patients Interest is increasing in the area of prognosis in noncancer patients, as a result of population aging and the increased frequency of noncancer diseases in the elderly. Individuals in the advanced stage of nonneoplastic disease often have needs similar to those of cancer patients; however, the access to palliative care services for these patients usually takes place later in the disease trajectory.84 This is probably highly related to the fact that the “typical” terminal phase in some noncancer diseases may not even exist19 or is difficult to identify, due to its variability and complex clinical factors presentation with complex clinical factors.85,86 Access to hospices can be limited by the fact that, in some countries, reimbursements are only granted if patients can produce certification specifying that they have “a life expectancy of 6 months or less, should the disease take its usual course.” The National Hospice Organization (NHO) prognostic guidelines, although published some years ago, may still be useful in predicting prognosis in noncancer patients,15,85 even though their accuracy has been criticized, not taking into account the efficacy of modern pharmacologic treatments.

General prognostic indicators in noncancer diseases In October 2011, Salpeter et al. published a systematic review identifying a group of prognostic factors in noncancer diseases that indicate progression toward the end-of-life phase: poor PS, advanced age, malnutrition, comorbid illnesses, organ

Prognostic Indicators of Survival

711

TABLE 74.4  Palliative Prognostic Index (PPI) Prognostic Factor

Partial Score

PPS 10–20% PPS 30–50% PPS > 50% Delirium Delirium Dyspnea at rest Dyspnea at rest Oral intake Oral intake

Present Absent Present Absent Mouthfuls or less Reduced but more than mouthfuls Oral intake Normal Edema Present Edema Absent Total score (sum of partial scores) and expected survival Risk groups Total score A: Greater than 6 weeks < 2, 0 B: 3–6 weeks 2, 0–4 C: Less than 3 weeks > 4, 0 Source:

4 2, 5 0 4 0 3, 5 0 2, 5 1 0 1 0

Ref [55] (with permission).

dysfunction, and hospitalization for acute decompensation. A median survival of 6 months or less was generally associated with the presence of 2–4 of these factors.15,87,88 More recent studies have confirmed that simple clinical data can be associated with an increased risk of short-term mortality in nononcologic patients. Bedridden status, severely reduced kidney function, recent hospital admissions, severe dementia, and hypoalbuminemia were all seen to be associated to a higher risk of 3-month mortality in nononcologic patients after discharge from internal medicine and geriatric hospital wards. 89 Dynamic variables, such as functional, nutritional and cognitive progression, have been shown to have better prognostic ability in patients with advanced chronic conditions than static and stable variables.90

Specific prognostic indicators in noncancer diseases Heart disease

Unpredictable response to therapy and the specter of sudden cardiac death make the prediction of proximity to death especially difficult in end-stage cardiac disease. In the absence of a precipitating factor, survival normally ranges from 6 months to 4 years. Functional status described according to the New York Heart Association Classification (NYHA) is the most important prognostic factor: class IV, that is, symptoms of congestive heart failure at rest despite optimal treatment with diuretics and vasodilators, is correlated with the worst prognosis. Factors that contribute to poorer prognoses include a left ventricular ejection fraction of 20% or less, aging, intractability of underlying heart disease, dilated cardiomyopathy, uncontrolled arrhythmia, contractility changes over time, high cardiothoracic ratio measured on a standard chest radiograph, and oxygen consumption.15,87,88,91,92 Biological factors like anemia and low serum

sodium were also seen to be predictors of outcome for this group of patients.93 Triggers to evaluate the hypothesis of palliative care include recurring episodes of heart failure within the past 6 months despite optimization of medical therapy, appearance of malignant arrhythmia, frequent or continuous need for intravenous therapy, chronic worsening of quality of life, intractable NYHA stage IV symptoms, and signs of cardiac cachexia.94 The presence of such events indicates the need for coordination and continuity of care among the various specialists (cardiologists, internists, and palliativists) involved in caring for the patient.95 Furthermore, the increasing use of implantable cardiac defibrillators (ICDs), resynchronization therapy, and left ventricular assist devices (LVADs) can alter prognosis by modifying disease trajectory. Numerous prognostic scoring systems have been developed in cardiology, some of the most widely used96 being Hart Failure Risk Scoring System (HFRSS),97 Seattle Heart Failure Model,98 the Cardiovascular Medicine Heart Failure (CVM-HF) index,99 the cardiac and comorbid conditions HF (3C-HF) score,100 Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico-Heart Failure (GISSI-HF),101 and the Meta-analysis Global Group in Chronic Heart Failure (MAGGIC).102

Lung disease

Making a prognostic prediction for lung diseases at an advanced stage is extremely difficult. Far advanced COPD is characterized by dyspnea at rest with little or no response to bronchodilators; increased hospitalization or home care visits for respiratory infections or respiratory failure; hypoxemia at rest and on room air; secondary right heart failure, pulmonary heart disease; weight loss >10% in the past 6 months; tachycardia at rest >100.103 However, these findings do not correlate always well with mortality in some patients, making it hard to predict prognosis.104 Forced expiratory volume in one second (FEV1) has been considered the main prognostic factor for a long time, but others such as exercise tolerance, pulmonary hyperinflation, systemic manifestations in the cardiovascular area, and exacerbations of the disease have emerged as further predictors of death.87,88,105,106 Patients hospitalized following exacerbation of COPD have a median survival of ≤6 months when 3 or more of the following factors are present: age >70 years, right heart failure, worsening of functional status, need for home care after discharge from hospital, malnutrition, blood creatinine >2 mg/dL, repeated hospitalization in the previous 2 months, history of intubation, or mechanical ventilation.88,107 Prognostic scores are also available for patients with COPD. Of these, prognostic scores such as BODE, BODEx and ADO have undergone external validation.104

Dementia

The overall trajectory of patients affected by dementia is characterized by progressive decline until death. The mean survival rate of patients with dementia ranges from 5 to 8 years, and the “advanced” stage of the disease may last 2 years. Difficulty in formulating a prognosis is one of the obstacles for hospices who accept patients with dementia. The main prognostic indicator is functional status, measured with Functional Assessment Staging (FAST). Stage 7 FAST patients have a mean survival of 6.9 months and a median survival of 4 months.108 Other factors include type of dementia (vascular dementia appears to lead to death more rapidly than Alzheimer’s disease), age, gender, severity of dementing illness (inability to walk without assistance), and presence of medical complications. Mitchell et al developed the

712 advanced dementia prognostic tool (ADEPT), a risk score to estimate survival in nursing home residents with advanced dementia. This score predicted survival with moderate accuracy and proved better at estimating 6-month mortality than hospice eligibility guidelines simulated with MDS data.109,110 Results showed that survival was lower than 6 months when a patient was hospitalized for an acute illness or admitted to a nursing facility, in association with one of the following conditions: malnutrition, at least one pressure ulcer (bedsore), comorbidities, male >90 years, nasogastric tube, or gastrostomy. A recent prospective study with a follow-up over an 8-year period of patients with frontotemporal dementia revealed shorter disease duration at presentation, greater atrophy in the anterior cingulate cortex, older age and a higher burden of behavioral symptoms to be relevant clinical predictors of survival and progression.111 Numerous prognostic tools have been studied in patients with dementia: dementia prognostic model,112 minimum data set (MDS),113 and survival in Alzheimer’s model (SAM).114 Although biomarkers could be useful in disease diagnosis and prognostication, up to date, no validated biomarkers exist for dementia.115 Data driven models and artificial intelligence techniques, based on imaging, cognitive test scores and biomarkers, have been used for the diagnosis and prognostication of diseases like Alzheimer.116,117

HIV disease

Mortality due to acquired immune deficiency syndrome (AIDS) has substantially improved since the early 1990s. The advent of highly active antiretroviral therapy (HAART), together with treatment of opportunistic infections and symptom palliation, has positively altered the prognosis of a disease that previously led to death within a few months from its diagnosis. The definition of late-stage HIV can, however, be applied to patients with long-standing symptomatic disease, severe immunosuppression, cumulative morbidity, and failure or inability to tolerate antiretroviral therapy.118 Consequently, the prognostic validity of some of the traditional prognostic indicators used, for example, CD4 cell count, viral load, specific opportunistic infections, may lessen.19 These factors should thus be integrated with more recent ones, for example, noncompliance or nonreaction to HAART, functional deficits (impaired ability to conduct routine activities, cognitive impairment), and/or the existence of other life-threatening conditions predictive of short-term survival, that is, weight loss and neurological abnormalities.118 Shen et al. reported that age and markers of functional status were more predictive of mortality than traditional HIV prognostic variables.119 Despite advances in treatment, AIDS and associated comorbidities remain important causes of death, with a marked decrease in the incidence of some AIDS-defining illnesses such as Kaposi’s sarcoma and cerebral lymphoma and an increase in the proportion of deaths from infections not typically associated with AIDS, for example, HCC derived from cirrhosis and HAART-related toxicity. The proportion of death from AIDS has decreased substantially with time but mortality from nonAIDS malignancy has increased substantially.120,121 A national survey conducted in France demonstrated that 36% of deaths in in human immunodeficiency virus (HIV) infected patients were cancer-related and that the proportion of deaths releated to non-AIDS/non-hepatitis-related cancers significantly increased from 2000 to 2010.122 The development of new prognostic models

Textbook of Palliative Medicine and Supportive Care and life expectancy estimates should be updated to account for the new treatment options and mortality causes in HIV infected patients.123

Amyotrophic lateral sclerosis

Palliative care in amyotrophic lateral sclerosis (ALS) begins when the patient is informed of the diagnosis. It provides constant support for the patient throughout the disease, and even continues in the intensive care unit after intubation and artificial ventilation until death.124,125 NHO criteria enable clinicians to predict a survival of 70 years and two or

Prognostic Indicators of Survival KEY LEARNING POINTS • Awareness of prognostic survival indicators can help clinicians in the difficult decisionmaking process and can lead to better communication with both patients and their families. Prognostication has only a probabilistic value, and this should be taken into consideration when examining the possible course of each individual’s illness. • In advanced cancer patients prognostication can help in the decision-making process, limiting the frequency of chemotherapy administration close to death. • The heterogeneous trajectories of noncancer chronic disease make prognosis prediction for these diseases more complex than that of the palliative phase of cancer. • Prognostic indicators in palliative care patients differ from those used for the early and advanced stages. • CPS and other prognostic indicators can be included in simple models or prognostic scores. The prognostic ability of CPS increases when it is used “together with” rather than “instead of” clinical judgment and it has shown to be a good indicator in palliative care cancer patients. • Prognostic indicators can also be found in noncancer diseases; some are common to more than one disease (functional status and nutritional status), whereas others are specific to individual diseases. • Several prognostic scores are available; however, one should always try to identify the appropriate prognostic tool for a given setting. • The main aim of prognostication is to personalize the treatment of patients when dealing with the severest stage of their disease, while simultaneously continuing to fully consider the individual value of the patient’s remaining lifetime.

more of the following conditions: poor PS, significant comorbidities, malnutrition, resident in a skilled nursing facility, admission to an intensive care unit for an acute illness, or hip fracture with inability to ambulate.88 Wong et al.’s observational study showed that the Stoke Comorbidity Grade (SCG) was an independent prognostic factor in patients who chose not to undergo dialysis.138 For patients in chronic dialysis who suspend treatment, life expectancy is extremely short, around 7 days.

Conclusions The estimation of patients’ survival is necessary in order to make an appropriate decision, not only for the health-care providers but also for patients and their families. Awareness of prognostic indicators can help physicians in making a more accurate prognosis. However, different prognostic scores have different accuracy levels, therefore, an agreement should be reached on the best scores to be used for different populations.

713 When communicating a prognosis, ethical, cultural, religious, and psychological issues should be considered by carers to avoid causing even greater distress to a gravely ill patient: while patients have a right to be informed, they do not have a duty to be informed. In conclusion, appropriate use of life expectancy prognostication to improve and personalize the treatment of patients in the advanced and terminal stages of disease can only be achieved if it forms an integral part of a multidisciplinary palliative care program, which holds high the value of life remaining.

References

1. Feyi K, Klinger S, Pharro G, Mcnally L, James A, Gretton K, et al. Predicting palliative care needs and mortality in end stage renal disease: use of an at-risk register. BMJ Support Palliat Care 2015 March;5(1):19–25. 2. Mudge AM, Douglas C, Sansome X, Tresillian M, Murray S, Finnigan S, et al. Risk of 12-month mortality among hospital inpatients using the surprise question and SPICT criteria: a prospective study. BMJ Support Palliat Care 2018 Junuary;8(2):213–220. 3. Satchidanand N, Servoss TJ, Singh R, Bosinski AM, Tirpak P, Horton LL, et al. Development of a risk tool to support discussions of care for older adults admitted to the ICU with pneumonia. Am J Hosp Palliat Med 2018;35(9):1201–1206. 4. Bruera E, Hui D. Integrating supportive and palliative care in the trajectory of cancer: establishing goals and models of care. J Clin Oncol 2010;28:4013–4017. 5. Tripodoro VA, Llanos V, De Lellis S, Güemes CS, De Simone GG, Gomez-Batiste X. Prognostic factors in cancer patients with palliative needs identified by the NECPAL CCOMS-ICO© tool. Medicina (Buenos Aires) 2019;79(2):95–103. 6. Earle CC, Neville BA, Landrum MB, et al. Trends in the aggressiveness of cancer care near the end of life. J Clin Oncol 2004;22:315–321. 7. Earle CC, Park ER, Lai B, et al. Identifying potential indicators of the quality of end-of-life cancer care from administrative data. J Clin Oncol 2003;21:1133–1138. 8. Earle CC, Landrum MB, Souza JM, et al. Aggressiveness of cancer care near the end of life: is it a quality-of-care issue? J Clin Oncol 2008;26:3860–3866. 9. Finlay E, Casarett D. Making difficult discussions easier: using prognosis to facilitate transitions to hospice. CA Cancer J Clin 2009;59:250–263. 10. Temel JS, Greer JA, Admane S, et al. Longitudinal perceptions of prognosis and goals of therapy in patients with metastatic nonsmall-cell lung cancer: results of a randomized study of early palliative care. J Clin Oncol 2011;29:2319–2326. 11. Lamont EB, Christakis NA. Physician factors in the timing of cancer patient referral to hospice palliative care. Cancer 2002;94:2733–2737. 12. Daly BJ, Douglas SL, Gunzler D, Lipson AR. Clinical trial of a supportive care team for patients with advanced cancer. J Pain Symptom Manage 2013;46(6):775–784. 13. Sutradhar R, Seow H, Earle C, Dudgeon D, Atzema C, Husain A, et al. Modeling the longitudinal transitions of performance status in cancer outpatients: time to discuss palliative care. J Pain Symptom Manage 2013;45(4):726–734. 14. Maltoni M, Caraceni A, Brunelli C, et al. Prognostic factors in advanced cancer patients: Evidence-based clinical recommendations: A study by the Steering Committee of the European Association for Palliative Care. J Clin Oncol 2005;23:6240–6248. 15. Standards and Accreditation Committee. Medical Guidelines Task Force of the National Hospice Organization. Medical Guidelines for Determining Prognosis in Selected Non-Cancer Diseases, 2nd edn. Arlington, VA: National Hospice Organization, 1996. 16. Smith JL. Commentary: Why do doctors overestimate? BMJ 2000;320:472–473. 17. Scarpi E, Maltoni M, Miceli R, et al. Survival prediction for terminally ill cancer patients: revision of palliative prognostic score with incorporation of delirium. Oncologist 2011;16(12):1793–1799. 18. Bennett MI, Davies EA, Higginson IJ. Delivering research in endof-life care: problems, pitfalls and future priorities. Palliat Med 2010;24:456–461.

714 19. Lunney JR, Lynn J, Foley D, et al. Patterns of functional decline at the end of life. JAMA 2003;289:2387–2392. 20. Hayden JA, van der Windt, Danielle A, Cartwright JL, Côté P, Bombardier C. Assessing bias in studies of prognostic factors. Ann Intern Med 2013;158(4):280–286. 21. Hui D, Parsons HA, Damani S, et al. Quantity, design, and scope of the palliative oncology literature. Oncologist 2011;16(5):694–703. 22. Stevinson C, Preston N, Todd C, Cancer Experiences Collaborative (CECo). Defining priorities in prognostication research: results of a consensus workshop. Palliat Med 2010;24:462–468. 23. Balachandran VP, Gonen M, Smith JJ, DeMatteo RP. Nomograms in oncology: more than meets the eye. Lancet Oncol 2015;16(4):e173–e180. 24. Avati A, Jung K, Harman S, Downing L, Ng A, Shah NH. Improving palliative care with deep learning. BMC Med Inform Decis Mak 2018;18(4):122. 25. Vigano A, Dorgan M, Buckingham J, et al. Survival prediction in terminal cancer patients: a systematic review of the medical literature. Palliat Med 2000;14:363–374. 26. Glare P, Virik K, Jones M, et al. A systematic review of physicians’ survival predictions in terminally ill cancer patients. BMJ 2003;327:195–200. 27. Christakis NA, Lamont EB. Extent and determinants of error in doctors’ prognoses in terminally ill patients: prospective cohort study. BMJ 2000;320:469–472. 28. Amano K, Maeda I, Shimoyama S, Shinjo T, Shirayama H, Yamada T, et al. The accuracy of Physicians’ clinical predictions of survival in patients with advanced cancer. J Pain Symptom Manage 2015;50(2):139–146. e1. 29. Cheon S, Agarwal A, Popovic M, Milakovic M, Lam M, Fu W, et al. The accuracy of clinicians’ predictions of survival in advanced cancer: a review. Ann Palliat Med 2015;5(1):22–29. 30. Selby D, Chakraborty A, Lilien T, et al. Clinician accuracy when estimating survival duration: The role of the patient’s performance status and time-based prognostic categories. J Pain Symptom Manage 2011;42:578–588. 31. Thai V, Ghosh S, Tarumi Y, Wolch G, Fassbender K, Lau F, et al. Clinical prediction survival of advanced cancer patients by palliative care: a multi-site study. Int J Palliat Nurs 2016;22(8):380–387. 32. Neuberger J, Guthrie C, Aaronovitch D. More care, less pathway: a review of the Liverpool Care Pathway. Department of Health, 2013. 33. White N, Reid F, Harris A, Harries P, Stone P. A systematic review of predictions of survival in palliative care: how accurate are clinicians and who are the experts? PLOS ONE 2016;11(8):e0161407. 34. Hui D, Kilgore K, Nguyen L, et al. The accuracy of probabilistic versus temporal clinician prediction of survival for patients with advanced cancer: a preliminary report. Oncologist 2011;16(11):1642–1648. 35. Stiel S, Bertram L, Neuhaus S. Evaluation and comparison of two prognostic scores and the physicians’ estimate of survival in terminally ill patients. Support Care Cancer 2010;18:43–49. 36. Stone CA, Tiernan E, Dooley BA. Prospective validation of the palliative prognostic index in patients with cancer. J Pain Symptom Manage 2008;35:617–622. 37. Pirovano M, Maltoni M, Nanni O, et al. A new palliative prognostic score (PaP Score). A first step for the staging of terminally ill cancer patients. J Pain Symptom Manage 1999;17:231–239. 38. Temel JS, Greer JA, Muzikansky A. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 2010;363:733–742. 39. Kaasa S, Loge JH, Aapro M, Albreht T, Anderson R, Bruera E, et al. Integration of oncology and palliative care: a Lancet Oncology Commission. Lancet Oncol 2018;19(11):E588–E653. 40. Ferrell BR, Temel JS, Temin S, Alesi ER, Balboni TA, Basch EM, et al. Integration of palliative care into standard oncology care: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2017 January;35(1):96–112. 41. Mackillop WJ. Differences in Prognostication Between Early and Advanced Cancer. In: Glare P, Christakis NA eds. Prognosis in Advanced Cancer. Oxford, U.K.: Oxford University Press, 2008, pp. 13–23 42. Hui D, dos Santos R, Chisholm G, Bansal S, Silva TB, Kilgore K, et al. Clinical signs of impending death in cancer patients. Oncologist 2014 June;19(6):681–687. 43. Hui D, Paiva CE, Del Fabbro EG, Steer C, Naberhuis J, van de Wetering M, et al. Prognostication in advanced cancer: update and directions for future research. Support Care Cancer 2019;27(6):1973–1984.

Textbook of Palliative Medicine and Supportive Care 44. Perez-Cruz PE, Dos Santos R, Silva TB, Crovador CS, de Angelis Nascimento, Maria Salete, Hall S, et al. Longitudinal temporal and probabilistic prediction of survival in a cohort of patients with advanced cancer. J Pain Symptom Manage 2014;48(5):875–882. 45. White N, Kupeli N, Vickerstaff V, Stone P. How accurate is the ‘Surprise Question’at identifying patients at the end of life? A systematic review and meta-analysis. BMC Med 2017;15(1):139. 46. Hui D, Ross J, Park M, Dev R, Vidal M, Liu D, et al. Predicting survival in patients with advanced cancer in the last weeks of life: How accurate are prognostic models compared to clinicians’ estimates? Palliat Med 2019;34(1):126–133. 47. Maltoni M, Nanni O, Derni S, et al. Clinical prediction of survival is more accurate than the Karnofsky performance status in estimating life span of terminally-ill cancer patients. Eur J Cancer 1994;30:764–766. 48. Schonwetter RS, Robinson BE, Ramirez G. Prognostic factors for survival in terminal lung cancer patients. J Gen Intern Med 1994;9:366–371. 49. Rosenthal MA, Gebski VJ, Kefford RF, Stuart-Harris RC. Prediction of life-expectancy in hospice patients: identification of novel prognostic factors. Palliat Med 1993;7:199–204. 50. Morita T, Tsunoda J, Inoue S, Chihara S. Survival prediction of terminally ill cancer patients by clinical symptoms: development of a simple indicator. Jpn J Clin Oncol 1999;29:156–159. 51. Glare P, Sinclair C, Downing M, et al. Predicting survival in patients with advanced disease. Eur J Cancer 2008;44:1146–1156. 52. Jang RW, Caraiscos VB, Swami N, Banerjee S, Mak E, Kaya E, et al. Simple prognostic model for patients with advanced cancer based on performance status. J Oncol Pract 2014;10(5):e335–e341. 53. Reuben DB, Mor V, Hiris J. Clinical symptoms and length of survival in patients with terminal cancer. Arch Intern Med 1988;148:1586–1591. 54. Maltoni M, Pirovano M, Scarpi E, et al. Prediction of survival of patients terminally ill with cancer. Results of an Italian prospective multicentric study. Cancer 1995;75:2613–2622. 55. Morita T, Tsunoda J, Inoue S, Chihara S. The palliative prognostic index: A scoring system for survival prediction of terminally ill cancer patients. Support Care Cancer 1999;7:128–133. 56. LeBlanc TW, Nipp RD, Rushing CN, Samsa GP, Locke SC, Kamal AH, et al. Correlation between the international consensus definition of the Cancer Anorexia-Cachexia Syndrome (CACS) and patient-centered outcomes in advanced non-small cell lung cancer. J Pain Symptom Manage 2015;49(4):680–689. 57. Viganò A, Bruera E, Jhangri GS, et al. Clinical survival predictors in patients with advanced cancer. Arch Intern Med 2000;160:861–868. 58. Caraceni A, Nanni O, Maltoni M, et al. Impact of delirium on short term prognosis of advanced cancer patients. Cancer 2000;89:1145–1149. 59. Glare P, Sinclair C. Palliative medicine review: Prognostication. J Palliat Med 2008;11:84–103 60. Glare PA, Eychmueller S, Mcmahon P. Diagnostic accuracy of the palliative prognostic score in hospitalized patients with advanced cancer. J Clin Oncol 2004;22:4823–4828. [Comparative study]. 61. Dolan RD, McSorley ST, Horgan PG, Laird B, McMillan DC. The role of the systemic inflammatory response in predicting outcomes in patients with advanced inoperable cancer: systematic review and meta-analysis. Crit Rev Oncol 2017;116:134–146. 62. Maltoni M, Nanni O, Pirovano M, et al. Successful validation of the palliative prognostic score in terminally ill cancer patients. Italian multicenter study group on palliative care. J Pain Symptom Manage 1999;17:240–247. 63. Hui D, Dev R, Pimental L, Park M, Cerana MA, Liu D, et al. Association between multi-frequency phase angle and survival in patients with advanced cancer. J Pain Symptom Manage 2017;53(3):571–577. 64. Pereira MME, Queiroz, MSC, de Albuquerque, NMC, Rodrigues J, Wiegert EVM, Calixto-Lima L, et al. The prognostic role of phase angle in advanced cancer patients: a systematic review. Nutr Clin Pract 2018;33(6):813–824. 65. Reid VL, McDonald R, Nwosu AC, Mason SR, Probert C, Ellershaw JE, et al. A systematically structured review of biomarkers of dying in cancer patients in the last months of life: an exploration of the biology of dying. PLOS ONE 2017;12(4):e0175123. 66. Simmons CP, McMillan DC, McWilliams K, Sande TA, Fearon KC, Tuck S, et al. Prognostic tools in patients with advanced cancer: a systematic review. J Pain Symptom Manage 2017;53(5):962–970. e10.

Prognostic Indicators of Survival 67. Elahi MM, McMillan DC, McArdle CS, Angerson WJ, Sattar N. Score based on hypoalbuminemia and elevated C-reactive protein predicts survival in patients with advanced gastrointestinal cancer. Nutr Cancer 2004;48(2):171–173. 68. Chou W, Kao C, Wang P, Chang H, Wang H, Chang P, et al. The application of the palliative prognostic index, Charlson Comorbidity Index, and Glasgow Prognostic Score in predicting the life expectancy of patients with hematologic malignancies under palliative care. BMC Palliat Care 2015;14(1):18. 69. Glare P, Eychmueller S, Virik K. The use of the palliative prognostic score in patients with diagnoses other than cancer. J Pain Symptom Manage 2003;26:883–885. 70. Stone PC, Lund S. Predicting prognosis in patients with advanced cancer. Ann Oncol 2007;18:971–976. 71. Maltoni M, Scarpi E, Pittureri C, et al. Prospective comparison of prognostic scores in palliative care cancer populations. Oncologist 2012;17(3):446–454. 72. Anderson F, Downing GM, Hill J, et al. Palliative performance scale (PPS): a new tool. J Palliat Care 1996;12:5–11. 73. Lau F, Maida V, Downing M, et al. Use of palliative performance scale for end-of-life prognostication in a palliative medicine consultation service. J Pain Symptom Manage 2009;37:965–972. 74. Olajide O, Hanson L, Usher BM, et al. Validation of the palliative performance scale in the acute tertiary care hospital setting. J Palliat Med 2007;10:111–117. 75. Downing M, Lau F, Lesperance M, et al. Meta-analysis of survival prediction with palliative performance scale. J Palliat Care 2007;23:245–252. 76. Tavares EA. Comparing the accuracy of four methods to predict survival in terminally ill patients referred to a hospital-based palliative medicine team. Eur J Palliat Care (Abstracts of the 12th Congress European Association Palliative Care, Lisbon, Portugal, May 18–21, 2011); Abstract FC1.5:48. 77. Baba M, Maeda I, Morita T, Inoue S, Ikenaga M, Matsumoto Y, et al. Survival prediction for advanced cancer patients in the real world: a comparison of the Palliative Prognostic Score, Delirium-Palliative Prognostic Score, Palliative Prognostic Index and modified Prognosis in Palliative Care Study predictor model. Eur J Cancer 2015;51(12):1618–1629. 78. Bruera E, Miller MJ, Kuehn N, et al. Estimate of survival of patients admitted to a palliative care unit: a prospective study. J Pain Symptom Manage 1992;7:82–86. 79. Yun HY, Heo Ds, Heo BY, et al. Development of terminal cancer prognostic score as an index in terminally ill cancer patients. Oncol Rep 2001;8:795–800. 80. Chuang RB, Hu WY, Chiu TY, Chen CY. Prediction of survival in terminal cancer patients in Taiwan: constructing a prognostic scale. J Pain Symptom Manage 2004;28:115–122. 81. Hyodo I, Morita T, Adachi I, et al. Development of a predicting tool for survival of terminally ill cancer patients. Jpn J Clin Oncol 2010;40:442–448. 82. Chen Y, Ho C, Hsu H, Huang P, Lin C, Liu C, et al. Objective palliative prognostic score among patients with advanced cancer. J Pain Symptom Manage 2015;49(4):690–696. 83. Gwilliam B, Keeley V, Todd C, et al. Development of Prognosis in Palliative Care Study (PiPS) predictor models to improve prognostication in advanced cancer: Prospective cohort study. BMJ 2011;343:d4920. 84. Stiel S, Heckel M, Seifert A, Frauendorf T, Hanke RM, Ostgathe C. Comparison of terminally ill cancer vs. non-cancer patients in specialized palliative home care in Germany–a single service analysis. BMC Palliat care 2015;14(1):34. 85. Brickner L, Scannell K, Marquet S, Ackerson L. Barriers to hospice care and referrals: Survey of physicians’ knowledge, attitudes, and perceptions in a health maintenance organization. J Palliat Med 2004;7(3):411–418. 86. Tsai Y, Tzeng I, Chen Y, Hsieh T, Chang S. Survival prediction among patients with non-cancer-related end-stage liver disease. PLOS ONE 2018;13(9):e0202692. 87. Fox E, Landrum-McNiff K, et al. Evaluation of prognostic criteria for determining hospice eligibility in patients with advanced lung, heart, or liver disease. SUPPORT investigators. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments. JAMA 1999;282:1638–1645. 88. Salpeter SR, Luo EJ, Malter DS, Stuart B. Systematic review of noncancer presentations with a median survival of 6 months or less. Am J Med 2012;125(5):512.e1–512.e16.

715 89. Pasina L, Cortesi L, Tiraboschi M, Nobili A, Lanzo G, Tettamanti M, et al. Risk factors for three-month mortality after discharge in a cohort of non-oncologic hospitalized elderly patients: results from the REPOSI study. Arch Gerontol Geriatr 2018;74:169–173. 90. Amblas-Novellas J, Murray SA, Espaulella J, Martori JC, Oller R, Martinez-Munoz M, et al. Identifying patients with advanced chronic conditions for a progressive palliative care approach: a cross-sectional study of prognostic indicators related to end-of-life trajectories. BMJ Open 2016 September 19;6(9):e012340–2016-012340. 91. Jaagosild P, Dawson NV, Thomas C, et al. Outcome of acute exacerbation of severe congestive heart failure: Quality of life, resource use, and survival. SUPPORT investigators. The Study to Understand Prognosis and Preferences for Outcomes and Risks of Treatment. Arch Intern Med 1998;158:1081–1089. 92. Azad N, Lemay G. Management of chronic heart failure in the older population. J Geriatr Cardiol 2014 December;11(4):329–337. 93. Gavazzi A, De Maria R, Manzoli L, Bocconcelli P, Di Leonardo A, Frigerio M, et al. Palliative needs for heart failure or chronic obstructive pulmonary disease: results of a multicenter observational registry. Int J Cardiol 2015;184:552–558. 94. Jaarsma T, Beattie JM, Ryder M, et al. Palliative care in heart failure: a position statement from the palliative care workshop of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2009 May;11(5):433–443. 95. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: Developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009;119(14):e391–e479. 96. Coventry PA, Grande GE, Richards DA, Todd CJ. Prediction of appropriate timing of palliative care for older adults with nonmalignant life-threatening disease: a systematic review. Age Ageing 2005;34(3):218–227. 97. Lee DS, Austin PC, Rouleau JL, et al. Predicting mortality among patients hospitalized for heart failure: derivation and validation of a clinical model. JAMA 2003;290(19):2581–2587. 98. Levy WC, Mozaffarian D, Linker DT, et al. The Seattle heart failure model: prediction of survival in heart failure. Circulation 2006;113(11):1424–1433. 99. Senni M, Santilli G, Parrella P, et al. A novel prognostic index to determine the impact of cardiac conditions and co-morbidities on one-year outcome in patients with heart failure. Am J Cardiol 2006;98(8):1076–1082. 100. Senni M, Parrella P, De Maria R, et al. Predicting heart failure outcome from cardiac and comorbid conditions: the 3C-HF score. Int J Cardiol 2013;163(2):206–211. 101. Barlera S, Tavazzi L, Franzosi MG, Marchioli R, Raimondi E, Masson S, et al. Predictors of mortality in 6975 patients with chronic heart failure in the Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico-Heart Failure trial: proposal for a nomogram. Circulation: Heart Fail 2013;6(1):31–39. 102. Sartipy U, Dahlström U, Edner M, Lund LH. Predicting survival in heart failure: validation of the MAGGIC heart failure risk score in 51 043 patients from the Swedish Heart Failure Registry. Eur J Heart Fail 2014;16(2):173–179. 103. Abrahm JL, Hansen-Flaschen J. Hospice care for patients with advanced lung disease. Chest 2002;121:220–229. 104. Smith LE, Moore E, Ali I, Smeeth L, Stone P, Quint JK. Prognostic variables and scores identifying the end of life in COPD: a systematic review. Int J Chron Obstruct Pulmon Dis 2017 Jul 31;12:2239–2256. 105. Casanova C, Cote T, de Torres JP. Inspiratory total lung capacity ratio predicts mortality in patient with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;171:591–597,611. 106. Oga T, Nishimura K, Tsukino M. Analysis of the factors related to mortality in chronic obstructive pulmonary disease. Role of exercise capacity and health status. Am J Respir Crit Care Med 2003;167:544–549. 107. Selecky PA, Elliasson CAH, Hall RI, et al. Palliative and endof-life care for patients with cardiopulmonary diseases: American College of Chest Physicians position statement. Chest 2005;128:3599–3610. 108. Luchins DJ, Hanrahan P, Murphy K. Criteria for enrolling dementia patients in hospice. J Am Geriatr Soc 1997;45:1054–1059.

716 109. Mitchell SL, Miller SC, Teno JM, et al. The advanced dementia prognostic tool: a risk score to estimate survival in nursing home residents with advanced dementia. J Pain Symptom Manage 2010;40(5):639–651. 110. Mitchell SL, Miller SC, Teno JM, et al. Prediction of 6-month survival of nursing home residents with advanced dementia using ADEPT vs hospice eligibility guidelines. JAMA 2010;304(17):1929–1935. 111. Agarwal S, Ahmed R, D’Mello M, Foxe D, Kaizik C, Kiernan M, et al. Predictors of survival and progression in behavioural variant frontotemporal dementia. Eur J Neurol 2019;26(5):774–779. 112. Schonwetter RS, Han B, Small BJ, et al. Predictors of six-month survival among patients with dementia: an evaluation of hospice Medicare guidelines. Am J Hosp Palliat Care 2003;20(2):105–113. 113. Hartmaier SL, Sloane PD, Guess HA, et al. Validation of the minimun data set cognitive performance scale: agreement with the Mini-Mental State Examination. J Gerontol A Biol Sci Med Sci 1995;50:M128–M133. 114. Paradise M, Walker Z, Cooper C, et al. Prediction of survival in Alzheimer’s disease the LASER-AD longitudinal study. Int J Geriatr Psychiatry 2009;24(7):739–747. 115. Ho G, Takamatsu Y, Waragai M, Wada R, Sugama S, Takenouchi T, et al. Current and future clinical utilities of Parkinson’s disease and dementia biomarkers: can they help us conquer the disease? Expert Rev Neurother 2019;19(11):1149–1161. 116. Young AL, Oxtoby NP, Daga P, Cash DM, Fox NC, Ourselin S, et al. A data-driven model of biomarker changes in sporadic Alzheimer’s disease. Brain 2014;137(9):2564–2577. 117. Dai P, Gwadry-Sridhar F, Bauer M, Borrie M. A hybrid manifold learning algorithm for the diagnosis and prognostication of Alzheimer’s disease. AMIA Annu Symp Proc 2015 November 5; 2015:475–483. 118. Selwyin PA, Forstein M. Overcoming the false dichotomy of curative vs palliative care for late-stage HIV/AIDS: “Let me live the way I want to live, until I can’t”. JAMA 2003;290:806–814. 119. Shen JM, Blank A, Selwyn PA. Predictors of mortality for patients with advanced disease in an HIV palliative care program. J Acquir Immune Defic Syndr 2005;40(4):445–447. 120. Smith CJ, Ryom L, Weber R, Morlat P, Pradier C, Reiss P, et al. Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration. Lancet 2014;384(9939):241–248. 121. Ingle SM, May MT, Gill MJ, Mugavero MJ, Lewden C, Abgrall S, et al. Impact of risk factors for specific causes of death in the first and subsequent years of antiretroviral therapy among HIV-infected patients. Clinical Infectious Diseases 2014;59(2):287–297. 122. Vandenhende M, Roussillon C, Henard S, Morlat P, Oksenhendler E, Aumaitre H, et al. Cancer-related causes of death among HIVinfected patients in France in 2010: evolution since 2000. PloS one 2015;10(6):e0129550.

Textbook of Palliative Medicine and Supportive Care 123. Trickey A, May MT, Vehreschild J, Obel N, Gill MJ, Crane HM, et al. Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies. Lancet HIV 2017;4(8):e349–e356. 124. Borasio GD, Voltz R. Palliative care in amyotrophic lateral sclerosis. J Neurol 1997;244(Suppl 4):S11–S17. 125. Bede P, Oliver D, Stodart J, et al. Palliative care in amyotrophic lateral sclerosis: a review of current international guidelines and initiatives. J Neurol Neurosurg Psychiat 2011;82(4):413–418. 126. McCluskey L, Houseman G. Medicare hospice referral criteria for patients with amyotrophic lateral sclerosis: a need for improvement. J Palliat Med 2004;7:47–53. 127. Mandrioli J, Faglioni P, Nichelli P, et al. Amyotrophic lateral sclerosis: prognostic indicators of survival. Amyotroph Lateral Scler 2006;7(4):211–220. 128. Zoccolella S, Beghi E, Palagano G, et al. Analysis of survival and prognostic factors in amyotrophic lateral sclerosis: a population based study. J Neurol Neurosurg Psychiatry 2008;79(1):33–37. 129. Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60(8):646–649. 130. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001;33(2):464–470. 131. Jalan R, Saliba F, Pavesi M, Amoros A, Moreau R, Ginès P, et al. Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. J Hepatol 2014;61(5):1038–1047. 132. Jalan R, Pavesi M, Saliba F, Amorós A, Fernandez J, Holland-Fischer P, et al. The CLIF Consortium Acute Decompensation score (CLIF-C ADs) for prognosis of hospitalised cirrhotic patients without acute-onchronic liver failure. J Hepatol 2015;62(4):831–840. 133. Moss AH, Holley JL, Davison S, et al. Core curriculum in nephrology. Palliative care. Am J Kidney Dis 2004;43:172–173. 134. Al-Aly Z, Cepeda O. Rate of change in kidney function and the risk of death: the case for incorporating the rate of kidney function decline into the CKD staging system. Nephron Clin Pract 2011;119(2):c179–c185. 135. Webster AC, Nagler EV, Morton RL, Masson P. Chronic kidney disease. Lancet 2017;389(10075):1238–1252. 136. Tangri N, Stevens LA, Griffith J, Tighiouart H, Djurdjev O, Naimark D, et al. A predictive model for progression of chronic kidney disease to kidney failure. JAMA 2011;305(15):1553–1559. 137. Tangri N, Grams ME, Levey AS, Coresh J, Appel LJ, Astor BC, et al. Multinational assessment of accuracy of equations for predicting risk of kidney failure: a meta-analysis. JAMA 2016;315(2):164–174. 138. Wong CF, McCarthy M, Howse ML, et al. Factors affecting survival in advanced chronic kidney patients who choose not to receive dialysis. Ren Fail 2007;29(6):653–659.

75

PALLIATIVE SEDATION

Nathan I. Cherny A.M.

Contents Key Learning Points...........................................................................................................................................................................................................717 Transient controlled sedation..........................................................................................................................................................................................718 Sedation in the management of refractory symtoms at the end of life (palliative sedation)..............................................................................718 Symptoms at the end of Life.......................................................................................................................................................................................718 Refractory symptoms at the end of life....................................................................................................................................................................718 Epidemiology of refractory symptoms at the end of life......................................................................................................................................718 Sedation at the end of life as a clinical dilemma....................................................................................................................................................718 Case conference approach to decision-making.....................................................................................................................................................719 Discussing sedation with the patient and their family members.......................................................................................................................719 Discussing sedation with the ancillary staff members......................................................................................................................................... 720 Consent and “DNR” status........................................................................................................................................................................................ 720 Administration............................................................................................................................................................................................................. 720 Patient monitoring...................................................................................................................................................................................................... 720 Emergency sedation...........................................................................................................................................................................................................721 The context....................................................................................................................................................................................................................721 Administration..............................................................................................................................................................................................................721 Respite sedation..................................................................................................................................................................................................................721 The context....................................................................................................................................................................................................................721 Use of sedation in the management of refractory existential or psychological distress......................................................................................721 Medications used for sedation in palliative care..........................................................................................................................................................722 Opioids...........................................................................................................................................................................................................................722 Bezodiazepines.............................................................................................................................................................................................................722 Midazolam...............................................................................................................................................................................................................722 Lorazepam...............................................................................................................................................................................................................722 Neuroleptics/Antipsychotics.....................................................................................................................................................................................722 Levomepromazine..................................................................................................................................................................................................722 Chlorpromazine......................................................................................................................................................................................................722 Haloperidol..............................................................................................................................................................................................................722 Barbiturates and anesthetic agents...........................................................................................................................................................................722 Phenobarbital..........................................................................................................................................................................................................722 Propofol................................................................................................................................................................................................................... 723 Ethical considerations...................................................................................................................................................................................................... 723 Ethical issues regarding Nutrition and hydration when patients are sedated................................................................................................ 723 Conclusions........................................................................................................................................................................................................................ 724 References........................................................................................................................................................................................................................... 724

Key Learning Points • At the end of life, all patients have the right to the adequate relief of physical symptoms. • There is need to ensure that appropriate infrastructural measures are addressed to enhance the likelihood that this right will be fulfilled. • Symptoms at the end of life must be assessed. • The adequacy of symptom relief is determined by the patient. • Inadequately received symptoms in dying patients must be relieved to the patient’s satisfaction. • Symptoms that are difficult to control must be evaluated by clinicians expert in symptom control at the end of life.

• When a symptom is refractory to normal palliative approaches and only sedation can provide the needed relief, this should be made known to patients (with appropriate infrastructural guidelines to prevent the inappropriate application of this approach) Sedation in the context of palliative medicine is the monitored use of medications intended to induce varying degrees of unconsciousness to induce a state of decreased or absent awareness (unconsciousness) in order to relieve the burden of otherwise intractable suffering. The intent is to provide adequate relief of distress.1 Sedation is controversial insofar as it diminishes capacity: capacity to interact, function, and, in some cases, live. In the context of a field of endeavor committed to helping the ill and

717

Textbook of Palliative Medicine and Supportive Care

718 suffering to live better, there is a potential contradiction of purpose.2 Sedation for the relief of suffering touches at the most basic conflict of palliative medicine: are we doing “enough” or are we doing “too much.” This issue exemplifies the tensions in achieving the duel goals of palliative care: first, to relieve suffering and, second to do so in such a manner so as to preserve the moral sensibilities of the patient the professional carers and concerned family and friends. Sedation is used in palliative care in several settings: 1. Transient controlled sedation for noxious procedures 2. Sedation used in end of life weaning from ventilator supports 3. Sedation in the management of refractory symptoms at the end of life 4. Emergency sedation 5. Respite sedation 6. Sedation for psychological or existential suffering Each of these will be discussed describing the context of application, practical, and ethical considerations.

Transient controlled sedation Transient controlled sedation is routinely and uncontroversially used to manage the severe pain and anxiety associated with noxious procedures. Sedation enables patients to endure interventions that would otherwise be intolerable. Procedural guidelines exist for transient sedation for noxious procedures3 and in burn care.4 The depth of sedation required is influenced by the nature of the noxious stimulus, the level of relief achieved by other concurrent approaches, and individual patient factors. When these techniques are well applied, reports of pain and suffering are infrequent. Since these patients are expected to recover, careful attention is paid to maintaining adequate ventilation, hydration, and nutrition. Occasionally transient sedation will be needed for a self-limiting severe exacerbation of pain.5 In the full anticipation that this will be a reversible intervention, close monitoring of respiratory and homodynamic stability is essential. In one case report this was achieved with midazolam administered by a patient controlled analgesia device.5

Sedation in the management of refractory symtoms at the end of life (palliative sedation) At the end of life, the goals of care may shift and the relief of suffering may predominate over other considerations relating to functional capacity. In this setting, the designation of a symptom as “refractory,” may justify the use of induced sedation, particularly since this is the only option that is capable of providing the necessary relief with certainty and speed. Various names have been applied to the issue of sedation in this setting: Terminal sedation, palliative sedation, and palliative sedation therapy.6 Though no single term has achieved universal support, of these options, palliative sedation is generally preferred.7–10

Symptoms at the end of Life

Among patients with advanced cancer, clinical experience suggests that optimal palliative care can effectively manage the symptoms of most cancer patients during most of the course

of the disease. Although physical and psychological symptoms cannot be eliminated, but they are usually relieved enough to adequately temper the suffering of the patient and family. This phase may be referred to as the ambulatory phase of advanced cancer. As the disease progresses and the end of life approaches and patients commonly suffer more physical and psychological symptoms (including pain), it often becomes more difficult to achieve adequate relief.11–17 For some patients, the degree of suffering related to these symptoms may be intolerable. Despite intensified efforts to manage such problems, some patients do not achieve adequate relief and they continue to suffer from inadequately controlled symptoms that may be termed “refractory.” An important study reviewing the data on the prevalence of symptoms in far advanced cancer, AIDS, heart disease, chronic obstructive pulmonary disease (COPD), and renal disease found that breathlessness, pain, and fatigue were a shared common pathway.18

Refractory symptoms at the end of life

The term “refractory” can be applied to symptoms that cannot be adequately controlled despite aggressive efforts to identify a tolerable therapy that does not compromise consciousness. The diagnostic criteria for the designation of a refractory symptom include that the clinician must perceive that further invasive and noninvasive interventions are either (1) incapable of providing adequate relief, (2) associated with excessive and intolerable acute or chronic morbidity, or (3) unlikely to provide relief within a tolerable time frame.1 The implication of this designation is that the pain will not be adequately relieved with routine measures and that sedation may be needed to attain adequate relief.1

Epidemiology of refractory symptoms at the end of life

The prevalence of refractory symptoms at the end of life remains controversial. Prevalence data reporting the use of sedation in the management of refractory symptom has been reported in a number of studies over the past 20 years (Table 75.1) and in most settings it is between 15 and 30% of dying patients. The phenomenology of severe symptoms at the end of life is well studied in patients with malignant and nonmalignant diseases. A comparative analysis of published data on the prevalence of symptoms in far advanced cancer, AIDS, heart disease, COPD, and renal diseases found that breathlessness, pain and fatigue were a shared common pathway that were the predominant symptoms in more than 50% of patients.18 The use of sedation for the relief of refractory symptoms, particularly dyspnea is described in end-stage COPD,19 after ventilator weaning,20 in heart failure,21,22 and motor neuron disease.23,24

Sedation at the end of life as a clinical dilemma

Persistent severe pain at the end of life challenges the clinician clinically, emotionally, and morally and contributes to the onerous nature of clinical decision-making in this setting. It is useful to recognize both the clinical and the ethical dimensions of this dilemma. From a moral perspective, there is a major dilemma related to non-malfeasance. Clinicians neither want to subject severely distressed patients to therapies that provide inadequate relief or excessive morbidity, nor to sacrifice conscious function when viable alternatives remain unexplored. The clinical corollary of this moral dilemma is the need to distinguished a “refractory” pain state from a “the difficult situation,”

Palliative Sedation

719

TABLE 75.1  Surveys of the Use of Sedation in the Management of Refractory Symptoms

Ventafridda Fainsinger Morita Stone Fainsinger Chiu Muller Busch Sykes Morita Kohara Vitetta Rietjens Maltoni Mercendante Schur Imai

Year

N

1990 1991 1996 1997 1998 2001 2002 2003 2004 2005 2005 2008 2009 2009 2016 2018

120 100 143 115 76 251 548 237 124 102 157 518 77 2414 398

Place Home Inpatient Hospice IP and Home IP hospice IP palliative care IP palliative care Hospice Multicenter IP palliative care Hopsice IP palliative care Multicenter IP palliative care IP palliative care IP palliative care

which could potentially respond within a tolerable time frame to noninvasive or invasive interventions and yield adequate relief and preserved consciousness without excessive adverse effects. The challenge inherent in this decision-making requires that patients with unrelieved symptoms undergo repeated evaluation prior to progressive application of routine therapies.

Case conference approach to decision-making

Since individual clinician bias can influence decision-making, a case conference approach is prudent when assessing a challenging case. This conference may involve involving the participation of oncologists, palliative care physicians, specialists from other fields relevant to the prevailing symptom control problem, nurses, social workers, and others. The discussion attempts to clarify the remaining therapeutic options and the goals of care. Clearly, it is critical that clinicians who are expert in symptom control be involved in the patient evaluation. When local expertise is limited, telephone consultation with physicians who are expert in palliative medicine is strongly encouraged.

Discussing sedation with the patient and their family members

If the clinician perceives that there is no treatment capable of providing adequate relief of intolerable symptoms without compromising interactional function, or that the patient would be unable to tolerate specific therapeutic interventions, refractoriness to standard approaches should be acknowledged. In this situation, the clinician should explain that by virtue of the severity of the problem and the limitations of the available techniques, the goal of providing the needed relief without the use of drugs that may impair conscious state is probably not possible. The offer of sedation as an available therapeutic option is often received as an empathic acknowledgment of the severity of the degree of patient suffering. The enhanced patient trust in the commitment of the clinician to the relief of suffering may, in itself, influence decision-making, particularly if there are other tasks or life issues that need to be completed before a state of diminished function develops. Indeed, patients can, and often

% Sedated for Refectory Symptoms

Reference

52% 16% 43% 26% 30% 28% 14% 48% < 10–50% 50% 67% 43% 25% 54% 21% 14%

(86) (87) (35) (88) (43) (89) (90) (91) (92) (93) (94) (95) (96) (97) (98) (30)

do, decline sedation, acknowledging that symptoms will be unrelieved but secure in the knowledge that if the situation becomes intolerable this decision can be rescinded. Alternatively, the patient can assert comfort as the paramount consideration and accept the initiation of sedation. With the hope and knowledge that it may be possible to achieve adequate relief without compromising interactional function, the patient who equally prioritizes comfort and function may elect to pursue only those approaches with modest morbidity, despite a relatively low or indeterminate likelihood of success. As the goals of prolonging survival and optimizing function become increasingly unachievable, priorities often shift. When comfort is the overriding goal of care, and the principal intent of any further intervention is to achieve lasting relief, there may be no tolerable time frame for exploring other therapeutic options. In this situation, interventions of low or indeterminate likelihood of success are often rejected in favor of more certain approaches, even if they may involve impairment of cognitive function or possibly foreshortened duration of survival. This situation becomes more complicated when the clinician is less certain that the available approaches will fail. Therapeutic decision-making is strongly influenced by the patient’s readiness to accept the risk of morbidity and enduring discomfort until adequate relief is achieved. As always, patient evaluation of therapeutic options requires a candid disclosure of the therapeutic options, including information regarding the likelihood of benefit, the procedural morbidity, the risks of side effects, and the likely time to achieve relief. If these are acceptable to the patient, then further trials of standard therapies should be pursued. If the patient requires relief and either the procedural morbidity, the risks of adverse effects or the likely time to achieve relief are unacceptable, then refractoriness should be acknowledged and sedation should be offered. These decisions are usually made by consensus between the clinicians, the patient, and the patient’s family. The process of this decision-making is predicated on an understanding of the goals of care for the individual patient. These goals can generally be grouped into three broad categories: (1) prolonging survival, (2) optimizing comfort (physical, psychological, and existential),

720 and (3) optimizing function. The processes of goal prioritization and informed decision-making require candid discussion that clarifies the prevailing clinical predicament and presents the alternative therapeutic options. Other relevant considerations, including existential, ethical, religious, and familial concerns, may benefit from the participation of a religious counselor, social worker, or clinical ethics specialist. With the patients’ consent, it is prudent to involve the family in these discussions. They suffer with the patient and will survive with the memories, pain, and the potential for guilt at not having been effective advocates for their loved one: either because the patient died in unrelieved pain or remorseful that the patient may have been sedated when other options were not given a fair chance. If it is agreed that sedation is the most humane and appropriate way to control symptoms, it is advisable to ask the patient and family members if they have any specific goals that need to be met prior to starting sedation or if they would appreciate a chaplain/ spiritual support prior to starting sedation.

Discussing sedation with the ancillary staff members

Involvement of ancillary staff such as social workers, primary care nurse, psychologist and other health professionals is essential. All participating staff members need to understand the rationale for sedation and goals of care. Whenever possible, this should be addressed at team meetings or case conferences, both before and after the event, to discuss the professional and emotional issues related to such decisions. Distress can be mitigated by fostering a culture of sensitivity to the emotional burdens involved in care, participating in the deliberative processes leading up to a treatment decision, sharing information, and engaging in multidisciplinary discussions that offer the group or individuals opportunities to express their feelings.

Consent and “DNR” status

When patients with advanced illness are at risk of intolerable suffering, physicians should discuss the option of palliative sedation at a time before the patient is in a crisis situation. The discussion of this option should include review of the aims, benefits, and risks of palliative sedation, as well as the alternatives to its use. For patients experiencing severe or refractory distress but who are still conscious, alert, and communicative, a discussion on palliative sedation should be a part of a more comprehensive conversation that includes the following: 1. The patient’s general condition and the cause of the distress 2. Acknowledgment that prior treatments have not been successful 3. Current prognosis, including predictions about survival 4. Rationale, aims, and methods available for the use of palliative sedation, including the depth of planned sedation, patient monitoring, and if appropriate, the possibility of planned weaning from sedation and even discontinuation 5. Alternative treatment options, the likelihood that they may relieve distress, and the expected survival associated with each 6. Anticipated effects of sedation, including degree of reduction in consciousness levels and the estimated effects on mental activities, communication, and oral intake 7. Potential risks such as paradoxical agitation, delayed or inadequate relief, and the possibility of hastened death

Textbook of Palliative Medicine and Supportive Care For patients who lack decisional capacity, the advance care plan of the patient should be followed. If there is no advance directive, the discussion regarding palliative sedation (including consent) must be obtained from a legally recognized proxy. For terminally ill patients who are actively dying and are in severe distress, an opportunity to obtain consent by the patient or his/her health-care proxy may not be present. In the absence of an advance directive or health-care proxy, the provision of comfort measures (including, if necessary, the use of sedation) should be considered standard of practice and the default strategy for clinician treatment decisions.25 Regardless of whether the patient has decisional capacity or not, patients and their families should be reassured that they will receive the best possible care during this time, irrespective of decisions to proceed with palliative sedation or an alternative treatment. In addition, patients should be informed that medical treatments and nursing care will be provided to ensure that the patient’s comfort is maintained and that the patient’s and family’s wishes are respected. Sedating pharmacotherapy for refractory symptoms at the end of life should not be initiated until a discussion about CPR has taken place with the patient, or, if appropriate, with the patient’s proxy, and there is agreement that CPR will not be initiated.

Administration

Sedation for the management of refractory symptoms is usually performed in an inpatient setting. However, substantial experience has been reported in home care settings26–29 which may be a reasonable alternative for some patients. Irrespective of the agent selected, administration initially requires dose titration to achieve adequate relief, followed subsequently by provision of ongoing therapy to ensure maintenance of effect. 30 The depth of sedation that is required to achieve adequate relief is highly variable. In some situations, patients may require only light sedation to achieve adequate relief, in other situations, particularly at the end of life, deep sedation may be required. In some circumstances, deep sedation may be initiated from the outset and continued until death. This is called continuous deep sedation. 30,31 This approach could be selected first: (1) if the suffering is intense, definitely refractory, death is anticipated within a relatively short time, and the patient’s wish to be permanently unaware is explicit, or (2) in the setting of an end of life catastrophic event such as massive hemorrhage or severe terminal dyspnea. Regular, “around the clock” administration can be maintained by continuous infusion or intermittent bolus. The route of administration can be IV, SC, or rectal. In some situations, drugs can be administered via a stoma or gastrostomy. In all cases, provision for emergency bolus therapy to manage breakthrough symptoms is recommended.

Patient monitoring

Once adequate relief is achieved the parameters for patient monitoring and the role of further dose titration is determined by the goal of care: 1. If the patient is imminently dying: In this setting the only salient parameters for ongoing observation are those pertaining to comfort. Symptoms should be assessed until death; observations of pulse blood pressure and temperature do not contribute to the goals of care and can be discontinued. Respiratory rate is monitored

Palliative Sedation primarily to ensure the absence of respiratory distress and tachypnea. Since downward titration of drug doses places the patient at risk for recurrent distress, in most instances it is not recommended even as the patient approaches death. 2. If the patient wishes to be less sedated and dying is not imminent: In this context, comfort, the level of sedation, and routine physiological parameters such as heart rate, blood pressure, and oxygen saturation are monitored. In these cases, the drug should be administered by the lowest effective dose that provides adequate comfort. If physiological parameters are compromised by the sedating medications, doses may need to be adjusted. The depth of sedation necessary to control symptoms varies greatly. Once sedation and symptom control is achieved, doses can be titrated down to reestablish lucidity if appropriate, and, if it was desired by the patient, prior to sedation. This enables an opportunity to reevaluate the patient’s condition and his or her preferences regarding sedation. It may also allow for patient–family communication. However, lucidity may not be restored, symptoms may reoccur, and death may intervene. The role of nutrition and hydration: Decisions regarding the administration of hydration and/or artificial nutrition therapy are independent of the decision about whether to administer palliative sedation. Opinions and practices vary. This variability reflects the heterogeneity of attitudes of involved clinicians, ethicists, patients, families, and local norms of good clinical and ethical practice. Individual patients, family members, and clinicians may regard the continuation of hydration as a non-burdensome humane supportive intervention that represents (and may actually constitute) one means of reducing suffering. Alternatively, hydration may be viewed as a superfluous impediment to inevitable death that can be appropriately withdrawn because it does not contribute to patient comfort or the prevailing goals of care. Often, the patient will request relief of suffering and give no direction regarding hydration and nutrition. Under these circumstances, family members and health-care providers must work to reach a consensus on what constitutes a morally acceptable plan based on the patient’s best interests. If adverse effects of artificial hydration and/or nutrition therapy exacerbate patient suffering, then reduction or withdrawal of artificial hydration/nutrition should be considered.

Emergency sedation The context

Emergency sedation refers to the use of sedation to provide urgent relief of overwhelming symptoms in dying patients. Emergency situations may include massive hemorrhage, asphyxiation, severe terminal dyspnea, 32,33 overwhelming pain crisis33 or severe terminal agitation. 33,34 If a catastrophic situation is anticipated, advance care directives should be discussed with the patient, family members, and health-care providers (See “Obtaining consent” above.) For patients who are at home and at risk of a catastrophic event, sedating medications should be prepared in advance and accompanied by a clear plan for emergency administration. In situations where family members or other home carers feel that they would be unable to administer emergency medications, consideration should be given to inpatient care.

721 Administration

As in the previous scenario, midazolam is recommended as the drug of choice. Initial sedation can be achieved with a bolus of 2.5 mg SC/IV which can be repeated after 5 minutes if adequate sedation is not achieved. Once the patient is calm, a subcutaneous or intravenous infusion can be used. In the immediately preterminal patient, the only salient parameters for ongoing observation are those pertaining to comfort. Symptoms should be assessed until death; observations of pulse blood pressure and temperature are superfluous. Respiratory rate is monitored primarily to ensure that absence of respiratory distress and tachypnea.

Respite sedation The context

Respite sedation refers to the transient use of sedation to relieve severe symptoms (e.g., malaise, pain, agitation, and nausea) that are not necessarily refractory, and to provide adequate relief before continuing with further trial of nonsedating palliative approaches. After such respite, some patients will be sufficiently rested to consider further trials of symptomatic therapy. 35 Since the aim of respite sedation is to ultimately restore the patient to their pretreatment state of consciousness, precautions are required to ensure patient safety and minimize risks. These include: • Administration of the lowest effective dose of the sedative agent chosen that provides adequate comfort. • Monitoring routine physiological parameters. If midazolam is used, flumazenil should be readily available in case of inadvertent overdose. Despite these precautions, this approach is associated with significant risks (including the risk that level of consciousness may not be completely restored) that should be considered in the consent process.

Use of sedation in the management of refractory existential or psychological distress Sedation in the management of refractory psychological symptoms and existential distress is different from other situations due to four major reasons: (1) by virtue of the nature of the symptoms being addressed it is much more difficult to establish that they are truly refractory, (2) the severity of distress of some of these symptoms may be very dynamic and idiosyncratic and psychological adaptation and coping is common, (3) the standard treatment approaches have low intrinsic morbidity, and (4) the presence of these symptoms does not necessarily indicate a far advanced state of physiological deterioration. 36–38 The European Association for Palliative Care guidelines address this issue with the following caveats:39 1. This approach should be reserved for patients in advanced stages of a terminal illness. 2. The designation of such symptoms as refractory should only be done following a period of repeated assessment by clinicians skilled in psychological care who have established a relationship with the patient and his or her family along with trials of routine approaches for anxiety, depression, and existential distress.

Textbook of Palliative Medicine and Supportive Care

722 3. The evaluation should be made in the context of a multidisciplinary case conference, including representatives from psychiatry, chaplaincy, and ethics, as well as those providing care at the bedside, because of the complexity and frequently multifactorial nature of this situation. 4. In the rare situations that this strategy is indeed appropriate and proportionate to the situation, it should be initiated on a respite basis for 6–24 hours with planned downward titration after a preagreed interval. 5. Only after repeated trials of respite sedation with intensive intermittent therapy have been performed, should continuous sedation be considered.

Medications used for sedation in palliative care The published literature describing the use of sedation in the management of refractory symptoms at the end of life is anecdotal and refers to the use of opioids, neuroleptics, benzodiazepines, barbiturates, and propofol.

Opioids

In the management of pain, an attempt is usually made to first escalate the opioid dose. Although some patients will benefit from this intervention, inadequate sedation or the development of neuroexcitatory side effects, such as myoclonus or agitated delirium, often necessitate the addition of a second agent.40–42

Bezodiazepines Midazolam35,43–50

General: Midazolam is the most commonly used agent. Pharmacology: Water soluble, short-acting benzodiazepine. It is metabolized to a lipophilic compound that rapidly penetrates the central nervous system. Brief duration of action because of rapid redistribution, therefore administration by continuous infusion is generally required to maintain a sustained effect. Advantages: Rapid onset. Can be administered IV, SC Starting dose: 0.5–1 mg/hour, 1–5 mg as needed Usual effective dose: 1–20 mg/hour Adverse effects: paradoxical agitation, respiratory depression, withdrawal if dose is rapidly reduced after continual infusion, tolerance Antagonist: Flumazenil

Lorazepam

General: Intermediate-acting benzodiazepine that has a peak effect approximately in 30 minutes after IV administration. It is less amenable to rapid titration up or down than midazolam, because of its slower pharmacokinetics. Pharmacology: Elimination is not altered by renal or hepatic dysfunction. Advantages: Rapid onset. Can be administered IV Starting dose: 0.05 mg/kg every 2–4 hours when administered by intermittent bolus Adverse effects: paradoxical agitation, respiratory depression, withdrawal if dose is rapidly reduced after continual infusion, tolerance Antagonist: Flumazenil

Neuroleptics/Antipsychotics

Neuroleptics may be effective when the patient is manifesting signs and symptoms of delirium. Delirium is an acute confusional state that can be difficult to differentiate from anxiety, yet the distinction is important, because the administration of opioids or benzodiazepines as initial treatment for delirium can worsen the symptom.

Levomepromazine

General: Levomepromazine is an antipsychotic phenothiazine Advantages: Rapid onset, antipsychotic effect in cases of delirium, some analgesic effect; can be administered orally or parenterally (IV, SC, or IM). Starting dose: stat dose 12.5–25 mg and 50–75 mg continual infusion Usual effective dose: 12.5 or 25 mg q8h and q1h prn for breakthrough agitation or up to 300 mg/day continual infusion Adverse effects: Orthostatic hypotension, paradoxical agitation, extrapyramidal symptoms, anticholingeric effects

Chlorpromazine

General: Widely available antipsychotic, can be administered orally, parenterally (IV or IM), and rectally. Advantages: Antipsychotic effect for delirious patients Starting dose: IV or IM 12.5 mg q 4–12 hours, or 3–5 mg/hour IV or 25–100 mg q 4–12 hours PR Usual effective dose: parenteral 37.5–150 mg/day, PR 75–300 mg/day Adverse effects: orthostatic hypotension, paradoxical agitation, extrapyramidal symptoms, anticholingeric effects

Haloperidol

General: Butyrophenome antipsychotic Advantages: Antipsychotic, less sedating than chlorpromazine or methotrimeprazine; can be administered IV, SC or PO Starting dose: for mild delirium 0.5–1 mg parentrally q4–6 hour, in cases of severe agitation start with 2.5 mg with option to repeat dose in 30 minutes. Pharmacodynamics: slow effect orally, rapid effect parenterally Usual effective dose: 5–6 0mg/day divided doses or continual infusion Adverse effects: orthostatic hypotension, paradoxical agitation, extrapyramidal symptoms, and anticholingeric effects

Barbiturates and anesthetic agents

Barbiturates and propofol reliably and rapidly cause unconsciousness, and, since their mechanism of action differs from the opioids and benzodiazepines, they may be useful in patients who have developed extreme levels of tolerance to these other medications. They do not have analgesic effect, therefore opioids will probably be necessary for patients with pain.

Phenobarbital

General: Barbiturate 51,52 Advantages: rapid onset, anticonvulsant Dose: 1–3 mg/kg SQ or IV bolus dose, followed by starting infusion of 0.5 mg/kg/hour

Palliative Sedation Usual maintenance dose: 50–100 mg/hour Adverse effects: Paradoxical excitement in the elderly, hypotension, nausea and vomiting, Steven’s Johnson syndrome, angioedema, rash, agranulocytosis, thrombocytopenia

Propofol

General: Propofol is very similar to the short-acting barbiturates but it has a short duration of action and a very rapid onset.47,53–56 These characteristics make it relatively easy to titrate.54 Dose: In one report, the patient was started on a loading dose of 20 mg, followed by an infusion of 50–70 mg/hour.55

Ethical considerations Good clinical practice is predicated on careful patient evaluation, which incorporates assessment of current goals of care. Since all medical treatments involve risks and benefits, each option must be evaluated for its potential to achieve the goals of care. The risks of treatment must be proportionate to the gravity of the clinical indication. In these deliberations, clinician considerations are guided by an understanding of the goals of care and should be within accepted medical guidelines of beneficence and nonmaleficence. Ultimately, the decision to act on these considerations relies on either obtaining informed consent from the patient (or his or her surrogate) or by previously determined advanced directive. In this context, the decision to offer the use of sedation to relieve intolerable suffering to terminally ill patients presents no new ethical problem57,58 and is supported by legal precedent.59–61 Distinction from “slow euthanasia”: Palliative sedation is distinct from euthanasia.62 Voluntary euthanasia refers to the deliberate termination of the life of a patient by active intervention at the request of the patient. Palliative sedation, in contrast, is utilized for refractory suffering and: 1. The intent of the intervention is to provide symptom relief, not to end the life of the suffering patient; 2. The intervention is proportionate to the prevailing symptom, its severity, and the prevailing goals of care; 3. Unlike euthanasia, death of the patient is not the criterion used to gauge the success of the treatment. Some authors assume that palliative sedation requires the concurrent discontinuation of nutrition and hydration.63–67 Therefore, they argue that while sedation in the relief of uncontrolled symptoms may be justifiable, it almost certainly hastens death by allowing for starvation and dehydration. As a result, palliative sedation is practically the same as “slow euthanasia.” However, it is important to reassert that the discontinuation of hydration and nutrition is not an essential element to the administration of sedation in the management of refractory symptoms. 39,68 Ethically problematic practices: Palliative sedation is not meant to be a means of hastening the patient’s death. 39 Clinicians involved in the palliative care of patients, especially those using palliative sedation, need to be aware of the potential for harm from abusive, injudicious, or unskilled use of sedation. Potential harm is illustrated in the following examples: Sedation as a means of hastening the patient’s death: This is the most common abuse of sedation and is essentially the practice of “slow euthanasia.”69–76 This may occur by the deliberate use of

723 deep sedation in patients who have no refractory symptoms, or in the deliberate use of doses that far exceed what is necessary to provide adequate comfort.77 Sedation applied inappropriately: Injudicious palliative sedation occurs when sedation is applied with the intent of relieving symptoms but in clinical circumstances which are not appropriate. In this situation, sedation is applied with the intent of relieving distress and is carefully titrated to effect but the indication is inadequate to justify such a radical intervention. The following are representative examples of injudicious use: 1. Instances of inadequate patient assessment in which potentially reversible causes of distress are overlooked.70,78 2. Situations in which before resorting to sedation, there is a failure to engage clinicians expert in relief of symptoms despite their availability.70,79 3. The case of an overwhelmed physician resorting to sedation because he is fatigued and frustrated by the care of a complex symptomatic patient.80 4. Situations in which the demand for sedation is generated by the patient’s family and not the patient him/herself.80 Sedation withheld when it is appropriate: This may occur when clinicians rule out or do not offer the option of palliative sedation in favor of other therapeutic options that do not provide adequate relief. This may occur when anxiety about having to deal with all of the difficult discussions about sedation and end-of-life care results in continued futile therapeutic trials of nonsedating therapies or when there are reservations based on undue concerns about potentially hastening death.

Ethical issues regarding Nutrition and hydration when patients are sedated

Although sedation is clearly beneficent in terms of providing relief from otherwise intolerable suffering, the beneficence of withdrawal of nutrition and hydration in the already sedated and comfortable patient is not self-evident, and indeed it may be perceived as harmful. This debate has both medical and ethical dimensions. Medically, there is little data to support the clinical benefit of hydration or artificial nutrition in the imminently dying, or to suggest that it prolongs life or contributes to comfort. 81–83 Ethically, the withdrawal of potentially death-deferring treatments (such as hydration) among dying patients is, for some, controversial. 64,84 For reasons of clarity, the issue of sedation must be distinguished from the distinct and separate issue of hydration. Opinions and practices vary. This variability reflects the heterogeneity of attitudes of the involved clinicians, ethicists, the patient, family, and local norms of good clinical and ethical practice.44 Individual patients, family members, and clinicians may regard the continuation of hydration as a non-burdensome humane supportive intervention that represents (and may actually constitute) one means of reducing suffering.64,84 Alternatively, hydration may be viewed as a superfluous impediment to inevitable death that does not contribute to patient comfort or the prevailing goals of care and that can be appropriately withdrawn.85 Often, the patient will request relief of suffering and give no direction regarding supportive measures. In this circumstance the family and health-care providers must reach consensus as to what constitutes a morally and personally acceptable approach based on the ethical principles of beneficence, non-malfeasance and respect for personhood.

Textbook of Palliative Medicine and Supportive Care

724 In cases where there are religious or culturally based reservations regarding the discontinuation of nutritional support, it should be maintained unless there is evidence of direct patient harm by the intervention.

Conclusions Sedation is a critically important therapeutic tool of last resort. It enables the clinician to provide relief from intolerable distress to the patient when other options are not adequately effective. Because sedation undermines the capacity to interact, it must be used judiciously. Clear indications and guidelines for use are necessary to prevent abuse of this approach to facilitate the deliberate killing of patients, which while benevolently intended, may have untoward sociological and ethical consequences for palliative care clinicians and the image of palliative medicine as a profession.

References







1. Cherny NI, Portenoy RK. Sedation in the management of refractory symptoms: guidelines for evaluation and treatment. J Palliat Care. 1994;10(2):31–38. 2. Maeda S, Morita T, Ikenaga M, Abo H, Kizawa Y, Tsuneto S. Changes in opinions on palliative sedation of palliative care specialists over 16 years and their effects on clinical practice. Support Care Cancer 2019 June;27(6):2211–2219. 3. Hinkelbein J, Lamperti M, Akeson J, Santos J, Costa J, De Robertis E, et al. European Society of Anaesthesiology and European Board of Anaesthesiology guidelines for procedural sedation and analgesia in adults. Eur J Anaesthesiol (EJA) 2018;35(1):6–24. 4. Gregoretti C, Decaroli D, Piacevoli Q, Mistretta A, Barzaghi N, Luxardo N, et al. Analgo-sedation of patients with burns outside the operating room. Drugs 2008;68(17):2427–2443. 5. del Rosario MA, Martin AS, Ortega JJ, Feria M. Temporary sedation with midazolam for control of severe incident pain. J Pain Symptom Manage 2001 May;21(5):439–442. 6. de Graeff A, Dean M. Palliative sedation therapy in the last weeks of life: a literature review and recommendations for standards. J Palliat Med. 2007 February;10(1):67–85. 7. Rousseau PC. Palliative sedation. Am J Hosp Palliat Care 2002 September-October;19(5):295–297. 8. Jackson WC. Palliative sedation vs. terminal sedation: what’s in a name? Am J Hosp Palliat Care 2002 March-April;19(2):81–82. 9. Beel A, McClement SE, Harlos M. Palliative sedation therapy: a review of definitions and usage. Int J Palliat Nurs 2002;8(4):190–199. 10. Cowan JD, Walsh D. Terminal sedation in palliative medicine: definition and review of the literature. Support Care Cancer 2001 September;9(6):403–407. 11. Conill C, Verger E, Henriquez I, Saiz N, Espier M, Lugo F, et al. Symptom prevalence in the last week of life. J Pain Symptom Manage 1997;14(6):328–331. 12. Storey P. Symptom control in advanced cancer. Semin Oncol 1994;21(6):748–753. 13. Lichter I, Hunt E. The last 48 hours of life. J Palliat Care 1990;6(4):7–15. 14. Johanson GA. Symptom character and prevalence during cancer patients’ last days of life. Am J Hosp Palliat Care 1991;8(2):6–8, 18. 15. Kutner JS, Bryant LL, Beaty BL, Fairclough DL. Time course and characteristics of symptom distress and quality of life at the end of life. J Pain Symptom Manage 2007 September;34(3):227–236. 16. Tranmer JE, Heyland D, Dudgeon D, Groll D, Squires-Graham M, Coulson K. Measuring the symptom experience of seriously ill cancer and noncancer hospitalized patients near the end of life with the memorial symptom assessment scale. J Pain Symptom Manage 2003 May;25(5):420–429. 17. Kutner JS, Kassner CT, Nowels DE. Symptom burden at the end of life: hospice providers’ perceptions. J Pain Symptom Manage 2001 June;21(6):473–480. 18. Solano JP, Gomes B, Higginson IJ. A comparison of symptom prevalence in far advanced cancer, AIDS, heart disease, chronic obstructive pulmonary disease and renal disease. J Pain Symptom Manage 2006 January;31(1):58–69.

19. Ambrosino N, Simonds A. The clinical management in extremely severe COPD. Respir Med 2007 March 23;101(8):1613–1624. 20. Jakob SM, Lubszky S, Friolet R, Rothen HU, Kolarova A, Takala J. Sedation and weaning from mechanical ventilation: effects of process optimization outside a clinical trial. J Crit Care 2007 September;22(3):219–228. 21. Reisfield GM, Wilson GR. Palliative care issues in heart failure #144. J Palliat Med 2007 February;10(1):247–248. 22. Goodlin SJ. Palliative care for end-stage heart failure. Curr Heart Fail Rep 2005 September;2(3):155–160. 23. Low JA, Pang WS, Chan DK, Chye R. A palliative care approach to endstage neurodegenerative conditions. Ann Acad Med Singapore 2003 November;32(6):778–784. 24. Elman LB, Houghton DJ, Wu GF, Hurtig HI, Markowitz CE, McCluskey L. Palliative care in amyotrophic lateral sclerosis, Parkinson’s disease, and multiple sclerosis. J Palliat Med 2007 April;10(2):433–457. 25. Hamano J, Morita T, Mori M, Uchitomi Y. Talking about palliative sedation with the family: informed consent vs. assent and a better framework for explaining potential risks. J Pain Symptom Manage 2018 September;56(3):e5–e8. 26. Caraceni A, Speranza R, Spoldi E, Ambroset CS, Canestrari S, Marinari M, et al. Palliative sedation in terminal cancer patients admitted to hospice or home care programs: does the setting matter? results from a national multicenter observational study. J Pain Symptom Manage 2018 July;56(1):33–43. 27. Calvo-Espinos C, Ruiz de Gaona E, Gonzalez C, Ruiz de Galarreta L, Lopez C. Palliative sedation for cancer patients included in a home care program: a retrospective study. Palliat Support Care 2014 April;24:1–6. 28. Mercadante S, Porzio G, Valle A, Aielli F, Casuccio A. Palliative sedation in patients with advanced cancer followed at home: a prospective study. J Pain Symptom Manage 2014 May;47(5):860–866. 29. Rosengarten OS, Lamed Y, Zisling T, Feigin A, Jacobs JM. Palliative sedation at home. J Palliat Care 2009 Spring;25(1):5–11. 30. Imai K, Morita T, Yokomichi N, Mori M, Naito AS, Tsukuura H, et al. Efficacy of two types of palliative sedation therapy defined using intervention protocols: proportional vs. deep sedation. Support Care Cancer 2018;26(6):1763–1771. 31. Feen E. Continuous deep sedation: consistent with physician’s role as healer. Am J Bioeth 2011 June;11(6):49–51. 32. Campbell ML. Terminal dyspnea and respiratory distress. Crit Care Clin 2004 July;20(3):403–17, viii-ix. 33. Schrijvers D, van Fraeyenhove F. Emergencies in palliative care. Cancer J (Sudbury, Mass.) 2010 September-October;16(5):514–520. 34. Kress JP, Hall JB. Delirium and sedation. Crit Care Clin 2004 July;20(3):419–433, ix. 35. Morita T, Inoue S, Chihara S. Sedation for symptom control in Japan: the importance of intermittent use and communication with family members. J Pain Symptom Manage 1996;12(1):32–38. 36. Rousseau P. Existential distress and palliative sedation. Anesth Analg 2005 August;101(2):611–612. 37. Taylor BR, McCann RM. Controlled sedation for physical and existential suffering? J Palliat Med 2005 February;8(1):144–147. 38. Ciancio AL, Mirza RM, Ciancio AA, Klinger CA. The use of palliative sedation to treat existential suffering: a scoping review on practices, ethical considerations, and guidelines. J Palliat Care 2020;35(1):13–20. 39. Cherny NI, Radbruch L. European Association for Palliative Care (EAPC) recommended framework for the use of sedation in palliative care. Palliat Med 2009 October;23(7):581–593. 40. Portenoy RK. Continuous intravenous infusion of opioid drugs. Med Clin North Am 1987;71(2):233–241. 41. Potter JM, Reid DB, Shaw RJ, Hackett P, Hickman PE. Myoclonus associated with treatment with high doses of morphine: the role of supplemental drugs [see comments]. BMJ 1989;299(6692):150–153. 42. Dunlop RJ. Excitatory phenomena associated with high dose opioids. Curr Ther 1989;30(6):121–123. 43. Fainsinger RL, Landman W, Hoskings M, Bruera E. Sedation for uncontrolled symptoms in a South African hospice. J Pain Symptom Manage 1998;16(3):145–152. 44. Chater S, Viola R, Paterson J, Jarvis V. Sedation for intractable distress in the dying: a survey of experts. Palliat Med 1998;12(4):255–269. 45. Nordt SP, Clark RF. Midazolam: a review of therapeutic uses and toxicity. J Emerg Med 1997;15(3):357–365. 46. Burke AL. Palliative care: an update on “terminal restlessness”. Med J Aust 1997;166(1):39–42.

Palliative Sedation 47. Collins P. Prolonged sedation with midazolam or propofol [letter; comment]. Crit Care Med 1997;25(3):556–557. 48. Johanson GA. Midazolam in terminal care. Am J Hosp Palliat Care 1993;10(1):13–14. 49. Power D, Kearney M. Management of the final 24 hours. Ir Med J 1992;85(3):93–95. 50. Burke AL, Diamond PL, Hulbert J, Yeatman J, Farr EA. Terminal restlessness: its management and the role of midazolam [see comments]. Med J Aust 1991;155(7):485–487. 51. Greene WR, Davis WH. Titrated intravenous barbiturates in the control of symptoms in patients with terminal cancer. South Med J 1991;84(3):332–337. 52. Truog RD, Berde CB, Mitchell C, Grier HE. Barbiturates in the care of the terminally ill. N Engl J Med 1992;327(23):1678–1682. 53. Tobias JD. Propofol sedation for terminal care in a pediatric patient. Clin Pediatr (Phila) 1997;36(5):291–293. 54. Krakauer EL, Penson RT, Truog RD, King LA, Chabner BA, Lynch TJ, Jr. Sedation for intractable distress of a dying patient: acute palliative care and the principle of double effect. Oncologist 2000;5(1):53–62. 55. Mercadante S, De Conno F, Ripamonti C. Propofol in terminal care. J Pain Symptom Manage 1995;10(8):639–642. 56. Moyle J. The use of propofol in palliative medicine. J Pain Symptom Manage 1995;10(8):643–646. 57. Miller FG, Fins JJ, Bacchetta MD. Clinical pragmatism: John Dewey and clinical ethics. J Contemp Health Law Policy 1996;13(1):27–51. 58. Fins JJ, Bacchetta MD, Miller FG. Clinical pragmatism: a method of moral problem solving. Kennedy Institute Ethics J 1997;7:129–145. 59. Gevers S. Terminal sedation: a legal approach. Eur J Health Law 2003 December;10(4):359–367. 60. Devlin P. Easing the Passing. London: Bodley Head, 1985. 61. Burt RA. The Supreme Court speaks–not assisted suicide but a constitutional right to palliative care. N Engl J Med 1997;337(17):1234–1236. 62. Materstvedt LJ. Distinction between euthanasia and palliative sedation is clear-cut. J Med Ethics 2020;46:55-56. 63. Brody H. Causing, intending, and assisting death. J Clin Ethics 1993;4(2):112–117. 64. Craig GM. On withholding artificial hydration and nutrition from terminally ill sedated patients. The debate continues [published erratum appears in J Med Ethics 1996 Dec;22(6):361]. J Med Ethics 1996;22(3):147–153. 65. Craig GM. On withholding nutrition and hydration in the terminally ill: has palliative medicine gone too far? [see comments]. J Med Ethics 1994;20(3):139–143; discussion 44-5. 66. Craig G. Is sedation without hydration or nourishment in terminal care lawful? Med Leg J 1994;62(Pt 4):198–201. 67. Orentlicher D. The Supreme Court and physician-assisted suicide– rejecting assisted suicide but embracing euthanasia. N Engl J Med 1997;337(17):1236–1239. 68. Hahn MP. Review of palliative sedation and its distinction from euthanasia and lethal injection. J Pain Palliat Care Pharmacother 2012;26(1):30–39. 69. Levy MH, Cohen SD. Sedation for the relief of refractory symptoms in the imminently dying: a fine intentional line. Semin Oncol 2005 April;32(2):237–246. 70. Hasselaar JG, Reuzel RP, van den Muijsenbergh ME, Koopmans RT, Leget CJ, Crul BJ, et al. Dealing with delicate issues in continuous deep sedation. Varying practices among Dutch medical specialists, general practitioners, and nursing home physicians. Arch Intern Med 2008 March 10;168(5):537–543. 71. Kuhse H, Singer P, Baume P, Clark M, Rickard M. End-of-life decisions in Australian medical practice. Med J Aust 1997;166(4):191–196. 72. Stevens CA, Hassan R. Management of death, dying and euthanasia: attitudes and practices of medical practitioners in South Australia. Arch Intern Med 1994;154(5):575–584. 73. Willems DL, Daniels ER, van der Wal G, van der Maas PJ, Emanuel EJ. Attitudes and practices concerning the end of life: a comparison between physicians from the United States and from The Netherlands [In Process Citation]. Arch Intern Med 2000;160(1):63–68. 74. Meier DE, Emmons CA, Wallenstein S, Quill T, Morrison RS, Cassel CK. A national survey of physician-assisted suicide and euthanasia in the United States [see comments]. N Engl J Med. 1998;338(17):1193–1201.

725 75. Douglas CD, Kerridge IH, Rainbird KJ, McPhee JR, Hancock L, Spigelman AD. The intention to hasten death: a survey of attitudes and practices of surgeons in Australia. Med J Aust 2001 November 19;175(10):511–515. 76. Rietjens JA, van der Heide A, Vrakking AM, Onwuteaka-Philipsen BD, van der Maas PJ, van der Wal G. Physician reports of terminal sedation without hydration or nutrition for patients nearing death in the Netherlands. Ann Intern Med 2004 August 3;141(3):178–185. 77. Twycross R. Regarding palliative sedation. J Pain Symptom Manage 2017 June;53(6):e13–e15. 78. Fainsinger RL, De Moissac D, Mancini I, Oneschuk D. Sedation for delirium and other symptoms in terminally ill patients in Edmonton. J Palliat Care 2000 Summer;16(2):5–10. 79. Murray SA, Boyd K, Byock I. Continuous deep sedation in patients nearing death. BMJ. 2008;336(7648):781–782. 80. Higgins PC, Altilio T. Palliative sedation: an essential place for clinical excellence. J Social Work in End-of-Life & Palliat Care 2007;3(4):3–30. 81. Ahronheim JC. Nutrition and hydration in the terminal patient. Clin Geriatr Med 1996;12(2):379–391. 82. Barber MD, Fearon KC, Delmore G, Loprinzi CL. Should cancer patients with incurable disease receive parenteral or enteral nutritional support? Eur J Cancer 1998;34(3):279–285. 83. Koshuta MA, Schmitz PJ, Lynn J. Development of an institutional policy on artificial hydration and nutrition. Kennedy Inst Ethics J 1991;1(2):133–139; discussion 9-40. 84. Jansen LA, Sulmasy DP. Sedation, alimentation, hydration, and equivocation: careful conversation about care at the end of life. Ann Intern Med 2002;136(11):845–849. 85. Ashby M, Stoffell B. Artificial hydration and alimentation at the end of life: a reply to Craig. J Med Ethics 1995;21(3):135–140. 86. Ventafridda V, Ripamonti C, De Conno F, Tamburini M, Cassileth BR. Symptom prevalence and control during cancer patients’ last days of life. J Palliat Care 1990;6(3):7–11. 87. Fainsinger R, Miller MJ, Bruera E, Hanson J, Maceachern T. Symptom control during the last week of life on a palliative care unit. J Palliat Care 1991;7(1):5–11. 88. Stone P, Phillips C, Spruyt O, Waight C. A comparison of the use of sedatives in a hospital support team and in a hospice. Palliat Med 1997;11(2):140–144. 89. Chiu TY, Hu WY, Lue BH, Cheng SY, Chen CY. Sedation for refractory symptoms of terminal cancer patients in Taiwan. J Pain Symptom Manage 2001 June;21(6):467–472. 90. Muller-Busch HC, Andres I, Jehser T. Sedation in palliative care: a critical analysis of 7 years experience. BMC Palliat Care 2003 May 13;2(1):2. 91. Sykes N, Thorns A. Sedative use in the last week of life and the implications for end-of-life decision making. Arch Intern Med 2003 February 10;163(3):341–344. 92. Morita T. Differences in physician-reported practice in palliative sedation therapy. Support Care Cancer. 2004 Feb;28(8):584–592. 93. Kohara H, Ueoka H, Takeyama H, Murakami T, Morita T. Sedation for terminally ill patients with cancer with uncontrollable physical distress. J Palliat Med 2005 February;8(1):20–25. 94. Vitetta L, Kenner D, Sali A. Sedation and analgesia-prescribing patterns in terminally ill patients at the end of life. Am J Hosp Palliat Care 2005 November-December;22(6):465–473. 95. Rietjens JA, van Zuylen L, van Veluw H, van der Wijk L, van der Heide A, van der Rijt CC. Palliative sedation in a specialized unit for acute palliative care in a cancer hospital: comparing patients dying with and without palliative sedation. J Pain Symptom Manage 2008 September;36(3):228–234. 96. Maltoni M, Pittureri C, Scarpi E, Piccinini L, Martini F, Turci P, et al. Palliative sedation therapy does not hasten death: results from a prospective multicenter study. Ann Oncol 2009 July;20(7):1163–1169. 97. Mercadante S, Intravaia G, Villari P, Ferrera P, David F, Casuccio A. Controlled sedation for refractory symptoms in dying patients. J Pain Symptom Manage 2009 May;37(5):771–779. 98. Schur S, Weixler D, Gabl C, Kreye G, Likar R, Masel EK, et al. Sedation at the end of life-a nation-wide study in palliative care units in Austria. BMC Palliat Care 2016;15(1):50.

76

STAFF STRESS AND BURNOUT IN PALLIATIVE CARE

Aimee E. Anderson and Eduardo Bruera

Contents Defining burnout���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������727 The clinician burnout epidemic�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������727 The unique challenges of palliative care�����������������������������������������������������������������������������������������������������������������������������������������������������������������������727 How does palliative care measure up?��������������������������������������������������������������������������������������������������������������������������������������������������������������������������728 The consequences of burnout�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������728 Management and prevention of burnout: Interventions for the organization and the individual�������������������������������������������������������������������729 A secret weapon for combating burnout���������������������������������������������������������������������������������������������������������������������������������������������������������������������731 References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������731 Recent studies have shown that the incidence of burnout in physicians and other health-care professionals in the United States has been increasing, with similar trends observed in other countries as well. 3–6 The US physician burnout epidemic is gaining increasing prominence not only in health-care circles but also in the popular media. While there are many contributing factors to burnout in the health-care environment, palliative care professionals may be at even higher risk.20,21 However, there are many steps that both individuals and their organizations can take to support professional engagement, prevent burnout, and maximize professional satisfaction. In this chapter, we delineate the burnout epidemic in the context of palliative care and discuss strategies to combat it.

Defining burnout Because there is much misunderstanding about the way the word “burnout” is used, understanding its scholarly definition is a vital cornerstone in any effort to reduce or prevent burnout in the workplace. Burnout is an occupational phenomenon—fundamentally, it is a syndrome that can develop when there is a problem in the relationship between workers and their workplace.24 While workers have long used the term “burnout” colloquially to refer to a phenomenon of exhaustion related to work, this syndrome was specifically defined by Christina Maslach as part of her early work to develop a validated tool, the Maslach Burnout Inventory, for measuring burnout.17,25–27 In Maslach’s conceptual model, there are three dimensions of burnout: emotional exhaustion (EE), depersonalization (DP), and a reduced sense of personal accomplishment (PA).24,26 EE is the best understood dimension of burnout, causing individuals to detach from their work at both cognitive and emotional levels.28 DP encompasses seeing one’s clients, patients, and/or coworkers as objects, rather than people, and is characterized by cynicism. Reduced PA is a sense of inefficacy; it can be particularly sensitive to work overload and a lack of resources needed to accomplish work. The three dimensions have complex relationships with each other and can feed into each other or develop in parallel depending on the stressors specific to a particular work situation. High levels of EE and DP, and low levels of PA, are associated with burnout28; fulfillment of any one of these conditions can be classified as burnout.

All three dimensions are impacted by occupational and organizational demands and by the characteristics of an individual; it is the interaction of these elements that ultimately changes the balance between engagement and burnout. Thus, “burnout” is not a problem with the individual but with the relationship between people and their workplace.24 Recently, the World Health Organization’s International Classification of Diseases (ICD-11) recognized burnout as a distinct occupational phenomenon, defining it as “a syndrome conceptualized as resulting from chronic workplace stress that has not been successfully managed.”29 Although not yet recognized as a medical or psychological diagnosis, occupational burnout is highly associated with consequences to mental and physical health, described in detail later.

The clinician burnout epidemic Workers employed in “helping professions” like medicine are often characterized as especially vulnerable to burnout. Indeed, the potential vulnerability of medical professionals to burnout has been recognized for some time, and much of the original work defining and measuring burnout was conducted in health-care workers.26 However, the reality of burnout in medicine was highlighted when a nationwide survey showed that rates of burnout in the US physicians greatly exceeded that of the general working population.5 This dire situation was further exposed in a followup study that suggested physician burnout had increased over a 3-year period.6 The realization that more than 50% of physicians were experiencing at least one symptom of burnout, and that the trend was worsening, has mobilized a worldwide dialogue on the work-life and employment conditions of health-care workers. These studies reported variable rates of burnout among different medical specialties;6 however, a comprehensive study of burnout in US palliative care professionals was lacking.

The unique challenges of palliative care There are a number of workplace conditions that may place palliative care professionals at even higher risk of burnout, including constant exposure to death, dying, and the suffering of patients and their loved ones (Figure 76.1).2,18,20,30–32 In settings where 727

728 TABLE 76.1  Domains of Burnout EE: Emotional exhaustion DP: Depersonalization PA: Personal accomplishment

clinicians may observe patients undergoing futile care with limited power to intervene, moral distress can occur, and this has been associated with burnout. 33–36 The high volume of ethical decision-making also takes a toll, 37 and dealing with children who are dying or bereaved is particularly stressful for many. 38 Moreover, in a specialty focused on the suffering of patients and their families, avoidance of compassion fatigue can be challenging, 39–41 and caring for patients with intractable symptoms despite administration of the best possible evidence-based care can be very stressful10; compassion fatigue has been associated with burnout in palliative care providers.42 When dealing with particularly troubling cases, vicarious exposure to trauma is a significant risk.43 One of the greatest challenges to providers is the extremely rapid growth in demand for palliative care services, with supply of palliative care workers greatly outpaced by need and demand44,45 and an outlook suggesting that an aging population will further accelerate demand well into the future.46 This situation places the palliative care workplace at risk for work overload and long hours, factors that research shows are major drivers of burnout.21,24,47 Moreover, as the field grows, conflict with other specialties is

Textbook of Palliative Medicine and Supportive Care a reported source of stress for many.10 While not unique to the palliative care setting, organizational constraints and demands, such as bureaucracy, pressure to generate revenue, insurance issues, conflicting requests for time, limited resources and staffing, and electronic medical record woes, can further compound workplace stress.12

How does palliative care measure up? While nationwide surveys of physician burnout in the United States broke down the population into many specialties, the burnout rates of clinicians in palliative care were not considered separately until a series of surveys of American Academy hospice and palliative care workers.21,48,49 In these studies, a burnout rate of nearly 39% among all respondents was reported. Burnout was also associated with younger clinicians.21,48,49 The correlation of burnout with younger age is consistent with other studies of medical professionals that suggest earlier career stages are more susceptible, 50 and longer hours and weekend work are consistent with overload as a driver of burnout.24,47 Alarmingly, a survey of the palliative care workforce conducted jointly with the burnout survey suggested that a significant proportion of respondents intend to leave the field in the next 5–15 years; behind retirement, the most common reason cited by respondents was burnout.51 Thus, there is evidence that burnout in palliative care may have dire implications for the profession and for the provision of care to patients with serious illness; clearly, burnout and workplace wellness deserve significant attention. Mirroring the situation in palliative care clinicians, US palliative care chaplains report higher levels of distress than non-palliative care chaplains.19 These findings suggest that the entire palliative care team may be at risk. In the past, high variability in the methodology used to define and measure burnout has made comparisons between professions and settings difficult (Table 76.2).52 For example, a survey conducted in 2010–2011 focused on all specialties involved in endof-life care found a lower rate of burnout in those physicians and in US physicians in general, but differences in inclusion criteria, instrument for measuring burnout, and response rate make comparison difficult.53 Moreover, the rapidly changing health-care landscape may come into play when comparing burnout scores from different time periods. Nonetheless, it is interesting to note that geographic factors, such as the health-care environment or cultural issues, may play a role, as in some settings outside the United States, the rate of burnout in palliative care professionals has varied and in some cases has not differed significantly from other medical professions.8,23,47,54–57 Recent evidence also suggests that the clinical setting in which palliative care is provided can impact burnout, with those practicing exclusively in mobile teams more likely to score highly in EE, 58 while a recent survey of pediatric palliative care providers in the United States showed a relatively low rate of burnout using a simplified burnout measure.59

The consequences of burnout

FIGURE 76.1  Drivers of burnout in the palliative care workforce.

Burnout has serious consequences to the individual and the workplace, as well as considerable implications to the palliative care workforce, the health-care system as a whole, and the patients they serve. Psychological and emotional symptoms, such as depression and anxiety, may occur.61 By its very nature, burnout pushes workers toward cynicism and DP of patients and coworkers24,28; in

Staff Stress and Burnout in Palliative Care

729

TABLE 76.2  Reported Palliative Care Burnout Rates by Country, Year, and Profession Reference

Measurement Method

Country

Year Surveyed

Kamal et al.

United States

2013

Rizo-Baeza et al.47 Yoon et al.53 Dunwoodie and Auret54 Ercolani et al.23

Mexico United States Australia

2015 2010–2011 2005

MBI (custom cutoffs; DP and EE only) MBI Custom survey MBI

Italy

2016

MBIb

Kaur et al.55 Koh et al.9 Pattison et al.56

India Singapore United Kingdom

Not reported 2013 2017

ProQoL MBI MBIb

Dréano-Hartz et al.58

France

2012–2013

MBIb

Kase et al.59

United States

Not reported

CFST

48,49,60

Burnout Rate, By Profession Physician

AHP

Nurse

Psychologist

41.9%

Other 37.1%

34.6% 20%a 24%a 66% (DP) 19% (Low PA) 14% (EE)

65% (DP) 27% (Low PA) 7% (EE)

75% (DP) 7% (Low PA) 7% (EE) 53%c

33% 22% (DP) 6% (Low PA) 0% (EE) 4% (DP) 23% (Low PA) 9% (EE) 12%

33% (DP) 33% (Low PA) 0% (EE)

25% (DP) 46% (Low PA) 0% (EE)

12%d,e

Abbreviations: MBI, Maslach Burnout Inventory; ProQoL, Professional Quality of Life—Version 5; CFST, Compassion Fatigue and Satisfaction Self-Test for helpers. a Includes palliative care and other “end-of-life specialties.” b Overall burnout rate not reported. c Overall value for entire palliative care workforce, including physician, nurse, counselor, psychologist, social worker, pharmacist, or physiotherapist. d Pediatric palliative care only. e Physicians and nurses combined.

the clinic, burnout is associated with decreased quality of patient care,10,62 increased frequency of mistakes,63 absenteeism and tardiness, and engagement in maladaptive behaviors such as alcoholism and drug use.61,64 Serious psychological issues, including depression and suicidal ideation, are also associated with burnout.65,66 Importantly, when providers and other employees begin to display these behaviors on the job, burnout can spread through the insidious phenomenon of “burnout contagion.”28 Thus, when burnout begins to become a problem in the workplace, the need to intervene is urgent. Therefore, it should be kept in mind that if working conditions lead any component of the workforce to burnout—be it physicians, nurses, advanced practice providers, social workers, chaplains, or administrative and research staff— there is the potential for burnout to spread to other work units and severely impact the entire team. Extensive work has connected burnout with poor physical health.28,61 Mechanistically, the health consequences may be explained by evidence suggesting that burnout may impact physiological markers of stress; for example, studies have suggested that palliative care workers under chronic occupational stress may have elevated levels of markers for oxidative stress,67 and elevations in salivary cortisol have been associated with burnout in the palliative care workforce.68 Stress and longer working hours in early-career-stage physicians were recently associated with markers of cellular aging, including telomere shortening.69 Particularly worrying in the palliative care field, where demand exceeds supply, burnout is associated with desire to leave the job or even the profession.21 Moreover, replacing a worker who leaves due to burnout is expensive for organizations and the healthcare system. It was estimated that the cost to replace a single

primary care physician in 2013 exceeded $250,00070; for a specialist such as a palliative care physician, it can safely be assumed the cost would be significantly higher. Although salaries vary, attrition and replacement of employees of all kinds are a major cost to organizations and can include less tangible factors such as the time it takes to train a new employee and integrate them smoothly into the team. Thus, loss of palliative care professionals can be a major setback to provision of high-quality care, with ripple effects throughout the institution and the profession.

Management and prevention of burnout: Interventions for the organization and the individual At the individual level, burnout prevention focuses on increasing the worker’s resiliency to the stresses of work-life. Previously, these resiliency-based strategies have been the most commonly employed measures. Indeed, resiliency-building strategies have been proposed frequently71; logistically, they are easier to conceptualize and implement. Palliative care involves many stressors; however, professionals have identified a number of elements they perceive to be protective. Strategies such as improving physical well-being, working in a variety of clinical settings,8 and meditation, recalling the passion for work, reflecting on patients, finding meaning in work,72 and maintaining realistic expectations, have been correlated with less burnout in published studies.9 One of the most commonly employed individual resiliency strategies is the practice of mindfulness and meditation, which has been shown to have a significant impact on burnout and related measures in the

730 TABLE 76.3 Coping Strategies Reported by Palliative Care Professionals • Reflection on the rewards of palliative care work and the opportunity to make a difference in the lives of patients and their families1,2 • Attending to physical wellness1 • Practicing personal spirituality7–9 • Personal coping strategies and self-care10–18 • Pursuing professional relationships (including mentoring and receiving mentorship)1,12,19 • Hobbies1 • Time away from work1 • Setting realistic expectations1 • Humor1 • Maintaining appropriate personal and professional boundaries1,10,22,23

health-care setting, 38,57,73–75 and related cognitive–behavioral and mind–body interventions have also been explored.76 Education in palliative care may also be protective,15,77,78 and Balint group meetings aimed at increasing professional efficacy have been associated with improved burnout scores.79 Recently, combining several interventions into a comprehensive employee wellness program was reported as a successful strategy, with significant uptake of multiple interventions within the program and measurable impact on staff well-being.80 Anecdotal reports of other interventions to combat burnout have had encouraging results but may lack concrete evidence of their success in reducing burnout. Examples include forums allowing health-care workers to openly discuss death in a group setting, 81,82 support groups,12 and orientation programs to prepare new clinicians for the challenges of palliative care. 83 Research increasingly suggests that focusing solely on individual resiliency is less powerful than combining individual- and organizational-based interventions,28,84–86 and it is recognized that organizational measures are necessary to fully address palliative care burnout.64,85 In fact, organizational measures may have a greater impact than resiliency-focused interventions.87 In the work environment, six factors are thought to fundamentally impact employee burnout: workload, control, reward, community, fairness, and values.28 Thus, effective organizational strategies directly target one or more of these factors. The influence of each of these factors on burnout seems intuitive. For example, excessive workload exhausts employees and may make them feel that they can never effectively complete their work or perform their work at the highest level. Executives and other leaders increasingly indicate their recognition of the importance of an engaged workforce. Unfortunately, while organizational leaders may theoretically embrace practices that support providers, the actual systemic implementation of concrete measures to reduce burnout can prove difficult88 in the face of pressures to maintain productivity and fiscal viability. However, organizational approaches can be implemented at any level, from the small team to a health-care institution or system. For example, for physicians, key drivers of the burnout/engagement balance may include optimized workload and job demands, efficiency and resources, meaning, culture and values, control, social support and community, and work-life integration.64 At the team level, a clinical supervision model gleaned from mental health practice, in which less experienced team members form an apprenticeship relationship with more experienced team members, was implemented in the palliative care setting with reported

Textbook of Palliative Medicine and Supportive Care success.89 It has also been suggested that the interdisciplinary nature of palliative care teams and the shared decision-making these teams naturally employ may be protective. 37 At the institutional level, there is significant evidence that excessive workload and increased hours worked per week correlate strongly with burnout,9,21 in line with overload as a key driver,24 and thus, strategies to reduce the number of hours worked by clinicians are likely to be successful interventions. Unsurprisingly, the leadership qualities of clinical managers are also associated with the engagement/burnout balance.90 In the absence of institutional support, palliative care staff and clinicians can take basic steps to ensure their self-care remains a priority. Honest reflection of stress levels and seeking help when stress becomes a problem is important. At the same time, clinicians are unlikely to thrive in a work environment that is consistently unsupportive, unresponsive, or toxic, or conflicts with their values.91 For both individual and organizational interventions, success may depend on the context. Therefore, understanding what drives the balance between engagement and employees in any group is essential in choosing interventions that are likely to succeed. It makes sense for leaders in palliative care to measure burnout and job satisfaction in the work unit in order to identify potential targets and focus on those interventions most likely to make a meaningful difference. It also makes sense for leaders to ensure that burnout, engagement, and job satisfaction are measured using validated tools—both before and after the intervention—to ensure that only those measures proving valuable to the workforce continue. Indeed, participating in burnout research has been identified as a useful strategy for combating burnout itself.92 We, therefore, submit that leaders in palliative care proactively implement “universal precautions” to prevent burnout and maintain engagement. Chief among these is frequent, anonymous surveys of staff and faculty to measure the frequency, severity, and drivers of burnout. Leaders must then act to improve working conditions in a meaningful way, keeping in mind the importance of workload, control, reward, community, fairness, and values. Here, the survey information will prove invaluable to finding the interventions most likely to make a significant impact. The response must be swift and transparent to reassure the workforce that their voices have been heard, and that their survey responses matter: doing so will have an immediate positive impact on morale when employees see that leadership cares about their well-being and will likely increase the response rate for future surveys. Next, it is important to find out if the changes to the workplace have made a positive change in burnout and engagement in the next anonymous survey, and on a continuous basis by listening to employees and striving to understand their concerns. Beyond survey feedback, leaders can also find opportunities to enhance office or clinic life through small acts of workplace engineering, such as the addition of artwork or soft music, or through larger strategic initiatives, such as changing the structure of meetings or altering schedules. Leaders can also give their employees reminders and examples of self-care strategies. However, leaders cannot simply prescribe self-care to their teams: they must practice it, live it, and actively model it. Doing so will reassure workers that their leaders really do want them to engage in self-care, even if it takes a few minutes from their other tasks. Leaders must make it clear that taking care of one’s physical and psychosocial needs is a core value that extends to the entire workforce.

Staff Stress and Burnout in Palliative Care

A secret weapon for combating burnout Despite the inherently stressful aspects of palliative care, palliative care professionals can thrive when they are supported and engaged, benefiting from the rewarding aspects of their work. 32,78 Many find the personal interactions with their patients, focusing intensively on the quality of life of these individuals and their families at a highly significant time in their lives, to be highly motivating and meaningful.2,18,78 Moreover, palliative care workers do have one secret weapon to combat burnout that is less available to other medical professionals: as members of an interdisciplinary care team, they can take advantage of their colleagues’ expertise for advice on physical, psychosocial, and spiritual interventions that can really help them cope.12,19,35,82 Even more importantly, the emotional support and community of colleagues who face the same challenges can be an invaluable resource to replenish energy, and even the act of helping one’s colleagues who themselves are in distress can have a reciprocal positive effect on engagement and well-being.18,19 By leveraging the very same strengths and skills palliative care professionals employ to help their patients, the potential to overcome the burnout epidemic in the palliative care setting is even greater than the forces conspiring to worsen it.

References









1. Swetz KM, Harrington SE, Matsuyama RK, Shanafelt TD, Lyckholm LJ. Strategies for avoiding burnout in hospice and palliative medicine: peer advice for physicians on achieving longevity and fulfillment. J Palliat Med 2009;12(9):773–777. 2. Zambrano SC, Chur-Hansen A, Crawford GB. The experiences, coping mechanisms, and impact of death and dying on palliative medicine specialists. Palliat Support Care 2014;12(4):309–316. 3. Asai M, Morita T, Akechi T, et al. Burnout and psychiatric morbidity among physicians engaged in end-of-life care for cancer patients: a cross-sectional nationwide survey in Japan. Psycho-oncology 2007;16(5):421–428. 4. Bany Hamdan A, Alshammary S, Javison S, Tamani J, AlHarbi M. Burnout among healthcare providers in a comprehensive cancer center in Saudi Arabia. Cureus 2019;11(1):e3987. 5. Shanafelt TD, Boone S, Tan L, et al. Burnout and satisfaction with work-life balance among US physicians relative to the general US population. Arch Intern Med 2012;172(18):1377–1385. 6. Shanafelt TD, Hasan O, Dyrbye LN, et al., eds. Changes in burnout and satisfaction with work-life balance in physicians and the general US working population between 2011 and 2014. Mayo Clinic Proceedings 2015: Elsevier. 7. Holland JM, Neimeyer RA. Reducing the risk of burnout in end-oflife care settings: the role of daily spiritual experiences and training. Palliat Support Care 2005;3(3):173–181. 8. Koh M, Hum A, Wenwei XI. Clinical variety may help prevent burnout after a decade in palliative care. J Pain Symptom Manage 2018;55(2):e3–e5. 9. Koh MY, Chong PH, Neo PS, et al. Burnout, psychological morbidity and use of coping mechanisms among palliative care practitioners: a multi-centre cross-sectional study. Palliat Med 2015;29(7):633–642. 10. Kavalieratos D, Siconolfi DE, Steinhauser KE, et al. “It is like heart failure. It is chronic … and it will kill you”: a qualitative analysis of burnout among hospice and palliative care clinicians. J Pain Symptom Manage 2017;53(5):901–910.e1. 11. Kearney MK, Weininger RB, Vachon ML, Harrison RL, Mount BM. Self-care of physicians caring for patients at the end of life: “being connected… a key to my survival”. JAMA 2009;301(11):1155–1164.E1. 12. Meier DE, Beresford L. Preventing burnout. J Palliat Med 2006;9(5):1045–1048. 13. Montross-Thomas LP, Scheiber C, Meier EA, Irwin SA. Personally meaningful rituals: a way to increase compassion and decrease burnout among hospice staff and volunteers. J Palliat Med 2016;19(10):1043–1050.

731 14. Nyatanga B. Avoiding burnout syndrome in palliative care. Br J Commun Nurs 2014;19(10):515. 15. Sanchez-Reilly S, Morrison LJ, Carey E, et al. Caring for oneself to care for others: physicians and their self-care. J Support Oncol 2013;11(2):75–81. 16. Sanso N, Galiana L, Oliver A, Pascual A, Sinclair S, Benito E. Palliative care professionals’ inner life: exploring the relationships among awareness, self-care, and compassion satisfaction and fatigue, burnout, and coping with death. J Pain Symptom Manage 2015;50(2):200–207. 17. Schutte N, Toppinen S, Kalimo R, Schaufeli W. The factorial validity of the Maslach Burnout Inventory-General Survey (MBI-GS) across occupational groups and nations. J Occup Organ Psychol 2000;73(1):53–66. 18. Taylor J, Aldridge J. Exploring the rewards and challenges of paediatric palliative care work – a qualitative study of a multi-disciplinary children’s hospice care team. BMC Palliat Care 2017;16(1):73. 19. White KB, Murphy PE, Jeuland J, Fitchett G. Distress and self-care among chaplains working in palliative care. Palliat Support Care 2019:1–8. 20. Hynes J, Maffoni M, Argentero P, Giorgi I, Giardini A. Palliative medicine physicians: doomed to burn? BMJ Support Palliat Care 2019;9(1):45–46. 21. Kamal AH, Bull JH, Wolf SP, et al. Prevalence and predictors of burnout among hospice and palliative care clinicians in the U.S. J Pain Symptom Manage 2016;51(4):690–696. 22. Ablett JR, Jones RS. Resilience and well-being in palliative care staff: a qualitative study of hospice nurses’ experience of work. Psychooncology 2007;16(8):733–740. 23. Ercolani G, Varani S, Peghetti B, et al. Burnout in home palliative care: what is the role of coping strategies? J Palliat Care 2019:825859719827591. 24. Maslach C, Leiter MP. The Truth about Burnout: How Organizations Cause Personal Stress and What To Do About It: John Wiley & Sons; 2008. 25. Cordes CL, Dougherty TW. A review and an integration of research on job burnout. Acad Manage Rev 1993;18(4):621–656. 26. Maslach C, Jackson SE. The measurement of experienced burnout. J Occup Behav 1981;2(2):99–113. 27. Schaufeli WB, Bakker AB, Hoogduin K, Schaap C, Kladler A. on the clinical validity of the Maslach burnout inventory and the burnout measure. Psychol Health 2001;16(5):565–582. 28. Maslach C, Schaufeli WB, Leiter MP. Job burnout. Annu Rev Psychol 2001;52(1):397–422. 29. WHO. International Classification of Disease 11th Revision. 2019. Available from: https://icd.who.int/en/. 30. Baumrucker SJ. Palliative care, burnout, and the pursuit of happiness. Am J Hosp Palliat Care 2002;19(3):154–156. 31. Ramirez A, Addington-Hall J, Richards M. ABC of palliative care. The carers. BMJ (Clin Res ed) 1998;316(7126):208–211. 32. Samson T, Shvartzman P. Association between level of exposure to death and dying and professional quality of life among palliative care workers. Palliat Support Care 2018;16(4):442–451. 33. Chamberlin P, Lambden J, Kozlov E, et al. Clinicians’ perceptions of futile or potentially inappropriate care and associations with avoidant behaviors and burnout. J Palliat Med 2019. 34. Lambden JP, Chamberlin P, Kozlov E, et al. Association of perceived futile or potentially inappropriate care with burnout and thoughts of quitting among health-care providers. Am J Hosp Palliat Care 2018:1049909118792517. 35. Parola V, Coelho A, Sandgren A, Fernandes O, Apostolo J. Caring in palliative care: a phenomenological study of nurses’ lived experiences. J Hosp Palliat Nurs: JHPN 2018;20(2):180–186. 36. Rushton CH, Kaszniak AW, Halifax JS. A framework for understanding moral distress among palliative care clinicians. J Palliat Med 2013;16(9):1074–1079. 37. Hernandez-Marrero P, Pereira SM, Carvalho AS, DeliCaSp. Ethical decisions in palliative care: interprofessional relations as a burnout protective factor? Results from a mixedmethods multicenter study in Portugal. Am J Hosp Palliat Care 2016;33(8):723–732. 38. O’Mahony S, Gerhart J, Abrams I, et al. A multimodal mindfulness training to address mental health symptoms in providers who care for and interact with children in relation to end-of-life care. Am J Hosp Palliat Care 2017;34(9):838–843.

732 39. Cross LA. Compassion fatigue in palliative care nursing: a concept analysis. J Hosp Palliat Nurs: JHPN 2019;21(1):21–28. 40. McCloskey S, Taggart L. How much compassion have I left? An exploration of occupational stress among children’s palliative care nurses. Int J Palliat Nurs 2010;16(5):233–240. 41. O’Mahony S, Ziadni M, Hoerger M, Levine S, Baron A, Gerhart J. Compassion fatigue among palliative care clinicians: findings on personality factors and years of service. Am J Hosp Palliat Care 2018;35(2):343–347. 42. Slocum-Gori S, Hemsworth D, Chan WW, Carson A, Kazanjian A. Understanding compassion satisfaction, compassion fatigue and burnout: a survey of the hospice palliative care workforce. Palliat Med 2013;27(2):172–178. 43. O’Mahony S, Gerhart JI, Grosse J, Abrams I, Levy MM. Posttraumatic stress symptoms in palliative care professionals seeking mindfulness training: Prevalence and vulnerability. Palliat Med 2016;30(2):189–192. 44. Hughes MT, Smith TJ. The growth of palliative care in the United States. Annu Rev Public Health 2014;35:459–475. 45. Lupu D, American Academy of Hospice and Palliative Medicine Workforce Task Force. Estimate of current hospice and palliative medicine physician workforce shortage. J Pain Symptom Manage 2010;40(6):899–911. 46. Smith BD, Smith GL, Hurria A, Hortobagyi GN, Buchholz TA. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol 2009;27(17):2758–2765. 47. Rizo-Baeza M, Mendiola-Infante SV, Sepehri A, Palazon-Bru A, GilGuillen VF, Cortes-Castell E. Burnout syndrome in nurses working in palliative care units: an analysis of associated factors. J Nurs Manage 2018;26(1):19–25. 48. Kamal A, Bull JH, Wolf SP, et al. Letter to the Editor regarding “Prevalence and predictors of burnout among hospice and palliative care professionals” from 2016 Apr;51(4):690–696. J Pain Symptom Manage 2019. 49. Kamal AH, Wolf SP, Troy J, et al. Policy changes key to promoting sustainability and growth of the specialty palliative care workforce. Health Aff (Millwood) 2019;38(6):910–918. 50. Dyrbye LN, West CP, Satele D, et al. Burnout among US medical students, residents, and early career physicians relative to the general US population. Acad Med 2014;89(3):443–451. 51. Kamal AH, Bull JH, Swetz KM, Wolf SP, Shanafelt TD, Myers ER. Future of the palliative care workforce: preview to an impending crisis. Am J Med 2017;130(2):113–114. 52. Parola V, Coelho A, Cardoso D, Sandgren A, Apostolo J. Prevalence of burnout in health professionals working in palliative care: a systematic review. JBI Database System Rev Implementation Rep 2017;15(7):1905–1933. 53. Yoon JD, Hunt NB, Ravella KC, Jun CS, Curlin FA. Physician burnout and the calling to care for the dying: a national survey. Am J Hosp Palliat Care 2017;34(10):931–937. 54. Dunwoodie DA, Auret K. Psychological morbidity and burnout in palliative care doctors in Western Australia. Intern Med J 2007;37(10):693–698. 55. Kaur A, Sharma MP, Chaturvedi SK. Professional quality of life among professional care providers at cancer palliative care centers in Bengaluru, India. Indian J Palliat Care 2018;24(2):167–172. 56. Pattison N, Droney J, Gruber P. Burnout: caring for critically ill and end-of-life patients with cancer. Nurs Crit Care. 2019. 57. Podgurski L, Greco C, Croom A, Arnold R, Claxton R. A brief mindfulness-based self-care curriculum for an interprofessional group of palliative care providers. J Palliat Med 2019;22(5):561–565. 58. Dréano-Hartz S, Rhondali W, Ledoux M, et al. Burnout among physicians in palliative care: impact of clinical settings. Palliat Support Care 2016;14(4):402–410. 59. Kase SM, Waldman ED, Weintraub AS. A cross-sectional pilot study of compassion fatigue, burnout, and compassion satisfaction in pediatric palliative care providers in the United States. Palliat Support Care 2019;17(3):269–275. 60. Kamal AH, Shanafelt TD. Measuring burnout in palliative care: authors’ reply. J Pain Symptom Manage 2016;52(2):e2. 61. Kahill S. Symptoms of professional burnout – a review of the empirical-evidence. Can Psychol 1988;29(3):284–297. 62. Carrieri D, Peccatori FA, Boniolo G. Supporting supportive care in cancer: the ethical importance of promoting a holistic conception of quality of life. Crit Rev Oncol/Hematol 2018;131:90–95.

Textbook of Palliative Medicine and Supportive Care 63. Shanafelt TD, Balch CM, Bechamps G, et al. Burnout and medical errors among American surgeons. Ann Surg 2010;251(6):995–1000. 64. Shanafelt TD, Noseworthy JH, eds. Executive leadership and physician well-being: nine organizational strategies to promote engagement and reduce burnout. Mayo Clinic Proceedings 2017: Elsevier. 65. Shanafelt TD, Balch CM, Dyrbye L, et al. Special report suicidal ideation among American surgeons. Arch Surg 2011;146(1):54–62. 66. Shirom A. Reflections on the study of burnout. Work Stress 2005;19(3):263–270. 67. Casado A, Castellanos A, Lopez-Fernandez ME, et al. Determination of oxidative and occupational stress in palliative care workers. Clin Chem Lab Med 2011;49(3):471–477. 68. Fernandez-Sanchez JC, Perez-Marmol JM, Blasquez A, SantosRuiz AM, Peralta-Ramirez MI. Association between burnout and cortisol secretion, perceived stress, and psychopathology in palliative care unit health professionals. Palliat Support Care 2018;16(3):286–297. 69. Ridout KK, Ridout SJ, Guille C, Mata DA, Akil H, Sen S. Physician-training stress and accelerated cellular aging. Biol Psychiatry 2019. 70. Linzer M, Levine R, Meltzer D, Poplau S, Warde C, West CP. 10 bold steps to prevent burnout in general internal medicine. J Gen Intern Med 2014;29(1):18–20. 71. Back AL, Steinhauser KE, Kamal AH, Jackson VA. Building resilience for palliative care clinicians: an approach to burnout prevention based on individual skills and workplace factors. J Pain Symptom Manage 2016;52(2):284–291. 72. Moreno-Milan B, Cano-Vindel A, Lopez-Doriga P, Medrano LA, Breitbart W. Meaning of work and personal protective factors among palliative care professionals. Palliat Support Care 2019:1–7. 73. Dharmawardene M, Givens J, Wachholtz A, Makowski S, Tjia J. A systematic review and meta-analysis of meditative interventions for informal caregivers and health professionals. BMJ Support Palliat Care 2016;6(2):160–169. 74. Lehto RH, Heeter C, Allbritton M, Wiseman M. Hospice and palliative care provider experiences with meditation using mobile applications. Oncol Nurs Forum 2018;45(3):380–388. 75. Orellana-Rios CL, Radbruch L, Kern M, et al. Mindfulness and compassion-oriented practices at work reduce distress and enhance selfcare of palliative care teams: a mixed-method evaluation of an “on the job” program. BMC Palliat Care 2017;17(1):3. 76. Mehta DH, Perez GK, Traeger L, et al. Building resiliency in a palliative care team: a pilot study. J Pain Symptom Manage 2016;51(3):604–608. 77. Pereira SM, Fonseca AM, Carvalho AS. Burnout in palliative care: a systematic review. Nurs Ethics 2011;18(3):317–326. 78. Siegel M. Palliative care as life support for my career. J Emerg Med 2017;52(1):121–122. 79. Popa-Velea O, Trutescu CI, Diaconescu LV. The impact of Balint work on alexithymia, perceived stress, perceived social support and burnout among physicians working in palliative care: a longitudinal study. Int J Occup Med Environ Health 2019;32(1):53–63. 80. Slater PJ, Edwards RM, Badat AA. Evaluation of a staff well-being program in a pediatric oncology, hematology, and palliative care services group. J Healthcare Leadersh 2018;10:67–85. 81. Hammer R, Ravindran N, Nielsen N. Can Death Cafes resuscitate morale in hospitals? Med Humanit 2019. 82. Morris SE, Kearns JP, Moment A, Lee KA, deLima TJ. “Remembrance”: a self-care tool for clinicians. J Palliat Med 2019;22(3):316–318. 83. Kamau C, Medisauskaite A, Lopes B. Orientations can avert psychosocial risks to palliative staff. Psycho-oncology 2014;23(6):716–718. 84. Awa WL, Plaumann M, Walter U. Burnout prevention: a review of intervention programs. Patient Educ Counsel 2010;78(2):184–190. 85. Harrison KL, Dzeng E, Ritchie CS, et al. Addressing palliative care clinician burnout in organizations: a workforce necessity, an ethical imperative. J Pain Symptom Manage 2017;53(6):1091–1096. 86. Shanafelt T, Trockel M, Ripp J, Murphy ML, Sandborg C, Bohman B. Building a program on well-being: key design considerations to meet the unique needs of each organization. Acad Med 2019;94(2):156–161. 87. Panagioti M, Panagopoulou E, Bower P, et al. Controlled interventions to reduce burnout in physicians: a systematic review and meta-analysis. JAMA Intern Med 2017;177(2):195–205. 88. Gilligan MC, Osterberg LG, Rider EA, et al. Views of institutional leaders on maintaining humanism in today’s practice. Patient Educ Counsel 2019.

Staff Stress and Burnout in Palliative Care 89. Edmonds KP, Yeung HN, Onderdonk C, Mitchell W, Thornberry K. Clinical supervision in the palliative care team setting: a concrete approach to team wellness. J Palliat Med 2015;18(3):274–277. 90. Shanafelt TD, Gorringe G, Menaker R, et al. Impact of organizational leadership on physician burnout and satisfaction. Mayo Clinic Proc 2015;90(4):432–440.

733 91. Bruera E. Some Notes For Physicians Contemplating A Career In Palliative and Person-Centered Care. 1st ed. Houston, TX: The University of Texas MD Anderson Cancer Center, 2019. 82 p. 92. Maslach C, Leiter MP, Jackson SE. Making a significant difference with burnout interventions: researcher and practitioner collaboration. J Organ Behav 2012;33(2):296–300.

77

SPIRITUAL CARE

Marvin Omar Delgado-Guay and Alexander Harding

Contents Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������735 Spirituality and religiosity�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������735 Spiritual needs and spiritual/existential concerns in patients with advanced illness and their caregivers�����������������������������������������������737 Providing spiritual care to patients with advanced illness and their caregiver in distress���������������������������������������������������������������������������738 Spiritual interventions������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������738 References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������740

Introduction Spirituality is recognized as a factor that contributes to health in many people and is an important component in the care of patients with life-threatening illnesses, such as cancer and congestive heart failure.1–4 Spiritual and religious beliefs can affect the way patients cope with their illnesses, creating distress and worsening the burden of the illness.1,5 The concept of spirituality is found in all cultures and societies. Its meaning is not limited to participation in organized religion but is rather much broader than that—encompassing belief in God, family, naturalism, rationalism, humanism, and even the arts.1,5–9 Spirituality is a dimension of personhood, a part of our being. Religion is a construct of human making which enables the conceptualization and expression of spirituality.10,11 A key goal of palliative care services is to alleviate patient’s suffering. Suffering is a biopsychosocial, multidimensional construct that includes physical, emotional, as well as spiritual pain. The spirituality and religiosity field is important to consider when we evaluate patients with advanced and terminal illness because it can influence coping strategies and quality of life. The presence of spiritual pain can be an important component of the patients with chronic or acute pain and other physical and psychological symptoms.12 Spiritual care is an important part of health care, especially when facing the crisis of advanced cancer and at the end of life. When spiritual needs and spiritual distress are not addressed, patients are at risk of depression and reduced sense of spiritual meaning and peace13 and dignity.14 The purpose of this chapter is to provide an overview about the role of spirituality and religiosity in advanced illness patients’ way of coping and the importance of providing a comprehensive spiritual assessment and spiritual care in an interdisciplinary team setting, such as palliative care.

Spirituality and religiosity Many authors have highlighted the considerable overlap and the distinct characteristics of religion and spirituality.11,15–17 Main themes include a relationship with a God, spiritual being, Higher Power, or a reality greater than the self (not of the self); transcendence or connectedness unrelated to a belief in a higher being; existential, not of the material world; meaning and purpose in life; life force of the person, integrating aspect of the person and a combination of multiple themes.9,18 Spirituality can be defined

as “the aspect of humanity that refers to the way individuals seek and express meaning and purpose and the way they experience their connectedness to the moment, to self, to others, to nature, and to the significant or sacred”.1 Spirituality is a dimension of personhood, a part of our being, while religion is a construct of human making, which enables the conceptualization and expression of spirituality 11; this encompass structured belief systems that address spiritual issues, often with a code of ethical behavior and philosophy.17 Religious rituals enact and manifest the meaning of the sacred; they establish shared meaning, foster belonging, and bridge the boundary between the personal and the social.17 Both religious practices and spiritual beliefs are common in the United States.19,20 Gallup,20 reported in 2018 that religion/spirituality was noted as “very important” by 50% of Americans and “fairly important” by another 21%. A percentage of 50–95 patients living with cancer consider spirituality/religion an important part of their life.21–25 Many also report the need for a sense of connectedness or spirituality.6,26–30 It has also been documented that those who report greater religiosity/spirituality also report more adaptive coping styles, physical well-being, and a better quality of life.8,26,31–35,104 Thus, in the context of coping with a life-threatening illness such as cancer, one possibility is that spiritual well-being may serve as a buffer against depression, hopelessness, and desire for death in patients with advanced disease.21,30,36,104 Another possibility is that greater spirituality/religiosity is associated with more negative religious coping (illness as a consequence of God’s punishment), which can lead to distress and decreased quality of life and suffering.7,37,38 In a cohort of advanced cancer patients evaluated in the palliative care outpatient clinic, almost all of them considered themselves spiritual (98%) and religious (98%). The patients also reported that spirituality and/or religiosity help them in coping with their illness (99%), is a source of strength (100%), and have a positive impact on their physical (69%) and emotional (84%) symptoms.12 Moreover, advanced cancer patients expressed their inner strength and meaning of life in terms of the Divine (through praying, hope, faith, communication with God) in 76%; in terms of their own value as human beings in 17%, and in terms of the relationships with others (family members, friends, and partners) in 7%.39 Different models of spirituality have been developed for a health-care context. Farran and her colleagues proposed the use of a functional definition of spirituality operating through seven major dimensions such as belief and meaning, authority 735

736

Textbook of Palliative Medicine and Supportive Care

and guidance, and ritual and practice. These dimensions are set within a context of universal events and experiences (such as health, illness, pain, and suffering), which provide the possibility for expanded or limited spiritual functioning and spiritual growth.40 Models of spirituality have been developed explicitly for palliative care. Kellehear’s descriptive model is focused on the need of patients to find meaning beyond their suffering through situational, moral, biographical, and religious transcendence.41 Also, Wright proposes an inclusive model of spirituality based on a synthesis of ideas that includes activities of “transcending,” “connecting,” “finding meaning,” and “becoming” that operate through the dimensions of the self, others, and the cosmos.42 Spirituality is lived and experienced in the lives of patients with life-limiting conditions and also in their caregivers. That allows them to cope with different situations in their life and respond to them either with or without distress or suffering (Figure 77.1). Spirituality serves several purposes in different stages of life, which is similar to the concept of different needs and conflicts associated with different ages.43 In addition, Fowler recognized six stages of faith and also recognized the fact that individual development may stop at any stage44,45:

2. Mythic–literal faith (ages 7–12 years): When family specified perspectives and meanings of morals and God are internalized 3. Synthetic–conventional faith (adolescence onward): When faith is accepted without critical evaluation 4. Individuative-reflective faith: When an individual’s own belief is critically examined and reconstructed 5. Conjunctive faith (midlife and beyond): When disillusionment with that belief system sets in, and one is caught between it and openness to other religious traditions 6. Universalizing faith (late life): Brings oneness with the power of being or divinity, willingness to promote justice in the world, and fellowship with others, regardless of their faith stage or religious tradition.

1. Intuitive–projective faith (ages 2–7 years): When child becomes aware of God

The theories of faith development emphasize the evolution of faith in late life after the completion of all developmental cognitive stages. Spirituality is a lifelong developmental task, lasting until death.46,47 Dying is no longer a part of human’s daily consciousness or an accepted final event of life. The continuing advances of medical technology have altered attitudes toward dying. The dying stage in our life can be experienced as the most profound event of our life experience. Dying begins when the facts of life are finally recognized, communicated, and accepted.48 Older people tend to think about dying and death more than any other age group.49

FIGURE 77.1  Spirituality and religiosity as a lived experience in coping strategies and their impact in symptom distress and quality of life in patients with advanced illnesses.

Spiritual Care The fear of dying is considered the most prevalent emotion. The findings about the relationship of age and fear of dying are mixed.50,51 Other emotions linked to death and dying are hope and the continuity of hope, 52 the feeling of loss (e.g., of control, competence, independence, people or dreams for the future), 53 loneliness, 54 dignity/integrity, 55 forgiveness, 56 and love.57 As a society, we shy away from death and the idea of termination. In recent years, research has led people toward greater awareness and an increase of interest in the dying process and death. Spirituality and storytelling can be used as resources in aging successfully and in dying, given the constraints of the modernday Western culture.58 The end of life can be a spiritual crisis, and having a sense of spirituality has been identified as an important coping resource. A needs assessment can identify the specific services and assistance the patient most desires and is the first step in designing needs-tailored interventions.59

Spiritual needs and spiritual/existential concerns in patients with advanced illness and their caregivers

Spiritual needs should be met in an individualized reciprocal process. Patients like conversations that allow them to set the pace and agenda. Patients selected simple questions such as “What principles do you live by?”, “Do you have a personal faith?”, and “Have you ever prayed about your situation?” as useful ways to start discussions. The words patients use to communicate the perceptions of their end-of-life needs reveal how important it is to assess the dynamics of patient–clinician communication.59,60 It is important to recognize also that patients who have spiritual distress and, thus, need spiritual care are the least likely to ask for it.61 Although the importance of religion and spirituality in coping with cancer and other diseases is high for many people and well documented, health-care providers and medical institutions often do not do a good job of attending to this dimension of the patient’s care.62 It has been reported that more than 70% of cancer patients said that their spiritual needs were minimally or not at all supported by the medical system.9 Most important is that the attention to religious/spiritual issues has been shown to have a significant influence on several important indicators of quality care. Several studies have documented the positive relationship between meeting spiritual needs and patient satisfaction.63,64 Several other findings suggest that attention to spiritual needs improves the quality of life4 and reduces the use of aggressive care at the end of life.65 It was reported in a sample of 248 ethnically diverse, urban cancer patients that 75% had at least one spiritual need. Fifty-one percent of these patients wanted help to overcome their fears, 42% in finding hope, and 40% in finding meaning. Hispanics and African-American patients more frequently endorsed spiritual needs than Caucasians.66 In another study of patients at an outpatient cancer clinic, 73% reported at least one spiritual need.64 In a study by Delgado-Guay et al.,105 among a palliative care population, 40% of advanced patients reported experiencing “spiritual pain.” Patients with spiritual pain had significantly lower self-perceived religiosity and spiritual quality of life. Likewise, in a study by Alcorn et al.67 of advanced cancer patients receiving palliative radiation therapy, 85% identified one or more spiritual issues with a median of 4 issues per patient among 14 spiritual issues assessed. Key spiritual issues among patients included “seeking a closer connection

737 with God or one’s faith,” 54%; “seeking forgiveness (of oneself or others),” 47%; and “feeling abandoned by God,” 28%. Surprisingly, among the 22% of patients who said that religion/spirituality was “not important” to their cancer experience, two-thirds had at least one spiritual issue and 40% reported four or more spiritual issues. It is important also to notice that caregivers of patients of advanced illnesses have spiritual needs/concerns and suffering. Concerns about spiritual issues also arise in the caregiver population. Previous studies have shown that caregivers who are facing significant physical, social, and emotional hardships rely heavily on their faith to cope with these burdens.68 In a study of caregivers of patients with advanced cancer, 58% of caregivers report spiritual pain or distress associated with caring for their loved ones.108 Persons who take responsibility for caregiving are engaging in “meaning-making” activities by expressing important values such as hope, dignity, togetherness, involvement, and continuity, and demonstrating their desire to strengthen family ties and deepen personal growth.69 People who are more religious feel more positively about their role as caregivers, get along better with those for whom they provide care, and express less caregiver distress.70 Faith communities foster belief systems of responsibility and compassion that are likely to help caregivers doing the emotionally difficult work of caring for others.69 Because spirituality provides caregivers hope and sustenance and helps them express themselves more fully during difficult times of change, feel the presence of a greater power, practice rituals, be one with nature, and interact with family and friends.71 Although caregivers have reported that their satisfaction in the spirituality and meaning domains increased over time, they might be less satisfied during the bereavement period,72 most likely because their spiritual needs have not been optimally addressed during the dying phase.71,73 Caregivers’ quality of life might decrease in direct proportion to declines in the patient’s functioning and health and increases in the patient’s need for care and the intensity of his/her symptoms and distress.74 There is a high prevalence of spiritual needs/concerns among patients facing life-threatening diseases and their caregivers, particularly among ethnic minorities, and that even among patients who do not consider themselves religious/spiritual, spiritual needs remain frequent. In a study of Latin American patients with advanced cancer, 52% reported the presence of spiritual pain.106 Black patients with advanced cancer who are identified as spiritual report lower levels of symptom burden compared to those that are not spiritual.107 It is extremely important to explore, assess, and support their spiritual needs/concerns and work as a team to decrease suffering and improve their quality of life. Spiritual assessment is a conversation in which the patient is encouraged to tell and explore their spiritual story. As in spiritual screening, there are several options in the literature for taking a spiritual history. Allowing the patient to guide their disclosure of his or her spiritual needs is a patient-centered approach to assessment. There are several tools available for taking a spiritual history, including the Systems of Belief Inventory-15R,75 Brief Measure of Religious Coping,76 Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being,77,78 SPIRITual History,79 HOPE, 80 and FICA Spiritual History. 81 Some of these instruments are intended primarily for research, whereas the others have been used primarily in the clinical setting for nonchaplain clinicians.

Textbook of Palliative Medicine and Supportive Care

738 TABLE 77.1  FICA Tool FICA Tool F—Faith, Belief, Meaning

I—Importance and Influence

C—Community

A—Address in Care

Questions Do you consider yourself spiritual or religious? Do you have spiritual beliefs that help you cope with stress? What gives your life meaning What importance does your faith or belief have in your life? On a scale of 0 (not important) to 5 (very important), how would you rate the importance of faith/belief in your life? Have your beliefs influenced you in how you handle stress? What role do your beliefs plan in your health-care decision-making? Are you a part of a spiritual or religious community? Is this of support to you and how? Is there a group of people you really love or who are important to you? How would you like your healthcare provider to use this information about your spirituality as they care for you?

The FICA tool (Faith, Importance, Community, Address in care) developed at the George Washington Institute for Spirituality and Health (Table 77.1) has been tested and validated.81 It is recommended that it be incorporated into the social history section of the overall history and physical. In incorporating this area into a history, providers should be conscious of not imposing their own beliefs on the patient or trying to answer any questions or concerns that the patient may have in this area. Such questions and concerns should be referred to a professional chaplain. They also should be clear that this process does not oblige them to discuss their own beliefs and practices. The main goal of this process is to understand the role of spiritual and religious beliefs and practices in the patient’s life and the role they play in coping with illness. As in the screening, a basic goal of the history is to diagnose spiritual distress, which should be referred to the professional chaplain.62,82 Through active listening it is established a relationship between the patients and provided and/or the professional chaplain. The chaplain then extracts themes and issues from the story to explore further with the patient. These themes might include meaning, making God as judge versus God as comforter, grief, despair, and forgiveness. This assessment should result in a spiritual care plan that is fully integrated into the patient’s and family’s total plan of care, which should be communicated to the rest of the treatment team.82

Providing spiritual care to patients with advanced illness and their caregiver in distress

The process of good spiritual care involves all health-care professionals and mimics the process for other domains of care. Patients have stated that all health-care professionals should be able to assess and provide spiritual care. The process is built around the premise that spiritual care, like all other domains

of care, should focus on quickly identifying and attending to distress in this domain. Thus, the interdisciplinary palliative care model of spiritual care proposes inclusion of the spiritual domain in the overall screening and history-taking process as well as a full spiritual assessment by the professional chaplain as needed. Again, the generalist/specialist model presumes the professional chaplain as the specialist.62 The plan should include the spiritual care interventions for all members of the healthcare team. Developing interventions will raise awareness of the dying process and, ultimately, result in a more peaceful experience. These interventions will likely improve the experience of death and dying for the patient and their families in various medical settings, such as palliative care, hospice, long-term care, and primary care settings.1,9 Spiritual care is an essential domain of quality palliative care.1,4 Studies have consistently indicated the desire of patients with serious illness and end-of-life concerns to have spirituality included in their care.7,9 While there is an emerging scholarly body of literature to support the inclusion of spiritual care as part of a biopsychosocial-spiritual approach to health care,9 palliative care programs are working to include strategies for affecting institutional change and creating resources to assist in improving the delivery of spiritual care.83,84 One of the issues that often arises with regard to spiritual care is that, even when teams accept the necessity of participation in spiritual screening and history taking, they are uncomfortable taking on any role in the delivery of spiritual care itself. A large barrier is that many doctors feel that if they are not spiritual or religious, they cannot provide spiritual care.109 However, the provision of spiritual care is shared by all members of the team in the same way that documentation of spiritual need is shared. It is important to remember that taking the time to be empathetic and compassionate with a patient is spiritual care. Any staff member can take the time to listen to a patient’s story, listen to a patient’s angst, and be a compassionate presence with that patient. Many times this is all that the patient asks. The patient is not looking for answers. What is spoken as a spiritual question is most often not a question at all but an expression of spiritual pain. Practitioners who are personally uncomfortable with religious/spirituality should respectfully identify if a patient has spiritual needs and then refer the patient to chaplaincy or clergy. This approach, however, might best be understood as what is minimally appropriate in spiritual care rather than its gold standard. 84–88 Pastoral care of the dying and the bereaved is a core activity for all parish clergy. It was reported that the majority of clergy perceived the need for further training in this area. Clergy training colleges, although offering placements to clergy within pastoral care settings, were constrained by the amount of time given to this area during clergy training. The training in care of the dying and the bereaved (including communication skills) should be part of the core curriculum within clergy training colleges and regularly revisited by all those who provide continual ministerial training for clergy.84,87

Spiritual interventions

Spiritual interventions can be understood as therapeutic strategies that incorporate a spiritual or religious dimension as a central component of the intervention. This practice advocates for a holistic view of health. Spirituality is interwoven in the therapeutic process and cannot be separated from it.89

Spiritual Care Religious or spiritual activities can be practiced through the continuum of care to help support persons with life-threatening illness. Religious interventions are more structured, cognitive, denominational, external, ritualistic, and public, whereas spiritual interventions are more crosscultural, affective, transcendent, and experiential. Interventions should be agreed with the patient and tailored to their worldly perspectives to help them during an illness or crisis.90 Spiritual interventions are contraindicated in cases of psychotic illnesses when dealing with poor “ego boundaries,” or when a patient does not want to participate.90,91 Prayer is a powerful form of coping that helps people physically and mentally. Nearly 60% of Americans report praying daily.92 Prayer is a communication or conversation with divine powers or a “higher self.” Prayer is practiced by all Western theistic religions and several of the Eastern traditions (e.g., Hinduism, Sikhism, Buddhism, and Taoism). Group prayer is associated with a greater well-being and happiness, while solitary prayer is associated with depression and loneliness.93 Worship and religious rituals are encouraged by most religions. It is important to recognize that potentially therapeutic elements of worship include music, esthetic surroundings, rituals, prayer and contemplation, and opportunities to socialize with others.94 Bibliotherapy involves the use of literature to help gain insight into feelings and behaviors and to assist with positive coping. All major world religions have a text that their followers view as holy and use as a source of comfort, wisdom, and guidance.95,96 In medical settings, forgiveness and repentance are within the purview of a pastoral counselor and clergyperson. Both prayer and bibliotherapy with sacred writings must be consistent with patients’ needs and requests.84,95 Meditation produces a sense of calm through limited thought and attention. Meditation is widely used as an alternative therapy for physical ailments.97 Meditation, essentially, is a physiological state of reduced metabolic activity that elicits physical and mental relaxation and is reported to enhance psychological balance and emotional stability.97 Meditation involves either the narrowing or focusing of the attention on internal events, such as breathing, an object, one point in space or a mantra (in Buddhist or yoga practices), or expanding the attention nonjudgmentally on moment-to-moment experiences, and observing thoughts and feelings from a meta-cognitive awareness state (Mindful Meditation, Vipassana, and Zen Buddhist practices).97,98 While evidence is not yet definitive, preliminary studies suggest health benefits of meditation for improved reaction time, creativity, and comprehension.97 Meta-analysis of the available literature finds that meditation and meditative movement therapies are associated with improved health-related quality of life.110 Ethical considerations should be taken into account when practicing or recommending spiritual interventions by health-care professionals, to avoid promoting self-interest or imposing personal beliefs on patients via linking religious practices to better health outcomes; acknowledging limitations of current research into the effects of spirituality on health and, most importantly, respecting patients boundaries and beliefs by obtaining their informed consent to share their spiritual history and choosing spiritual interventions should be recognized.97 Psychotherapy involving religiosity and spirituality offer spiritual benefits to the patients with emotional distress. The patients receiving these therapies improve on spiritual outcomes more

739 than patients in alternate therapy.100 For patients and contexts in which spiritual outcomes are highly valued, spirituality and religiosity psychotherapy can be considered a treatment of choice.100 Importantly also is that the incorporation of religiosity and spirituality should follow the desires and needs of the patients. Religiously oriented cognitive-behavioral therapy (CBT) is shown to be more beneficial for self-reported religious patients.111 CBT represents a unique category of psychological interventions based on scientific models of human behavior, cognition, and emotion CBT intends to directly reduce distress, target symptoms, re-evaluate thinking, and promote helpful behavioral responses. Cognitive interventions refer to how patients create meaning about symptoms, situations, and events in their lives, as well as beliefs about themselves, others, and the world. CBT and psychodynamic therapy are the most commonly used psychotherapeutic treatments of mental disorders in adults. There is evidence from randomized controlled studies that CBT is an efficacious treatment of many mental disorders, especially depression and anxiety.99 Provision of spiritually oriented or spiritually attuned approaches to psychodynamic psychotherapy pays special attention to the role religious beliefs, God-representations, and spirituality play in the psychic world and health of the patient.99 The psychodynamic approach to spirituality goes beyond sole consideration of consciously held religious beliefs and practices. This therapy plays attention on understanding the person’s experience of their relationship to the transcendent realities. This might provide insight into the ways they relate to themselves and to others.101 Another important intervention is the religiously oriented mindfulness-based cognitive therapy.101 This therapy has been aimed at helping patients suffering from depression or anxiety disorders to relate to their experience in a new way, always placing particular emphasis of religious and spiritual aspects of the patient.102 In this therapy, the patients are taught to experience their thoughts, feelings, and sensations in an accepting manner, helping them to develop a new mode of mind in which they “recognize and disengage from mind states characterized by self-perpetuating patterns of ruminative, negative thought. This involves moving from a focus on content to a focus on process, away from cognitive therapy’s emphasis on changing the content of negative thinking, toward attending to the way all experience is processed.”102 The patients receiving this type of cognitive therapy learn to develop an action plan to prevent relapse of depressive symptoms over the course of treatment. This action plan consists of three phases: (1) take a breathing space and decenter from unpleasant emotions and maladaptive thoughts, (2) choose a practice that is helpful for grounding the person in the present, and (3) take action that gives a sense of pleasure or mastery and break the activity down into smaller parts.102 At the same time the practice of gratitude therapy could provide a heightened well-being over time.103 Additional realms of psychotherapy used to address patients with spiritual distress, including life review therapy, dignity therapy, and meaning-based therapy, are shown to be beneficial for patients with advanced disease when compared to standard therapies.112 Life review therapy includes guided recall of life events with documentation to help patient’s develop a sense of legacy. Dignity therapy has been shown to improve the end of life experience though its effects on symptom burden are not as well proven. Future spiritual interventions that aim to enhance coping and improve quality of life of patients with life-threatening illness and their caregivers must consider spiritual diversity and develop

Textbook of Palliative Medicine and Supportive Care

740 targeted programs that offer choices of health care based on individual spiritual beliefs, thus creating a basis for biopsychospiritual personalized approach of care. Future research should test culturally appropriate interventions tailored to the needs of different populations, which combine methods demonstrated to be effective in reducing stress and improving well-being and coping. Another priority in the development of this biopsychospiritual personalized approach is the training of health-care professionals in assessing and integrating spirituality into health care, and the active participation also a trained chaplain to be involved in the care of patients with complex spiritual suffering. It will be important to continue to develop interdisciplinary training programs through a comprehensive curriculum for medical schools, schools of nursing and social work, allied health, and clinical pastoral programs. A comprehensive multidimensional model that combines psychological, social, genetic, and neurobiological factors, based on previous research and theory, is needed to guide future research in the area of spirituality in patients with life-threatening illness and their caregivers.

References





KEY LEARNING POINTS • Religion and spirituality play an important role in coping with disease-related symptoms, improves quality of life, and impacts medical decisionmaking near death. • Many patients report spiritual concerns and needs arising within illness. • Many patients desire spiritual care from medical providers but its provision remains infrequent. • Existential and spiritual suffering is among the most debilitating conditions in end-of-life care, and yet it lacks a clear definition, concept, effective assessment, and measurement. • Spiritual assessment of patients and families ranges from spiritual screening, taking spiritual history, and in-depth spiritual assessment, of active listening to patient’s story and/or using specific measurement tools. • There are various tools and measurement techniques developed and validated, but no consensus on standardized processes yet across palliative care settings. • Family caregivers may experience typical patterns of spiritual well-being and distress in parallel with patients. • Future research is needed to better understand the role of medical professionals in spiritual care provision. • Open-ended questions always. • Asking for everything does not mean to give any and all invasive treatment. • Several interventions can be provided; the spiritual care is part of the all members of the team. • Integrative care with multidisciplinary approaches, to provide a touch of hope, a touch of love to decrease suffering, and to improve the quality of life of patients and families in distress.





1. Puchalski C, Ferrel B, Virani R, et al. Improving the quality of spiritual care as a dimension of palliative care: The report of the consensus conference. J Palliat Med 2009;10:885–904. 2. Puchalski C, Dorff R, Hendi I. Spirituality, religion, and healing in palliative care. Clin Geriatr Med 2004;20:689–714. 3. National Cancer Institute: Spirituality in cancer care. 2017. http:// www.nci.nih.gov/cancertopics/pdq/supportivecare/spirituality/ 4. National Consensus Project: The development of clinical practice guidelines for quality palliative care. 2018. http://www. nationalconsensusproject.org/ 5. Pargament KI, Koenig HG, Tarakeshwar N, Hahn J. Religious coping methods as predictors of psychological, physical and spiritual outcomes among medically ill elderly patients: a two year longitudinal study. J Health Psychol 2004; 9:713–730. 6. Hinshaw D. Spiritual issues at the end of life. Clin Fam Practice 2004;6:423–440. 7. Puchalski C. Spirituality in health: the role of spirituality in critical care. Crit Care Clin 2004;20:487–504. 8. Chochinov H, Cann B. Interventions to enhance the spiritual aspects of dying. J Palliat Med 2005;8:S-103-S-115. 9. Balboni T, Vanderwerker L, Block S, et al. Religiousness and spiritual support among advanced cancer patients and associations with end-of-life treatment preferences and quality of life. J Clin Oncol 2007;25:550–560. 10. Puchalski C, Romer A. Taking a spiritual history allows clinicians to understand patients more fully. J Palliat Med 2000;3:129–137. 11. Kearney M, Mount B. Spiritual care of the dying patient. In: Chochinov H., Breitbart W eds.: Handbook of Psychiatry in Palliative Medicine. New York, NY: Oxford University Press, 2000, pp. 357–373. 12. Delgado-Guay MO, Hui D, Parsons HA, et al. Spirituality, religiosity, and spiritual pain in advanced cancer patients. J Pain Symptom Manage. 2011 Jun; 41(6):986–994. 13. Pearce MJ, Coan AD, Herndon JE, Koenig HG, Abernethy AP. Unmet spiritual care needs impact emotional and spiritual well-being in advanced cancer patients. Support Care Cancer 2011. 20(10):2269-76. DOI 10.1007/s00520-011-1335-1. 14. Thompson GN, Chochinov HM. Dignity-based approaches in the care of terminally ill patients, Curr Opin Support Palliat Care 2008;2:49–53. 15. Koenig H, McCullough M, Larson D. Handbook of Religion and Health. Oxford, United Kingdom, Oxford University, Press 2001. 16. McGrath P. Creating a language for “spiritual pain” through research: a beginning. Support Care Cancer 2002;10:637–646. 17. Rousseau P. Spirituality and the dying patient. J Clin Oncol 2000;18:2000–2002. 18. Unruh A, Versnel J, Kerr N. Spirituality unplugged: a review of commonalities and contentions, and a resolution. Can J Occup The 2002;69:5–19. 19. Koenig H, George L, Titus P. Religion, spirituality, and health in medically ill hospitalized older patients. J Am Geriatr Soc 2004;52:554–562. 20. Gallup G. Religion Considered Important to 72% of Americans. Gallup Religion. December 24, 2018 (on-line). Available at https://news.gallup. com/poll/245651/religion-considered-important-americans.aspx. 21. Roberts J, Brown D, Elkins T, et al. Factors influencing views of patients with gynecologic cancer about end-of-life decisions. AM J Obst Gynecol 1997;176:166–172. 22. Jenkins R, Pargament K. Religion and spirituality as resources for coping with cancer. J Psychosoc Oncol 1995;13:51–74. 23. Gail T, Cornblat M. Breast cancer survivors give voice: A qualitative analysis of spiritual factors in long-term adjustment. Psychooncology 2002;11:524–535. 24. True G, Phipps E, Braitman L, et al. Treatment preferences and advance care planning at the end of life: the role of ethnicity and spiritual coping in cancer patients. Ann Behav Med 2005;30:174–179. 25. Kappeli S. Religious dimensions of suffering from and coping with cancer: a comparative study of Jewish and Christian patients. Gynecol Onc 2005;99:S135–S136. 26. McClain C, Rosendeld B, Breitbart W. Effect of spiritual well-being on end-of-life despair in terminally-ill cancer patients. Lancet 2003;361:1603–1607. 27. Kuin A, Deliens L. Spiritual issues in palliative care consultations in the Netherlands. Palliat Med 2006;20:585–592. 28. Moadel A, Morgan C, Fatone A, et al. Seeking meaning and hope: selfreported spiritual and existential needs among an ethically-diverse cancer patient population. Psychooncology 1999;8:378–385.

Spiritual Care 29. Holmes S, Rabow M, Dibble S. Screening the soul: communication regarding spiritual concerns among primary care physicians and seriously ill patients approaching the end of life. Am J Hosp Palliat Care 2006;23:25–33. 30. Grant E, Murray S, Kendall M, et al. Spiritual issues and needs: perspectives from patients with advanced cancer and nonmalignant disease – a qualitative study. Palliat Support Care 2004;2:371–378. 31. Nelson C, Rosenfeld B, Breitbart W, et al. Spirituality, religion, and depression in the terminally ill. Psychosomatics 2002;43:213–220. 32. Cotton S, Levine E, Fitzpatrick C, et al. Exploring the relationships among spiritual well being, quality of life, and psychological adjustment in women with breast cancer. Psychooncology 1999;8:429–438. 33. Tarakeshwar N, Vanderwerker L, Paulk E, et al. Religious coping is associated with the quality of life of patients with advanced cancer. J Palliat Med 2006;9:646–657. 34. Brady M, Peterman A, Fitchett G, et al. A case for including spirituality in quality of life measurement in oncology. Psychooncology 1999;8:417–428. 35. Simon C, Crowther M. The stage-specific role of spirituality among African American Christian women throughout the breast cancer experience. Cult Div Ethnic Min Psych 2007;13:26–34. 36. Breitbart W, Rosenfeld B, Pessin H, et al. Depression, hopelessness, and desire for death in terminally ill patients with cancer. JAMA 2000;284:2907–2911. 37. Hills J, Paice J, Cameron J, et al. Spirituality and distress in palliative care consultation. J Palliat Med 2005;8:782–788. 38. Sherman A, Simonton S, Latif U, et al. Religious struggle and religious comfort in response to illness: health outcomes among stem cell transplant patients. J Behav Med 2005;28:359–367. 39. Delgado-Guay MO, Parsons HA, Hui D, et al. Spirituality: an expression of Inner Strength and Meaning of life in patients with advanced cancer (ACAP) and their caregivers in the Palliative Care Setting. Support Care Cancer (2011) 19 (Suppl 2):S350. 40. Farran CJ, Fitchett G, Quiring-Emblen JD, et al. Development of a model for spiritual assessment and intervention. J Relig Health 1989; 28(3):185–194. 41. Kellehear A. Spirituality and palliative care: a model of needs. Palliat Med 2000;14(2):149–155. 42. Wright M. Hospice care and models of spirituality. Eur J Palliat Care 2004;11:75–78. 43. Erikson EH. Childhood and Society, 2nd ed. Norton, 1963, NY, USA. 44. Fowler JW. Stages of Faith: the Psychology of Human Development and the Quest for Meaning. Harper & Row, 1981 CA, USA. 45. Fowler JW. Weaving the New Creation: Stages of Faith and the Public Church. Harper & Row, 1991, CA, USA. 46. Koenig H. Aging & God. The Haworth Pastoral Press, 1994, NY, USA. 47. Moberg DO. Aging & Spirituality: Spiritual Dimensions of Aging Theory, Research, Practice, and Policy. The Haworth Press, Inc., 2001, NY, USA. 48. Kastenbaum RJ. Death, Society, and Human Experience 3rd ed. Columbus OH (Ed.). Charles E Merrill Publishing Company, 1986, NY, USA. 49. Blesky JK. The Psychology of Aging, 2nd ed. Brooks/Cole Publishing Company, 1990, CA, USA. 50. Feifel H, Branscomb AB. Who’s afraid of death? J Abnorm Psychol 1973;81:282–288. 51. Templer DI. Death anxiety as related to depression and health of retired persons. J. Gerontol 1971; 26:521–523. 52. Kalish R. Death, Grief, and Caring Relationships, 2nd ed. Brooks/Cole Publishing Company, 1985, CA, USA. 53. Bianchi EC. Aging as a Spiritual Journey. Crossroad Publishing Company, 1982, NY, USA. 54. Feifel H. New Meanings of Death. McGraw-Hill Book Company, 1977, NY, USA. 55. Johnson R. Forgiveness: our bridge to peace. Liguorian 1992;80:44–45. 56. Thibault JM. A Deepening Love Affair: The Gift of God in Later Life. Upper Room Books, 1993, TX, USA. 57. Fischer K. Winter Grace. Upper Room Books, 1998, TX, USA. 58. Schenck DP, Roscoe LA. In search of a good death. J Med Humanit 2009;30:61–72. 59. Lunder U, Furlan M, Simonic A. Spiritual needs assessments and measurements. Curr Opin Support Palliat Care 2011;5(3):273–278. 60. Arnold BL. Mapping hospice patients’ perception and verbal communication of end-of-life needs: an exploratory mixed methods inquiry. BMC Palliat Care 2011;10:1.

741 61. Fitchett G, Risk JL. Screening for spiritual struggle. J Pastoral Care Couns 2009;62(1, 2):1–12. 62. Handzo G. Spiritual care for palliative patients. Curr Probl Cancer 2011;35(6): 365–371. 63. Williams JA, Meltzer D, Arora V, Chung G, Curlin FA. Attention to inpatients’ religious and spiritual concerns: predictors and association with patient satisfaction. J Gen Intern Med 2011;26(11):1265–1271. 64. Astrow AB, Wexler A, Texeira K, He MK, Sulmasy DP. Is failure to meet spiritual needs associated with cancer patients’ perceptions of quality of care and their satisfaction with care? J Clin Oncol 2007;25(36): 5753–5757. 65. Balboni TA, Paulk ME, Balboni MJ, Phelps AC, Loggers ET, Wright AA, Block SD, Lewis EF, Peteet JR, Prigerson HG. Provision of spiritual care to patients with advanced cancer: associations with medical care and quality of life near death. J Clin Oncol 2010;28(3):445–452. 66. Moadel A, Morgan C, Fatone A, et al. Seeking meaning and hope: self-reported spiritual and existential needs among an ethnicallydiverse cancer patient population. Psychooncology 1999; 8:378–385. 67. Alcorn SR, Balboni MJ, Prigerson HG, et al. ‘If God wanted me yesterday, I wouldn’t be here today’: religious and spiritual themes in patients’ experiences of advanced cancer. J Palliat Med 2010; 13:581–588. 68. Weaver AJ, Flannelly KJ. The role of religion/spirituality for cancer patients and their caregivers. South Med J 2004;97(12):1210–1214. 69. Sand L, Olsson M, Strang P. What are motives of family members who take responsibility in palliative care? Mortality 2010; 15:64–80. 70. Kim Y, Wellisch DK, Spillers RL, Crammer C. Psychological distress of female cancer caregivers: effects of type of cancer and caregivers’ spirituality. Support Care Cancer 2007;15:1367–1374. 71. Pierce LL, Steiner V, Havens H, Tormoehlen K. Spirituality expressed by caregivers of stroke survivors west. J Nurs Res 2008 Aug;30(5):606–619. 72. Heyland DK, Frank C, Tranmer J, et al. Satisfaction with end-of-life care: a longitudinal study of patients and their family caregivers in the last months of life. J Palliat Care 2009;25:245–256. 73. Rosenbaum JL, Smith JR, Zollfrank R. Neonatal end-of life spiritual support care. J Perinat Neonatal Nurs 2011;25:61–69. 74. Stajduhar KI, Funk L, Toye C, et al. Part 1. Home-based family caregiving at the end of life: a comprehensive review of published quantitative research (1998–2008). Palliat Med 2010;24:573–593. 75. Holland JC, Kash KM, Passik S, et al. The title is : Share A brief spiritual beliefs inventory for use in quality of life research in life- threatening illness. Psychooncology 1998; 7:460–469. 76. Pargament KI, Smith BW, Koenig HG, Perez L. Patterns of positive and negative religious coping with major life stressors. J Sci Study Relig 1998;37:710–724. 77. Brady MJ, Peterman AH, Fitchett G, Mo M, Cella D. A case for including spirituality in quality of life measurement in oncology. Psychooncology 1999;8:417–428. 78. Cella DF, Tulsky DS, Gray G, et al. The functional assessment of cancer therapy scale: development and validation of the general measure. J Clin Oncol 1993;11:570–579. 79. Maugans TA. The SPIRITual history. Arch Fam Med 1996; 5:11–16. 80. Anandarajah G, Hight E. Spirituality and medical practice: using the HOPE questions as a practical tool for spiritual assessment. Am Fam Physician 2001; 63:81–89. 81. Borneman T, Ferrell B, Puchalski C. Evaluation of the FICA tool for spiritual assessment. J Pain Symptom Manage 2010; 20(2):163–173. 82. Fitchett G, Canada AL. The role of religion/spirituality in coping with cancer: evidence, assessment, and intervention In: Holland JC, ed. Psycho-Oncology, 2nd ed. New York, NY: Oxford University Press, 2010. 440–446. 83. Otis-Green, S, Ferrel B, Bomeman T, Puchalski C, Uman G, Garcia A. Integrating spiritual care within palliative care: an overview of nine demonstration projects. J Palliat Med 2012;15:154–162. 84. El Nawawi NM, Balboni MJ, Balboni TA. Palliative care and spiritual care: the crucial role of spiritual care in the care of patients with advanced illness. Curr Opin Support Palliat Care 2012, DOI:10.1097/ SPC.0b013e3283530d13. 85. Lo B, Kates LW, Ruston D, et al. Responding to requests regarding prayer and religious ceremonies by patients near the end of life and their families. J Palliat Med 2003;6:409–415. 86. Sulmasy DP. Spirituality, religion, and clinical care. Chest 2009;135:1634–1642. 87. Lloyd-Williams M, Cobb M, Shiels C, Taylor F. How well trained are clergy in care of the dying patient and bereavement support? J Pain Symptom Manage 2006;32:44–51.

742 88. Balboni MJ, Babar A, Dillinger J, et al. ‘It depends’: viewpoints of patients, physicians, and nurses on patient-practitioner prayer in the setting of advanced cancer. J Pain Symptom Manage 2011;41:836–847. 89. Brown O, Elkonin D, Naicker S. The use of religion and spirituality in psychotherapy: enablers and barriers. J Relig Health 2013 Dec;52(4):1131–1146. 90. Yoon DP, Lee EK. The impact of religiousness, spirituality, and social support on psychological well-being among older adults in rural areas. J Gerontol Soc Work 2007;48:281–298. 91. Richards PS, Bergin AE. A Spiritual Strategy for Counseling and Psychotherapy. American Psychological Association Press, Washington, DC, USA, 1997. 92. Boehnlein JK. Psychiatry and Religion: the Convergence of Mind and Spirit. American Psychiatric Press, Washington, DC, USA, 2000. 93. Poloma MM, Pendleton BF. The effects of prayer and prayer experience on measures of general well-being. J Psychol Theol 1991;19:71–83. 94. Benson H. Timeless Healing: The Power and Biology of Belief. The Gale Group, NY, USA, 1997. 95. Woll ML, Hinshaw DB, Pawlik TM. Spirituality and religion in the care of surgical oncology patients with life-threatening or advanced illnesses. Ann of Surg Oncol 2008;15(11):3048–3057. 96. Jarvis GK, Northcott HC. Religion and differences in morbidity and mortality. Soc Sci Med 1987;25:813–824. 97. Candy B, Jones L, Varagunam M, Speck P, Tookman A, King M. Spiritual and religious interventions for well-being of adults in the terminal phase of disease. Cochrane Database System Rev 2012;(5). Art. No.: CD007544. DOI:10.1002/14651858.CD007544.pub2. 98. Ivanovski B, Malhi GS. The psychological and neurophysiological concomitants of mindfulness forms of meditation. Acta Neuropsychiatrica 2007:19;76–91. 99. Leichsenring F, Hiller W, Weissberg M, Leibing E. Cognitivebehavioral therapy and psychodynamic psychotherapy: techniques, efficacy, and indications. Am J Psychother 2006:60(3):233–259. 100. Worthington EL, Hook JH, McDaniel MA. Religion and spirituality. J Clin Psychol 2011 In Session 67:204–214. 101. Shafranske EP. Spiritually oriented psychodynamic psychotherapy. J Clin Psycho 2009: In session 65:147–157.

Textbook of Palliative Medicine and Supportive Care 102. Hathaway W, Tan E. Religiously oriented mindfulness-based cognitive therapy. J Clin Psychol 2009 In Session 65:158–171. 103. Emmons RA, McCullough ME. Counting blessings versus burdens: an experimental investigation of gratitude and subjective well-being in daily life. J Person Soc Psychol 2003;84:377–389. 104. Jim HS, Pustejovsky JE, Park CL, et al. Religion, spirituality, and physical health in cancer patients: a meta-analysis. Cancer 2015;121:3760–3768. 105. Delgado-Guay M, Chisholm G, Williams J, Frisbee-Hume S, Ferguson A, Bruera E. Frequency, intensity, and correlates of spiritual pain in advanced cancer patients assessed in a supportive/palliative care clinic. Palliat Support Care 2016;14(4):341–348. 106. Delgado-Guay MO, Palma A, Duarte ER, et al. Spirituality, religiosity, spiritual pain, and quality of life among Latin American patients with advanced cancer (LAAdCa): a multicenter study. J Clin Oncol 2016;34(26_suppl):246–246. 107. Bai J, Brubaker A, Meghani SH, Bruner DW, Yeager KA. Spirituality and quality of life in black patients with cancer pain. J Pain Symptom Manage 2018 Sep. 108. Delgado-Guay MO, Parsons HA, Hui D, De la Cruz MG, Thorney S, Bruera E. Spirituality, religiosity, and spiritual pain among caregivers of patients with advanced cancer. Am J Hospice Palliat Med 2013;30(5):455–461. 109. Bar-Sela G, Schultz M, Elshamy K, et al. Training for awareness of one’s own spirituality: a key factor in overcoming barriers to the provision of spiritual care to advanced cancer patients by doctors and nurses. Palliat Support Care 2019;17(3):345–352. 110. Kelley GA, Kelley KS. Meditative movement therapies and healthrelated quality-of-life in adults: a systematic review of meta-analyses. PLOS ONE 2015;10(6):e0129181. 111. Koenig HG, Pearce MJ, Nelson B, et al. Religious vs. conventional cognitive behavioral therapy for major depression in persons with chronic medical illness: a pilot randomized trial. J Nervous Mental Disease. 2015 Apr;203(4):243–251. 112. Balboni TA, Fitchett G, Handzo GF, et al. State of the science of spirituality and palliative care research Part II: Screening, assessment, and interventions. J Pain Symptom Manage 2017 Sept.

78

FAMILY CAREGIVERS AND CULTURAL SENSITIVITY

Rony Dev and Ali Haider

Contents Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������743 Family caregiver distress��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������744 Family caregiver burnout������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������746 Interventions for family caregiver distress�������������������������������������������������������������������������������������������������������������������������������������������������������������������746 Barriers to communication with family member�������������������������������������������������������������������������������������������������������������������������������������������������������747 Information needs of family caregivers������������������������������������������������������������������������������������������������������������������������������������������������������������������������747 Family conferences�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������748 Family conferences in the ICU setting��������������������������������������������������������������������������������������������������������������������������������������������������������������������������748 Pain, symptom management, and practical concerns of family caregivers�����������������������������������������������������������������������������������������������������������749 Pain management and family caregivers����������������������������������������������������������������������������������������������������������������������������������������������������������������749 Symptoms at the end of life and family caregivers�����������������������������������������������������������������������������������������������������������������������������������������������749 Financial burden����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������750 Coping of family caregivers���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������750 Interventions to assist with the coping of family caregivers������������������������������������������������������������������������������������������������������������������������������751 Family function and caregivers���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������751 Cultural sensitivity������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������751 Cultural appropriate communication���������������������������������������������������������������������������������������������������������������������������������������������������������������������752 Cultural preferences and medical decision-making���������������������������������������������������������������������������������������������������������������������������������������������752 Disparities and end of life care���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������753 Conclusions������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������753 Acknowledgment��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������754 References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������754

Introduction Psychosocial support for both patients and their families is at the foundation of palliative care. The World Health Organization (WHO) defines palliative care “as an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual.”1 In addition to relieving the unnecessary suffering of patients, an interdisciplinary palliative care team should provide psychosocial support for family caregivers who may be overwhelmed with the care of chronically ill patients and may themselves have a difficult time coping. In addition, palliative care emphasizes the need to support family caregivers not only during the illness stage but also while grieving the death of a loved one. The definition of family is open-ended and should be defined by the patient. One definition of family developed by the Canadian Palliative Care Association is “…those closest to the patient in knowledge care and affection. This includes the biological family, the family of acquisition (related by marriage/contract), and the family of choice and friends (not related biologically, by marriage/ contract).”2 Caregivers have also been defined as the family member who provide uncompensated care, usually in the home setting, and participate in tasks that require energy and time, months to years, which potentially are emotionally, socially, financially, and physically exhausting. 3 Family caregivers are often classified as

primary or secondary. Primary caregivers are defined as those who provide the majority of unpaid care, while secondary caregivers either provide the minority of unpaid care or split the care with another family member.4 The primary caregivers, who voluntarily or involuntarily assume the responsibility of caregiving, often carry the greatest burden5,6 and have been branded the hidden patient.7 Health-care providers do not commonly inquire about a family caregiver’s distress and burden, which has a significant impact on their own health and psychosocial needs.8 In the majority of cases, the primary caregiver is the spouse, partner, parent, or adult child. In some cases, friends or even neighbors may carry the burden of caregiving. A South Australian study suggests that the caregiving burden is distributed not just on the backs of the primary caregiver but also often to family/community network of caregivers who collectively provide the majority of the care and are often invisible to the health-care team.9 Family caregivers have also been identified as informal caregivers, distinguishing them from caregivers who receive compensation. In 2015, unpaid family or informal caregivers provided care for an adult or child with a serious or chronic illness in the preceding 12 months included an estimated 43.5 million in the United States alone, the majority being female (60%) with an average 49 years of age.10 The typical patient receiving care is female (85%), averaged 69.4 years of age, and roughly half were receiving care at home.10 Reason for why patients required a family caregiver included “old age,” Alzheimer’s or dementia, surgery or wounds, and common medical conditions requiring caregivers include cancer, mobility issues, and mental and 743

Textbook of Palliative Medicine and Supportive Care

744 emotional health issues.10 The financial value of informal caregiving exceeds the spending for formal compensated home health care and nursing home care.11 In 2013, for patients with dementia, the estimated cost of informal caregiving was reported at $56,290 annually per patient.12 The following section will outline the burden that family caregivers may experience and the interventions that palliative care and interventions that health-care professionals can provide to alleviate or minimize caregiver distress. Research examining family caregivers has identified the following: caregiver distress can be overwhelming and result in burnout; the importance of meeting the information needs of both patients and their family in order to reduce distress; the need to address the practical burdens of day-to-day care of frail chronically ill patients; and the significance of providing culturally sensitive care at the end of life. The majority of caregiver research involves the care of patients with dementia or cancer but can be applicable for caregivers of patients with other chronic life-threatening illnesses.

Family caregiver distress Modern medicine has been successful in treating acute illnesses and increasing the life span of the general population; however, it has been less successful in improving the functional ability and quality of life of patients afflicted with chronic illnesses.13 The burden of caregiving for aged, demented, or patients with cancer or other chronic illnesses can be overwhelming. Zarit and colleagues have proposed the following definition for caregiver burden: “The extent to which caregivers perceive that caregiving has had an adverse effect on their emotional, social, financial, physical, and spiritual functioning.”14 The definition of caregiver burden emphasizes the impact of caregiving on family caregivers across multiple dimensions.15 Most chronically ill people when surveyed often prefer to live at home16,17 as opposed to institutions, such as nursing homes, resulting in family caregivers providing the majority of care.18,19 Family caregiver’s responsibilities may include the following: shopping and preparing food; assisting a patient with eating and administering their medications at the appropriate time; bathing and grooming the patient; providing financial support and paying the bills; managing medical problems such as changing catheter bags or providing wound care, coordinating care, and contacting health-care providers in emergencies; and supporting the psychological well-being of a loved one. Positive aspects of caregiving have been reported20,21 and include the opportunity to “give back” to loved ones,22 affirm family ties as well as save family resources.23 Often, family caregivers view with pride their ability to provide care,24 and a survey of family caregivers conducted in the United States reported increased personal strength and opportunities for growth when providing care for a loved one.25 Although there are positive aspects associated with the act of caregiving, the burden of providing care can lead to physical or emotional distress.26 The caregiver burden has been defined as the distress that family caregivers experience as a result of providing care, which is different from other emotional responses.27,28 Caregiver distress that impacts physical, psychological, social, and financial well-being can be perceived as “burdensome”29 and may result in caregiver burnout. The level of caregiver distress was noted to have a close association with caregiving outcomes, even being a better predictor than the functional status of the patient being cared for.30,31 In the research setting, caregiver burden has been measured by multiple tools, including the Zarit Burden Inventory

29-item original version,32 which has multiple abbreviated versions in various languages, the Caregiver Burden Inventory,33 and the Caregiver Strain Index.34 In the clinical setting, the less burdensome caregiver Edmonton Symptom Assessment System has been reported to be a quick and feasible tool to assess caregiver distress.35 General risk factors for caregiver distress include female sex, cohabitation with the patient, financial burden, around the clock obligations, need to transition care from hospital to home, and the lack of choice involved in being a caregiver36 as shown in Table 78.1. Other major contributors to caregiver distress include the following: a caregiver’s loss of independence secondary to the responsibilities of caregiving, time constraints that may result in social isolation, and an unpredictable trajectory of illness or rapid deterioration of a patient’s condition.37 In addition, a primary caregiver’s social network and spiritual support may also contribute to the level of caregiver distress.38–41 Recent research indicates that the perceived strength of social support was more important than the actual size of a caregiver’s social network with regard to caregiver outcomes.42 In addition, family caregivers who can recruit extended family and friends to provide assistance with caregiving were more likely to have loved ones supported at home until death.9 In studies of caregiver burden associated with dementia, researchers have identified two main dimensions: the patient characteristics and the traits of the caregiver. Literature review has identified specific factors that increase caregiver distress associated with dementia, including patients’ type of dementia, degree of personality change, the extent of psychiatric symptoms, including frequency of delusions, and frequency of behavioral disturbances such as wandering.43 Risk factors in caregivers of patients with dementia associated with increased burden include TABLE 78.1 General Risk Factors for Increased Caregiver Distress Family caregiver characteristic

Patient characteristic

Female gender Less education Cohabitation with patient Decreased socioeconomic status High caregiver’s psychological burden Greater degree of kinship with patient Financial burden Loss of independence Around the clock obligations of caregiving Social isolation and low perception of social support Decreased family support Increased duration of caregiver role Decreased access to spiritual support Severity of illness or rapid deterioration Decreased physical function Weight loss High symptom burden Increased psychological distress Limitation in social activity Difficulties with activities of daily living

Family Caregivers and Cultural Sensitivity sociodemographic factors such as monthly income, educational level, female gender, cultural values, relationship with the patient and cohabitation status, and the caregivers’ physical and mental health, including psychological health and coping skills.43 In addition, for family caregivers of patients with dementia, a Brazilian study identified the strongest association with caregiver distress with the duration of the caregiver role, the degree of kinship between the patient and the caregiver, as well as the patient’s neuropsychiatric symptoms.44 In a study of 96 patients with advanced cancer, the primary caregivers’ psychological burden was found to have a greater impact than the physical burden of caregiving.45 Most primary caregivers were found to have increased anxiety that was significantly higher than the norm during the initiation of the palliative phase to the start of the terminal stage of a patient’s life.45,46 Of note, female primary caregivers experienced more psychological morbidity and strain than male caregivers when patients were in the palliative phase.47 In a systematic review of family caregivers of elderly cancer patients, family caregiver characteristics associated with higher burden included younger age, caring for a patient with a solid tumor, and providing assistance with activities of daily living, while patient characteristics associated with higher burden included lower physical function, cancer cachexia, high symptom or psychological distress, limitations in social activities, and lower score of self-efficacy.48 Even in cancer patients who have survived their illness, a systematic review of patients and their spouses reported a high frequency of anxiety in both, with some studies reporting higher anxiety in spouses than cancer survivors.49 Studies of caregiver burden may be limited by a focus on homogenous diagnostic groups, which may limit generalizability but some disease states may result in a higher caregiver burden than others and more research is needed.50 The transition from curative treatment to palliative care often elicits a strong emotional response in both patients and their family, and the degree of caregiver distress depends on multiple factors, including their understanding of options for further treatment and symptom management, the coping abilities of caregivers, and the capability of caregivers to navigate a fragmented health-care network.51 Previous studies52–54 have revealed an increased feeling of helplessness among caregivers, which was associated with the progression of a patient’s illness, the degree of struggle undergone to obtain needed medical services, and the inability of caregivers to relieve a patient’s pain and discomfort. Of note, the caregiver burden was shown to escalate during the final 3 months of the life of a chronically ill patient.55 In the last days of life, family caregivers may hold vigil at the patient’s bedside, often providing emotional and spiritual support. In this critical period of time, family caregivers may develop emotional exhaustion resulting in caregiver burnout. Ideally, an interdisciplinary team, including a physician, health-care providers, a social worker, and the case manager, is required to perform a complete assessment of caregiver distress and identify additional community resources to provide supportive services. The palliative care interdisciplinary team, by treating patients and their family members as a “unit of care,” is able to assess family caregivers’ distress levels, including symptoms of depression, social isolation, or emotional exhaustion. It is critical that health-care providers be vigilant for caregiver burnout since assessments may only occur during brief or sporadic visits.7 Assessment of the health and well-being of the family caregiver is often not routine56 and requires the identification of risk factors for caregiver distress, including financial stresses, overwhelming

745 physical demands, conflicts between a patient and the caregiver or other family members, and the caregiver’s ability to cope.57 The National Consensus Development Conference for Caregiver Assessment has developed a toolkit to help health-care providers and recommend the following: (1) identify the primary and secondary caregivers; (2) integrate the preferences and needs of not only the care recipient but also the caregiver in aspects of care planning; (3) educate caregivers on their role and teach skills necessary to provide care; (4) reassess periodically the care needs for both patient and family caregivers; and (5) explore the informal caregiver’s sense of well-being, confidence in ability to provide care, and need for additional support58 (Box 78.158). BOX 78.1  DISCUSSION CATALYSTS FOR ENGAGING FAMILY CAREGIVERS (FROM REFENCE [58] WITH PERMISSION) Caregiver health • To provide the very best patient care, I find, I need to also pay attention to my patients’ caregivers. Can you tell me a bit about how you are feeling/doing? • We know that caregivers often neglect their own health. When was the last time you saw your physician? • Do you have your own physician? Is she or he aware of your caregiving situation? What has she or he advised about it? Quality of life • I know that many family caregivers find the role to be very stressful. How are you coping with these responsibilities? • How would you describe your quality of life these days? • How often do you get out? • What do you do for fun? Support • Many caregivers do not want to burden others— especially their children. Are there times when you really need help but do not ask for fear of being a burden? • Who gives you support? How helpful is this support? • We work with a social worker who is an expert in assisting caregivers. May I refer you to this individual? • Caregiving is a very hard job and the best way to do it well is to take advantage of some of the resources available for help. Are you using any of these? May I help you with a referral? In the case of emergency • If anything should happen to you, have you made arrangements for someone to take care of (name patient here)?

Textbook of Palliative Medicine and Supportive Care

746

Family caregiver burnout The burden and responsibilities of caregiving are often carried by the primary caregiver and not shared with other family members. 59 Family caregivers often lack positive feedback from the patient, as well as from society, which may contribute to a sense of low self-accomplishment. 60 Burnout has been well studied in the workplace, often in health-care settings involving paid caregivers. However, a growing number of studies exist—mainly of caregivers of patients with dementia—which indicate the presence of family caregiver burnout. 61–63 Burnout is characterized by the following: emotional exhaustion, depersonalization, and feelings of decreased personal accomplishment. 64 Predictors of burnout for the family caregiver include restrictions in social life, personal history of poor health or comorbidities, and a negative outlook regarding the role of being a family caregiver. In a recent study, caregiver burnout and depression were the most significant factors associated with a caregiver’s poor quality of life. 65 The reciprocal nature of cancer patients’ experiences and the family caregivers’ burden has been well documented. As patients experience more pain, the caregivers’ distress increases, 66 their psychological health is negatively impacted, 67 and caregiver’s burden increases. 68 The psychological distress such as depression and health-related problems experienced by caregivers directly influences the psychological well-being of the patient. 69–71 In addition, caregiver distress negatively impacts their ability to coordinate care, provide psychological support for a loved one, or recall treatment instructions provided to the patient.72

Interventions for family caregiver distress Practical approaches to reduce caregiver distress include encouraging caregivers to participate as a member of the health-care team, promoting self-care and attention to a caregiver’s health needs, and providing education and information on caregiving. Caregivers may be reluctant to share with health-care providers their burden during clinic visits, and physicians should not only assess chronically ill patients but also their family caregiver.73 In addition, a split visit, evaluation of a patient and their caregiver separately, is useful to communicate confidential information such as elder mistreatment.74 When meeting with the family members who are not participating in caregiving responsibilities, palliative health-care providers should emphasize the burden of caregiving and stress the importance of self-care for family caregivers in order to recruit secondary caregivers to assist. Practical education about wound care, how to safely mobilize patients, or the management of surgical drains and other medical devices may be provided to multiple family caregivers. Caregiving tasks that are taxing are often perceived as manageable by health-care providers, since they are executed in a detached and impersonal manner75; however, tasks may be difficult for family caregivers who are emotionally attached to the patient and inexperienced with delivering health care. It is important to understand that family caregivers may need more education than a paid healthcare provider in order to have the confidence to perform the tasks correctly. Positive reinforcement by the health-care team of the care provided by family caregivers may alleviate some distress. Research on psychoeducational interventions that reduce the distress of family caregivers has been conducted mainly in patients with dementia and cancer (Table 78.2). Psychoeducational

TABLE 78.2 Psychoeducational Interventions that Reduce the Distress of Family Caregivers Expressive–supportive therapy Cognitive behavioral therapy

Family/couples therapy

Interpersonal therapy Psychoeducational

Palliative care consultation

Integrative medicine

Address emotional needs of caregiver Reduce caregivers’ perceived burden Decrease psychological distress Improve function of the family unit Couples therapy Counseling on intimacy issues Individual counseling Medical information Problem solving techniques Coping skills Self-care Subspecialty care Improve symptom management Advanced care planning Reduce psychological and existential distress Mind–body Yoga Meditation Music therapy Massage therapy Healing touch

interventions or support groups for caregivers of patients with dementia were moderately effective. A family caregiver’s selfesteem, confidence in caregiving, and amount of social network, including family support, have been shown to alleviate caregiver distress and enhance their ability to provide care.76,77 Feeling prepared for the role of a caregiver of a critically ill patient has been a critical factor associated with caregiver outcomes, and psychoeducational interventions should aim to improve caregiver’s preparedness to care.78 In addition, caregiver groups with peer support may help one to alleviate distress. In a small qualitative study of family caregivers of patients with dementia, support groups with peer volunteers helped family caregivers feel that they were “not alone” in their experiences and emotions, facilitated their ability to talk freely about the difficult experiences of caregiving, and increased their caregiving capability by learning how other caregivers cope.79 In studies of caregivers of cancer patients, a meta-analysis of psychoeducational interventions published from 1983 through 2009, skills training, and therapeutic counseling for caregivers reported a reduction in caregiver burden; however, improvements diminished with time. 80 A more recent meta-analysis from 2010 through 2017, not only reinforced findings of the previous study but also noted increased randomized controlled trials involving family caregivers, changes in the format of interventions from face-to-face visits to interactions conducted by a telephone or using Web-based technology, and increased emphasis on caregiver self-care and coping skills. 81 In general, clinicians should discuss with caregivers pain-management skills, including physical care such as the proper technique to transfer debilitated patients to avoid injury, symptoms assessment, and management of side effects. 82 Limitations of research on interventions for family caregivers include the exclusion

Family Caregivers and Cultural Sensitivity of ethnic minorities with a preponderance of white caregivers being sampled which neglects the current demographic trends of the United States as well as the reported strong cultural influences on family caregiving. 83–85 Increasingly, technology is being integrated into health-care, including interventions that promote patient independence and decrease caregiver burden. Technological interventions include emergency response systems that can be activated by frail but cognitively intact patients in order to obtain help from monitoring centers, mobility monitoring devices that can track wandering patients with dementia, medication dispensers with voice reminders, lift systems for immobile patients, and electronic social networks such as Skype and FaceTime which can potentially connect homebound elders to their family or support groups as well as for caregivers.86 A systematic review of caregiver-focused, Web-based intervention of education or psychological support or electronic monitoring of the patient evaluating caregiver outcomes, including burden, self-efficacy, strain, and social support, reported small-tomedium beneficial effects.87 More research is needed in evaluating interventions to decrease caregiver distress and burnout. Research should focus on identifying caregivers at risk of burnout; interventions, including the incorporation of technology, that target increasing caregiver resources and improve clinical outcomes as well as raising their perception of support; increasing caregivers’ confidence in delivering care at home; and enhancing their ability to adaptively cope with the burden of caregiving.

Barriers to communication with family member Vachon identified multiple barriers related to family communication that can be summarized by three key problematic areas, including concealing feelings, information exchange, and coping with helplessness.88 Families of critically ill patients often will conceal feelings in order to shield their loved ones from emotional suffering. Hinton studied couples coping with the terminal phase of cancer and identified the following barriers to communication: (1) consciously concealing negative feelings in order to maintain a positive attitude, (2) patients minimizing symptoms to avoid burdening their primary caregivers, and (3) patients and family members avoiding discussions of the patient’s illness to maintain an optimistic outlook.89 In the last stages of life, patients and family often need increased support from health-care providers to prevail over these barriers. Issues of death may overwhelm patients and their family caregivers who may have little experience with the dying process. Health-care providers need to encourage caregivers to express concealed emotions and be an empathetic audience willing to take the time to listen. Family dysfunction and low-quality family relationships can exacerbate concealed emotions and increase communication constraints resulting in caregiver distress.90,91 Recently, research has highlighted family communication patterns that govern the content and frequency of discussions regarding serious illness and hierarchy among family caregivers.92 Four family caregiver communication types have been identified, including the manager, carrier, partner, and lone caregivers, and the Family Caregiver Communication Tool, a 10-item questionnaire that assesses family conversations and conformity, has been developed to promote end-of-life communication based on family communication patterns.93

747 The manager and carrier type of family caregivers were reported to have more difficulty with communication and did not wish to share information with the patient, while the partner and lone caregivers were noted to have less difficulty communicating and less distress.94 For critically ill patients and their family, general guidelines for therapeutic communication to promote psychological well-being include the following: health-care professionals actively listening and displaying empathy; clinicians providing information about current illness, options for treatment, and what to expect in the future without excessive medical jargon; and patients and family member being encouraged to express their emotions in a safe environment.95 In addition, studies have shown that to improve communication, clinicians should also spend more time listening than speaking, express non-abandonment, ensure discussions are patient centered, be more accessible, and avoid missed opportunities to provide emotional support for family members.96–101 Conflict between family caregivers and health-care staff may occur when there is poor communication regarding advanced care planning and the difference in understanding of the disease, or when caregivers misinterpret words, perceive information negatively, or feel that the health-care providers are dismissive.102

Information needs of family caregivers In addition to concealed feelings, family caregivers may not have adequate information to provide high-quality end-of-life care. The lack of information may exacerbate the distress level of family caregivers. For example, commonly held deficiencies with respect to pain management, including fear of respiratory depression, drug tolerance, or addiction, may lead to inadequate (or even excessive) opioid administration. Inadequate communication with family caregivers can result in additional distress (stress, anxiety, and dissatisfaction) due to unmet information needs, the lack of knowledge and understanding, the lack of shared decision-making, conflict with staff and among family members, as well as the lack of trust in healthcare providers.103 Family caregivers often mediate interactions between the patient and the health-care provider and act as a patient advocate. If they feel that they have not provided the best possible care for their loved one, distress in the family caregiver can escalate. In a study examining the quality of palliative care, researchers showed a high family satisfaction with the care provided to dying cancer patients with the highest level of satisfaction with the following: nurse availability, hospital bed availability, coordination of care, and clinicians’ attention to symptom control, including pain relief; however, family members had low satisfaction with the following interventions—family conferences conducted to discuss the patient’s illness, information provided regarding medication side effects, a patient’s prognosis, pain management, and tests.104 It is critical that the interdisciplinary team answer the questions of both patients and their family caregivers. Individual members of the palliative care team should be utilized, such as the pharmacist who may be deployed to review the indications, side effects, and how to safely administer the patient’s medications as well as a social worker who can assist with expressive supportive counseling. Studies show that end-of-life discussions improve a patient’s understanding of their prognosis and increase enrollment in hospice care.105 A prospective, longitudinal, cohort study revealed that frequency of end-of-life discussions varied at different

Textbook of Palliative Medicine and Supportive Care

748 medical institutions, which was attributed to their unique institutional cultures and increased when patients had a lower performance status and a higher symptom burden.106 End-of-life discussions were not associated with increased patient psychological distress but were associated with fewer aggressive medical treatments (i.e., mechanical ventilation, resuscitation, and admission into an intensive care unit [ICU]). Bereaved family caregivers who had end-of-life discussions initiated by health-care providers were less likely to have symptoms of anxiety or depression after a patient had died.106 Qualitative studies have revealed a variable degree of information needs107–109 for patients and family caregivers that are often divergent as the patient’s illness progresses. A study involving focus groups consisting of 19 patients with advanced cancer and 24 caregivers has revealed that caregivers have distinct information needs concerning end-of-life issues and prognosis, which often differ from the needs of patients.107 Patient surveys reveal that one in five patients with terminal cancer would prefer not to discuss prognosis.108 Preferences for information may change over time, and requests for information by patients with terminal cancer often decline as their illness progresses.109 It is critical for health-care providers, prior to discussing issues such as prognosis with a critically ill patient, to ask what the patient and family already know and what questions they would like to be answered before providing information regarding the end of life. Open and regular communication is critical to meet the information needs of patients and family caregivers. Medical information may have to be repeated with care to avoid using medical terminology. Written material, question prompt lists,110 and consultations recorded with audiocassettes or digital devices can increase satisfaction with information exchange.111 Written summaries and recordings of the consultation can be used to communicate with family members who are not able to physically be with the patient at the time of the meeting. In addition, family caregivers report difficulty accessing medical information, often are overloaded with too much information or too little information, and often themselves are reluctant to interrupt busy health-care providers and ask questions.112,113 Health-care providers may lack the ability to break bad news such as a poor prognosis114 or when they do, often use medical jargon, which is difficult for patients and family to understand. In addition, when oncologists communicate information in an optimistic manner regarding the benefits of chemotherapy, they were rated as better communicators by patients and their family caregivers.115 Patients and family preference for an optimistic message may reinforce the avoidance of discussing bad news and honest disclosure of information such as a poor prognosis.

Family conferences Family conferences have been championed by palliative care providers as a useful clinical tool to improve information exchange between health-care providers. Patients and family caregivers who participated in family meetings placed value on the “simultaneous presence” of attendees resulting in family caregivers and the health-care team being on “the same page” 116 and improved perception of empathy from staff.117 A family conference is defined as a “meeting which involves a patient and their family members, including the primary caregiver, and health-care professionals (defined as physicians, nurses, a social worker, case manager, and the chaplain) in discussions concerning cancer treatment, optimal symptom management, prognostication, advanced directives, and

discharge planning.”118,119 Currently, a paucity of research exists evaluating the impact of family conferences on clinical outcomes, including patient and caregivers’ satisfaction with information giving and assessments of quality palliative care (i.e., hospice enrollment, bereavement outcomes).120 Guidelines121,122 on conducting family meetings have been developed and are based on expert opinion and qualitative studies and extrapolated from studies of conferences conducted in ICUs. Pilot work investigating the benefits of family meetings using clinical guidelines proved useful and reduced the information needs of family caregivers.123 In the same study, benefits of family meetings for participants included meeting the healthcare team, providing a forum to ask questions and obtain information, clarifying goals of care, and allowing them to express feelings and mediate differences within the family. In a prospective study of 140 family meetings in a palliative care unit in the United States, family conferences were found to have a high frequency of emotional expression by cancer patients and their family members and frequently involved discussions regarding a patient’s goals of care, information regarding prognosis, and how to manage symptoms, but less frequently regarding issues of the well-being of the family caregiver, advanced directives, and what symptoms to expect at the end of life.124 Of note, patient participation in the family conference was associated with discussions regarding prognosis and what dying patients may experience to less likely occur.124 However, in an Australian study of family conferences, the majority of patients participated in the meeting and the researchers reported that both patients and families were spontaneously able to share end-of-life concerns and prepare for death.125 In addition, patients who participate in a family conference may often misunderstand and are unable to recall what was discussed during the meetings, including issues such as prognosis.126 One study reported that the majority (60%) of dying patients did not recall end-of-life discussions that had recently been conducted.106 Interestingly, patients with lower functional status and increased symptom burden had a higher recollection of these discussions.106 Currently, it is unclear if critically ill patients and family caregivers are able to grasp the information provided to them during family meetings and the quality of the discussions requiring more research.

Family conferences in the ICU setting Researchers have observed that in an ICU, a family conference improves communication between health-care providers and a patient’s family.95–100,127 In the ICU setting, a landmark trial128 using the mnemonic VALUE (V, value and appreciate what family members say; A, acknowledge the family member’s emotions; L, listen; U, understand who the patient is as a person by asking open-ended questions; and E, elicit questions from all family members)129 to provide consistency of therapeutic communication in family conferences led to measurable benefits, including decreased posttraumatic stress disorder, anxiety, and depression. Studies on family conferences in the ICU setting have also shown improvements in communication,95–100 reductions in the burden of bereavement,128 family caregiver distress and even reductions in the length of stay,130–132 but not all studies.133 Of note, studies of end-of-life conferences in the ICU setting often lack active participation by patients in the meetings, which was noted to be less than 5%,128,134 since patients are often too critically ill, intubated, or too sedated.

Family Caregivers and Cultural Sensitivity A systematic review of interventions to meet the needs of family caregivers with critically ill patients in an ICU identified the following interventions: support—support groups, journal or diary writing, and training in coping strategies; assurance—faceto-face meetings with health-care staff and family participation in ICU rounds; proximity—changes in visitation policies; information—handouts and brochures, incorporate technology to communicate with family caregivers, family caregiver education, and information initiatives; and comfort—changes in the ICU physical environment.135 A study on communication with family caregivers of patients admitted to an ICU reported that health-care providers exchanged outside of traditional family meetings and involved predominantly informal bedside updates from nursing staff,136 highlighting the need for tools to support best practice in the ICU. Web-based educational tools to assist family caregivers in the role of surrogate decision-making have been developed and need further testing.137 Distress in surrogate family members of patients in ICU was associated with the failure of the clinicians explaining how the patient’s pain would be managed, perception of a family that physicians did not listen to concerns, and the lack of religious or spiritual support.138 In addition, family caregiver attendance in ICU rounds may enhance communication.139,140

Pain, symptom management, and practical concerns of family caregivers Chronically ill patients, such as those with advanced cancer, may experience severe physical and psychosocial symptoms, including pain, dyspnea, fatigue, anorexia/cachexia, depression, and sleep disorders,141,142 which are often inadequately treated.143,144 Healthcare providers’ attention to symptom relief of critically ill patients may improve quality of life (QOL) and reduce caregiver distress.145

Pain management and family caregivers

The management of pain is reported to be a major concern of family caring for patients with a life-threatening illness and54,146,147 uncontrolled pain at the end of life and can result in distress and feelings of guilt or helplessness in family caregivers.148 It is not uncommon for family caregivers to fear the use of opioids secondary to concerns of addiction and side effects such as respiratory depression or misunderstanding health-care providers who have communicated poorly, which can increase the difficulty in controlling pain in the home setting.149,150 An exploratory study reported caregivers who were male, employed, less educated, or retired had greater concerns about pain management, which resulted in more difficulty in managing a patients’ pain.151 In addition, African American caregivers, as compared to Caucasian caregivers, had more concerns about side effects and addiction as well as less baseline knowledge about pain management prior to Hospice admission.152 Unfortunately, they are limited well-designed trials of interventions addressing caregiver’s ability to manage symptoms, including pain control, at the end of life and the majority of studies involve primarily patients with a cancer diagnosis and family caregivers who were predominantly female.153 After-hours telephone and videophone services have been studied and found to be simple, effective, and valued by patients and family caregivers who could access these services even when they were not in close proximity to a hospital.154–156 Educational programs administered in the patient’s home consisting of a diary recording the intensity of pain and administration of opioids, video demonstration of how to safely transfer patients without pain, and

749 education pamphlet describing the proper use of opioids resulted in improved administration of pain medications and increased confidence in caregivers.54 Home care nurses, as well as having 24 hours access to a health-care provider, who provide paid assistance with caregiving and emotional support for both patients and the primary caregiver were reported to be a valuable source of information.112,157 In another study where caregivers participated via videophone in hospice interdisciplinary team meetings as opposed to nonparticipation, there was a significant increase in the discussion and exchange of information regarding pain management.158 A trial examining caregiver-guided pain interventions, including educational information about pain management and a cognitive–behavioral pain coping strategy for caregivers, reported that caregivers had an increased sense of confidence in managing pain, but unfortunately, the patient’s pain level was not significantly reduced,159 which highlights the difficulty in managing pain.

Symptoms at the end of life and family caregivers

Delirium is a medical emergency and is a common complication in hospitalized patients and those receiving palliative care. Delirium is characterized by sudden onset of confusion, periods of inattention, perceptual disturbances that fluctuate in intensity and is associated with distress in family caregivers.160 Predictors of distress in family caregivers of patients with dementia included the severity of both dementia and delirium, increased with the age of the caregivers who were predominantly female, and the inversely proportional to the time spent in care.161 Caregiver distress can also be exacerbated by the irreversibility of delirium in the palliative setting.162 In a study of cancer patients who had recovered from delirium, the majority of patients and all family caregivers could recall the distressing experience and attributed the confusion to pain medications.163 A systematic review evaluating educational interventions for family caregivers of patients with delirium reported that interventions improved knowledge, reduced the incidence of delirium in the elderly, and potentially decreased caregiver distress.164 Dyspnea, the sensation of shortness of breath, is a common symptom in patients with cancer, heart failure, and lung disorders such as chronic obstructive pulmonary disease. Dyspnea not only results in distress for patients but also impacts their caregiver’s quality of life.165 Breathlessness has been reported to be associated with low family well-being and an increased likelihood of death in the hospital setting for cancer patients.166 The caregiver’s burden of patients with dyspnea was higher than patients without shortness of breath,167 noted to be the most common symptoms of palliative care appropriate patients who presented to the emergency department,168 and associated with a higher burden equally in lung cancer patients as well as severe heart failure.167 Interventions targeting caregivers of patients with dyspnea need to be developed in order to maintain better control of symptoms and prevent caregiver burnout. Loss of appetite and weight loss are common symptoms at the end of life and can result in distress in family caregivers.170 A survey of the impact of poor oral intake among bereaved caregivers has recommended interventions to decrease the sense of helplessness and guilt associated with a loved one losing weight such as providing education on hydration and nutrition at the end of life as well as emotional support to family caregivers.171 Health-care providers should educate family caregivers that weight loss secondary to an illness is not equivalent to starvation and is difficult to reverse, stress the pleasure of tasting small bites of food over

750 attempting to increase caloric intake, and emphasize the need to participate in the social aspects of eating at the dinner table with the family. Unfortunately, a qualitative study involving bereaved family caregivers highlights the limited communication provided to families regarding nutrition at the end of life.172 Practical information provided by health-care providers on the administration of medications, feeding, dressing, and bathing patients to family caregivers can also be helpful. Family caregivers often take over many roles, which may have been previously assigned to the patient, such as managing the household finances, working to provide income for the family, or coordinating the schedule and care of the children. Role reversal may lead to distress for both patients and their primary caregivers if they are unable to adapt to their new responsibilities. When the caregiving responsibilities become overwhelming, respite services are indicated. By admitting patients temporarily to a hospital or inpatient hospice or by providing assistance at home at night, family caregivers are relieved briefly from the burden of caregiving and allowed to rest and reenergize. Family caregivers often are deprived of sleep,173 and research examining a community-based night respite service for critically ill cancer patients reported positive outcomes, including family caregivers being able to manage patients at home allowing for a home death and reduced overall costs secondary to fewer patients being hospitalized.174 For caregivers of patients with dementia, evening daycare programs may provide temporary relief from the burden of caregiving. In the last days of life, distress often escalates for both patients and their family caregivers. Family caregivers have expressed fears concerning providing care when patients are at the end of life and at the actively dying stage and appreciate knowing the signs of imminent death.174–177 Preparing family caregivers for the last stages of life can lessen the emotional distress of witnessing the actively dying stage and normalize the process so as not to confuse signs of death with symptoms of increased pain or shortness of breath. For instance, the “death rattle” or signs of agonal breathing may be perceived by family members that the patient is short of breath, and appropriate medical interventions to control symptoms should be initiated when indicated as well as reassurance and clarification of what is a normal or an expected sign associated with the actively dying stage.

Financial burden

In addition, financial distress is not uncommon in chronically ill patients178 and can contribute to the burden facing family caregivers. In many countries, medical care has been migrating from the hospital setting to an outpatient/home setting, which results in patients and their family caregivers being responsible for a larger share of health-care costs. Family caregivers often have to sell assets, borrow money, or work additional jobs in order to meet the financial costs of health care.172 In the United States, approximately 40 million family caregivers are providing unpaid assistance, estimated 37 billion hours, for ill patients with an estimated economic value of $470 million in the year 2013, up from an estimated $450 billion in 2009.179 Family caregivers were reported to forgo work or work fewer hours in order to provide care for a loved one.180 In a study conducted in Canada, unpaid caregiving was the largest cost for providing care at the end of life with monthly costs increasing exponentially with proximity to death,181 and many families may have to declare bankruptcy in order to escape the accumulated financial burden.

Textbook of Palliative Medicine and Supportive Care Often, there are limited or no resources available for patients and their family caregivers, which forces patients to choose from continuing their medications versus using their income to pay for food or other essentials. Health-care providers can assess the financial burden for patients and family caregivers and identify resources available to lessen the cost of care to some degree. One simple intervention is to review a patient’s medications and substitute more affordable medication for expensive drugs or even eliminate unnecessary medications that have been ineffective at controlling symptoms or found to be unnecessary.

Coping of family caregivers Both chronically ill patients and their family caregivers rely on coping mechanisms during this stressful period in their lives. Coping has been defined as “a person’s cognitive and behavioral efforts to manage (reduce, minimize, master, or tolerate) the internal and external demands of the person-environment transaction that is appraised as taxing or exceeding the person’s resources.”182 Over the trajectory of a patient’s illness, types of coping strategies of both patient and family caregiver may vary and include cognitive, behavioral, spiritual, practical, existential, and other approaches.183 Health-care providers should incorporate assessments of coping strategies for both patients and caregivers. Unfortunately, no gold standard for the assessment of coping styles currently exists. Examples of coping inventories used in the research setting include the COPE inventory,184 RCOPE—assessment of religious coping,185 and Cancer Behavior Inventory—assessment of coping in cancer patients.186 Research on coping has categorized into multiple domains, including problem-focused, emotion-focused, and meaningfocused domains.187 Others have conceptualized coping mechanisms based on engagement to reflect either engagement, an active or approach-orientated strategy to manage stress, or disengagement, in which individuals avoid or withdraw for dealing with stress.188 Coping also has been characterized in functional terms to include either adaptive, or resilient, strategies such as planning, positive reframing, acceptance, humor, and use of emotional and instrumental support versus maladaptive approaches, including self-distraction, denial, venting, substance use, behavioral disengagement, and self-blame.189 To help with caring for a patient with a chronic illness, various adaptive or positive coping strategies used by family of caregivers have been identified such as reliance on social support, rationalization, viewing the positive aspects of caregiving, and acceptance.190,191 In one study, an adaptive or positive coping strategy identified as “taking one day at a time” was noted to be helpful in managing the uncertainty about the future.192 Other adaptive coping strategies include accepting responsibility, planful problem solving, and positive reappraisal.76,182 A growing body of research indicates that adaptive or positive coping strategies prevent depression in the caregiver and are associated with a better functional status of the patient.193–196 Family caregivers, engaging in maladaptive or negative expectation that included excessive worrying, expecting the worst, taking tension out on others, or perceiving that they were poorly coping with the caregiving role, were more likely to experience a sense of entrapment in their responsibilities as a caregiver and emotional fatigue.197 These negative expectations coping strategies were associated with symptoms of anxiety, guilt, and depression, while positive coping mechanisms such as hoping for improvement, finding purpose, setting goals, and taking one step

Family Caregivers and Cultural Sensitivity at a time were associated with less emotional exhaustion.197 In addition, spiritual coping has been associated with either adaptive or maladaptive strategies for chronically ill patients and family caregivers. In a study of caregivers of patients with advanced cancer, 58% reported spiritual pain that was associated with maladaptive coping strategies.198 Family caregivers who engaged in maladaptive or negative religious coping (e.g., feeling abandoned or punished by God) were more likely to have increased caregiver burden, decreased QOL, and worse depressive and anxiety disorders.199 The dyadic relationship among chronically ill patients and their informal family caregivers may contribute to how they both cope. Patients who resorted to acceptance coping were associated with their family caregiver having less symptoms of depression, as opposed to patients seeking emotional support to cope who had caregivers with higher ratings of depressive symptoms.200 In addition, family caregivers had increased anxiety associated with patient distress, both psychological distress and pain.201

Interventions to assist with the coping of family caregivers

Promising interventions to support the psychosocial well-being of family caregivers should include educational approaches, skills training to develop adaptive coping strategies and problem-solving skills to manage the responsibilities of caregiving, techniques to enhance communication between patient and caregiver, emphasis on the self-care, and therapeutic counseling for both patient and family caregivers.202,203 An intervention trial that reported significant benefits for family caregivers involved five 2-hour home visits by a psychologist, two 30-minute sessions over the telephone, and a follow-up telephone session at 6 months with both patient and primary caregiver.204 Sessions involved meeting the information needs of the primary caregiver, interventions directed at enhancing a patient’s body image, and techniques for both patient and caregiver to improve coping and problem-solving skills.204 In patients with cancer and their caregivers, the FOCUS program incorporated the following content areas—family involvement which included facilitated open dyadic communication and support; optimistic outlook; coping effectiveness; uncertainty reduction; and symptom management—have been studied and reported positive outcomes, including less hopelessness and symptoms, greater self-efficacy and coping, improved dyadic communication, and better quality of life in participants compared to controls.205–207 In Memorial Sloan Kettering Cancer Center, the Caregivers Clinic, staffed by clinical psychologist and psychiatrists, provided support for caregivers using a variety of approaches, including cognitive–behavioral therapy and existential, supportive, and bereavement interventions. Also, Web-based and designed screening tools are being developed to conveniently screen for caregiver distress addressing their psychosocial wellbeing and needs in a standardized manner. Recently, a randomized, unblinded psychosocial intervention for family caregivers of cancer patients undergoing autologous and allogeneic hematopoietic stem cell transplantation which integrated treatmentrelated education and self-care with cognitive–behavioral skills to promote coping was also noted to be feasible and researchers reported could potentially improve QOL, mood, coping, and self-efficacy reducing the family caregiver burden.208 In addition, home-based specialized palliative care and dyadic psychological support for both advanced cancer patients and their caregivers led to better coping among couples but not parent–child dyads.209

751 More studies are needed in examining interventions for primary caregivers and patients that promote adaptive, resilient coping styles resulting in less distress and caregiver burden.

Family function and caregivers

Families who have open and effective communication prior to the development of an illness have been reported to cope and function better than families who have difficulty communicating with each other.210 In addition, caring for patients with a chronic illness may cause family conflict resulting in less support from family or friends, which only exacerbates the distress of the primary caregiver.211 Care of a chronically ill patient requires the availability of caregivers throughout the day and night. The primary caregiver in a dysfunctional family may be unable to recruit or persuade other family members to assist in the role of a secondary family caregiver. Also, if the goals of care differ between the patient and individuals within the family, conflict can develop resulting in the patient having to align themselves with one family member over another. In addition, studies have shown that poor family function results in an increased burden of bereavement after the patient has died,212,213 and family-focused grief therapy may be indicated for dysfunctional families in order for them to accept the loss of a loved one.214

Cultural sensitivity Health-care professionals working with family members of chronically ill patients must also be mindful of the cultural and ethnic diversity as they communicate with and provide psychosocial support to critically ill patients and their family caregivers. Culture, a broad concept that encompasses race, socioeconomic status (SES), norms, traditions, beliefs, and customs, and acculturation, assimilation to a different culture, can influence attitudes, beliefs, preferences, and behaviors with respect to health care, including the experience of illness and death. Issues regarding disclosure of medical information, gender-determined role restrictions for caregivers, intergenerational shifts in values, and acceptance of the psychosocial sequelae of a chronic illness may vary across different cultures. Ideally, optimal care of seriously ill patients should be personalized and take into consideration a patient’s and family caregivers’ preferences, hopes, and values. Health-care providers not only should be familiar with attitudes, beliefs, and norms of different groups but also be cognizant of their own cultural assumptions, both personal and professional, as they provide culturally appropriate care. Cultural humility, providing culturally appropriate care, is defined as a process of self-awareness and openness to interact and deliver care with diverse patient populations and incorporates self-reflection and critique215 and also acknowledges that culture is uniquely defined by a patient’s life experiences and beliefs which can change over time. In addition, to maintain a therapeutic relationship, a healthcare provider should tactfully and in a nonjudgmental manner acknowledge patients’ cultural differences, including their attitudes toward sexuality and gender roles. Also, a patient’s physical pain, emotional distress, and existential suffering are subjective and often modified by cultural values, norms, and expectations,216 and can all contribute to the burden patients and family experience at the end of life. A patient’s worldview, religion, or spiritual beliefs have a significant impact on health and illness encompassing dietary practices, folk remedies, and bereavement customs; in addition, the mysteries of death and the dying process can elicit

752 patients and family to seek meaning and comfort through spirituality or religion.

Cultural appropriate communication

In the United States and other Western European countries, there has been a shift in the ethical framework for communication during the end of life toward an emphasis on patient autonomy and full disclosure of information. In contrast, non-Western cultures emphasize the ethical principle of nonmaleficence and feel that honest disclosure regarding death and end-of-life issues will result in more harm than good for the patient. Research has emphasized three areas of end-of-life care that cultural attitudes, which if not taken into consideration, may result in patient and family distress and include breaking “bad news,” decision-making preferences for medical care, willingness to complete advanced directives, and acceptance of end-of-life care. In addition, health-care providers need to be aware that compared to whites of European descent, ethnic minorities exhibit a greater degree of variability in their cultural views and preferences.217 In order to communicate medical information effectively and ensure a high degree of patient and family satisfaction, healthcare providers need to be cognizant of a patient’s and families’ acceptance of “truth-telling.” In many countries, health-care professionals will conceal a patient’s diagnosis or a poor prognosis from patients and communicate bad news only to their family.218 For example, in many Asian cultures, it is felt to be unacceptably cruel to inform a cancer diagnosis to a patient.219 A survey of Chinese physicians and cancer patients reported that physicians were the least likely to favor full disclosure of cancer diagnosis compared to patients and sighted five reasons for concealment, including the lack of awareness of patients’ right to knowledge, cultural influences, insufficient medical training, families’ financial concerns, and need to protect clinicians from violence.220 In a Japanese study, most physicians reported disclosing the malignant nature of the illness to patients but not the exact diagnosis, often modifying disclosure based on histopathological grading and the availability of patient’s psychological support systems and family’s wishes.221 In addition, in many countries, including the Middle East, Africa, and South Asia, the male family caregiver is the spokesperson for the family and may act as a protector or gatekeeper to prevent their loved one from receiving “bad news.” Also, recent Bosnian immigrants to America reported a preference for Bosnian physicians who indirectly communicate the seriousness of an illness as opposed to American physicians whose blunt truth-telling was perceived to be unnecessarily harsh.222 In addition, some cultures believe that the acknowledgment of impending death may become a self-fulfilling prophecy.223 Native Americans, for example, will emphasize thinking and speaking in a “positive way” 224 and discussions of death and dying are generally considered a violation of cultural values.225 Among African American patients, studies have reported conflicting results. One survey of 205 elderly African Americans noted a reluctance to discuss and prepare for death,226 less likely to discuss their prognosis, and acknowledge that they were terminally ill as compared with white patients.227 However, an older survey of 200 elderly black patients reported to prefer disclosure of life-threatening disease and know about a terminal prognosis as compared to Korean-American or Mexican-Americans.217 In cases where patients and family request nondisclosure, a clinician not only can offer to divulge the diagnosis and treatment options in order to respect cultural norms but also allow the patient to refuse medical information and direct communication to either

Textbook of Palliative Medicine and Supportive Care their family, friend, or confidant responsible for the medical decision-making.228 In addition, medical jargon or terminology that obscures the seriousness of diagnosis is often used by physicians outside the United States. Japanese and African physicians have been reported to use terms, including “growth,” “mass,” “blood disease,” or “unclean tissue,” rather than disclosing that the patient has cancer.217 In the United States, family members of patients from minority groups may also conceal information by intentionally not translating the diagnosis or accurate treatment information to the patient,229 which emphasizes the need for a professional medical translator when communicating end-of-life issues to a non-English-speaking patient.230

Cultural preferences and medical decision-making

Decisional role preferences may vary across cultures and ethnic groups. In the United States, patient autonomy takes precedence as long as a patient has an intact cognitive function or is not impaired by a psychiatric illness or medication. In minority groups, alternative models of decision-making are emphasized and include family based, a physician based, and shared physician and family based.40 For African-American families, a systematic review emphasized that African Americans utilize advance care planning less often than non-Hispanic Whites.231 As compared to African-Americans, non-Hispanic white patients preferred to be more exclusive with family member participation in end-oflife discussions.232 In the same study, African-Americans had a preference for greater spiritual support and protection of life at all costs, while non-Hispanic whites favored more medical information, valued information regarding the cost of treatment, and had more concerns concerning maintaining their quality of life.232 Another study reported that Korean-Americans and MexicanAmericans were more likely to favor the family-centered model of medical decision-making as opposed to an emphasis on patient autonomy favored by European-Americans and AfricanAmericans.217 African-American preferences for autonomy reflect a shared core American value between white and black patients and may be due to distrust of the modern medical system and health-care professionals by black Americans.233 Mexican-Americans, as compared to individuals of European descent, prefer that family members, rather than the patient, have decision-making power regarding end-of-life issues such as requesting life support.227 Hispanic-American patients preferred a higher degree of patient autonomy than Hispanic-Latin Americans; however, the majority in each group favored a shared decision-making, family-centered approach to decisions regarding end-of-life care.234 These findings highlight the process of acculturation of Hispanic-American immigrants whose decisional role preferences may often quickly shift. Even among a specific ethnic group, variations in preferences for end-of-life care may exist, and health-care providers need to assess for these preferences and then communicate information in a culturally sensitive way. In many traditional East Asian cultures, patients prefer a family-centered decision-making model and often the family is expected to be informed of patient’s health-care concerns and treatment options.217 In addition, many cultural groups have a high degree of respect and admiration for physicians. Pakistani physicians often are adopted into a family unit, which allows them to participate in sensitive end-of-life discussions.235 In Russia, physicians, rather than patients, have been reported to make decisions regarding continuing life support.236 In addition,

Family Caregivers and Cultural Sensitivity Eastern European immigrants preferred physicians who took a paternalistic approach to decision-making and cited that physicians are the experts and should be the ones with the knowledge to make a difficult medical decision, which reduces the burden on the family.222 Research also shows significant discrepancies in end-of-life care within different ethnic groups. Asians, AfricanAmericans, and Hispanics have lower rates of advanced directive completion.237,238 Low rates of completion of advanced directives could be attributed to distrust of the health-care system, disparities in health-care delivery, or cultural preferences regarding death.239 African-American patients were less likely to accept DNR status, more likely than white patients to change DNR status to a more aggressive treatment plan,231,240 and less likely to enroll in hospice care. 39 In addition, white critically ill patients enroll in Hospice more than any other group.241 Researchers initially postulated that black patients’ preferences for life-prolonging treatment and limited access to a family caregiver at home-restricted enrollment; however, the authors discovered that nonprofit ownership and larger hospice budgets predicted larger proportion of patients in both racial groups, while regions with higher proportion of generalist, as opposed to specialist, had higher enrollment of black patients.242 By obtaining a better understanding of a patient’s and family members’ cultural views and decisionmaking preferences, health-care providers can apply a culturally sensitive approach to end-of-life care.

Disparities and end of life care

In the United States, emerging evidence suggests that patients with lower SES and ethnic minorities encounter structural and interpersonal barriers to optimal health care. The Department of Health and Human Services defines disparities as “differences in health outcomes that are closely linked with social, economic, and environmental disadvantages,”243 and the National Institute of Health designated U S health disparity populations to include Blacks/African Americans, Hispanics/Latinos, American Indians/Alaska Natives, Asian Americans, Native Hawaiians, and other Pacific Islanders, socioeconomically disadvantaged populations, underserved rural populations, and sexual and gender minorities.244 Research is emerging highlighting differences in care received by black, Hispanic, and Native American patients as well as lower SES compared with white patients and those with higher SES. In the outpatient palliative care setting, racial and ethnic minority groups and those with lower SES are referred less often than non-Hispanic white patients.245,246 Pain scores, total opioids prescribed, and number of visits to the clinic were higher in patients who were either uninsured or receiving Medicaid compared with private insurance,245 suggesting that patients with lower SES despite having more visits received less effective pain management, were unable to afford their prescriptions, or received less psychosocial support. In addition, homeless people face unique challenges, including accessing outpatient palliative care, lack of family and social support, and fears of dying anonymously and alone.247,248 In the inpatient setting, several studies have reported that black patients are more likely to receive palliative care consultation than white patients.249–251 Among patients who died in the hospital, palliative care consultation was 30% higher for black, 20% higher for Asian or Pacific Islander, 13% higher for Hispanic patients compared with white patients.249 In addition, palliative care consultation was roughly 1 week earlier in the hospital stay for black patients than they were for white patients.251

753 Unfortunately, the studies in the inpatient setting are observational and other factors may account for more frequent palliative consultation for minority groups in the inpatient setting and more research is needed.

Conclusions Distress is not uncommon for family caregivers of patients with chronic illnesses. Family caregivers are often unpaid, are underappreciated, and lack the support of health-care providers resulting in increased risk for emotional exhaustion and burnout. Multiple factors contribute to the distress of the family caregiver, and health-care professionals should routinely assess and intervene to diminish the suffering experienced by both patients and their caregivers. Health-care professional providing timely and appropriate medical information can give the family caregiver the confidence to provide care, and clinicians encouraging caregivers to express emotions to lessen the psychological distress that accompanies the role of being a caregiver and encouraging successful adaptive coping strategies enabling caregivers to handle the responsibilities of caring for a critically ill spouse, parent, friend, or child. Psychoeducational interventions, such as peer support groups, emphasis on the importance of self-care, and education directed at increasing the confidence of the family caregivers to provide care of their loved one, show potential in decreasing caregiver distress and preventing burnout. In addition, health-care providers not only should be familiar with attitudes, beliefs, and norms of different groups, including ethnic and racial minorities but also be cognizant of their own cultural assumptions, both personal and professional, as they provide culturally appropriate care.

KEY LEARNING POINTS • Psychosocial support for both patients and their family caregivers is at the foundation of palliative care. • The definition of a family caregiver is open ended and should be defined by the patient. • Although there are positive aspects associated with the act of caregiving, distress from the burden of providing care can lead to a combination of physical and emotional suffering. • Research reveals an increased feeling of helplessness among family caregivers, which was associated with the progression of a patient’s illness, the degree of struggle undergone to obtain needed medical services, and the inability of caregivers to relieve a patient’s pain and discomfort. • Predictors of caregiver burnout for the family caregiver include restrictions in social life, indicators of poor health or comorbidities, and a negative outlook regarding the role of being a family caregiver. • A family caregiver’s self-esteem, confidence in caregiving, and amount of social network, including family support, have been shown to alleviate the caregiver distress and enhance their ability to provide care.

Textbook of Palliative Medicine and Supportive Care

754 • Barriers related to family communication that can be summarized by three key problematic areas include concealing feelings, information exchange, and coping with helplessness. • Preliminary studies of family conferences were found to be useful, facilitated patient, family, and health-care professionals to be on the “same page,” and were an emotional experience for both patients and their family members. • Benefits of family conferences for participants included meeting the health-care team, providing a forum to ask questions and obtain information, and allowing for the clarification of the goals of care. • The management of pain is reported to be a major concern of family caring for patients with a lifethreatening illness. • Educational programs administered in the patient’s home consisting of a diary recording the intensity of pain and administration of opioids, a video demonstration of how to safely transfer patients without pain, and education pamphlet describing the proper use of opioids resulted in improved administration of pain medications and confidence in caregivers. • After-hours telephone and videophone services have been found to be simple, effective, and valued by patients and family caregivers in meeting their information needs and can be accessed even when they were not in close proximity to a hospital. • Respite services either in a facility or provided at home during the night for family caregivers allow for temporary relief from the burden of caregiving. • Family caregivers have expressed fears concerning providing care when patients are at the end of life and the actively dying stage and appreciate knowing the signs of imminent death. • Promising interventions to help one to support family caregivers include counseling sessions that stress problem–solving approaches to manage the responsibilities of caregiving, techniques to enhance communication between patient and caregiver, counseling to promote adaptive coping styles, and emphasizing self–care of caregivers. • Health–care professionals working with family members of chronically ill patients must also be mindful of the cultural and ethnic diversity of values as they communicate with and provide psychosocial support to critically ill patients and their family caregivers. • Patients with lower socioeconomic status (SES) and ethnic minorities encounter structural and interpersonal barriers to optimal health care, including access to palliative care.

Acknowledgment The authors would like to acknowledge Linda J. Kristjanson and Mary Dev for their previous work on the family care chapter in the previous editions.

References





1. www.who.int/cancer/palliative/definition/en/ 2. Canadian Palliative Care Association. Standards for Palliative Care Provision: Canadian Palliative Care Association, Ottawa, 1998. 3. Biegel DE, Sales E, Schulz R. Family Caregiving in Chronic Illness: Alzheirmer’s Disease, Cancer, Heart Disease, Mental Illness, and Stroke. Thousand Oaks, CA: Sage Publications; 1991. 4. Longacre ML. Cancer caregivers information needs and resource preferences. J Cancer Educ 2013;28(2):297–305. 5. Brody EM. The Donald P. Kent Memorial Lecture. Patient care as normative family stress. Gerontologist 1985;25(1):19–29. 6. Bass DM, Noekler LS. The influence of family caregivers on elders’ use of in-home services: an expanded conceptual framework. J Health Soc Behav 1987;28(2):184–196. 7. Kristjanson LJ, Aoun S. Palliative care for families: remembering the hidden patients. Can J Psychiatry 2004;49(6):359–365. 8. Schoenmakers B, Buntinx F, Delepeleire J. What is the role of the general practitioner towards the family caregiver of a communitydwelling demented relative? A systematic literature review. Scand J Prim Health Care 2009;27(1):31–40. 9. Burns CM, Abernethy AP, Dal Grande E, Currow DC. Uncovering an invisible network of direct caregivers at the end of life: a population study. Palliat Med 2013;27(7):608–615. 10. National Alliance for Caregiving and AARP Caregiving in the United States 2015. www.caregiving.org/wp-content/uploads/2015/05/2015_ CaregivingintheUS_Executive-Summary-June-4_WEB.pdf. 11. Arno PS, Levine C, Memmott MM. The economic value of informal caregiving. Health Aff (Millwood) 1999;18(2):182–188. 12. Hurd MD, Martorell P, Delavande A, Mullen KJ, Langa KM. Monetary costs of dementia in the United States. N Engl J Med 2013;368(14):1326–1334. 13. Mitchell JM, Kemp BJ. Quality of life in assisted home living. J Gerontol B: Psychol Sci 2000;55(2):117–127. 14. Zarit SH, Todd PA, Zarit JM. Subjective burden of husbands and wives as caregivers: a longitudinal study. Gerontologist 1986;26(3):260–266. 15. Gillich MR. The critical role of caregivers in achieving patient-centered care. JAMA 2013;310(6):575–576. 16. Tang ST, McCorkle R. Determinants of congruence between the preferred and actual place of death for terminally ill cancer patients. J Palliat Care 2003;19(4):230–237. 17. Hunt RW, Fazekas BS, Luke CG, Roder DM. Where patients with cancer die in South Australia, 1990–1999: a population-based review. Med J Aust 2001;175(10):526–529. 18. Noekler LS, Bass DM. Home care for elderly persons: linkages between formal and informal caregivers. J Gerontol 1989;44(2):S63–S70. 19. John R, Hennessy CH, Dyeson TB, Garrett MD. Toward the conceptualization and measurement of caregiver burden among Pueblo Indian family caregivers. Gerontologist 2001;41:210–219. 20. Lawton M, Moss M, Kleban MH, Glicksman A, Rovine M. A twofactor model of caregiving appraisal and psychological well–being. J Gerontol 1991;46:181–189. 21. Young RF. Elders, families, and illness. J Aging Stud 1994;8(1):1–15. 22. Merz EM, Consedine NS. The association of family support and wellbeing in later life depends on adult attachment style. Attach Hum Dev 2009;11(2):203–221. 23. Tarlow BJ, Wisniewski SR, Belle SH, Rubert M, Ory MG, GallagherThompson D. Positive aspect of caregiving: contributions of the REACH project to the development of new measures for Alzheimer’s caregiving. Res Aging 2004;26(4):429–453. 24. Grbick C, Parker D, Maddocks I. The emotions and coping strategies of caregivers of family members with a terminal cancer. J Palliat Care 2001;17(1):30–36. 25. Kim Y, Schulz R, Carver CS. Benefit–finding in the cancer caregiving experience. Psycosom Med 2007;69(3):283–291. 26. Foley KL, Tung HJ, Mutran EJ. Self-gain and self-loss among African American and white caregivers. J Gerontol B Psychol Sci Soc Sci 2002;57(1):S14–S25. 27. Ferrel B, Mazanec P. Family Caregiver. In: Hurria A, Balducci L, eds. Geriatric Oncology: Treatment, Assessment, and Management. Springer, New York, 2009, 135–155. 28. Montgomery RV, Gonyea J, Hooyman N. Caregiving and the experience of subjective and objective burden. Fam Relat 1985;34(1):19–26.

Family Caregivers and Cultural Sensitivity 29. Aneshensel CS, Pearlin LI, Schuler RH. Stress, role captivity, and the cessation of caregiving. J Health Soc Behav 1993;34(1):54–70. 30. Colerick EF, George LK. Predictors of institutionalization among caregivers of patients with Alzheimer’s disease. J Am Geriatr Soc 1986;34(7):493–498. 31. Hills GA. Caregivers of the elderly: hidden patients and health team members. Top Geriatr Rehabil 1998;14(1):1–8. 32. Zarit SH, Reever KE, Back-Pererson J. Relatives of the impaired elderly: correlates of feelings of burden. Gerontologist 1980;20:649–655. 33. Novak M, Guest CI. Application of a multidimensional Care-giver Burden Inventory. Gerontologist 1989;29:798–803. 34. Robinson BC. Validation of a Caregiver Strain Index. J Gerontol 1983;38(3):344–348. 35. Tanco K, Vidal M, Arthur J, et al. Testing the feasibility of using the Edmonton Symptom Assessment System (ESAS) to assess caregiver symptom burden. Palliat Support Care 2018;16(1):14–22. 36. Adelman RD, Tmanova LL, Delgado D, Dion S, Lach MS. Caregiver burden: a clinical review. JAMA 2014;311(10):1052–1060. 37. Braithwaite VA. Bound to Care. Allen Unwin, Sydney, New South Wales, Australia, 1992. 38. Field MJ, Cassell CK., eds. Approaching death: improving care at the end of life. Institute of Medicine Committee on Care at the End of Life, National Academy Press, Washington, DC, 1997. 39. McKinley ED, Garrett JM, Evans AT, Danis M. Differences in endof-life decision making among black and white ambulatory cancer patients. J Gen Intern Med 1996;11(11):651–656. 40. Hern HE, Koenig BA, Moore LJ, Marshall PA. The difference that culture can make in end-of-life decision making. Camb Q Healthc Ethics 1998;7(1):27–40. 41. Pearce MJ, Singer JL, Prigerson HG. Religious coping among caregivers in terminally ill patients, main effects on psychosocial mediators. J Health Psychol 2006;11(5):743–759. 42. Burton AM, Sautter JM, Tulsky JA, et al. Burden and well-being among a diverse sample of cancer, congestive heart failure, and chronic obstructive pulmonary disease caregivers. J Pain Symptom Manage 2012;44(3):410–420. 43. Chiao CY, Wu HS, Hsiao CY. Caregiver burden for informal caregivers of patients with dementia: a systematic review. Int Nurs Rev 2015;62(3):340–350. 44. Garrido R, Menezed PR. Impact on caregivers of elderly patients with dementia treated at a psychogeriatric service. Rev Saude Publica 2004;28(6):835–841. 45. Grov EK, Dahl AA, Moum T, Fossa SD. Anxiety, depression, and quality of life in caregivers of patients with cancer in late palliative phase. Ann Oncol 2005;16(7):1185–1191. 46. Grunfeld E, Coyle D, Whelan T, et al. Family caregiver burden: results of a longitudinal study of breast cancer patients and their principal caregivers. Can Med Assoc J 2004;170(12):795–801. 47. Payne S, Smith P, Dean S. Identifying the concerns of informal carers in palliative care. Palliat Med 1999;13(1):37–44. 48. Ge L, Mordiffi SZ. Factors associated with higher caregiver burden among family caregivers of elderly cancer patients: a systematic review. Cancer Nurs 2017;40(6):471–478. 49. Mitchell AJ, Ferguson DW, Gill J, Paul J, Symonds P. Depression and anxiety in long-term cancer survivors compared with spouses and healthy controls: a systematic review and meta-analysis. Lancet Oncol 2013;14:721–732. 50. Bevans MF, Sterberg EM. Caregiving burden, stress, and health effects among family caregivers of adult cancer patient. JAMA 2012;307(4):398–403. 51. LoBiondo-Wood G, Williams L, Kouzekanani K, McGhee C. Family adaptation to a child’s transplant: pretransplant phase. Prog Transplant 2000:10(2):81–87. 52. Oldham L, Kristjanson LJ. Development of a pain management program for family carers of advanced cancer patients. Int J Palliat Nurs 2004;10(2):91–99. 53. Perreault A, Fothergill-Bourbonnais F, Fiset V. The experience of family members caring for a dying loved one. Int J Palliat Nurs 2004;10(3):133–143. 54. Andershed B. Relatives in end-of-life care. Part 1: A systematic review of the literature from the five last years, January 1999–February 2004. J Clin Nurs 2006;15(9):1158–1169. 55. Brazil K, Bedard M, Willison K, Hode M. Caregiving and its impact on families of the terminally ill. Aging Ment Health 2003;7(5):376–382. 56. Collins LG, Swartz K. Caregiver care. Am Fam Physician 2011;83(11):1309–1317.

755 57. Aldrich N. CDC Seeks to Protect Health of Family Caregivers. https:// www.cdc.gov/aging/caregiving/index.htm. 58. Family Caregiver Alliance. Caregivers Count Too! A Toolkit to Help Practitioners Assess the Needs of Family Caregivers. https://www. caregiver.org/sites/caregiver.org/files/pdfs/Assessment_Toolkit_ 20060802.pdf. Accessed 10/29/2020. 59. Schulz R, Martire LM. Family caregiving of person with dementia: prevalence, health effects, and support strategies. Am J Geriatr Psychiatry 2004;12(3):240–249. 60. Hubbell L, Hubbell K. The burnout risk for male caregivers providing care to spouses afflicted with Alzheimer’s disease. J Health Hum Serv Adm 2002;25:115–132. 61. Almberg B, Grafstrom M, Winblad B. Caring for a demented elderly person—burden and burnout among caregiving relatives. J Adv Nurs 1997;25(1):109–116. 62. Truzzi A, Valente L, Ulstein I, Engelhardt E, Laks J, Engedal K. Burnout in familial caregivers of patients with dementia. Rev Bras Psiquiatr 2012;34(4):404–412. 63. Takai M, Takahashi M, Iwamitsu Y, et al. The experience of burnout among home caregivers of patients with dementia: relations to depression and quality of life. Arch Gerontol Geriatr 2009;49(1):e1–e5. 64. von Kanel R. The burnout syndrome: a medical perspective. Praxis (Bern) 1994;97(9):477–487. 65. Takai M, Takahashi M, Iwamitsu Y, Oishi S, Miyaoka H. Subjective experiences of family caregivers of patients with dementia as predictive factors of quality of life. Psychogeriatrics 2011; 11(2):98–104. 66. Badr H, Gupta V, Sikora A, Posner M. Psychological distress in patients and caregivers over the course of radiotherapy for head and neck cancer. Oral Oncol 2014;50:1005–1011. 67. Magurire R, Hanly P, Hyland P, Sharp L. Understanding burden in caregivers of colorectal cancer survivors: what role do patient and caregivers factors play? Eur J Cancer Care 2018.27(1):e12527. 68. Grunfeld E, Coyle D, Whelan T, et al. Family caregiver burden: results of a longitudinal study of breast cancer patients and their principal caregivers. CMAJ 2004;170:1795–1801. 69. Milbury K, Badr H, Fossella F, Pisters KM, Carmack CL. Longitudinal associations between caregiver burden and patient and spouse distress in couples coping with lung cancer. Support Care Cancer 2013;21:2371–2379. 70. Litzelman K, Yabroff KR. How are spousal depressed mood, distress, and quality of life associated with risk of depressed mood in cancer survivors? Longitudinal findings from a national sample. Cancer Epidemiol Biomarkers Prev. 2015;24:969–977. 71. Ejem DB, Drentea P, Clay OJ. The effects of caregiver emotional stress on the depressive symptomatology of the care recipient. Aging Ment Health. 2014;19:55–62. 72. Litzelman K, Kent EE, Mollica M, Rowland JH. How does caregiver well-being relate to perceived quality of care in patients with cancer? Exploring associations and pathways. J Clin Oncol. 2016;34:3554–3561. 73. Schoenmakers B, Buntinx F, Delepeleire J. What is the role of the general practitioner towards the family caregiver of a communitydwelling demented relative? A systematic literature review. Scand J Prim Health Care. 2009;27(1):31–40. 74. Adelman RD, Greene MG, Ory MG. Communication between older patients and their physicians. Clin Geriatr Med 2000;16(1):1–24, vii. 75. Maslach C, Schaufeli WB, Leiter MP. Job burnout. Annu Rev Psychol 2001;52:397–422. 76. Pearlin LI, Mullan JT, Semple SJ, Skaff MM. Caregiving and the stress process: an overview of concepts and their measures. Gerontologist 1990;30(5):583–594. 77. Braithwaite V. Contextual or general stress outcomes: making choices through caregiving. Gerontologist 2000;40(6):706–717. 78. Henriksson A, Arestedt K. Exploring factors and caregiver outcomes associated with feelings of preparedness for caregiving in family caregivers in palliative care: a correlational, cross-sectional study. Palliat Med 2013;27(7):639–646. 79. Greenwood N, Habibi R, Mackenzie A, Drennan V, Easton N. Peer support for carers: a qualitative investigation of the experiences of carers and peer volunteers. Am J Alzheimers Dis Other Demen 2013;28(6):617–626. 80. Northouse LL, Katapodi MC, Song L, Zhang L, Mood DW. Interventions with family caregivers of cancer patients: meta-analysis of randomized trials. CA Cancer J Clin 2010;60(5):317–339. 81. Ferrell B, Wittenberg E. A review of family caregiving intervention trials in oncology, CA Cancer J Clin 2017;67(4):318–325.

756 82. Chambers SK, Girgis A, Occhipinti S, et al. A randomized trial comparing two low-intensity psychological interventions for distressed patients with cancer and their caregivers. Oncol Nurs Forum 2014;41:E256–E266. 83. Juarez G, Branin J, Rosales M. The cancer caregiving experience of Mexican ancestry. Hispanic Health Care Int 2014;12:120–129. 84. Yennurajalingam S, Noguera A, Parson MA, et al. A multicenter survey of Hispanic caregiver preferences for patient decision control in the United States and Latin America. Palliat Med 2013;27:692–698. 85. Rote S, Angel JL, Markides K. health of elderly Mexican American adults and family caregiver distress. Res Aging 2015;37:306–331. 86. Adelman RD, Tmanova LL, Delgado D, Dion S, Lachs MS. Caregiver burden: a clinical review. JAMA 2014;311(10):1052–1060. 87. Ploeg J, Ali MU, Markle-Reid M, et al. Caregiver-focused, web-based interventions: systematic review and meta-analysis (Part 2). J Med Internet Res 2018;20(10):e11247. 88. Vachon MLS. Emotional problems in palliative medicine: patient, family, and professional. In: Doyle D, Hanks GWC, MacDonald N, eds. Oxford Textbook of Palliative Medicine. Oxford University Press, Oxford, UK, 1993, 575–605. 89. Hinton J. Sharing or withholding awareness of dying between husband and wife. J Psychosom Res 1981;25(5):337–343. 90. Kramer BJ, Kavanaugh M, Trentham-Dietz A, Walsh M, Yonker JA. Complicated grief symptoms in caregivers of persons with lung cancer: the role of family conflict, intrapsychic strains, and hospice utilization. Omega (Westport) 2010;62:201–220. 91. Siminoff LA, Wilson-Genderson M, Baker S Jr. Depressive symptoms in lung cancer patient and their family caregivers and the influence of the family environment. Psychooncology 2010;19:1285–1293. 92. Fitzpatrick MA. Family communication patterns theory: observations on development and application. J Fam Commun 2004;4:167–179. 93. Wittenberg E, Ferrell B, Golsmith J, Ruel NH. Family caregiver communication tool: a new measure for tailoring communication with cancer caregivers. Psycholoncology 2017;26:1222–1224. 94. Wittenberg E, Kravits K, Goldsmith J, Ferrell B, Fujinami R. Validation of a model of family caregiver communication types and related caregiver outcomes. Palliati Support Care 2017;15:3–11. 95. National Breast Cancer Center. Clinical Practice Guidelines for the Psychosocial Care of Adults with Cancer. National Health and Medical Research Council, Canberra, Australian Capital Territory, Australia, 2003. 96. Stapleton RD, Engelberg RA, Wenrich MD, Goss CH, Curtis JR. Clinician statements and family satisfaction with family conferences in the intensive care unit. Crit Care Med 2006;34(6):1679–1685. 97. West HF, Engelberg RA, Wenrich MD, Curtis JR. Expressions of nonabandonment during the intensive care unit family conference. J Palliat Med 2005;8(4):797–807. 98. Curtis JR, Engelberg RA, Wenrich MD, Shannon SE, Treece PD, Rubenfeld GD. Missed opportunities during family conferences about end-of-life care in the intensive care unit. Am J Respir Crit Care Med 2005;171 (8):844–849. 99. McDonagh JR, Elliott TB, Engelberg RA, Treece PD, Shannon SE, Rubenfeld GD, Patrick DL, Curtis JR. Family satisfaction with family conferences about end-of-life care in the intensive care unit: increased proportion of family speech is associated with increased satisfaction. Crit Care Med 2004;32(7):1484–1488. 100. Curtis JR. Communicating about end-of-life care with patients and families in the intensive care unit. Crit Care Clin 2004; 20(3):363–380. 101. Lilly CM, De Meo DL, Sonna LA, Haley KJ, Massaro AF, Wallace RF, Cody S. An intensive communication intervention for the critically ill. Am J Med 2000;109(6):469–475. 102. Francois K, Lobb E, Barclay S, Forbat L. The nature of conflict in palliative care: a qualitative exploration of the experiences of staff and family members. Patient Educ Couns 2017;100:487–494. 103. Boyle DK, Miller PA, Forbes-Thompson SA. Communication and endof-life care in the intensive care unit: patient, family, and clinician outcomes. Crit Care Nurs Q 2005;28(4):302–316. 104. Ringdal G, Jordhoy M, Kaasa S. Measuring quality of palliative care: psychometric properties of the FAMCARE Scale. Qual Life Res 2003;12:167–176. 105. Prigerson HG. Socialization to dying: social determinants of death acknowledgement and treatment among terminally ill geriatric patients. J Health Soc Behav 1992;33(4):378–395.

Textbook of Palliative Medicine and Supportive Care 106. Wright A, Zhang B, Ray A, et al. Association between end-of-life discussions, patient mental health, medical care near death, and caregiver bereavement adjustment. JAMA 2008;300(14):1665–1673. 107. Clayton JM, Butow PN, Tattersall MH. The needs of terminally ill cancer patients versus those of caregivers for information regarding prognosis and end-of-life issues. Cancer 2005;103(9):1957–1964. 108. Hagerty R, Butow P, Ellis P, et al. Cancer patients’ preferences for communication in the metastatic setting. J Clin Oncol 2004;22:1721–1730. 109. Butow PN, Maclean M, Dunn SM, et al. The dynamics of change: cancer patients’ preferences for information, involvement and support. Ann Oncol 1997;8:857–863. 110. Clayton JM, Butow PN, Tattersall MH, et al. Randomized controlled trial of a prompt list to help advanced cancer patients and their caregivers to ask questions about prognosis and end-of-life care. J Clin Oncol 2007;25(6):715. 111. Tattersall MH, Butow PN, Griffin AM, Dunn SM. The take-home message: patients prefer consultation audiotapes to summary letters. J Clin Oncol 1994;12(6):1305. 112. Kristjanson LJ. Caring for families of people with cancer: evidence and interventions. Cancer Forum 2004;28(3):13–15. 113. Northouse PG, Northouse LL. Communication and cancer: issues confronting patients, health professionals, and family members. J Psychosoc Oncol 1998;5(3):17–46. 114. Szmuilowicz E, el-Jawahri A, Chiappetta L, Kamdar M, Block S. Improving residents’ end-of-life communication skills with a short retreat: a randomized controlled trial. J Palliat Med 2010;13(4):439–452. 115. Weeks JC, Catalano PJ, Cronin A, et al. Patients’ expectations about effects of chemotherapy for advanced cancer. N Engl J Med 2012;367:1616–1625. 116. Fineberg IC, Kawashima M, Asch SM. Communication with families facing life-threatening illness: a research-based model for family conferences. J Palliat Med 2011;14(4):422–427. 117. Forbat L, Francois K, O’Callaghan L, Kulikowski J. Family meetings in inpatient specialist palliative care: a mechanism to convey empathy. J Pain Symptom Manage 2018;55(5):1253–1259. 118. Moneymaker K. The family conference. J Palliat Med 2005;8(1):157. 119. Hansen P, Cornish P, Kayser K. Family conferences as forums for decision making in hospital settings. Soc Work Health Care 1998;27(3):57–74. 120. Cahill PJ, Lobb EA, Sanderson C, Phillips JL. Palliat Med 2017;31(3):197–211. 121. Hudson P, Quinn K, Hanlon B, Aranda S. Family meetings in palliative care: multidisciplinary clinical practice guidelines. BMC Palliat Care 2008;7:12. 122. Clayton JM, Hancock KM, Butow PN, et al. Clinical practice guidelines for communication prognosis and end-of-life issues with adults in the advanced stages of a life-limiting illness, and their caregivers. Med J Aust 2006;186(12 Suppl):S77–S108. 123. Hudson P, Thomas T, Quinn K, Aranda S. Family meetings in palliative care: are they effective? Palliat Med 2009;23(2):150–157. 124. Dev R, Coulson L, Del Fabbro E, et al. A prospective study of family conferences: effects of patient presence on emotional expression and end-of-life discussions. J Pain Symptom Manage 2013;46(4): 536–545. 125. Sanderson CR, Cahill PJ, Phillips JL, Hohnson A, Lobb EA. Ann Palliat Med 2017;6(Suppl 2):S195–S205. 126. Hagerty RG, Butow PN, Ellis PM, et al. Communicating with realism and hope: incurable cancer patient’s views on the disclosure of prognosis. J Clin Oncol 2005;23(6):1278–1288. 127. Curtis JR, Patrick DL, Shannon SE, Treece PD, Engelberg RA, Rubenfeld GD. The family conference as a focus to improve communication about end-of-life care in the intensive care unit: opportunities for improvement. Crit Care Med 2001;29(2 Suppl):N26–N33. 128. Lautrette A, Darmon M, Megarbane B, et al. A communication strategy and brochure for relatives of patients dying in the ICU. N Engl J Med 2007;356(5):469–478. 129. Curtis JF, Patrick DL, Shannon SE, et al. The family conference as a focus to improve communication about end-of-life care in the intensive care unit: opportunities for improvement. Crit Care Med 2001;29(2 Suppl):N26–N33. 130. Ahrens T, Yancey V, Kollef M. Improving family communications at the end of life: implications for length of stay in the intensive care unit and resource use. Am J Crit Care 2003;12(4):317–334. 131. Mun E, Ceria-Ulep C, Umbarger L, Nakatsuka C. Trend of decreased length of stay in the intensive care unit (ICU) and in the hospital with palliative care integration into the ICU. Perm J 2016;20(4):16–36.

Family Caregivers and Cultural Sensitivity 132. White DB, Angus DC, Shields AM, et al. A randomized trial of a family-support intervention in intensive care units. N Engl J Med 2018;378(25):2365–2375. 133. Carson SS, Cos CE, Wallenstein S, et al. Effect of palliative care-led meetings for families of patients with chronic critical illness: a randomized clinical trial. JAMA 2016;316(1):51–62. 134. Luce JM. Making decision about the forgoing of life-sustaining therapy. Am J Respir Crit Care Med 1997;156:1715–1718. 135. Kynoch K, Chang A, Coyer F, McArdle A. The effectiveness of interventions to meet family needs of critically ill patients in an adult intensive care unit: a systematic review update. JBI Database System Rev Implement Rep 2016;14(3):181–234. 136. Au SS, rose des Ordons AL, Amir Ali A, Soo A, Stelfox HT. Communication with patients’ families in the intensive care unit: a point prevalence study. J Crit Care 2019;54:235–238. 137. Suen AO, Butler RA, Arnold R, et al. Developing the family support tool: an interactive, web-based tool to help families navigate the complexities of surrogate decision making in ICUs. J Crit Care 2019;56:132–139. 138. Wendlandt B, Ceppe A, Chaudhury S, et al. Modifiable elements of ICU supportive care and communication are associated with surrogates PTSD symptoms. Intensive Care Med 2019;45(5):619–626. 139. Au SS, Roze des Ordons AL, Parsons Leigh J, et al. A multicenter observational study of family participation in ICU rounds. Crit Care Med 2018;46 (8):1255–1262. 140. Allen SR, Parcual J, Martin N, et al. A novel method of optimizing patient-and family-centered care in the ICU. J Trauma Acut Care Surg 2017;82(3):582–586. 141. Trask PC, Griffith KA. The identification of empirically derived cancer patient subgroups using psychosocial variables. J Psychosom Res 2004;57:287–295. 142. Walsh D, Donnelly S, Rybicki L. The symptoms of advanced cancer: relationship to age, gender, and performance status in 1,000 patients. Support Care Cancer 2000;8(3):175–190. 143. Lynn J, Teno JM, Phillips RS, et al. Perceptions by family members of the dying experience of older and seriously ill patients. SUPPORT investigators. Study to understand prognoses and preferences for outcomes and risks of treatments. Ann Intern Med 1997;126(2):97–106. 144. Teno JM, Clarridge BR, Casey V, et al. Family perspectives on end-oflife care at the last place of care. JAMA 2004;291(1):88–93. 145. Ornstein K, Wajnberg A, Kaye-Kauderer H, et al. Reduction in symptoms for homebound patients receiving home-based primary palliative care. J Pallait Med 2013;1699:1048–1054. 146. Bucher JA, Trostle GB, Moore M. Family reports of cancer pain, pain relief and prescription access. Cancer Pract 1999;7(2):71–77. 147. Ferrel B. Pain observed: the experience of pain from the family caregiver’s perspectives. Clin Geriatr Med 2001;17(3):595–609. 148. Ferrel B, Rhiner M, Cohen MZ, Grant M. Pain as a metaphor for illness. Part I: Impact of cancer pain on family caregivers. Oncol Nurs Forum 1991;18(8):1303–1309. 149. Ward SE, Berry PE, Misiewicz H. Concerns about analgesics among patients and family caregivers in a hospice setting. Res Nurs Health 1996;19(3):205–211. 150. Baldwin PK, Wittenberg-lyles E, Kruse RL, Demiris G, Parker Oliver D. Pain management and the African American hospice caregiver: a case report. Am J Hosp Palliat Care 2013;30(8):795–798. 151. Letizia M, Creech S, Norton E, Shanahan M, Hedges L. Barriers to caregiver administration of pain medication in hospice care. J Pain Symptom Manage 2004;27(2):114–124. 152. Cagel JG, Zimmerman S, Cohen LW, Porter LS, Hanson LC, Reed D. EMPOWER: an intervention to address barriers to pain management in hospice. J Pain Symptom Manage 2015;49(1):1–12. 153. Chi NC, Demiris G. Family caregivers’ pain management in end-of-life care: a systematic review. Am J Hosp Palliat Care 2017;34(5):470–485. 154. Bradford N, Irving H, Smith AC, Pedersen LA, Herbert A. Palliative care afterhours: a review of a phone support service. J Pediatr Oncol Nurs 2012;29(3):141–150. 155. Hudson P, Trauer T, Kelly B, et al. Reducing the psychological distress of family caregivers of home-based palliative care patients: short-term effects from a randomized controlled trial. Psychooncology 2013;22(9):1987–1993. 156. Demiris G, Parker Oliver D, Wittenberg-Lyles E, et al. A non-inferiority trial of a problem-solving intervention for hospice caregivers: in person versus videophone. J Palliat Med 2012;15(6):653–660. 157. Kristjanson LJ. Quality of terminal care: salient indicators identified by families. J Palliat Care 1989;5:21–28.

757 158. Oliver D, Demiris G, Wittenberg-Lyles E, et al. Caregiver participation in hospice interdisciplinary team meetings via videophone technology: a pilot study to improve pain management. Am J Hosp Palliat Care 2010;27(7):465–473. 159. Keefe F, Ahles T, Sutton L, et al. Partner-guided cancer pain management at the end of life: a preliminary study. J Pain Symptom Manage 2005;29(3):263–272. 160. Schmitt EM, Gallagher J, Albuquerque A, et al. Perspectives on the delirium experience and its burden: common themes among older patients, their family caregivers, and nurses. Gerontologist 2019;59(2):327–337. 161. Grossi E, Luchhi E, Gentiale S, Trabucchi M, Bellelli G, Morandi A. Preliminary investigation of predictors of distress in informal caregivers of patients with delirium superimposed on dementia. Aging Clin Exp Res 2020;32(2):339–344. 162. Finucane AM, Lugton J, Kennedy C, Spiller JA. The experiences of caregivers of patients with delirium, and their role in its management in palliative care settings: an integrative literature review. Pschooncology 2017;26(3):291–300. 163. Cohen MZ, Pace EA, Kaur G, Bruera E. Delirium in advanced cancer leading to distress in patients and family caregivers. J Palliat Care 2009;25(3):164–171. 164. Bull MJ, Boaz L, Jerme M. Educating family caregivers for older adults about delirium: a systematic review. Worldviews Evid Based Nurs 2016;13(3):232–240. 165. Booth S, Silvester S, Todd C. Breathlessness in cancer and chronic obstructive pulmonary disease: using a qualitative approach to describe the experience of patients and carers. Palliat Support Care 2003;1(4):337–344. 166. Edmonds P, Higginson I, Altmann D, et al. Is the presence of dyspnea a risk factor for morbidity in cancer patients? J Pain Symptom Manage 2000;19(1):15–22. 167. Emanuel EJ, Fairclough DL, Slutsman J, et al. Understanding economic and other burdens of terminal illness: the experience of patients and their caregivers. Ann Intern Med 2000;132(6):451–459. 168. Beynon T, Gomes B, Murtagh FE, et al. How common are palliative care needs among older people who die in the emergency department? Emerg Med J 2011;28(6):491–495. 169. Malik FA, Gysels M, Higginson IJ. Living with breathlessness: a survey of caregivers of breathless patient with lung cancer or heart failure. Palliat Med 2013;27(7):647–656. 170. Amano K, Morita T, Koshimoto S, Uno T, Katayam H, Tatara R. Eatingrelated distress in advanced cancer patients with cachexia and family members: a survey in palliative and supportive care settings. Support Care Cancer 2019;27(8):2869–2876. 171. Yamagishi A, Morita T, Miyashita M, et al. The care strategy for families of terminally ill cancer patients who become unable to take nourishment orally: recommendations from a nationwide survey of bereaved family members’ experiences. J Pain Symptom Manage 2010;40(5):671–683. 172. Raijmakers NJH, Clark JB, van Zuylen L, Allan SG, van der Heide A. Bereaved relatives’ perspectives of the patient’s oral intake towards the end of life: a qualitative study. Palliat Med 2013;27(7):665–672. 173. Bramwell L, MacKenzie J, Laschinger H, Cameron N. Need for overnight respite for primary caregivers of hospice clients. Cancer Nurs 1995;18(5):337–343. 174. Kristjanson LJ, Cousins K, White K, Andrews L, et al. Evaluation of a night respite community palliative care service. Int J Palliat Nurs 2004;10(2):84–90. 175. Krsitjanson LJ, Hudson P, Oldham L. Working with families in palliative care. In: Aranda S, O’Connor M, eds. Palliative Care Nursing: A Guide to Practice. 2nd ed. AUSMED Publications, Melbourne, Victoria, Australia, 2003. 176. Grbich C, Parker D, Maddocks I. Communication and information needs of caregivers of adult family members at diagnosis and during treatment of terminal cancer. Prog Palliat Care 2000;8(6):345–350. 177. Vachon M. Psychosocial needs of patients and families. J Palliat Care 1998;14(3):49–56. 178. Delgado-Guay M, Ferrer J, Rieber AG, et al. Financial distress and its associations with physical and emotional symptoms and quality of life among advanced cancer patients. Oncologist 2015;20(9):1092–1098. 179. Reinhard S, Feinberg L, Choula R, Houser A. Valuing the Invaluable: 2015 Update, Undeniable Progress, but Big Gaps Remain. (AARP PPI 2015), available at http://www.aarp.org/content/dam/aarp/ppi/2015/ valuing-the-invaluable-2015-update-undeniable-progress.pdf.

758 180. Schofield HL, Herman HE, Bloch S, Howe A, Singh B. A profile of Australian family caregivers: diversity of roles and circumstances. Aust N Z J Public Health 1997;21(1):59–66. 181. Chai H, Guerriere DN, Zagorski B, Coyte PC. The magnitude, share and determinants of unpaid care costs for home-based palliative care service provision in Toronto, Canada. Health Soc Care Community 2013;22(1):30–39. 182. Folkman S, Lazarus RS, Dunkel-Schetter C, DeLongis A, Gruen RJ. Dynamics of a stressful encounter: cognitive appraisal, coping, and encounter outcomes. J Pers Soc Psychol 1986;50:992–1003. 183. Jacobsen J, Kvale E, Rabow M, et al. Helping patients with serious illness live well through the promotion of adaptive coping: a report from the improving outpatient palliative care (IPAL-OP) initiative. J Palliat Med 2014;17:463–468. 184. Carveer CS, Scheier MF, Weintraub JK. Assessing coping strategies: a theoretically based approach. J Pers Soc Psychol 1989;56:267–283. 185. Pargament KI, Koenig HG, Perez LM. The many methods of religious coping: development and initial validation of the RCOPE. J Clin Psychol 2000;56:519–543. 186. Merluzzi TV, Martinez Sanchez MA. Assessment of self-efficacy and coping with cancer: development and validation of the cancer behavior inventory. Health Psychol 1997;16:163–170. 187. Folkman S, Greer S. Promoting psychological well-being in the face of serious illness: when theory, research and practice inform each other. Psychooncology 2000;9:11–19. 188. Skinner EA, Edge K, Altman J, et al. Searching for the structure of coping: a review and critique of category systems for classifying ways of coping. Psychol Bull 2003;129:216–269. 189. Meyer B. Coping with severe mental illness; relations of the Brief COPE with symptoms, functioning, and well-being. J Psychopathol Behav Assess 2001;23:265–277. 190. Hull MM. Coping strategies of family caregivers in hospice home care. Oncol Nurs Forum 1992;19(8):1179–1187. 191. Epiphaniou E, Hamilton D, Bridger S, et al. Adjusting to the caregiving role: the importance of coping and support. Int J Palliat Nurs 2012;18(11):541–545. 192. Higginson IJ, Wade AM, McCarthy M. Effectiveness of two palliative support teams. J Public Health Med 1992;14(1):50–56. 193. Carter PA, Acton GJ. Personality and coping: predictors of depression and sleep problems among caregivers of individuals who have cancer. J Gerontol Nurs 2006;32:45–53. 194. Schumacher KL, Dodd MJ, Paul SM. The stress process in family caregivers of persons receiving chemotherapy. Res Nurs Health 1993;16:395–404. 195. Schrank B, Ebert-vogel A, Amering M, et al. Gender differences in caregiver burden and its determinants in family members of terminally ill cancer patients. Psychooncology 2016;25:808–814. 196. Rumpold T, Schur S, Amering M, et al. Hope as determinant for psychiatric morbidity in family caregivers of advanced cancer patients. Psycholoncolgy 2017;26:672–678. 197. Gaugler JE, Eppinger A, King J, Sanberg T, Regine WF. Coping and its effects on cancer caregiving. Support Care Cancer 2013;21: 385–395. 198. Delgado-Guay MO, Parson HA, Hui D, et al. Spirituality, religiosity, and spiritual pain among caregivers of patients with advanced cancer. Am J Hosp Palliat Care 2013;30:455–461. 199. Perace MJ, Singer JL, Prigerson HG. Religious coping among caregivers of terminally ill cancer patients: main effects and psychosocial mediators. J Health Pshchol 2006;11:743–759. 200. Nipp RD, El-Jawahri A, Fishbein JN, et al. Factors associated with depression and anxiety symptoms in family caregivers of patients with incurable cancer. Ann Oncol 2016;27:1607–1612. 201. Harding R, Higginson IJ, Donaldson N. The relationship between patient characteristics and carer psychological status in home palliative cancer care. Support Care Cancer 2003;11:638–643. 202. Northouse LL, Katapodi MC, Song L, Zhang L, Mood DW. Interventions with family caregivers of cancer patients: meta-analysis of randomized trials. CA Cancer J Clin 2010;60:317–339. 203. Blanchard C, Toseland R, McCallion P. The effects of a problemsolving intervention with spouses of cancer patients. J Psychosoc Oncol 1996;14:1–21. 204. Scott JL, Halford WK, Ward BG. United we stand? The effects of a coupling-coping intervention on adjustment to early stage breast or gynecological cancer. J Consult Clin Psychol 2004;72:1122–1135.

Textbook of Palliative Medicine and Supportive Care 205. Northhouse L, Mood DW, Schafenacker A, et al. Randomized clinical trial of a brief and extensive dyadic intervention for advanced cancer patients and their family caregivers. Psychooncology 2013;22(3):555–563. 206. Northouse L, Kershaw T, Mood D, Schafenacker A. Effects of a family intervention on the quality of life of women with recurrent breast cancer and their family caregivers. Psychooncology 2005;14(6):478–491. 207. Northhouse LL, Mood DW, SChafenacker A, et al. Randomized clinical trial of a family intervention for prostate cancer patients and their spouses. Cancer 2007;110(12):2809–2818. 208. El-Jawahri A, Jacobs JM, Nelson AM, et al. Multimodal psychosocial intervention for family caregivers of patients undergoing hematopoietic stem cell transplantation: a randomized clinical trial. Cancer 2020 [Epub ahead of print]. 209. von Heymann-Horan A, Bidstrup PE, Hohansen C, et al. Dyadic coping in specialized palliative care intervention for patients with advanced cancer and their caregivers. Effects and mediation in a randomized controlled trial. Psychooncology 2019;28:264–270. 210. Kissane DW, Bloch S. Family grief. Br J Psychiatry 1994;164:728–740. 211. Charlesworth G, Shepstone L, Wilson E, et al. Befriending carers of people with dementia: randomized controlled trial. BMJ 2008;336(7656):1295–1297. 212. Kissane DW, Bloch S, Burns WI, McKenzie DP, Posterino M. Psychological morbidity in the families of patients with cancer. Psychooncology 1994;3:47–56. 213. Kissane DW, Bloch S, Burns WI, Patrick JD, Wallace CS, McKenzie DP. Perceptions of family functioning and cancer. Psychooncology 1994;3:259–269. 214. Kissane DW, McKenzie M, Bloch S, et al. Family focused grief therapy: a randomized, controlled trial in palliative care and bereavement. Am J Psychiatry 2006;163(7):L1208–L1218. 215. Ferrell BR, Twaddle ML, Melnick A, Meier DE. National Consensus Project Clinical Practice Guidelines for Quality Palliative Care Guidelines, 4th ed. J Palliat Med 2018; 21(12):1684-1689. 216. Lovering S. Cultural attitudes and beliefs about pain. J Transcult Nurs 2006;17(4):389. 217. Blackhall LJ, Murph ST, Frank G, Michel V, Azen S. Ethnicity and attitudes toward patient autonomy. JAMA 1995;274:820–825. 218. Holland JL, Geary N, Marchini A, Tross S. An international survey of physician attitudes and practice in regard to revealing the diagnosis of cancer. Cancer Invest 1987;5:151–154. 219. Matsumura S, Bito S, Liu H, et al. Acculturation of attitudes toward end-of-life care: a cross-cultural survey of Japanese Americans and Japanese. J Gen Intern Med 2002;17:531–539. 220. Gan Y, Zheng L, Yu NX, Zhou G, Miao M, Lu Q. Why do oncologists hide the truth? Disclosure of cancer diagnoses to patients in China: a multisource assessment using mixed methods. Psychooncology 2018;27(5):1457–1463. 221. Yamamoto F, Hashimoto N, Kagwa N, et al. A survey of disclosure of diagnosis to patients with glioma in Japan. Int J Clin Oncol 2011;16(3):230–237. 222. Searight HR, Gafford J. “It’s like playing with your destiny”: Bosnian immigrants’ views of advance directives and end-of-life decision-making. J Immigr Health 2005;7(3):195–203. 223. Liu JM, Lin WC, Chen YM, et al. The status of the do-not-resuscitate order in Chinese clinical trial patients in a cancer centre. J Med Ethics 1999;25:309–314. 224. Carrese JA, Rhodes LA. Western bioethics on the Navajo reservation. Benefit or harm? JAMA 1995;274:826–829. 225. Colclough YY. Native American death taboo: implications for health care providers. Am J Hosp Palliat Care 2017;34(6):584–591. 226. Johnson KS, Kuchibhatla M, Tulsky JA. What explains racial differences in the use of advance directives and attitudes toward hospice care? J Am Geriatr Soc 2008;56(10):1953–1958. 227. Smith AK, McCarthy EP, Paulk E, et al. Racial and ethnic differences in advance care planning among patients with cancer: impact of terminal illness acknowledgement, religiousness, and treatment preferences. J Clin Oncol 2008;26(25):4131–4137. 228. Freedman B. Offering truth. One ethical approach to the uninformed cancer patient. Arch Intern Med 1993;153:572–576. 229. Kaufert JM, Putsch RW. Communication through interpreters in healthcare; ethical dilemmas arising from differences in class, culture, language, and power. J Clin Ethics 1997;8:71–87. 230. Herndon E, Joyce L. Getting the most from language interpreters. Fam Pract Manag 2004;11:37–40.

Family Caregivers and Cultural Sensitivity 231. Wicher CP, Meeker MA. What influences African American end-oflife preferences? J Health Care Poor Underserved 2012;23(1):28–58. 232. Shrank WH, Kutner JS, Richardson T, Mulaski RA, Fischer S, KagawaSinger M. Focus group findings about the influence of culture on communication preferences in end-of-life care. J Gen Intern Med 2005;20(8):703–709. 233. Sanders JJ, Robinson MT, Block SD. Factors impacting advance care planning among African Americans: results of a systematic integrated review. J Palliat Med 2016;19(2):202–227. 234. Yennurajalingam S, Noguera A, Parson HA, et al. A multicenter survey of Hispanic caregiver preferences for patient decision control in the United States and Latin America. Palliat Med 2013;27(7):692–698. 235. Moazam F. Families, patients, and physicians in medical decisionmaking: a Pakistani perspective. Hasting Cent Rep 2000;30:28–37. 236. Karakuzon M. Russia. In: Crippen D, Kilcullen JK, Kelly DF, eds. Three Patients: International Perspectives on Intensive Care at the End-ofLife. Kluwer Academic Publishers, Boston, MA, 2002, 67–72. 237. Pietch JH, Braun KL. Autonomy, advance directives, and the patient self-determination act. In: Braun K, Pietsch JH, Blanchette PL, eds. Cultural Issues in End-of-Life Decision Making. Sage, Thousand Oaks, CA, 2000, 37–53. 238. Baker ME. Economic, political and ethnic influences on end-of-life decision-making: a decade in review. J Health Soc Policy 2002;14:27–39. 239. Ersek M, Kagawa-Singer M, Barnes D, Blackhall L, Koenig BA. Multicultural considerations in use of advance directives. Oncol Nurs Forum 1998;25:1683–1690. 240. Tulsky JA, Casssileth BR, Bennett CL. The effect of ethnicity on ICU use and DNR orders in hospitalized AIDS patients. J Clin Ethics 1997;8:150–157. 241. https://39k5cm1a9u1968hg74aj3x51-wpengine.netdna-ssl.com/wpcontent/uploads/2019/07/2018_NHPCO_Facts_Figures.pdf. 242. Johnson KS, Payne R, Kuchibhatla MN, Tulsy JA. Are hospice admission practices associated with hospice enrollment for older African American and whites? J Pain Symptom Manage 2016;51(4):697–705.

BK-TandF-BRUERA_9780367642037-200160-Chp78.indd 759

759 243. United States Department of Health and Human Services, HHS Action Plan to Reduce Racial and Ethnic Health Disparities, Washington, DC: Department of Health and Human Services, April 2011. http://minorityhealth.hhs.gov/npa/files/plans/hhs/hhs_pla_ complete.pdf. 244. National Institute on Minority Health and Health Disparities: Overview. https://nimhd.nih.gov/about/overview/. 245. Azhar A, Yennurajalingam S, Ramu A, et al. Timing of referral and characteristics of uninsured, Medicaid, and insured patients referred to the outpatient supportive care center at a comprehensive cancer center. J Pain Symptom Manage 2018;55:973–978. 246. Itty TL, Hodge FS, Martinez F. Shared and unshared barriers to cancer symptom management among urban and rural American Indians. J Rural Health 2014;30:206–213. 247. Henry B, Dosani N, Huynh L, et al. Palliative care as a public health issue: understanding disparities in access to palliative care for the homeless population living in Toronto, based on a policy analysis. Curr Oncol 2017;24:187–191. 248. Song J, Bartels DM, Ratner ER, et al. Dying on the streets: homeless persons’ concerns and desires about end of life care. J Gen Intern Med 2007;22:435–441. 249. Rosenfeld EB, Chan JK, Gardner AB, et al. Disparities associated with inpatient palliative care utilization by patients with metastatic gynecologic cancers: a study of 3337 women. Am J Hosp Palliat Care 2018;35:697–703. 250. Rubens M, Ramamoorthy V, Saxena A, et al. Palliative care consultation trends among hospitalized patients with advanced cancer in the United States, 2005 to 2014. Am J Hosp Palliat Care; 2019;36:294–301. 251. Sharma RK, Cameron KA, Chmiel JS, et al. Racial/ethnic differences in inpatient palliative care consultation for patients with advanced cancer. J Clin Oncol 2015;33:3802–3808.

24/06/21 11:53 AM

79

BEREAVEMENT

Victoria H. Raveis

Contents Bereavement in palliative care����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������761 Illness-related losses need to be mourned�������������������������������������������������������������������������������������������������������������������������������������������������������������761 Caregiving demands may complicate recovery from bereavement������������������������������������������������������������������������������������������������������������������761 Anticipatory and pre-loss grief���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������762 Experiencing death�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������762 Overview of the grief process�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������762 Duration of grief����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������762 Manifestations of grief�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������762 Normal, prolonged, and complicated grief������������������������������������������������������������������������������������������������������������������������������������������������������������������763 Vulnerability factors for adverse bereavement outcomes�����������������������������������������������������������������������������������������������������������������������������������������763 Protracted illness���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������763 Disease course��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������763 Stigmatized death��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������763 Nature of the loss��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������763 Life circumstances������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������763 Individual characteristics�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������763 Health consequences of bereavement���������������������������������������������������������������������������������������������������������������������������������������������������������������������������763 Principles of bereavement support in palliative care�������������������������������������������������������������������������������������������������������������������������������������������������764 View patient and family as one unit of care�����������������������������������������������������������������������������������������������������������������������������������������������������������764 Enable open discussion of illness and death-related concerns��������������������������������������������������������������������������������������������������������������������������764 Provide emotional support����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������764 Facilitate practical assistance������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������764 Respect cultural, ethnic, and religious practices���������������������������������������������������������������������������������������������������������������������������������������������������764 Bereavement resources, programs, and treatments���������������������������������������������������������������������������������������������������������������������������������������������������764 Supportive services�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������764 Psychotherapeutic interventions������������������������������������������������������������������������������������������������������������������������������������������������������������������������������765 Pharmacologic therapies��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������765 Conclusion��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������765 References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������766 Although bereavement and loss are familiar occurrences in palliative care, an appreciation of what constitutes grief and an understanding of the special circumstances of bereavement in the palliative care setting may aid clinicians in attending to the needs and preferences of families during this period of impending loss. A universal occurrence, bereavement, can also be a particularly potent and stressful life event. The death of someone significant represents a multifaceted challenge for the survivors. They must adapt to the social and economic readjustments emerging from this event and come to terms with changes in self-identity resulting from their loss while dealing with the psychological and physiological reactions engendered by the death.1 Mourning is the expression of grief and represents the process of coming to terms with this loss. Although bereavement can predispose people to physical and mental illness, precipitate illness and death, and aggravate existing illness, most individuals are resilient and adjust to their loss in time.2,3,4 A small proportion of bereaved, approximately 10–20%, experience debilitating grief reactions of such severity and chronicity that specialist care is warranted.2,5,6,7,8

Bereavement in palliative care The terminal period of an illness can be an extremely stressful time for the families of dying patients. Although bereavement is usually the specific event that precipitates the mourning process, for deaths that occur in the context of palliative care, a variety of circumstances occurring prior to the death are likely to impact survivors’ grief.

Illness-related losses need to be mourned

When death is preceded by a chronic illness, grieving is inexorably tied up with mourning the losses experienced during the course of an illness. These losses include altered relationships, changes in lifestyle, the forfeit of future dreams that will never be realized, as well as losses related to illness-induced changes (e.g., progressive debilitation, increasing dependence, cognitive decline, and excessive pain).9,10

Caregiving demands may complicate recovery from bereavement

Families are commonly involved in the provision of emotional and practical assistance to their ill family members in palliative 761

Textbook of Palliative Medicine and Supportive Care

762 care situations.11 While the benefits to the patient of familial caregiving are readily apparent, the provision of end-of-life care is not without cost to caregivers who experience financial stress, burden, decline of their own health, physical exhaustion, psychological distress, and the social isolation resulting from restricting outside activities.12,13,14,15 Caregivers who have multiple stresses, high illness-related burdens, and limited informational and practical support are at increased risk of adverse bereavement outcomes.10,16,17,18

Anticipatory and pre-loss grief

Anticipatory grief refers to the process whereby survivors rehearse the bereaved role and initiate working through the emotional changes associated with a death.9 It is generally thought that anticipatory grief mitigates the intensity of the grief reaction following the actual death, leaving the survivor less vulnerable to maladaptive reactions. Palliative care situations enable families to be forewarned about an impending death, and some investigations have shown that the bereaved who have had an opportunity for anticipatory grief adjust better to their loss.19,20 However, forewarning of a death does not ensure that individuals are prepared for the actual occurrence. The circumstances leading up to the death may contribute to severe pre-loss grief and adversely impact the extent to which the bereaved are capable of being able to prepare themselves for the loss. A long and protracted illness, one marked by multiple losses, high financial costs, or intensive caregiving demands in which caregivers direct all their energy and attention toward addressing the patient’s needs may impede caregivers’ ability to initiate preparations for the death as well as deplete the bereaved’s personal resources for coping with the loss13,19,21,22 The extant literature on pre-loss grief, preparedness, and bereavement outcomes has documented that severe pre-loss grief is associated with low preparedness for the death, complicated grief (CG), and post-loss depression.16,18,23 It has also been documented that grieving family members, who socially and emotionally withdrew from the dying patient in advance of the death, experience guilt post-death over having abandoned their dying relative.24

Experiencing death

In Western society, dying is “medicalized” and the family is generally distanced from death. 25 Death in a home setting is unfamiliar. With the provision of palliative care, families are intimately exposed to the dying process. Anticipating its occurrence and the resultant responsibility associated with this event can induce considerable distress and anxiety. Families worry that they will be unable to address their relative’s potential suffering at the end and express concern that they will be unable to cope with the challenges of being “in charge” during this dying event.13

Overview of the grief process Freud’s seminal essay on “Mourning and Melancholia” provided the foundation for contemporary understanding of grief and bereavement.26 His work conceptualized mourning as a prolonged inner struggle to adapt to and accept an irreversible loss. Two comprehensive theoretical models have informed current approaches to bereavement and grief therapy. Worden’s Task of Mourning1 delineates four tasks that define the mourning process. The bereaved needs to (1) accept the reality of the loss (i.e., face the reality that the person is dead will not return and that reunion is impossible); (2) process the pain of grief (i.e., acknowledge and

work through the emotional and behavioral pain associated with the loss); (3) adjust to a world without the deceased, a task that involves external adjustments (i.e., coming to terms with living alone, facing an empty house and managing finances alone), internal adjustments (i.e., adjusting to one’s own altered sense of self), and spiritual adjustments (i.e., making accommodations in basic beliefs and one’s sense of the world); and (4) find an enduring connection with the deceased in the midst of embarking on a new life (i.e., finding an appropriate place for the deceased in their emotional lives that will enable them go on living effectively in the world). Not necessarily performed in sequence, overlap and revisiting of tasks can occur. Stroebe and Schut’s dual process model of coping with bereavement 27 represents an integrative approach to describing the ways bereaved individuals come to terms with a significant loss. It posits that the bereaved undertake both loss- and restoration-oriented coping. Loss orientation refers to dealing with or processing some aspect of the loss experience itself, particularly relating to the deceased. Restoration orientation focuses on the secondary sources of stress that the bereaved need to deal with, such as changes in financial status or social loneliness, e.g., bereavement tasks outlined earlier.5 The dual process model also introduces a third concept—oscillation. Coping with bereavement is posited to be a dynamic process, one in which individuals confront their loss some of the time and at other times avoid such confrontation. Oscillation is necessary to provide a balance to this process and prevent the adverse mental and physical costs that can arise with unremitted grieving. Bereavement specialists and cross-cultural researchers note that understanding of the grief process has been strongly influenced by Western thought.25,28 Its’ applicability to non-Western societies merits reflection, given the fundamental world-view differences in how death, is perceived in different cultures. For example, in Asian cultures, through practices such as ancestor worship, death represents a transition to a different state in which deceased relatives remain important participants in the world of the living and communication is still considered possible.29 The dual process model accommodates individual, situational, and cultural variations in coping with bereavement.27 The Tasks of Mourning model also acknowledges that although mourning is universal, people do not grieve in the same way.1 As the approach and adaptation process are not held to a fixed pattern, the model implicitly takes account of cultural nuances and societal influences.

Duration of grief Although there is considerable variability in the temporal course at which individuals integrate their loss into their lives, griefrelated distress is generally most intense during the first year following the loss. The clinical and epidemiological literature support that in Western societies, after a period of acute grief, most bereaved individuals gradually return to a normal level of functioning 1–2 years after their loss.5,24,30 Societal and cultural mores can also influence the duration of grief. For example, Taiwanese cultural ideology proscribes “one man per lifetime” and widows are expected to grieve for the rest of their lives.29

Manifestations of grief Immediately following a death, bereaved individuals are usually in a state of shock. They feel numb and experience disbelief over the event, even when the death has been anticipated, as in

Bereavement palliative care.13 Cognitions may be impacted and the bereaved may experience a sense of confusion and have difficulty concentrating. During this acute mourning period, individuals can experience a variety of psychological and physiological reactions of varying intensity and duration.1 The most commonly expressed emotions include shock, numbness, sadness, anxiety, loneliness, fatigue, anger, relief, and guilt. Bereaved individuals often report somatic complaints as well, such as weakness, lethargy, loss of appetite, tightness in the throat or chest, shortness of breath, and sleeplessness. Such reactions are not necessarily indicative of a psychiatric problem or a physical disorder and should not be pathologized. They are normal manifestations of acute grief. Although grief reactions are universally experienced, the emotional and behavioral responses to a loss are culturally bound. In some societies, wailing, unrestrained crying, self-mutilation, or prostration may be a common and acceptable means of expressing grief,25 although these actions may be viewed as indicative of an intense or severe grief reaction in other cultural groups.

Normal, prolonged, and complicated grief Lindemann’s landmark study of bereavement, 31 following the Coconut Grove nightclub fire, focused attention on the intensity and trajectory of expressed grief and introduced the distinction between normal and pathological grief responses, attributes central to understanding the course, and outcome of the bereavement process. Most bereaved individuals are able to adjust to their loss over time and return to a level of functioning normal for their society and culture. Nonetheless, for a minority of the bereaved individuals, approximately 10–20%, bereavement is not a transient life crisis.2,5,6 Unable to integrate the loss into their lives, these individuals experience a severe, protracted emotional reaction that impairs everyday functioning and merit clinical attention. Current understanding of the grief process characterizes grief that is chronic, intense, disabling and persisting, beyond a period considered adaptive, may be indicative of a clinical condition, classified as prolonged grief disorder (PGD) in the International Statistical Classification of Diseases and Related Health Problems, 11th Revision ((ICD-11), 30,32 and referred to as persistent complex bereavement disorder (PCBD) in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).8,30,33 In contrast, to PGD or PCBD, CG is sustained grief that encompasses additional factors that impede the normal grieving process, such as bereavement-related depression.8,34,35 The DSM-5 allows a diagnosis of depression within 2 weeks of bereavement. 33

Vulnerability factors for adverse bereavement outcomes The clinical and research literature on bereavement suggests a constellation of situational, interpersonal, and individual factors that affect the course and outcome of the grieving process, influence the risk of mental and physical consequences following the loss, and increase the risk of prolonged or CG.4,35–37 Described later are some of the factors present in palliative care situations.

Protracted illness

The bereaved whose loved one suffered a long, lingering illness adjust more poorly to bereavement than those whose loved one died after a short illness. 37 This may reflect the caregiving burdens and demands they encountered providing informal support

763 and care over an extended period and the psychological and existential distress they experienced over the course of a protracted illness.10,13,15,17,19,38,39

Disease course

Terminal conditions that impact patients’ functioning and quality of life, such as severe, chronic pain, or progressive dementia, are difficult and stressful for family members to witness. The family members’ distress is exacerbated by feeling helpless in alleviating or managing these conditions and worrying over future escalation.19,40,41

Stigmatized death

When death is from an illness that is stigmatized such as HIV/ AIDS, or associated with unhealthy or socially unacceptable lifestyles, such as alcoholism or drug abuse, the family may be less open about the cause of death or the circumstances leading up to the event.42 As a consequence, the bereaved’s naturally occurring support systems may be less forthcoming. The family may also experience conflicting emotions or encounter difficulty resolving their feelings about the deceased. In communicable illnesses such as HIV/AIDS, the bereaved may be infected as well or may be dealing with multiple deaths or advanced disease of other family members.43

Nature of the loss

Although medical advances have prolonged life in terminal illness, the death of one’s spouse or child is considered to be one of the most stressful life events.44,45,46 In addition to the closeness of the relationship, the level of dependency or extent of ambivalence (feelings of love/hate, need/resentment) between the deceased and the bereaved often culminates in a severe grief reaction and difficulty in accepting and resolving the loss. 36,37,47 Ambiguous loss, the physical presence, but psychological loss of a loved one, characteristic of the situation faced by dementia caregivers has also been shown to increase the risk of CG.19,41

Life circumstances

Vulnerability for a poor post-death adjustment is increased by additional severe stresses concurrent to the bereavement, such as numerous traumatic events, multiple losses, or negative life chan ges.1,48,49 Deficits in social support or restricted social resources can also contribute to adverse grief outcomes.17,36 Limited financial resources pre-death or declining income as a consequence of the death can also precipitate problems in the grieving process.17,49 Widowhood can have especially adverse economic, social, and psychological ramifications for older adults.50

Individual characteristics

The bereaved’s preexisting physical health condition, history of substance abuse, and/or premorbid mental illness1 can contribute to adverse bereavement outcomes. Personality characteristics, such as low self-esteem or a low internal sense of control, are also associated with increased distress post-death. In Western societies, men are at higher risk for bereavement-related mortality; women experience more affective distress.16,36

Health consequences of bereavement A variety of physical and psychological health consequences have been associated with bereavement. The recently bereaved have been shown to display an increased incidence of depressive symptoms, somatic complaints, insomnia, as well as experiencing

Textbook of Palliative Medicine and Supportive Care

764 changes in their endocrine, immune, and cardiovascular systems. Higher rates of utilization of medical and mental healthcare services (i.e., increased hospitalizations, prescribed drug use, and physician and mental health clinician visits) have also been observed in the early weeks and months after loss compared to non-bereaved samples.4 Persons experiencing CG are at heightened risk for developing serious mental and physical health conditions and may also engage in behaviors injurious to their health, such as alcohol or substance abuse. 30,35,37,51

Principles of bereavement support in palliative care Palliative care offers the health-care practitioner multiple opportunities to attend to the well-being of affected family members. The provision of compassionate care during this stressful period may facilitate families’ grieving process and reduce adverse bereavement consequences. Five broad principles of bereavement support can be readily applied in palliative care situations: (1) view the patient and family as one unit of care; (2) enable open discussion of illness and death-related concerns; (3) provide emotional support; (4) facilitate practical assistance; and (5) respect cultural, ethnic, and religious practices.

View patient and family as one unit of care

The terminal illness period is stressful to the family. Patients and families should be viewed as one unit of care.40 Clinicians are in contact with families during this period of heightened vulnerability. Attending to the informational, emotional, and practical support needs of the family may make the dying experience less stressful for the family, help them cope with the illness demands, facilitate their grieving, and reduce their risk of adverse bereavement outcomes.52,53,54 As a secondary benefit, addressing family members’ needs during this period can facilitate their remaining engaged in the patient’s care provision.

Enable open discussion of illness and death-related concerns

Attending to families’ concerns about the patient’s condition and care, and providing reassurance that appropriate therapeutic and ameliorative measures are being utilized, can comfort families and reduce later recriminations. Enabling open communication, discussion of emerging concerns, and providing guidance as to what to expect during the dying process can avert the development of future regrets, facilitating families’ grieving process.21

Provide emotional support

Supporting families in their grief during the terminal phase of the illness is also important in facilitating adjustment after the death. In palliative care, most families are aware of the nature of their relative’s condition and its prognosis. Families can experience anger, sadness, regret, resentment, guilt or anxiety over the illness, the losses experienced, the burdens and responsibilities they are required to assume, and the impending death. 39,40 They may also feel isolated and alone. Families need to be supported in expressing their feelings and concerns and be reassured that these feelings are normal.21 A family’s contact with the clinical care team often ceases with the patient’s death. For many families, this is a significant loss. Its impact can be lessened by a condolence note or brief sympathy call from a member of the care team. Anniversaries of the death or important family events are also times when grief

is intensified.55 A follow-up note or call from the team on these occasions may be beneficial.

Facilitate practical assistance

Families often become very involved in the dying patient’s care, neglecting their own health, and setting unreasonable expectations of what they personally should accomplish. It is common for families to be fearful about leaving the patient for any length of time, curtailing outside activities and cutting themselves off from their broader social network.13 Clinicians may need to encourage family members to respect and attend to their own needs and actively support them in accepting help from relatives and friends. Families may also require guidance and aid in following through with a dying patient’s care preferences.

Respect cultural, ethnic, and religious practices

Bereavement takes place within a social context in which rituals and customs provide for a sanctioned public articulation of private distress to deal with death. When individuals are prevented from performing such activities, their mourning is adversely impacted, disrupting the necessary grieving process.56,57 Institutional policies that limit children’s visiting rights, restrict the number of visitors in a room, or bar the performance of religious and cultural ceremonies can impede families from carrying out specific practices required at death. Terminal illness provides forewarning of the death. This affords the care team opportunity to become aware of and address any particular needs and requirements associated with specific mourning customs and rituals.

Bereavement resources, programs, and treatments Consensus-based hospice and palliative care clinical practice guidelines and policies specify having in place an organized program of bereavement services available to families appropriate to their needs, preferences, and culture, beginning during the terminal period and continuing after the death. 58–60,61 In these settings, the use of valid, reliable tools, that differentiate between resilient and appropriate to individual need.62,63,64

Supportive services

Bereavement-related supportive services are provided in a variety of treatment modalities and venues. The duration of these various bereavement services can range from a single session or meeting to ongoing programs, initiated during the terminal illness period and continued post-death. Apart from the bereavement services available through hospice and palliative care settings, community groups, churches, and charitable organizations, such as Cruse Bereavement Care in Great Britain, also sponsor a range of bereavement support resources. Support or counseling may be delivered individually or through a group session by mental health clinicians or other trained professionals. Some programs use trained volunteers supported by professionals. These services help one to normalize the bereaved’s experiences while also supporting their grief. Self-help groups and peer-to-peer support resources, such as the Widowed Persons Service in the United States, involve bereaved individuals offering friendship and empathy of shared status to help each other in their grief and adjustment to their loss. Virtual communities of support, available through the Internet, such as GriefNet, provide individuals with another resource

Bereavement when coping with loss.65,66 Other Internet-based resources offer individual therapy on-line, conducted by a therapist or provide online support groups that are led or monitored by professionals. These Internet-based resources are not suitable for all bereaved persons, and careful screening and diagnosis and ongoing monitoring must be done before initiating any intervention deliver.1

Psychotherapeutic interventions

Most bereaved individuals will not require psychotherapy or specialized grief therapy.1,67 However, palliative care settings provide the opportunity to initiate preventive interventions in advance of the death with those individuals identified as being at high risk for adverse bereavement outcomes.16,68 Family Focused Grief Therapy (FFGT), a preventive intervention, has been found to be effective in reducing bereavement-related distress and depression by optimizing in the pre-death period a family’s relational functioning, mutual support and sharing of grief.52 A meta-analysis of randomized controlled trials initiated to treat bereaved individuals experiencing CG supports the efficacy of post-death psychotherapeutic interventions in diminishing the symptoms of CG and facilitating the normal grieving process.68 CG treatment (CGT), a psychotherapeutic intervention that has received empirical support in randomized trials, focuses on removing the psychological and social impediments that prevent the natural progression of the grief process.69,70 A recent, multisite, four-arm randomized controlled trial of CGT demonstrated the utility of CGT for CG and the benefit of including antidepressants (citalopram) for the relief of co-occurring depressive symptoms.71 Cognitive behavioral therapy (CBT) has been shown to be efficacious as an outpatient treatment for PGD. In a recent, small, randomized controlled clinical trial, Rosner and colleagues delivered a 10-month, 20-session integrative CBT program (PG-CBT) to bereaved outpatients diagnosed with PGD. The initial outpatient therapy improvement of grief symptoms were maintained, on average, 1.5 years post-assessment.72,73 A larger, multicenter, randomized controlled trial of PG-CBT is currently ongoing.74 In a small, baseline study, delivery of a 9-session CBT program, Grief-Help to bereaved children and adolescents, coincided with reductions in symptoms of PGD.75 A larger, randomized controlled trial is ongoing.76

Pharmacologic therapies

Pharmacological interventions are not clinically indicated for most bereaved individuals. The emotional expression of grief following a loss is a normal and natural aspect of the grieving process. In some clinical situations, antidepressants, tranquilizers, and sedatives have been prescribed to remediate severe and debilitating bereavement-related reactions that impede functioning.77 Such use, however, warrants discretion. If initiated early in the bereavement period, pharmacological treatment could interfere with the natural grieving process.6 A systematic review of case–control studies demonstrated that a beneficial pharmacologic treatment effect on depression and sleep quality in bereaved samples persisted only while the subjects received the medication.78 This review noted further that there was no demonstrated treatment impact on the bereaved’s resolution of grief. Although the evidence base is limited, the clinical reports and limited research studies on the pharmacological management of bereavement-related depression suggest that most pharmacotherapy was used to target depression and should be considered as an adjunct to psychotherapy. The efficacy of pharmacological treatments

765 as part of the treatment for CG merits further scientific investigation.79 As noted earlier, a recent multisite randomized controlled trial demonstrated the utility of using a serotonin-active antidepressant (citalopram) for relief of co-occurring depressive symptoms in combination with the delivery of CGT, a psychotherapeutic intervention.71

Conclusion Although there may be considerable individual variation in the experience and expression of grief, grieving is a normal, natural response to a significant loss. Understanding of the grief process has been substantially influenced by Western thought. Consequently, clinicians should be careful to not ascribe pathological or abnormal labels to mourning responses when the cultural meaning or appropriateness of these actions is not well understood. As grief specialists have noted, not only are there different cultural responses to loss, but responses can vary within subgroups. Clinicians involved in palliative care are in contact with families at a point of heightened vulnerability. The provision of emotional support and compassionate care by the health-care team during this stressful period may facilitate families’ grieving process and reduce adverse bereavement consequences. Grief specialists advise,1 supported by clinical evidence, 3,6,8 that clinical interventions are not necessary for most bereaved individuals, as the cognitive and emotional responses generally abate over time. Consensus opinion is that such an approach may do more harm than good, impeding the activation of the bereaved’s natural support systems and disrupting the process of normal grieving. 3,4,67 About 10–20% of individuals experience grief reactions of such severity or chronicity necessitating professional intervention. An understanding and appreciation of the normal grief process, along with an awareness of the individual and

KEY LEARNING POINTS • Grief is universally experienced, it is not a disease. • Grief is expressed with a constellation of psychological and physiological reactions. • Grieving is a process, most bereaved adapt to the loss over time. • Normal grief and mourning practices reflect cultural and ideological belief systems. • Benefits of anticipatory grief are mitigated by care provision, illness duration, and cause of death. • Patients and families should be viewed as a unit of care. • Attending to caregivers’ informational and support needs and preferences during the terminal phase of illness can support their grieving process. • Facilitating culturally appropriate death rites and mourning practices benefits the bereaved. • Bereavement can predispose some people to physical and mental illness and precipitate death. • Prolonged grief disorder (PGD), persistent complex bereavement disorder (PCBD), and complicated grief (CG) are present in a small proportion of bereaved and warrant therapeutic treatment.

Textbook of Palliative Medicine and Supportive Care

766 situational factors that may complicate mourning, will aid clinicians in determining those instances when specialist evaluation is indicated. As Raphael and colleagues succinctly state, “There can be no justification for routine intervention for bereaved persons in terms of therapeutic modalities – either psychotherapeutic or pharmacological – because grief is not a disease.” [p. 587]77

References













1. Worden JW. Grief Counseling and Grief Therapy: A Handbook for the Mental Health Practitioner, 5th ed. New York: Springer, 2018. 2. Bonanno GA, Boerner K, Wortman CB. Trajectories of grieving. In: Stroebe MS, Hansson RO, Schut H, Stroebe W, eds. Handbook of Bereavement Research and Practice: Advances in Theory and Intervention. Washington, DC: American Psychological Association, 2008, pp. 287–307. 3. Stroebe W, Schut H, Stroebe MS. Grief work, disclosure and counseling: do they help the bereaved? Clin Psychol Rev 2005;25(4):395–414. 4. Stroebe M, Schut H, Stroebe W. Health outcomes of bereavement. Lancet 2007;370(9603):1960–1973. 5. Bonanno GA, Kaltman S. The varieties of grief experience. Clin Psychol Rev 2001;21(5):705–734. 6. Schut H, Stroebe MS. Interventions to enhance adaptation to bereavement. J Palliat Med 2005;8(Suppl 1):S140–S147. 7. Lundorff M, Holmgren H, Zachariae R, Farver-Vestergaard I, O’Connor M. Prevalence of prolonged grief disorder in adult bereavement: systematic review and meta-analysis. J Affect Disord 2017; Apr;138–149. doi: 10.1016/j.jad.2017.01.030. Epub 2017 Jan 23. 8. Maciejewski P, Maercker A, Boelen PA, Prigerson HG. “Prolonged grief disorder” and “persistent complex bereavement disorder”, but not “complicated grief”, are one and the same diagnostic entity: an analysis of data from the Yale Bereavement Study. World Psychiatry 2016;15:266–275. 9. Rando TA. Understanding and facilitating anticipatory grief in the loved ones of the dying. In: Rando TA, ed. Loss & Anticipatory Grief. Lexington, MA: Lexington Books, 1986, pp. 97–130. 10. Schulz R, Beach SR, Lind B, et al. Involvement in caregiving and adjustment to death of a spouse: findings from the Caregiver Health Effects Study. JAMA 2001;285(24):3123–3129. 11. Rowland C, Hanratty B, Pilling M, van den Berg B, Grande G. The contributions of family care-givers at end of life: a national post-bereavement census survey of cancer careers’ hours of care and expenditures. Palliat Med 2017;31(4):346–355. 12. Williams AL, McCorkle R. Cancer family caregivers during the palliative, hospice, and bereavement phases: a review of the descriptive psychosocial literature. Palliat Support Care 2011;9(3):315–325. 13. Raveis VH. Psychosocial impact of spousal caregiving at the end-of-life: challenges and consequences. Gerontologist 2004;44(Special Issue 1): 191–192. 14. Grande G, Rowland C, van den Berg B, Hanratty B. Psychological morbidity and general health among family caregivers during end-of-life cancer care: a retrospective census survey. Palliat Med 2018;32(10):1605–1614. 15. Oechsle K. Current advances in palliative & hospice care: problems and needs of relatives and family caregivers during palliative and hospice care—an overview of current literature. Med Sci 2019;7(3):43. 16. Schulz R, Boerner K, Herbert RS. Caregiving and bereavement. In: Stroebe MS, Hansson RO, Schut H, Stroebe W, eds. Handbook of Bereavement Research and Practice: Advances in Theory and Intervention. Washington, DC: American Psychological Association, 2008, pp. 265–285. 17. Hudson P, Payne S. Family caregivers and palliative care: current status and agenda for the future. J Palliat Med 2011;14(7):864–869. 18. Nielsen M, Neergaard M, Jensen A, Vedsted P, Bro F, Guldin M. Preloss grief in family caregivers during end-of-life cancer care: a nationwide population-based cohort study. Psychooncology 2017;26:2048–2056. 19. Chan D, Livingston G, Jones L, Sampson EL. Grief reaction in dementia carers: a systematic review. Int J Geriatr Psychiatry 2013;28(1):1–17. 20. Parkes CM, Weiss RS. Recovery from Bereavement. New York: Basic Books, 1983. 21. Raveis VH. Facilitating older spouses’ adjustment to widowhood: a preventive intervention program. Soc Work Health Care 1999;29(4):12–32.

22. Caserta M, Utz R, Lund D, Supiano K, Donaldson G. Cancer caregivers’ preparedness for loss and bereavement outcomes: do preloss caregiver attributes matter? Omega 2017; Jan;1:30222817729610. 23. Nielsen MK, Neergaard MA, Jensen AB, Bro F, Guldin MB. Do we need to change our understanding of anticipatory grief in caregivers? A systematic review of caregiver studies during end-of-life caregiving and bereavement. Clin Psychol Rev 2016; Mar;44:75–93. 24. Zisook S, Irwin SA, Shear MK. 14. Understanding and managing bereavement in palliative care. In: Chochinov HM, Breitbart W, eds. Handbook of Psychiatry in Palliative Medicine, 2nd ed. New York: Oxford University Press, 2009, pp. 202–219. 25. Laungani P, Parkes YM, Young B. 12. Conclusions 1: implications for practice and policy. In: Parkes CM, Laungani P, Young B, eds. Death and Bereavement Across Cultures, 2nd ed. London: Routledge, 2015, pp. 178–191. 26. Freud S. Mourning and melancholia. In: Strachey J, ed. The Standard Edition of Complete Psychological Work of Sigmund Freud. London: Hogarth Press, 1957. 27. Stroebe M, Schut H. The dual process model of coping with bereavement: rationale and description. Death Stud 1999;23(3):197–224. 28. Klass D. Continuing bonds in the resolution of grief in Japan and North American. Am Behav Sci 2001;44(5):742–763. 29. Hsu MT, Kahn DL, Yee DH, Lee WL. Recovery through reconnection: a cultural design for family bereavement in Taiwan. Death Stud 2004;28(8):761–786. 30. Prigerson HG, Horowitz MJ, Jacobs SC, et al. Prolonged grief disorder: psychometric validation of criteria proposed for DSM-V and ICD-11. PLoS Med 2009;6(8):e1000121. 31. Lindemann E. Symptomatology and management of acute grief. Am J Psychiatry 1944;101(2):141–148. 32. World Health Organization. International Statistical Classification of Diseases and Related Health Problems (11th Revision). 2018. Available at: https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/ 1183832314 (Accessed Aug 30, 2019). 33. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: American Psychiatric Association, 2013. 34. Bonanno GA, Neria Y, Mancini A, Coifman KG, Litz B, Insel B. Is there more to complicate grief than depression and posttraumatic stress disorder? A test of incremental validity. J Abnorm Psychology 2007;116(2):342–351. 35. Lichtenthal WG, Cruess DG, Prigerson GH. A case for establishing complicated grief as a distinct mental disorder in DSM-V. Clin Psychol Rev 2004;24(6):637–662. 36. Burke LA, Neimeyer RA. Prospective risk factors for complicated grief: a review of the empirical literature. In: Stroebe M, Schut H, van den Bout J, eds. Complicated Grief: Scientific Foundations for Health Care Professionals .New York: Routledge, 2013, pp. 145–160. 37. Lobb EA, Kristjanson LJ, Aoun SM, Monterosso L, Halkett GKB, Davies A. Predictors of complicated grief: a systematic review of empirical studies. Death Stud 2013;34:673–698. 38. Rumpold T, Schur S, Amering M, et al. Informal caregivers of advanced-stage cancer patients: every second is at risk for psychiatric morbidity. Support Care Cancer 2016;24:1975–1982. 39. Thomas K, Hudson P, Trauer T, Remedios C, Clarke D. Risk factors for developing prolonged grief during bereavement in family carers of cancer patients in palliative care: a longitudinal study. J Pain Symptom Manage 2014;47(3):531–541. 40. Raveis VH, Pretter S. Existential plight of adult daughters following their mother’s breast cancer diagnosis. Psychooncology 2005;14(1):49–60. 41. Arruda EH, Paun O. Dementia caregiver grief and bereavement: an integrative review. West J Nurs Res 2017;39:825–851. 42. Houck JA. A comparison of grief reactions in cancer, HIV/AIDS, and suicide bereavement. J HIV/AIDS Soc Serv 2007;6(3):97–112. 43. Raveis VH, Siegel K. Impact of caregiving on informal or familial caregivers. AIDS Patient Care STDS 1991;5(1):39–43. 44. Christ GH, Bonanno G, Malkinson R, Rubin S. Appendix E: bereavement experiences after the death of a child. In: Field MJ, Behrman RE, eds. When Children Die: Improving Palliative and End-of-Life Care for Children and Their Families, Washington, DC: National Academies Press, 2003. 45. Dohrenwend BS, Krasnoff L, Askenasy AR, Dohrenwend BP. Exemplification of a method for scaling life events: The Peri Life Events Scale. J Health Soc Behav 1978; Jun;19(2):205–229.

Bereavement 46. Holmes TH, Rahe RH. The social readjustment rating scale. J Psychosom Res 1967;11:213–218. 47. Wagner B, Maercker A. The diagnosis of complicated grief as a mental disorder: a critical appraisal. Psychol Belg 2010;50(1–2):27–48. 48. Sanders C. Grief: The Mourning After Dealing with Adult Bereavement. New York: John Wiley and Sons, 1989. 49. Galatzer-Levy I, Bonanno GA. Beyond normality in the study of bereavement: heterogeneity in depression outcomes following loss in older adults. Soc Sci Med 2012;74(12):1987–1994. 50. Carr D. Factors that influence late-life bereavement: considering data from the changing lives of older couples study. In: Stroebe MS, Hansson RO, Schut H, Stroebe W, eds. Handbook of Bereavement Research and Practice: Advances in Theory and Intervention. Washington, DC: American Psychological Association, 2008, pp. 417–440. 51. Pérez S, Direk N, Milic J, Ikram MA, Hofman A, Tiemeier H. The impact of complicated grief on diurnal cortisol levels two years after loss: a population-based study. Psychosom Med 2017; May;79(4):426–433. 52. Kissane DW, Lichtenthal WG. Family focused grief therapy: from palliative care into bereavement. In: Stroebe MS, Hansson RO, Schut H, Stroebe W, eds. Handbook of Bereavement Research and Practice: Advances in Theory and Intervention. Washington, DC: American Psychological Association, 2008, pp. 485–510. 53. Candy B, Jones L, Drake R, Leurent B, King M. Interventions for supporting informal caregivers of patients in the terminal phase of a disease. Cochrane Database Syst Rev 2011 (6):CD007617. ISSN 1469-493X doi: 10.1002/14651858.CD007617.pub2. Accessed 23 December 2020. 54. vonHeymann-Horan A, Bidstrup P, Gudin MB, et al. Effect of homebased specialized palliative care and dyadic psychological intervention on caregiver anxiety and depression: a randomized controlled trial. Br J Cancer 2018;119:1307–1315. 55. Raphael B. The Anatomy of Bereavement. New York: Basic Books, 1983. 56. Firth S. Approaches to death in Hindu and Sikh communities in Britain. In: Dickenson D, Johnson M, Katz JS, eds. Death, Dying and Bereavement, 2nd ed. London: Sage Publications, 2000, ppm 28–34. 57. McGoldrick M, Almeida R, Hines PM, Garcia-Preto N, Rosen E, Lee E. Mourning in different cultures. In: Walsh F, McGoldrick M, eds. Living Beyond Loss: Death in the Family. New York, NY: WW Norton & Company, 1991, pp. 176–206. 58. National Consensus Project for Quality Palliative Care. Clinical Practice Guidelines for Quality Palliative Care, 4th ed. Richmond, VA: National Coalition for Hospice and Palliative Care, 2018. https://www. nationalcoalitionhpc.org/ncp (Accessed Aug 24, 2019). 59. Hudson P, Remedios C, Zordan R, et al. Clinical Practice Guidelines for the Psychosocial and Bereavement Support of Family Caregivers of Palliative Care Patients. Melbourne, Australia: Centre for Palliative Care, St Vincent’s Hospital Melbourne, 2010. https://www.centreforpallcare.org/page/70/publications (Accessed Aug 30, 2019). 60. Ahluwalia SC, Chen C, Raaen L, et al. A systematic review in support of the national consensus project clinical practice guidelines for quality palliative care, fourth edition. J Pain Symptom Manage 2018;56(6):831–870. 61. National Consensus Project for Quality Palliative Care. Clinical Practice Guidelines for Quality Palliative Care, 4th ed. Richmond, VA: National Coalition for Hospice and Palliative Care, 2018. https://www. nationalcoalitionhpc.org/ncp. 62. Agnew A, Manktelow R, Taylor B, Jones L. Bereavement needs assessment in specialist palliative care: a review of the literature. Palliat Med 2010;24(1):46–59.

BK-TandF-BRUERA_9780367642037-200160-Chp79.indd 767

767 63. NICE (UK) – National Institute for Clinical Excellence. Improving Supportive and Palliative Care for Adults with Cancer (CSG4). 2004 March. https://www.nice.org.uk/guidance/csg4 (Accessed Sept 4, 2019). 64. Djelantik AA, Smid GE, Kleber RJ, Boelen PA. Early indicators of problematic grief trajectories following bereavement. Eur J Psychotraumatol 2018;8:1423825. 65. Lynn C, Rath A. GriefNet: creating and maintaining an internet bereavement community. In: Sofka CJ, Cupit IN, Gilbert KR, eds. Dying, Death, and Grief in an Online Universe. New York: Springer, 2012, pp. 87–102. 66. Paulus T, Varga M. “Please know that you are not alone with your pain”: responses to newcomer posts in an online grief support forum. Death Stu 2015;39:633–640. 67. Stroebe M, Schut H, Boerner K. Cautioning health-care professionals: bereaved person are misguided through the stages of grief. Omega 2017;74(4):455–473. 68. Wittouck C, Van Autreve S, De Jaegere E, Portzky G, van Heeringen K. The prevention and treatment of complicated grief: a meta-analysis. Clin Psychol Rev 2011;31(1):69–78. 69. Shear MK, Frank E, Houck PR, Reynolds CF. Treatment of complicated grief: a randomized controlled trial. JAMA 2005;293(21):2601–2608. 70. Shear MK, Wang Y, Skritskaya N, Duan N, Mauro C, Ghesquiere A. Treatment of complicated grief in elderly persons: a randomized clinical trial. JAMA Psychiatry 2014; Nov;71(11):1287–1295. 71. Shear MK, Reynolds 3rd CF, Simon NM, et al. Optimizing treatment of complicated grief: a randomized clinical trial. JAMA Psychiatry 2016;73(7):685–694. 72. Rosner R, Bartl H, Pfoh G, Kotoučová M, Hagl M. Efficacy of an integrative CBT for prolonged grief disorder: a long-term follow-up. J Affect Disord 2015; Sept;183:106–112. 73. Rosner R, Pfoh G, Kotoučová M, Hagl M. Efficacy of an outpatient treatment for prolonged grief disorder: a randomized controlled clinical trial. J Affect Disord 2014;167:56–63. 74. Rosner R, Rimane E, Vogel A, Rau J, Hagl M. Treating prolonged grief disorder with prolonged grief-specific cognitive behavioral therapy: study protocol for a randomized controlled trial. Trials 2018; Apr;19(1):241. 75. Spuij M, van Londen-Huiberts A, Boelen PA. Cognitive-behavioral therapy for prolonged grief in children: feasibility and multiple baseline study. Cogn Behav Prac 2013;20:349–361. 76. Spuij M, Prinzie P, Dekovic M, van den Bout J, Boelen PA. The effectiveness of Grief-Help, a cognitive behavioural treatment for prolonged grief in children: study protocol for a randomised controlled trial. Trials 2013; Nov;14:395. 77. Raphael B, Minkov C, Dobson M. Psychotherapeutic and pharmacological intervention for bereaved persons. In: Stroebe MS, Hansson RO, Stroebe W, Schut H, eds. Handbook of Bereavement Research: Consequences, Coping, and Cure. Washington, DC: American Psychological Association, 2001, pp. 587–612. 78. Forte A, Hill M, Pazder R, Feudtner C. Bereavement care interventions: a systematic review. BMC Palliat Care 2004;3:3. 79. Bui E, Nadal-Viens M, Simon NM. Pharmacological approaches to the treatment of complicated grief: rationale and a brief review of the literature. Dialogues Clin Neurosci 2012;14(2):149–157.

24/06/21 11:54 AM

80

CHILDREN OF PALLIATIVE CARE PATIENTS

Estela Beale and Sujin Ann-Yi

Contents Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������769 Factors influencing a child’s response to a terminally ill parent������������������������������������������������������������������������������������������������������������������������������770 Developmental age������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������770 Situational factors�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������771 Communication�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������771 Short- and long-term effects of childhood bereavement������������������������������������������������������������������������������������������������������������������������������������������772 Interventions for the children of palliative care patients������������������������������������������������������������������������������������������������������������������������������������������772 Conclusions������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������773 Issues for the future...........................................................................................................................................................................................................774 References............................................................................................................................................................................................................................775

Introduction An estimated 18.3% of newly diagnosed cancer patients reported having at least one child under the age of 18 (Weaver et al., 2010). Cancer alone presents stressors for most adults; however, cancer patients with children often experience unique challenges in maintaining parental roles and responsibilities in addition to coping with a serious illness. Parental status has even been shown to be associated with patients with advanced cancer preferring aggressive treatment over palliative care and less likely to initiate advanced care planning (Yellen and Cella, 1995). In addition, parents with cancer have reported significant distress related to parenting efficacy and feeling inadequate on how to effectively communicate with their children regarding cancer diagnosis, particularly if one experiences recurrence or progression of disease (Walczak et al., 2018; Moore et al. 2015; Semple and McCance, 2010a; Semple and McCance, 2010b). Further, parenting concerns of patients with advanced cancer have been significantly associated with anxiety, depression, and decreased quality of life, particularly at end of life (Park et al., 2016a; Park et al., 2016b). Children and adolescents have reported significant emotional problems, worries, confusion, and loneliness in response to a parent’s cancer diagnosis (Morris et al., 2018; Moller et al., 2014; Karlsson et al., 2013; Visser et al., 2004; Zahlis, 2001; GazendamDonofrio et al., 2011). Despite children of cancer patients expressing the need and desire for parents’ health information, parents report feeling unprepared and distressed by these communication challenges (Walczak et al., 2018; Kennedy and LloydWilliams, 2009a). Cancer patients with young children reported interest in receiving resources on communicating with their children and information regarding psychosocial services to support their children and parenting (Sinclair et al., 2019; Ernst et al., 2013). Unfortunately, support and resources for parents with cancer to assist in these concerns and issues have been limited, particularly for patients with advanced cancer (Semple and McCance, 2010a,b; Turner et al., 2007). Significant others of cancer patients who co-parent children also have reported the need

for more information on how to support their children (Forrest et al., 2009). Some potential barriers for oncologists and health professionals in addressing parenting concerns of their patients include limited time pressures, not feeling equipped to provide recommendations or guidance, and due to their own emotional responses that may be elicited by talking with patients about their children (Rauch and Muriel, 2004). Several recently published papers reviewing the literature have found that children and adolescents of cancer patients were significantly impacted by their parent’s cancer diagnosis (Faccio et al., 2018; Morris et al., 2018; Walczak et al., 2018; Morris et al., 2016; Visser et al., 2004). Several factors have been identified to moderate the response of an offspring of a cancer patient such as the child’s gender, age, and quality of child’s support system (Huizinga et al., 2011). Parental factors that affected children’s responses to cancer diagnosis included the parent’s physical functioning, quality of parent’s support system, and the family structure. Other factors such as children’s coping strategies, the psychosocial functioning of parents’, family communication, and family functioning were found to be mediators of the child’s response to cancer diagnosis in the family (Faccio et al., 2018; Huizinga et al., 2011). One study reported parental depression predicted internalizing problems and family dysfunction predicted externalizing problems in children and adolescents of cancer patients (Thastum et al., 2009). Until very recently, children of cancer patients represented a hidden high-risk group whose needs were often minimized or overlooked by overwhelmed parents and were unknown to most of the medical staff. The reasons for the neglect of this population varied. A belief among parents and caretakers that children are generally resilient and that they will adapt to their circumstances was prevalent. Also, parents and caretakers sometimes voiced the belief that children, particularly younger ones, do not really understand what is going on (Kastenbaum, 1967; Pettle and Britten, 1995; Spinetta, 1974; Stambrook and Parker, 1987) and, therefore, it was best not to discuss the situation with them. Consequently, the children did not receive the attention they needed at this critical time.

769

Textbook of Palliative Medicine and Supportive Care

770 Over the past 20 years, research on childhood bereavement has increased, drawing attention to the need to provide intervention for children of palliative care patients (Christ, 2000b; Christ and Christ, 2006; Hames, 2003; Karns, 2002; Kornreich et al., 2008). The short- and long-term effects of the bereavement process of these children may be considerably mitigated by early intervention during the parent’s terminal phase (Christ and Christ, 2006; Dunning, 2006; Kennedy and McIntyre, 2008; Kornreich et al., 2008; Popplestone-Helm and Helm, 2009). Many factors must be taken into consideration in determining the best way to help a child cope with their parent’s terminal condition and adjust to the idea and subsequent reality of their parent’s death. Effective intervention must be appropriate to the developmental age of the child. Other critical factors that strongly influence children at this time are their relationship to the well parent, family characteristics, and the stability of their home environment, among others (Krauel et al., 2012; Christ and Christ, 2006; Haine et al., 2008; Schmitt et al., 2008). A patient with terminal cancer presents the palliative care professional with a unique set of situations that can create severe distress in children, due to the dramatic fluctuations of the patient’s symptoms. The potential of an extensive terminal phase with increasing physical and mental deterioration can exacerbate the family’s stress. Communicating the bad news of a cancer diagnosis is difficult enough for doctors (Buckman, 1984; Butow et al., 2002; Fallowfield and Jenkins, 1999; Maguire, 1999), so it is not surprising that parents dying of cancer, who are coming to terms with the existential issues surrounding dying, are often at a loss as to when, how, and what to tell their children about cancer and death. However, parent–child communication was found to be a significant factor in providing support for a child (Morris et al., 2016; Kennedy and Lloyd-Williams, 2009b; Visser et al., 2004). It often falls to a member of the palliative care team to advise and assist the parents in comforting and communicating with the children at this critical time. The research and clinical experience of a wide range of medical professionals from many countries and cultures is providing a foundation to assist us in developing effective interventions for the children of palliative care patients. This chapter reviews the research concerning the main issues that affect these children and the types of interventions that appear most promising.

Factors influencing a child’s response to a terminally ill parent Developmental age

Throughout the last several decades, developmental theorists have tried to understand the impact of parental loss on a young child. The attachment theory was first espoused by Bowlby (1980) who, in groundbreaking research, demonstrated that when primates are separated from the mother early in life, their reaction escalates from a state of protest to miasmas and death. Since then, other researchers have confirmed the instinctual roots of attachment, which assures the safety of infants who use intuitive behaviors to engage their caretakers and to guarantee their caretaker’s presence and attentiveness. Infants do not recognize death, feelings of separation, or loss. However, they react usually with behavioral and physical changes such as increased quietness, listlessness, unresponsiveness, weight loss, and changes in

sleep patterns. In other words, there is increased deregulation of physical functions. Internalization of primary caretakers is a process that becomes established by the time the child is 2 or 3 years of age. Once this process of internalization is accomplished, the child can sustain prolonged separations yet retain the memory of the parent. For the child to be able to obtain optimal emotional, social, and psychosexual maturity, a predictable, caring environment is required. Separation from the primary caretaker produces anxiety, which is manifested differently depending on the child’s developmental stage and is exacerbated by a terminal illness. While toddlers aged 2–3 years do not understand the concept of death, they have definite reactions shown by generalized distress, disturbances in sleep, and temper tantrums among others. By 3–5 years of age, comprehension has increased but there is still a tendency to rely on magical thinking. The idea of permanence is not present, so it is difficult to understand the finality of death (Black, 1998; Christ and Christ, 2006; Hames, 2003). By 5 years of age, most children can distinguish between separation and death. At this point, some characteristics of personality are most likely established. In addition, a variety of other factors will now influence the child’s development, such as the relationship to the well parent, the family structure, and the child’s general social circumstances, as well as genetic makeup. These children often become overprotective of the well parent and may withhold showing them any signs of distress. At the death of the parent, it is characteristic of this age group for there to be increased activity, often resulting in behavioral problems (Black, 1998). Several lines of research have indicated that children from 5 to 11 years old should be informed that the parent is terminally ill and should be told what to expect (Elizur and Kaffman, 1983; Hilden et al., 2000; Kroll et al., 1998; Pfeffer et al., 2000; Sourkes, 1992; Waechter, 1971). A study by Christ and Christ (2006), which included children in three different developmental groupings, 3–5, 6–8, and 9–11 years, suggests that children in all of these age groups be informed of their parent’s illness in a manner appropriate to their developmental age. Developmental factors also shape the adolescent’s response to the terminal illness of a parent. Support by health professionals, coping strategies, and the adolescents’ own mastery of adaptive tasks are posed by the terminal phase of the parent’s illness. Open communication between parents and children is of the utmost importance (Christ et al., 2002). Often, the parent’s illness creates the need for greater assistance in the home that clashes with the adolescent’s developmental tasks of withdrawing and achieving autonomy and emotional independence from the parents. Adolescent’s inconsistent behavior and mood swings typically become exaggerated under the stress of a parent’s illness. The adolescent’s advanced cognitive abilities may lead to more intense grief than that of younger children due to their increased ability to comprehend the enduring consequences of death. Some adolescents experience prolonged emotional disturbance during the parent’s illness and for several years after the parent’s death. These adolescents tend to exhibit severe depression, alcohol and/ or drug abuse, refusal to attend school, and oftentimes suicidal ideation (Christ, 2000a; Christ et al., 1994; Clark et al., 1994; Dehlin and Mertensson, 2009). Researchers studying the impact of development on children’s response to terminal illness and death of a parent have reported the emergence of behavioral patterns (Christ and Christ, 2006). Further clarification of such patterns could help the clinician determine more effective age-specific interventions.

Children of Palliative Care Patients Situational factors

The role of situational factors that can affect a child’s response and adjustment to the death of a parent has been gaining attention among researchers. Christ and Christ (2006) provide a list of situational factors that they categorize as either risk factors or protective factors that may mediate the coping of bereaved children. The risk factors they cite that may hinder the child’s bereavement process include concurrent stressful life events, a negative or non-supportive relationship with the surviving caregiver, a poor relationship with the parent who died, low selfesteem, preexisting mental health problems in the adolescent or the surviving parent or caregiver, and circumstances of the death, such as violent or traumatic death. They identified protective factors that may help mitigate the child’s bereavement process, including having a relationship with the surviving parent or caregiver characterized by open communication, warmth, and positive experiences; surviving parent able to sustain parenting competence; feeling accepted by peers and other adults, such as relatives and teachers; higher socioeconomic status; religiousness; intellectual and social competence; and the opportunity to express thoughts and feelings about the deceased parent and have them validated by others. Among these factors, the most consistently identified mediating variables are the quality of the relationship with the surviving parent or caregiver and their competence in parenting bereaved children (Baker et al., 1992; Buxbaum and Brant, 2001; Christ, 2002; Christ et al., 2002; Hahn et al., 1997; Raveis et al., 1999; Siegel et al., 1996). Haine et al. (2008) group situational factors as either malleable risk and protective factors or nonmalleable factors. Malleable risk and protective factors include increasing selfesteem, increasing child adaptive control beliefs, improving child coping skills, supporting adaptive expression of emotion that the child wishes to express, facilitating a positive parent– child relationship, parental warmth, parent–child communication, effective discipline, reducing parental distress, increasing positive family interactions, and reducing child exposure to negative life events. Nonmalleable factors include children’s developmental level, child gender, cause and type of death, time since the death, and cultural background (Haine et al., 2008; Sandler et al., 1999, 2003; Wolchik et al., 2008; Worden and Silverman, 1996; Zambelli and DeRosa, 1992).

Communication

The ability of the parents to engage in open communication with their children is a key mediating factor that can be addressed during early intervention that can positively influence the child’s response to a terminally ill parent (Forrest et al., 2006; Kennedy and Lloyd-Williams, 2009a,b). Hilden et al. (2000) found that when given the opportunity to communicate, children can conquer their fears as well as express their love in the terminal phase of a parent’s illness and that honesty is indeed the best policy with children of all ages. In this way, the reality of the situation, no matter how awful it is, can be shared in an open manner. Trying to protect children from knowledge about what is really happening often confuses the child even more than circumstances alone and escalates concerns about events that are beyond their control. A study conducted by Pfeffer et al. (2000) reported that the children in their sample were likely either denying or reluctant

771 to acknowledge problems in the emotional domains assessed, for reasons that were directly or indirectly related to the loss of their parent. For example, they may have been reluctant to acknowledge their own feelings of depression for fear that doing so would upset other family members. However, reports of bereaved parents regarding their children’s psychological distress and symptoms of depression reported lower levels than found in the children’s reports of their own distress and psychiatric symptomatology. Bereaved parents may be so overwhelmed by their own grief and mourning that they are not fully aware of the level of distress of their children, or they may not be able to cope with their children’s psychologically distressed states. There should be no curtain of silence drawn around the child’s worst fears. Kornreich et al. (2008) report that parents can minimize their child’s distress by maintaining open communication throughout the diagnosis, treatment, and recovery processes. Furthermore, an informative, timely, and supportive response from a multidisciplinary health-care team can successfully reduce stressors and guide the child through the experience. Children of cancer patients, when provided the opportunity, expressed significant worries and confusion related to parent’s cancer diagnosis, of parent dying and how the illness would impact not only the patient but also their family (Zahlis, 2001). Studies provide support for the belief that anxiety diminishes when a child is given opportunities to discuss his fears. Providing the child with understanding, acceptance of his feelings, and conveyance of permission to discuss any aspect of the parent’s illness can decrease feelings of isolation and alienation. Waechter (1971) points out the striking dichotomy between the child’s degree of awareness of the prognosis, as inferred from his imaginative stories, and the parent’s belief about the child’s degree of awareness of the parent’s prognosis. This dichotomy suggests that knowledge is communicated to the child by the changes that he encounters in his total environment after the diagnosis is made and by his perceptiveness of various nonverbal clues. This disparity may result in a deepening isolation that is exacerbated when the child becomes aware of the evasiveness that meets expressions of his concern. Children who are forewarned of the imminence and inevitability of death have lower levels of anxiety than those who are not, even children within the same family. Children and adolescents report that they value open communication with both parents about the illness and death, and research suggests that it helps them during their bereavement (Christ et al., 2005; Raveis et al., 1999). Family communication about the parent’s illness is one of the focuses of parent-guidance intervention programs (Siegel et al., 1990). The practitioner needs to be aware that some children may need specialized help in recovering from depression and other symptoms that are associated with bereavement. Several studies specifically related to parents dying of cancer reiterate the importance of communication between parents and children and provide support for the claim that parents underestimate the impact of a terminal illness on their children. The results suggest that emotional restraint in the surviving parent made it difficult for the child to express feelings. This led to a sense of intensified loneliness and increased anxiety and confusion. The ability of bereaved children to report grieving emotions correlated significantly with improved functioning (Christ and Christ, 2006; Elizur and Kaffman, 1983; Kranzler et al., 1990; Moore et al., 2010).

Textbook of Palliative Medicine and Supportive Care

772

Short- and long-term effects of childhood bereavement There has been some progress in assessing the short-term effects of the bereavement process in children. The Family Bereavement Program (FBP) at Arizona State University uses a theoretical model to study which factors are critical for the effect that bereavement of parental death has on psychological functioning. Factors targeted by the intervention included parental demoralization, negative life events, parental warmth, and stable positive events in the family. The program involved separate groups for caregivers, adolescents, and children, which were designed to change potentially modifiable risk and protective factors for bereaved children. The evaluation involved random assignment of 156 families (244 children and adolescents) to the FBP or a self-study condition. Families participated in assessments at pretest, posttest, and 11-month follow-up. Results indicated that the FBP led to improved parenting, coping, and caregiver mental health and to reductions in stressful events at posttest (Sandler et al., 2003). A study by Kwok et al. (2005) used a multirater, multimethod measurement model of positive parenting to study 214 bereaved children ages of 7–16 and their surviving parent or current caregiver. The authors reported a correlation between the surviving parent’s ability to express warmth and consistent discipline with the parentally bereaved children’s mental health problems. They believe this model has implications for understanding the development of mental health problems of parentally bereaved children. Cerel et al. (2006) interviewed 360 parent-bereaved children (ages 6–17) over a 2-year period after the death of a parent. They reported that the children who are at most risk of depression and overall psychopathology were those who experienced depression in combination with parental depression or in the context of other family stressors. Studies regarding the long-term effects of childhood parental loss have been inconsistent or inconclusive. The evidence from many of these studies provides mixed evidence for the changes in psychological symptoms of bereaved children. Some of the studies indicate a significant difference in depression and suicide in adults bereaved in childhood, while other studies show no significant difference in this group. There are several reasons for these inconsistencies, which range from nonrepresentative samples and small sample sizes to the use of a wide range of data collection methodologies, all of which make it difficult to compare otherwise similar studies.

Interventions for the children of palliative care patients Educational programs and guidelines have been developed to help parents and clinicians communicate with children about the ill parent’s situation and impending death, and support programs for children of palliative care patients have grown substantially (Stafford et al., 2017; Turner et al., 2009; Turner et al., 2008; Giesberg and Verdonck-de leeuw, 2010; Mondanaro, 2005; Popplestone-Helm and Helm, 2009; Saunders, 1996; Sweetland, 2005; Turner, 2004; Turner and Clavarino, 2007). However, there are still few qualitative and even fewer quantitative studies focused on interventions for the children of palliative care patients (Karns, 2002; Kennedy and McIntyre, 2008; Rauch and Durant, 2003).

A study by Sivesind and Beale (2002) showed a high percentage of children of a terminally ill parent sought reassurance, and most of them considered themselves to be caregivers of their dying parent. A strong wish to do everything possible to keep the parent alive was triggered. It also appeared that while the child was lost in frenetic activity, he or she was not faced with as much anxiety and grief as might otherwise occur. In contrast to the standard account (Matthews, 1989) of developmental stages, small children demonstrated a remarkable awareness of the parent’s medical condition and its implications. Disruptive behavior alternated with some desperate attempts to be helpful. The helpfulness was always associated with the wish to help the parent get better. These findings are consistent with the findings of Siegel et al. (1996). The latency age group tended to present academic difficulties, which the parents related to the disruptions caused by the cancer. The children, whose families were secure, provided enough stability for the children to free themselves from the worries of the illness and continue with their day-to-day life. Those where financial or family problems prevailed felt much more burdened by the implications of the illness. The children from this group attached themselves to the therapist, recognizing him or her as one trustworthy person in their life. Results of this study suggest that children with dying parents manifest significant distress as well as a greater understanding of their parent’s illness than it is usually suspected. Three types of interventions were found to be useful: normalization for both patient and family (50%), expressive–supportive counseling (100%), and occasional cognitive reframing (35%). Hahn et al. (1997) developed a parent-guidance mode of communicating the parent’s terminal illness to children to try to positively affect the children’s adjustment process to the terminal illness and death of a parent due to cancer. The specific goals of the intervention were to facilitate the competence of the parents and increase communication among the family members about the illness and impending death. The intervention consisted of 3 hours of providing information, advice, and communication training to both of the parents. The authors report that this model seems promising and points to the importance of a standardized intervention for children with a terminally ill parent. Christ (2000b) developed a psychoeducational intervention to facilitate the adjustment of children to the terminal illness and subsequent death of a parent. The intervention emphasized a parent-guidance approach. As part of this intervention, a telephone supportive intervention was also developed as a control condition. The goal of this intervention was to maintain contact with the well parent between psychological evaluations, to provide referrals to community-based therapists or support groups when such a referral was requested, or to appropriate hospital personnel when questions such as uncertainty about planned treatment procedures, billing, or untoward reactions of the ill parent were raised by the well parent. Since the data generated by this intervention was insufficient for qualitative analyses, only data from families who participated in the psychoeducational intervention was used for the qualitative arm of the analyses. Based on clinical experience, the interventions started during the terminal illness. The researchers found that the family member’s responses differed substantially during the terminal stage of the illness from responses following the death. “This clinical experience was confirmed by the quantitative analyses of depression and anxiety measures that indicated that children were significantly more anxious and depressed during the pre-death period than at the end of the reconstitution stage.” A typical psychoeducational

Children of Palliative Care Patients parent-guidance intervention spanned about 14 months and included 6 or more 60–90 minutes therapeutic interviews during the terminal stage of the illness and six or more after the death. The therapeutic engagement was emphasized during the second interview. It was the family’s option to include the patient in these interviews. At each meeting, ways of handling problems with the children were discussed. A separate interview was then done with each child. This was followed by an informing interview with the parent(s) in whom the parent(s) was given an assessment of the children’s adaptation to the illness. A family interview that included the well parent and all of the children in that family was then done and was followed by two or more biweekly to monthly parent interviews. Beginning 2–4 weeks after the death of the parent, a similar schedule of interviews was followed. Additional child and/or family interviews were scheduled as requested. After the final interview, the social worker initiated bimonthly to monthly telephone contacts with the surviving parent until the final postdeath psychological assessment was completed about 14 months after the death of the parent. Additional telephone contacts were scheduled if significant family crises emerged during the psychologist’s final assessment or the social worker’s final telephone contact. Finally, if necessary, individual parent, child, and/or family sessions were offered. Christ et al. (2005) conducted a second psychoeducational intervention program involving 184 families over a 12-month period. The research team reported, “children in the parentguidance intervention reported greater reduction in trait anxiety and greater improvement in their perceptions of the surviving parent’s competence and communication, a primary goal of the intervention.” Dr. Paula Rauch is the founder of a parent-guidance program at Massachusetts General Hospital called “Parenting at a Challenging Time.” The program provides individual and group parenting support by child psychiatrists and psychologists for cancer patients, their spouses, and children. Of the program, Dr. Rauch says, “I tell parents, – because it’s true - that they are the experts on their children… My role is to be a co-pilot navigating with them the unfamiliar waters of a life threatening illness.” Through lessons learned from this program for adults with cancer, Dr. Rauch has developed a series of guiding principles for clinicians who are supporting children of parent’s facing cancer (Rauch, 2000; Rauch and Durant, 2003; Rauch et al., 2002, 2003; Swick and Rauch, 2006). Children between the ages of 5 and 18 participated in a support program for families with a parent who had terminal cancer (Bugge and Helseth, 2008). The goals of the intervention were to increase the children’s understanding of the situation, to encourage them to talk about the ill parent, and to be assured there were people there to help them. Evaluation of the program was based on in-depth interviews with the children. The researchers reported that the intervention helped the children cope as the parent transitioned into palliative care. A study by Lewis et al. (2006) reports on the impact of a shortterm program on mothers’ and children’s adjustment to the mother’s diagnosis of breast cancer. Research reveals that both mothers and children have elevated distress attributed to cancer, struggle with how to talk about and deal with the impact of the cancer, and fear the mother will die. The Enhancing Connections Program was developed to reduce this cancer-related distress and morbidity. The program involves five 1-hour educational counseling sessions delivered at 2-week intervals by specially trained clinicians. Thirteen households were recruited within 7.5 months

773 of the mother’s diagnosis with early-stage breast cancer. Impact was evaluated within a single group design using data obtained from standardized questionnaires with established reliability and validity. Results revealed significant improvements in the mother’s depressed mood, anxiety, and self-confidence to assist her child (mother report). There were also significant decreases in the child’s behavioral problems (mother and father report), the child’s cancer-related worries (child report), and the child’s anxiety/depressed mood (mother and father report) (Lewis, 2011). Support for more research studies focused on developing effective intervention programs for children who have a parent with terminal cancer is slowly gaining ground. There is hope that these efforts will yield more effective intervention strategies for these children.

Conclusions The literature on children whose parents die of cancer is abundant. However, most of these studies focus on the process of bereavement. Only a few research studies have focused on children experiencing the terminal phase of their ill parent. Recent contributions to the literature that examines patient’s and their children’s experiences during the end of life process have developed the following themes: (1) the ability of the surviving parent to meet the needs of the child is crucial for the child’s well-being, (2) a child’s increased anxiety is directly correlated with a lack of information about his parent’s cancer diagnosis, (3) anxiety increases when information is available but there is no opportunity for discussion with the child, (4) children of parents who die of cancer are at a higher risk for psychological problems, (5) previous family history affects the child’s bereavement process, (6) meeting with a mental health professional can provide the child with a supportive adult who can clarify confusing thoughts and allay painful feeling and also serve as a model for family discussions, and (7) the professionals involved in this type of work need to maintain a clear understanding of their motivation for this work, as well as being attuned to the impact that serving this population may have on their lives. It is important to remember that making recommendations to families in such a situation is difficult. There is no clear-cut solution for dealing with a family’s reaction to terminal cancer. When a parent is dying of cancer, discussions among parents, children, and all other adult caretakers are important. However, these discussions are part of a process that should begin when the patient is first aware of his terminal condition. This may coincide with his referral to a palliative care team. The mental health professional should contact the family at this entry point and establish a connection. An assessment of the parent’s adaptation to the illness and of the family and other support systems is very important. The children should be assessed independently to determine developmental age, level of information, adaptation to the critical situation, understanding of the facts, and wishes and fantasies about the future. Finally, the interventions have to take place before despair or resignation sets in so that there is enough motivation to accomplish a higher level of communication and possibly resolution of conflicts before death is imminent. Interventions for children of palliative care patients and their families have two different aspects: the structure of the meetings and the content. The structure determines where the meeting takes place, when it happens, who is present, and how long it takes. The site should be comfortable, quiet, and relatively private to avoid distractions or interruptions. The family and the

Textbook of Palliative Medicine and Supportive Care

774 professional should meet when the patient first enters the palliative care service. Ideally, the ill parents will be conscious and have enough energy to be able to connect with the children as well as continue to participate in whatever limited way in their lives. Time should be sufficient so the meeting is not ended prematurely. The professional acts as a consultant to the family by promoting disclosure, clarifying the goals of the meeting, and eliciting information from the different participants, especially the children. The content of the meeting is determined by the discussion, which is not arbitrarily confined to this situation but uses this time to revisit events. It is of primary importance to explore the information, speculations, and conclusions that the children have reached so far. This provides a springboard for clarifications, providing more information and beginning a discussion of the ill parent’s prognosis. When this is a new information to a child, he will need time to react and possibly talk about feelings. It is also important to pay attention to the child’s tolerance for information and pace the discussion based on the child’s ability to absorb. The child may not want to hear or continue the discussion. The challenge is to know how much to push without assaulting the child with unwelcome facts and when to back off and wait. This discussion is personal, intimate, and private, requiring a great deal of acceptance and support. The professional will model this through empathetic statements and reassurance. This is a time when the expressions of love, regret for the truncated life, gratitude, and reassurance of unending memory will solidify the bonds and, paradoxically, facilitate the ability to let go. Because this is a very personal and intimate subject, parents are ideally the ones to have this conversation with the child. However, parents are so often burdened with the weight of the illness and all of their other responsibilities that they are not able to take on this task. As previously stated, the two parents, or just the well parent with a professional assistant, may create the optimal situation to clarify issues, provide reassurance, intensify trust and attachment, and prepare the child for the final farewell.

Issues for the future With the shift of providing a family-centered approach to care, there has been a substantial increase in research in the areas of cancer patients with young children, the impact of parental cancer on children and childhood bereavement, both in the United States and internationally. These research studies, theories, intervention strategies, support programs, and guidelines are providing a body of knowledge and clinical experience from which we hope to develop more effective intervention strategies for the children of palliative care patients. The complexity of developing and evaluating psychosocial intervention programs for these children has led to efforts to bridge the gap between the knowledge gained from the quantitative and qualitative studies. A literature review by Niemela et al. (2010) indicated a lack of valid psychosocial preventive intervention methods focusing on children with parental cancer and highlighted the need of intervention research with controlled study designs and long follow-up periods. The authors believe that by refining the practice-based experiences with scientific research evidence, it is possible to move to the next level in providing effective psychosocial support and prevention of mental health problems for children living in families with parental cancer.

KEY LEARNING POINTS • Cancer patients and their children report distress related to cancer diagnosis and not knowing how to communicate or support their children. • Children report interest in being informed of parent’s health status, and parents report need for resources, guidance, and support to communicate with their children. • Parent–child communication from diagnosis through course of cancer experience is the key in supporting a child’s coping and adjustment to parental cancer. • The child’s reaction to the ill parent will be affected by several factors, including the quality of the relationship to the well parent as well as the family integration. • For the child of a terminal cancer patient, increased anxiety will correlate with confusion about the parent’s condition. • Anxiety increases when there are no avenues for supportive discussions. • Previous family history as well as the social and financial conditions will affect the child’s adjustment to the parent’s illness and ultimate death. • Children of parents who die of cancer are at a higher risk for psychological problems. • Meeting with a mental health professional can provide opportunities for discussions as well as a model for family communication.

Christ and Christ (2006) propose three research directions for the 21st century, which they believe show promise for obtaining more specific and less confusing and contradictory findings: 1. Studying developmentally homogeneous subgroups of children and the differing effects of different types of deaths 2. Conducting longer term prospective studies that include critical experiences (e.g., terminal stage in predictable deaths, later responses) that may clarify different outcomes 3. Combining qualitative and quantitative analytic approaches to provide a way to understand the realistic complexity of the area and populations under study There are many difficulties associated with framing these types of studies. However, there is general agreement among investigators that early intervention for children of palliative care patients is important for the child’s bereavement process and ultimate adjustment to life. Future research efforts should focus on developing and validating evidence-based interventions to support parents with cancer for the entire family system throughout the trajectory of their cancer experience (Shah et al., 2017). As the terminal phase of cancer becomes extended and, thus, the length of palliative care, it is becoming increasingly important to be able to provide effective early interventions for the children of palliative care patients.

Children of Palliative Care Patients

References Baker JE, Sedney MA, Gross E. Psychological tasks for bereaved children. Am J Orthopsychiatry 1992;61(1):105–116. Black D. Coping with loss: bereavement in childhood. British Medical Journal 1998;316:931–933. Bowlby J. Attachment and Loss: Sadness and Depression, Vol. 3. New York: Basic Books, 1980, pp. 252–259. Buckman R. Breaking bad news: why is it still so difficult? Br Med J (Clin Res Ed) 1984;1597–1599. Bugge KE, Helseth S. Children’s experiences of participation in a family support program when their parent has incurable cancer. Cancer Nurs 2008;31(6):426–434. Butow PN, Brown RF, Cogar S. Oncologists’ reactions to cancer patients’ verbal clues. Psychooncology 2002;447–458. Buxbaum L, Brant JM. When a parent dies from cancer. Clin J Oncol Nurs 2001;5(4):135–140. Cerel J, Fristad MA, Verducci J, et al. Childhood bereavement: psychopathology in the 2 years post parental death. J Am Acad Child Adolesc Psychiatry 2006;45:683–690. Christ GH. Impact of development on children’s mourning. Cancer Pract 2000a;8(2):72–81. Christ GH. Healing Children’s Grief: Surviving a Parent’s Death from Cancer. New York: Oxford University Press, 2000b. Christ GH, Christ AE. Current approaches to helping children cope with a parent’s terminal illness. CA Cancer J Clin 2006;56:197–212. Christ GH, Siegel K, Christ AE. Adolescent grief: “It never hit me until it actually happened.” JAMA 2002;288:1269–1278. Christ GH, Siegel K, Karus D, Christ AE. Evaluation of a bereavement intervention. Soc Work End-of-Life Palliat Care .2005;1:57–81. Christ GH, Siegel K, Sperber D. Impact of parent terminal cancer on adolescents. Am J Orthopsychiatry 1994;64(4):604–613. Clark DC, Pynoos RS, Goebel AE. Mechanisms and processes of adolescent bereavement. In: Haggerty RJ, Sherrod LR, Garmezy N, Rutter M, eds. Stress, Risk and Resilience in Children and Adolescents: Processes, Mechanisms, and Interventions. New York: Cambridge University Press, 1994, pp. 100–146. Dehlin L, Mertensson RG. Adolescents’ experiences of a parent’s serious illness and death. Palliat Support Care 2009;7(1):13–25. Dunning S. As a young child’s parent dies: conceptualizing and constructing preventive interventions. Clin Soc Work J 2006;34(4):499–514. Elizur E, Kaffman M. Factors influencing the severity of childhood bereavement reactions. Am J Orthopsychiatry 1983;53:668–676. Ernst JC, Beierlein V, Romer G, Moller B, Koch U, Bergelt C. Use and need for psychosocial support in cancer patients: a population-based sample of patients with minor children. Cancer 2013;119(12):2333–2341. Faccio F, Ferrari F, Pravettoni G. When a parent has cancer: how does it impact on children’s psychosocial functioning? A systematic review. Eur J Cancer Care 2018;27:e12895. Fallowfield L, Jenkins V. Effective communication skills are the key to good cancer care. Eur J Cancer 1999;1592–1597. Forrest G, Plumb C, Ziebland S, Stein A. Breast cancer in the family— children’s perceptions of their mother’s cancer and its initial treatment: qualitative study. BMJ 2006;332:998. Forrest G, Plumb C, Ziebland S, Stein A. Breast cancer in young families: a qualitative interview study of fathers and their role and communication with their children following the diagnosis of maternal breast cancer. Psychooncology 2009;18:96–103. Gazendam-Donofrio SM, Hoekstra HJ, van der Graaf WTA, et al. Adolescents’ emotional reactions to parental cancer: effect on emotional and behavioral problems. J Pediatr Psychol 2011;36(3):346–359. Giesberg J, Verdonck-de leeuw M. Coping with parental cancer: web-based peer support in children. Psychooncology 2010;19(8):887–892. Hahn D, Kaats E, Stutterheim A, et al. Facilitation of children’s adjustment to the terminal illness and death of a parent due to cancer. Eur J Cancer Abstr 1997;33(1008):339. Haine RA, Ayers TS, Sandler IN, Wolchik SA. Evidence-based practices for parentally bereaved children and their families. Prof Psychol Res Pract 2008;39(2):112‒113. Hames C. Helping infants and toddlers when a family member dies. J Hosp Palliat Nurs 2003;5(2):103‒112. Hilden JM, Watterson J, Chrastek J. Tell the children. J Clin Oncol 2000;3193–3195. Huizinga GA, Visser A, Zelders-Steyn YE, Teule JA, Reijneveld SA, Roodbol PF. Psychological impact of having a parent with cancer. Eur J Cancer 2011;47(3):S239–S246.

BK-TandF-BRUERA_9780367642037-200160-Chp80.indd 775

775 Karlsson E, Andersson K, Ahlstrom BH. Loneliness despite the presence of others: adolescent’ experiences of having a parent who becomes ill with cancer. Eur J Oncol Nurs 2013;17:697–703. Karns JT. Children’s understanding of death. J Clin Act Assignments Handouts Psychother Pract 2002;2(1):43–50. Kastenbaum R. The child’s understanding of death: how does it develop? In: Grollman E, ed. Explaining Death to Children. Boston, MA: Beacon Press, 1967, pp. 89‒108. Kennedy KC, McIntyre R. Supporting children and families facing the death of a parent: Part 2. Int J Palliat Nurs 2008;14(5):230–237. Kennedy VL, Lloyd-Williams M. How children cope when a parent has advanced cancer. Psychooncology 2009a;18(8):886–892. Kennedy VL, Lloyd-Williams M. Information and communication when a parent has advanced cancer. J Affect Disor 2009b;114:149–155. Kornreich D, Harriet Mannheim H, Axelrod D. How children live with parental cancer. Prim Psychiatry 2008;15(10):64–70. Kranzler EM, Shaffer D, Wasserman G, Davies M. Early childhood bereavement. J Am Acad Child Adolesc Psychiatry 1990;29:513–520. Krauel K, Simon A, Krause-Hebecker N, Czimbalmos A, Bottomley A, Fletchner H. When a parent has cancer: challenges to patients, their families and health providers. Expert Rev Pharmacoecon Outcomes Res 2012;12(6):795–808. Kroll L, Barnes J, Jones AL. Cancer in parents: telling children. BMJ 1998;880. Kwok OM, Haine R, Sandler I. Positive parenting as a mediator of the relations between parental psychological distress and mental health problems of parentally bereaved children. J Clin Child Adolesc Psychol 2005;34:260–271. Lewis FM. Therapy for parental cancer and dependent children. In: Watson M, Kissane DW, eds. Handbook of Psychotherapy in Cancer Care, 2011. John Wiley & Sons. Lewis FM, Casey SM, Brandt PA, Shands ME, Zahlis EH. The enhancing connections program: pilot study of a cognitive-behavioral intervention for mothers and children affected by breast cancer. Psychooncology 2006;15(6):486–497. Maguire P. Improving communication with cancer patients. Eur J Cancer 1999;1415‒1422. Matthews GB. Children’s conceptions of illness and death. In: Kopelman LM, Moskop JC, eds. Children and Health Care: Moral and Social Issues. Boston, MA: Kluwer Academic Publishers, 1989, pp. 133–146. Moller B, Barkmann C, Krattenmacher T, et al. Children of cancer patients: prevalence and predictors of emotional and behavioral problems. Cancer 2014;120(15):2261–2270 Mondanaro J. Interfacing music therapy with other arts modalities to address anticipatory grief and bereavement in pediatrics. In: Dileo C, Loewy JV, eds. Music Therapy at the End of Life .Cherry Hill, NJ: Jeffrey Books, 2005, pp. 25–32. Moore CW, Pengelly M, Rauch PK. Communicating with children when a parent is dying. In: Kissane D, Bultz B, Butow P, Finlay I, eds. Handbook of Communication in Cancer and Palliative Care. New York: Oxford University Press, 2010, pp. 557‒572. Moore CW, Rauch PK, Baer L, Pirl WF, Muriel AC. Parenting changes in adults with cancer. Cancer 2015;121(19):3551–3557. Morris JN, Martina A, Preen A. The well-being of children impacted by a parent with cancer: an integrative review. Support Care Cancer 2016;24:3235–3251. Morris J, Turnbull D, Preen D, Zajaz I, Martini A. The psychological, social, and behavioral impact of a parent’s cancer on adolescent and young adult offspring aged 10–24 at time of diagnosis: a systematic review. J Adolesc 2018;65:61–71. Niemela M, Hakko H, Rasanen S. A systematic narrative review of the studies on structured child-centered interventions for families with a parent with cancer. Psychooncology 2010;19:451‒461. Park EM, Deal AM, Check DK, et al. Parenting concerns, quality of life, and psychological distress in patients with advanced cancer. Psychooncology 2016a;25:942–948. Park EM, Deal AM, Yopp JM, et al. End-of-life experiences of mothers with advanced cancer: perspectives of widowed fathers. 2016b;6:437–444. Pettle SA, Britten CM. Talking with children about death and dying. Child Care Health Dev 1995;395–404. Pfeffer CR, Karus D, Siegel K. Child survivors of parental death from cancer or suicide: depressive and behavioral outcomes. Psychooncology 2000;1‒10. Popplestone-Helm SV, Helm DP. Setting up a support group for children and their well carers who have a significant adult with a life-threatening illness. Int J Palliat Nurs 2009;15(5):214.

24/06/21 11:54 AM

776 Rauch P. Comment: supporting the child within the family. J Clin Ethics 2000;11:169‒170. Rauch PK, Durant S. Helping children cope with a parent’s cancer. In: Stern T, Sekeres M, eds. Facing Cancer: A Complete Guide for People with Cancer, Their Families, and Caregivers. New York: McGraw-Hill Professional, 2003, pp. 125–136. Rauch P, Muriel AC. The importance of parenting concerns among patients with cancer. Crit Rev Oncol Hematol 2004;49:37–42. Rauch P, Muriel A, Cassem N. The art of oncology: when the tumor is not the target. Parents with cancer: who’s looking after the children? J Clin Oncol 2002;21:4399–4402. Rauch P, Muriel A, Cassem N. Parents with cancer: who’s looking after the children? J Clin Oncol 2003;21(9 Suppl):117–121. Raveis VH, Siegel K, Karus D. Children’s psychological distress following the death of a parent. J Youth Adolesc 1999;28(21):165–180. Sandler IN, Ayers TS, Wolchik SA, Siegel K, Karus D. Children’s psychological distress following the death of a parent. J Youth Adolesc 1999;28:165–180. Sandler IN, Ayers TS, Wolchik SA, et al. The family bereavement program: efficacy evaluation of a theory-based prevention program for parentally bereaved children and adolescents. J Consult Clin Psychol 2003;71:587. Saunders J. Innovations in practice: anticipatory grief work with children. Br J Commun Health Nurs 1996;1(2):103–106. Schmitt F, Piha J, Helenius H, et al. Multinational study of cancer patients and their children: factors associated with family functioning. J Clin Oncol 2008;26(36):5877–5883. Semple CJ, McCance T. Experience of parents with head and neck cancer who are caring for young children. J Adv Nurs 2010a;66(6):1280–1290. Semple CJ, McCance T. Parents’ experience of cancer who have young children: a literature review. Cancer Nurs 2010b;33(2):110–118. Shah BK, Armaly J, Swieter E. Impact of parental cancer on children. Anticancer Res 2017;37:4025–4028. Siegel K, Karus D, Raveis VH. Adjustment of children facing the death of a parent due to cancer. J Am Acad Child Adolesc Psychiatry 1996;35:442–450. Siegel K, Mesagno R, Christ GH. A preventive program for bereaved children. Am J Orthopsychiatry 1990;60:168–175. Sinclair M, Schofield P, Turner J, et al. Maternal breast cancer and communicating with children: a qualitative exploration of what resources mothers want and what health professional provide. Eur J Cancer Care 2019;28(6):e13153. https://doi.org/10.1111/ecc.13153 Sivesind DM, Beale E. Children of terminally ill cancer patients: findings of psychosocial assessment and counseling. In: ASCO Annual Meetings, Abstract No: 1441, 2002. Sourkes BM. The child with a life threatening illness. In: Brandell J, ed. Countertransference in Psychotherapy with Children and Adolescents. New York: Jason Aronson, 1992, pp. 267‒284. Spinetta JJ. The dying child’s awareness of death: a review. Psychol Bull 1974;256‒260.

BK-TandF-BRUERA_9780367642037-200160-Chp80.indd 776

Textbook of Palliative Medicine and Supportive Care Stafford L, Sinclair M, Turner J, et al. Study protocol for enhancing parenting in cancer (EPIC): development and evaluation of a brief psycho-educational intervention to support parents with cancer who have young children. Pilot Feasibility Stud 2017;3:72–81. Stambrook M, Parker KCH. The development of the concept of death in childhood: a review of the literature. Merrill-Palmer Q 1987;133–157. Sweetland C. The palliative care nurse’s role in supporting the adolescent child of a dying patient. Int J Palliat Nurs 2005;11(6):294–298. Swick SD, Rauch PK. Children facing the death of a parent: the experiences of a parent guidance program at the Massachusetts General Hospital Cancer Center. Child Adolesc Psychiatr Clin N Am 2006;15(3):779‒794. Thastum M, Watson M, Kienbacher C, et al. Prevalence and predictors of emotional and behavioural functioning of children where a parent has cancer. Cancer 2009;115(17):4030–4039. Turner J. Children’s and family needs of young women with advanced breast cancer: a review. Palliat Support Care 2004;2:55‒64. Turner J, Clavarino A, Butow P, et al. Enhancing the capacity of oncology nurses to provide supportive care for parents with advanced cancer: evaluation of an educational intervention. Eur J Cancer 2009;45:1798–1806. Turner J, Clavarino A, Yates P, Hargraves M, Connors V, Hausmann S. Development of a resource for parents with advanced cancer: what do parents want? Palliat Support Care 2007;5:135–145. Turner J, Clavarino A, Yates P, Hargraves M, Connors V, Hausmann S. Enhancing the supportive care of parents with advanced cancer: development of a self-directed educational manual. Eur J Cancer 2008;44:1625–1631. Visser A, Huizinga GA, van der Graaf WTA, Hoekstra HJ, Hoekstra-Weebers JE. The impact of parental cancer on children and the family: a review of the literature. Cancer Treat Rev 2004;30:683–694. Weaver KE, Rowland JH, Alfano CM, McNeel TS. Parental cancer and the family .Cancer 2010;116:4395–4401. Waechter EH. Children’s awareness of fatal illness. Am J Nurs 1971;1168–1172. Walczak A, McDonald F, Patterson P, Dobinson K, Allison K. How does parental cancer affect adolescent and young adult offspring? A systematic review. Int J Nurs Stud 2018;77:54–80. Wolchik SA, Ma Y, Tein J-Y, Sandler IN, Ayers TS. Parentally bereaved children’s grief: self-system beliefs as mediators of the relations between grief and stressors and caregiver-child relationship quality. Death Stud 2008;32(7):597–620. Worden JW, Silverman PR. Parental death and the adjustment of school-age children. Omega 1996;33:91–102. Yellen SB, Cella DF. Someone to live for: social well-being, parenthood status, and decision-making in oncology. J Clin Oncol 1995;13(5):1255–1264. Zahlis EH. The child’s worries about the mother’s breast cancer: sources of distress in school-age children. Oncol Nurs Forum 2001;28(6):1019–1025. Zambelli GC, DeRosa AP. Bereavement support groups for school age children: theory, intervention and case example. Am J Orthopsychiatry 1992;62(4):484‒493.

24/06/21 11:54 AM

81

NEUTROPENIC FEVER

Hiroshi Ishiguro and Harumi Gomi

Contents Risk factors for infection in cancer patients����������������������������������������������������������������������������������������������������������������������������������������������������������������777 Local factors�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������777 Neutropenia�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������777 Cellular immune dysfunction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������777 Humoral immune dysfunction���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������777 Foreign bodies��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������778 Prevention of neutropenic fever������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������778 Controlling local factors��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������778 Vaccinations�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������778 Antimicrobial prophylaxis�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������778 Prophylactic use of granulocyte-colony stimulating factors (G-CSF)��������������������������������������������������������������������������������������������������������������778 Management of neutropenic fever��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������779 Definition of neutropenic fever��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������779 Evaluation of patients with neutropenic fever������������������������������������������������������������������������������������������������������������������������������������������������������779 Initial management of neutropenic fever���������������������������������������������������������������������������������������������������������������������������������������������������������������779 Catheter-related infections����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������781 Reassessment���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������781 Antifungal therapy������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������781 Therapeutic use of G-CSF�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������781 References............................................................................................................................................................................................................................781

Risk factors for infection in cancer patients Despite the progress made in supportive care in oncology, infection is a very common, and occasionally serious, problem. The following factors increase the susceptibility of cancer patients to infection.1

Local factors

Local factors that obstruct or disrupt normal anatomic barriers play an important role in infections occurring in cancer patients. Pneumonia and abscess can develop distal to obstruction of the major bronchi and respond poorly to antibiotic therapy. Obstruction of the biliary tract can result in ascending cholangitis. Urinary tract infections are common in patients with genitourinary tumors that obstruct the ureter or bladder neck, causing retention of urine. In such cases, one or more of the microorganisms colonizing the site of obstruction generally cause the infection. Mucosal surfaces (particularly of the gastrointestinal mucosa) damaged by antineoplastic chemotherapy frequently provide a portal of entry for pathogens. Radiation also causes local tissue damage, which can predispose to secondary infection.1

Neutropenia

Both the degree and the duration of neutropenia are risk factors for infection, and bacteremias can develop during the episodes of severe and/or prolonged neutropenia (>1 week). Patients with neutropenia often fail to develop the characteristic signs and symptoms of infection due to their impaired ability to mount an

adequate inflammatory response. Common sites of infection in patients with neutropenia include the lung, oropharynx, blood, urinary tract, skin, and soft tissues, including the perirectal area. Infections are generally caused by organisms colonizing the patient (Table 81.1).1

Cellular immune dysfunction

Cell-mediated immunity plays a primary role in protecting against intracellular pathogens (Table 81.1). In addition, T lymphocytes impact on practically all aspects of immunity. Patients with Hodgkin’s disease and chronic/acute lymphocytic leukemia have impaired cell-mediated immunity. Immunosuppressive therapy with cyclosporine, tacrolimus, azathioprine, corticosteroids, or some cytotoxic agents (fludarabine and other purine analogues) causes cellular immunity dysfunction. Radiation therapy results in depression of cell-mediated immunity lasting several months.1

Humoral immune dysfunction

B lymphocytes are responsible for antibody production. In disorders such as multiple myeloma, Waldenström macroglobulinemia, and the various “heavy-chain diseases,” overproduction of a specific subcomponent of an immunoglobulin occurs due to malignant proliferation of plasma cells or their precursors, which, in turn, results in low levels of normal immunoglobulins. Patients are then especially susceptible to infection by encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae because specific opsonizing antibodies are diminished (Table 81.1).1

777

Textbook of Palliative Medicine and Supportive Care

778 TABLE 81.1 Defects in Host Defense Mechanisms and Common Pathogens Neutropenia Cellular immune Dysfunction Humoral immune dysfunction Source:

Gram-positive cocci, Gram-negative bacilli, and fungus (Candida, Aspergillus) Pneumocystis, Cryptococcus, and Mycobacterium Toxoplasma, Listeria, Cryptosporidium, Candida, and Cytomegalovirus Encapsulated organisms (Streptococcus pneumonia, Haemophilus influenzae, and Neisseria meningitidis)

Data from Rolston VIK, Bodey PG. Infection in patients with cancer. In: Hong KW, Bast CR, Jr., Hait NW, et al., eds., Holland-Frei Cancer Medicine, 8th ed., London, UK: McGraw Hill, 2009, pp. 1921–1940.

Foreign bodies

Foreign bodies such as urinary and venous catheters can damage or circumvent normal anatomic barriers, thereby facilitating the entry of microorganisms into tissues and the bloodstream. Prosthetic devices such as stents can be infected.1

Prevention of neutropenic fever Patients with generalized malignancy, transplant recipients, and patients being treated with immunosuppressive or radiation therapy are all considered to have altered immunocompetence.2

Controlling local factors

It is often possible to prevent serious infection by proactive control of the aforementioned local factors.1 • Consider radiation therapy for obstructive pneumonia due to mass. • For patients with cholelithiasis, cholecystectomy may be indicated depending on the risk for acute cholecystitis. • Since the placement of a foreign body such as a urinary or venous catheter can be a port of entry for bacterial pathogens, consider removing them. • Poor oral hygiene or incompletely erupted wisdom tooth can be the source of periodontitis during profound neutropenia. Provide advice on improving oral hygiene and, when necessary, consult a specialist regarding tooth extraction before starting intensive chemotherapy. • Consider draining pleural effusion to prevent infection, which is occasionally difficult to control.

Vaccinations

Pneumococcal polysaccharide or pneumococcal conjugate vaccine is currently recommended by the Centers for Disease Control and Prevention for patients between 19 and 64 years of age with asplenia, HIV infection, or generalized malignancy, as well as those under immunosuppressive chemotherapy or corticosteroid therapy or who have received organ or bone marrow transplant.2 Whenever feasible, a single dose of the vaccine should be administered to these patients at least 2 weeks before starting cytotoxic or immunosuppressive therapy if they have not been previously vaccinated or if their previous vaccine history is unknown; otherwise, they are considered unprotected. 3 A study demonstrated that a 13-valent conjugate pneumococcal vaccine (PCV13) had superior antibody response among adults over 50 years of age compared with a 23-valent polysaccharide vaccine (PPSV23).4

Influenza infections in immunocompromised cancer patients are often associated with hospitalizations, delays in potentially life-saving chemotherapy, and occasionally death. Annual vaccination against influenza with the inactivated virus—not intranasal live influenza vaccine—is currently recommended. The guidelines also recommend annual immunization with the inactivated virus for all health-care professionals and household members or caregivers of cancer patients. 3

Antimicrobial prophylaxis

Patients at high risk who are expected to have profound, protracted neutropenia, which is defined as 100 neutrophils/mL for >7 days, or other risk factors, should receive antibacterial and antifungal prophylaxis. 3,5,6 Fluoroquinolone prophylaxis should be considered for patients at high risk for prolonged and profound neutropenia (absolute neutrophil count [ANC] ≤ 100 cells/μL [mm3] for >7 days). Levofloxacin has superior activity against certain Gram-positive pathogens to ciprofloxacin. Antibacterial prophylaxis is not routinely recommended for low-risk patients with severe neutropenia expected to last 20% risk of neutropenic fever), intermediate risk (10–20% risk), or low risk (90% specificity when a cut-off of 120 minutes is used.13 In patients with diarrhea, a stool specimen should be evaluated for Clostridioides difficile. Since enzyme immunoassay (EIA) testing for C. difficile toxin A and B is less sensitive than the cell cytotoxin assay, confirmation of C. difficile infection should involve a two-step strategy: recommended is EIA detection of glutamate dehydrogenase as initial screening, and, if positive, the cell cytotoxicity assay or toxigenic culture as the confirmatory test. Sending a stool specimen for bacterial pathogen culture is of limited value in most developed countries due to the time and costs involved; nevertheless, stool culture is the most sensitive test for C. difficile infection.14 Other diagnostic test includes polymerase chain reaction of toxin, which is more expensive.

Evaluation of patients with neutropenic fever

Initial management of neutropenic fever

Management of neutropenic fever Definition of neutropenic fever

Neutropenic fever is a true medical emergency. Without timely administration of proper antibiotics, sepsis syndrome and even death might occur. The education of patients and family members as well as appropriate initial management is of critical importance.11 The initial evaluation should focus on determining the potential sites and causative organisms of infection and assessing the patient’s risk for an infection-related complication. Since signs and symptoms of inflammation are often subtle or absent in neutropenic patients, the physical examination requires a careful search in the most commonly infected areas such as the skin (e.g., sites of previous procedures or catheters), oropharynx, alimentary tract, lungs, and perineum. 3,5 An initial laboratory/radiology evaluation should include a complete blood count with differential analysis and a blood chemistry test for liver function (e.g., total bilirubin, albumin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST)) and renal function (e.g., blood urea nitrogen, creatinine, and electrolytes). These tests should be repeated at least every 3 days. Chest radiographs should be taken for all patients with respiratory signs or symptoms since pneumonia during neutropenia can progress rapidly; radiographic findings may be absent however.3,5 At least two sets (one aerobic and one anaerobic blood culture bottles, 10 mL each) of blood culture specimens should be obtained, as a sufficient volume of blood must be cultured in order to detect bloodstream infection. The sensitivity of two blood culture sets is 80–90% for bloodstream pathogens. 3,5 Skin preparation with an alcohol solution of 0.5% chlorhexidine is more efficacious than that with an aqueous solution of 10% povidone-iodine in reducing contamination of blood culture (1.4 vs. 3.3%; odds ratio, 0.40; 95% confidence interval [CI], 0.21–0.75).12Routine cultures from various sites are rarely helpful in the absence of clinical signs and symptoms. Culture of urine

At presentation of neutropenic fever, risk assessment for complications should be performed. This may determine the type of empirical antibiotics (oral vs. intravenous [IV] therapy) and needs for inpatient care. With the use of the Multinational Association of Supportive Care in Cancer (MASCC) scoring system (Table 81.2), all high-risk patients (MASCC score < 21) should be initially admitted to the hospital for empirical IV antibiotics therapy. Carefully selected low-risk patients (MASCC score ≥21) may be candidates for oral and/or outpatient empirical antibiotic therapy.15 Elderly (≥60) patients with one risk factor such as hypotension, non-solid tumor, previous fungal infection, or chronic obstructive pulmonary disease can never be the low risk. Historically, Gram-negative bacteria have been the most common pathogens detected in neutropenic patients, but recently these have been overtaken by Gram-positive cocci, TABLE 81.2  Multinational Association of Supportive Care in Cancer Risk-Index Score Characteristics Burden of illness No or mild symptoms Moderate symptoms No hypotension No chronic obstructive pulmonary disease Solid tumor or no previous fungal infection No dehydration Outpatient status Age < 60 years Source:

Data from Klastersky J. et al. J Clin Oncol 2000;18:3038.

Weight 5 3 5 4 4 3 3 2

780 especially Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcal species, due to the increased use of chemotherapeutic agents that cause mucositis, increased use of central venous catheters, and the use of prophylactic agents against Gram-negative bacteria.5 However, Gram-negative bacteremias are associated with higher mortality than Gram-positive bacteremias (5 vs. 18%).16 Since Pseudomonas aeruginosa especially is associated with a high mortality rate, initial empirical antibiotic coverage for P. aeruginosa is essential.5,12 Only carefully selected adult patients with neutropenic fever who are at low risk for complications may be treated initially with oral antibiotics. Ciprofloxacin should not be used as empirical monotherapy because it has less activity against Gram-positive cocci.17 Although levofloxacin has better activity for Grampositive organisms, there are insufficient data to recommend fluoroquinolone monotherapy for this indication. Outcomes for low-risk patients treated with an empirical oral combination of ciprofloxacin and amoxicillin–clavulanate were comparable to those treated with IV antibiotic regimens.18,19 Ciprofloxacin 500–750 mg orally every 12 hours and amoxicillin–clavulanate 500 mg orally every 8 hours. 3 Remaining high-risk patients require hospitalization for IV empirical antibiotics therapy. As monotherapy, antipseudomonal beta-lactam agents such as cefepime, carbapenems (imipenem– cilastatin or meropenem), or piperacillin–tazobactam are recommended. 3 Local institutional bacterial susceptibilities, which are determined by antibiogram, should be considered when selecting the empirical antibiotic regimen. Ceftazidime is no longer a reliable agent because of its decreasing potency against Gram-negative organisms and its poor activity against many Gram-positive organisms. 5 Meta-analysis by The Cochrane Collaboration indicated that cefepime was associated with increased all-cause mortality when used as empiric therapy for neutropenic fever (RR 1.39, 95% CI 1.04–1.86) and all-cause mortality was significantly lower with piperacillin–tazobactam compared to other antibiotics (RR 0.56, 95% CI 0.34–0.92) (Figure 81.1).20 For concentration-dependent killing agents (e.g., fluoroquinolone and aminoglycosides), the higher the ratio of the concentration to the minimum inhibitory concentration (MIC), the greater

Textbook of Palliative Medicine and Supportive Care the killing occurs. On the other hand, for time-dependent (concentration-independent) killing agents (e.g., penicillins, cephalosporins, aztreonam, macrolides, and clindamycin), the time during which the serum drug concentration is greater than the MIC is important.19 What follows are the NCCN guideline–recommended dosages3: • • • •

Cefepime 2 g IV every 8 hours Imipenem–cilastatin 500 mg IV every 6 hours Meropenem 1 g (2 g for meningitis) IV every 8 hours Piperacillin–tazobactam 4.5 g IV every 6 hours

Since aminoglycoside use carries a risk for renal and otic toxicity, it should not be routinely added to standard initial empirical therapy, except in patients at high risk for Pseudomonas infection such as those with a history of previous Pseudomonas infections or the presence of ecthyma gangrenosum.5 Once-daily dosing of aminoglycoside may lower renal toxicity compared with multiple daily dosing (or shorter interval dosing).21 Vancomycin is not recommended for an initial antibiotic regimen due to the risk for emergence of vancomycin-resistant organisms. 3 Randomized studies comparing empirical regimens with or without vancomycin as the initial empirical regimen have shown no significant reduction in overall mortality.22,23 The addition of vancomycin was also found to be associated with increased renal and dermatological adverse events. When a single set of blood cultures is positive for coagulase negative staphylococci (the most commonly identified cause of bacteremia in neutropenic patients) and a second set is negative, it should be generally considered as contaminant. There is usually no urgent need to start treatment with vancomycin, and it should be reserved for the specific clinical indications listed next3,5,11: • Hemodynamic instability • Radiographically documented pneumonia • Positive blood culture for Gram-positive bacteria, before available identification and susceptibility • Clinically apparent, serious catheter-related infection • Skin or soft tissue infection

FIGURE 81.1  All-cause mortality of Cefepim (top) or Piperaciilin-tazobactam (bottom) versus others.

Neutropenic Fever

781

• Colonization with methicillin-resistant S. aureus, vancomycin-resistant enterococcus or penicillin-resistant S. pneumoniae • Risk factors for viridans group streptococcal bacteremia such as severe mucositis and prophylaxis with fluoroquinolones or trimethoprim/sulfamethoxazole

KEY LEARNING POINTS • Risk factors for infection in cancer patients include local factors, neutropenia, cellular and/or humoral immune dysfunction, and the presence of foreign bodies. • Some risk factors are controllable to prevent neutropenic fever. • Routine vaccination against pneumococcus and influenza is advised. • Prophylactic use of antibiotics and granulocytecolony stimulating factor is indicated in certain situations. • Source of infection and risks for complications should be evaluated in patients with neutropenic fever. • Proper use of antibiotics is important.

A vancomycin loading dose of 25–30 mg/kg (based on actual body weight) is used to achieve the target trough serum concentration rapidly and is followed by a daily dose of 15–20 mg/kg every 8–12 hours (not to exceed 2 g/dose) for most patients with normal renal function. Trough serum concentration is the most accurate and practical method for monitoring efficacy, and a serum concentration of 15–20 mg/L is recommended in complicated infections.24 Vancomycin should be discontinued within 2–3 days if susceptible bacteria are not recovered. 3,5

Catheter-related infections

Infections caused by S. aureus, P. aeruginosa, fungi or mycobacteria or by tunnel or port pocket site infection, septic thrombosis, endocarditis, hypodynamic instability, or persistent bloodstream infection despite ≥72 hours of appropriate antibiotics all require removal of catheters and the addition of vancomycin. For infections caused by coagulase-negative staphylococci, the catheter may be retained with the administration of vancomycin through the infected catheter lumen. 3,5

Reassessment

After 2–4 days of initial empirical antibiotics therapy, reassessment should be performed. Since it takes 2–7 days (median, 5 days) for patients with neutropenic fever to defervesce with appropriate initial antibiotics therapy, persistent fever alone in stable patients is rarely an indication to alter the antibiotic regimen. Modification of the initial empiric antibiotic therapy should occur based on new clinical and/or microbiological findings and not on recurrent or persistent fever alone, unless the patients are clinically unstable. 3,5 Patients with unexplained fever who are responding to initial empirical therapy should be maintained on that initial regimen until ANC recovers to ≥500 cells/μL (mm3) and antibiotics can be discontinued once they become afebrile for at least 24 hours. Lower risk patients can be switched to oral antibiotics until their neutropenia resolves. A switch from one empirical monotherapy to another or the addition of an aminoglycoside or vancomycin to the treatment regimen is not generally useful for persistent fever in asymptomatic and hemodynamically stable patients. 3,5 For recurrent or persistent fever >3 days in duration despite empirical antibiotic therapy, a search must be made for an infection source and should include an additional set of blood cultures and symptom-directed diagnostic tests, and a reassessment should be made of their antimicrobial therapy. For documented infections, the duration of antibiotic therapy should be guided by the infections identified. Pneumonia and most bacterial bloodstream or soft tissue infections require 10–14 days of appropriate antibiotic therapy, at least until ANC recovers to ≥500 cells/mm 3. 3,5

Antifungal therapy

Empirical antifungal therapy should be considered for patients with persistent or recurrent fever after 4–7 days of antibiotics and whose duration of neutropenia is expected to be >7 days because clinical examination and cultures are not sensitive enough for early detection of fungal infections. Because Candida species are

ubiquitous colonizers of human mucosal surfaces and they can cause bloodstream infection with mucosal barrier breakdown, fluconazole prophylaxis significantly reduces the incidence of invasive Candida infections in certain high-risk patients who have not received prior antifungal prophylaxis. Patients with profound neutropenia (≤100 cells/μL [mm3]) lasting longer than 10–15 days are at risk for invasive mold infection, such as aspergillosis. Fluconazole lacks any activity against mold infections, and infections by azole-resistant strains may also occur. Empirical antifungal therapy with antimold coverage is indicated in such cases. 3,5 In a subset of patients who are stable, have no clinical or chest/ sinus CT signs of fungal infections, have a negative serological assay for invasive fungal infections, and show no recovery of fungi from any body site, preemptive antifungal management is an alternative to empirical antifungal therapy. This has been made possible by advances in the early detection of fungal infections, such as with the serum test for fungal antigen or DNA, and advances in high-resolution chest CT. Antifungal therapy should be instituted if there are any signs of invasive fungal infections. 3,5

Therapeutic use of G-CSF

Compared with prophylactic use, there is less evidence to support the therapeutic use of G-CSF in patients with neutropenic fever. A meta-analysis showed no improvement in overall survival with therapeutic use of G-CSF, although a shorter length of hospitalization (hospitalization rate 0.63; 95% CI 0.49–0.82) was seen.25 Therapeutic use of G-CSF in nonfebrile neutropenic patients is not recommended, since it does not even improve a clinically important endpoint.26

References

1. Nesher L, Rolston VIK. Infection in patients with cancer. In: Bast Jr. CR, Croce MC, Hait NW, et al., eds. Holland-Frei Cancer Medicine, 9th ed. New Jersey, USA: Wiley & Sons, 2017. 1865–1877. 2. Centers for Diseases Control and Prevention. Pneumococcal diseases. Accessed at https://www.cdc.gov/pneumococcal/index.html (Last access on July 16, 2019) 3. Prevention and Treatment of Cancer-Related Infections, NCCN Clinical Practice Guidelines in Oncology™–v.1. 2019. Accessed April 10, 2019. 4. Paradiso PR. Pneumococcal conjugate vaccine for adults: a new paradigm. Clin InfectDis 2012;55:259–264.

Textbook of Palliative Medicine and Supportive Care

782













5. Taplitz RA, Kennedy EB, Bow EJ, et al. Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA Clinical Practice Guideline Update. J Clin Oncol 2018;36(30):3043–3054. 6. Bucaneve G, Micozzi A, Menichetti F, et al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. New Engl J Med 2005;353:977–987. 7. Hematopoietic Growth Factors, NCCN Clinical Practice Guidelines in Oncology™–v.2. 2019. Accessed April 10, 2019. 8. Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology Practice Guideline Update. J Clin Oncol 2015;33:3199–3212. 9. Kosaka Y, Rai Y, Masuda N, et al. Phase III placebo-controlled, doubleblind, randomized trial of pegfilgrastim to reduce the risk of febrile neutropenia in breast cancer patients receiving docetaxel/cyclophosphamide. Support Care Cancer 2015;23:1137–1143. 10. Papaldo P, Lopez M, Marolla P, et al. Impact of five prophylactic filgrastim schedules on hematologic toxicity in early breast cancer patients treated with epirubicin and cyclophosphamide. J Clin Oncol 2005;23:6908–6918. 11. Yeung JS, Escalante C. Oncologic emergency. In: Bast Jr. CR, Croce MC, Hait NW, et al. eds. Holland-Frei Cancer Medicine, 9th ed. New Jersey, USA: Wiley & Sons, 2017: 1879–1897. 12. Mimoz O, Karim A, Mercat A, et al. Chlorhexidine compared with povidone-iodine as skin preparation before blood culture. A randomized, controlled trial. Ann Intern Med 1999;131:834–837. 13. Gaur AH, Flynn PM, Giannini MA, et al. Difference in time to detection: a simple method to differentiate catheter-related from noncatheter-related bloodstream infection in immunocompromised pediatric patients. Clin Infect Dis 2003;37:469–475. 14. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 2018;66:e1–e48. 15. Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Association for Supportive Care in Cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000;18:3038–3051. 16. Klastersky J, Ameye L, Maertens J, et al. Bacteraemia in febrile neutropenic cancer patients. Int J Antimicrob Agents 2007;30 Supp 1:S51–S59. 17. Meunier F, Zinner SH, Gaya H, et al. Prospective randomized evaluation of ciprofloxacin versus piperacillin plus amikacin for empiric antibiotic therapy of febrile granulocytopenic cancer patients with















lymphomas and solid tumors. The European Organization for Research on Treatment of Cancer International Antimicrobial Therapy Cooperative Group. Antimicrob Agents Chemother 1991;35:873–878. 18. Kern WV, Cometta A, De Bock R, et al. Oral versus intravenous empirical antimicrobial therapy for fever in patients with granulocytopenia who are receiving cancer chemotherapy. International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer. New Engl J Med 1999;341:312–318. 19. Freifeld A, Marchigiani D, Walsh T, et al. A double-blind comparison of empirical oral and intravenous antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy. New Engl J Med 1999;341:305–311. 20. Paul M, Yahav D, Bivas A, Fraser A, Leibovici L. Anti-pseudomonal beta-lactams for the initial, empirical, treatment of febrile neutropenia: comparison of beta-lactams (Review). Cochrane Rev 2010; Issue 11. John Wiley & Sons, Ltd.1465–1858. 21. Mandell LG Bennett E, Dolin R, eds. Mandel, Douglas, and Bennett’s Principals and Practice of Infectious Disease, 8th ed. London, UK: Churchill Livingstone, Elsevier, 2014. 22. European Organization for Research and Treatment of Cancer (EORTC) International Antimicrobial Therapy Cooperative Group and the National Cancer Institute of Canada-Clinical Trials Group, Vancomycin added to empirical combination antibiotic therapy for fever in granulocytopenic cancer patients. European Organization for Research and Treatment of Cancer (EORTC) International Antimicrobial Therapy Cooperative Group and the National Cancer Institute of Canada-Clinical Trials Group. J Infect Dis 1991;163:951–958. 23. Paul M, Borok S, Fraser A, et al. Empirical antibiotics against Grampositive infections for febrile neutropenia: Systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother 2005;55:436–444. 24. Martin JH, Norris R, Barras M, et al. Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society Of Infectious Diseases Pharmacists. Clin Biochem Rev 2010;31:21–24. 25. Clark OA, Lyman GH, Castro AA, et al. Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of randomized controlled trials. J Clin Oncol 2005;23:4198–4214. 26. Hartmann LC, Tschetter LK, Habermann TM, et al. Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia. N Engl J Med 1997;336:1776–1780.

82

SIDE EFFECTS OF RADIATION THERAPY

Michael Wang, Elizabeth A. Barnes, and Alysa Fairchild

Contents Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������783 Preparation for palliative radiotherapy�������������������������������������������������������������������������������������������������������������������������������������������������������������������������783 Radiobiological principles of conventional palliative radiotherapy������������������������������������������������������������������������������������������������������������������������783 Impact of technological evolution on toxicity������������������������������������������������������������������������������������������������������������������������������������������������������������784 Side effects��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������786 Fatigue���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������786 Hematologic�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������786 Skin���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������786 Bone�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������786 Head and neck�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������786 Thorax����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������787 Abdomen����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������787 Pelvis������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������787 CNS (Central Nervous System)��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������787 Supportive care and palliative radiotherapy����������������������������������������������������������������������������������������������������������������������������������������������������������������788 Conclusion��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������788 References............................................................................................................................................................................................................................788

Introduction Radiation therapy (RT) is a fundamental component of cancer treatment. Approximately half of all cancer patients receive RT, with either radical or palliative intent, at some point during their course of their disease.1 The primary goals of palliative RT are to provide durable and timely symptom relief, thereby maintaining or improving quality of life (QoL) while minimizing toxicity, resource utilization, and the number of cancer center visits.2 The secondary aims include tumor regression and short recovery time. 3 Palliative RT can also prophylactically address an area with a high likelihood of becoming symptomatic in the future.

Preparation for palliative radiotherapy Patients who are unlikely to benefit from palliative RT should not be offered this treatment.4 Teams should consider whether an appropriate effective regimen is likely to be completed. In one retrospective series of 153 patients receiving palliative-intent RT to various sites, the treatment was terminated prematurely in 12% due to clinical deterioration, lack of efficacy, or death.5 In many circumstances, it can take 3–6 weeks to see the maximal benefit of palliative RT.6 However, patients with limited life spans still report improvements in symptoms after completing palliative RT,7 including single fraction (SF). Two studies describing patient cohorts who survived 90%). Total improvement in about 15%; most others report mild symptoms with no disruption of ADL.

Vinca alkaloids (vincristine, vinorelbine, vinblastine)

Disruption of axonal flow

Onset: Between cycles 1–6. Mostly gradual, but fast if DRG cells are affected. Oxaliplatin may have two phases: acute, transient, exacerbated by cold (85–95%), or chronic, persistent paresthesias (16–20%) Symptoms: Sensory. Less frequent: weakness, Lhermitte phenomenon, dysautonomia. Pearl: Oxaliplatin is associated with perioral or pharyngeal paresthesias, dysphagia, and myotonia. Decreased or absent stretch reflexes. Distribution: Symmetric, stocking–glove pattern. Improvement after drug withdrawal but can worsen for 3–4 more months before stabilization (coasting). Onset: Within 24–72 hours of administration. Toxicity: Dose cumulative, with no differences in dosing schedules, and 4× more likely with paclitaxel. Probability of neuropathy: 60–80%. Symptoms can disappear spontaneously after stopping the drug. Symptoms: Predominantly sensory. Motor and autonomic symptoms are less frequent Location: Similar to cisplatin. Onset: Probability of CIPN is the highest with vincristine, 2–3 weeks after administration. Cumulative dose is proportional to the risk of CIPN (6–8 mg). Pearl: Severe weakness before reaching the dose threshold suggests subclinical, preexisting neuropathy. Course: Mostly subacute onset but gradual course. Symptoms: Paresthesias; motor symptoms are more frequent; patients have weakness of foot and hand extensors Ankle areflexia is an early sign of neuropathy. Dysautonomia and mononeuropathies can also occur Location: Similar to cisplatin and taxanes.

Axonal.

Partial or complete 1–3 months after the end of treatment. Some patients do not recover.

Peripheral Neuropathy and Neurotoxicity

TABLE 86.1  Classic Chemotherapy Drugs that Can Cause CIPNa,b

Abbreviations: CIPN, chemotherapy-induced neuropathy; DRG, dorsal root ganglion. a This table is not a substitute for detailed descriptions or reviews. Most quantitative data are useful estimates for clinicians in assessments and decision-making. b In our clinical experience, there are always outliers that do not fit conventional descriptions. We have seen patients with bilateral but asymmetric sensory symptoms, with or without concurrent weakness. Patients with only motor symptoms and signs or as a predominant feature have other conditions that need identification for proper management.

813

Textbook of Palliative Medicine and Supportive Care

814 TABLE 86.2  Other Chemotherapy Drugs that Cause CIPN Drug Class

Pathophysiology

Clinical Course

Type of Neuropathy

Recovery

Antiangiogenic (thalidomide, lenalidomide)

Probably axonal injury

Sensorimotor, axonal, length-dependent neuropathy

Partial or total recovery in up to 50% of patients.

Proteasome inhibitors (bortezomib)

Interference of microtubular and mitochondrial function

Similar to thalidomide

Resolution or improvement in 70% of patients, after a median time of 1.5 months.

Epothilones (ixabepilone)

Same as taxanes

Sensory polyneuropathy, not well characterized yet

Improvement and resolution of symptoms are possible after dose adjustments or discontinuation of the drug within a median of 1.5 months.

Halichondrin B analogs (eribulin mesylate) Purine nucleoside analogs (nelarabine)

Same as taxanes

Slow, generally after months of treatment. The overall probability of neuropathy: 30%. Risk is higher if the treatment lasts longer. No clear dose-cumulative effect. Paresthesias in hands and feet can be painful; sometimes, symptoms appear after treatment (coasting). Gradual, progressive onset. Probability of neuropathy: 40%. Sensory symptoms, paresthesias, neuropathic pain. Minor weakness possible. Dose reductions or interruptions can improve or resolve symptoms Symptoms can appear after the first treatment, with a gradual course. Paresthesias are common; some patients can have autonomic symptoms. Probability of grade 3–4 neuropathy: up to 24%. The overall probability of CIPN: 35%.

Sensory polyneuropathy

Neurotoxicity is dose-limiting—the probability of neuropathy: 21%. Paresthesias, neuropathic pain in limbs and sensory ataxia.

Not studied

Possible after dose reduction or interruption. Recovery is possible once the drug discontinuation. For safety, nelarabine should stop if patients develop grade 2 or higher neuropathy.

Unknown

FIGURE 86.2  Variables dictating how soon CIPN can start, how severe it can be, and how difficult it can be to recover.

Peripheral Neuropathy and Neurotoxicity

815

TABLE 86.3  National Cancer Institute (NCI) CTCAE v.4.03 Neuropathy

Grade 1a

Grade 2

Grade 3

Grade 4

Grade 5

Sensory

Asymptomatic; loss of DTRs or paresthesias

Severe symptoms, limiting self-care ADL

Asymptomatic; clinical or diagnostic observations only. Interventions not indicated

Life-threatening consequences; urgent intervention indicated Life-threatening consequences; urgent intervention indicated

Death

Motor

Paresthesias, moderate intensity, limiting instrumental ADL Moderate symptoms, limiting instrumental ADL

Severe symptoms; limiting self-care ADL

Death

Abbreviations: DTR, deep-tendon reflexes; ADL, activities of daily living. a Patients with grade 1 neuropathy can have paresthesias, and therefore, they are no longer asymptomatic. However, the intensity is mild, and there is no interference at all with ADL.

conduction velocity studies, electromyography, and quantitative sensory tests are not helpful in CIPN because of inconsistency, low correlation, and low acceptance rates (Figure 86.1).

CIPN: Axonopathy, neuronopathy, or both Patients with axonal injury (axonopathy) present with lengthdependent, sensory, or sensorimotor polyneuropathy. The initial location is in the toes and feet, with proximal progression to hands and more proximal segments in some cases. The onset is subacute and gradual, and the progress is predictable. It is the most common presentation of CIPN. Neuronopathy is the result of direct damage to DRG cells. Patients with neuronopathy also have a length-dependent sensorimotor polyneuropathy. The onset and course can be rapid and more symptomatic. Symptoms start simultaneously or almost at the same time in feet and hands and may also involve cranial nerves. There is a diffuse loss of deep-tendon reflexes. There is no anatomic progression like in axonopathy; it is not gradual but persistent and permanent because the damage to DRG cells is irreversible. Weakness is mild if it is present. Pearl: when motor symptoms and signs predominate or coexist with sensory symptoms, it is not a neuronopathy.

Prevention of CIPN Prevention is the ideal strategy against CIPN, but until now, there is no effective intervention. Studies with vitamins, electrolytes, amino acids, and other compounds have given negative or dubious results.5 Ninjin’yoeito, a Kampo medicine, and goshajinkigan, a Japanese herbal, are also ineffective.9,10 Limb cryotherapy has not provided a clear therapeutic benefit.11,12

Treatment of CIPN The treatment of CIPN is symptomatic. The best intervention for patients still on chemotherapy is • To stop the drug causing toxicity and resume with the recommended drug adjustment or • To switch to a different drug with no neurotoxicity. Once patients conclude treatment, pharmacotherapy and integrative medicine take center stage. There is consensus that opioid use is limited to selected patients, and now it is a third-choice drug although population-based data revealed that many survivors use opioids.15,16

It is possible to relieve pain in some patients using any of the drugs listed in Table 86.4. Some patients require more than one medication. Numbness can be distressing and unresponsive to treatment. The only drug with a positive, proven effect on pain, is duloxetine.1,13,14 An earlier study with venlafaxine to treat oxaliplatin-induced acute neurotoxicity was also positive, but its effect size needs replication.17 Alternative approaches (acupuncture, yoga, meditation, rehabilitation, and exercise) are promising for symptom control in CIPN.18–22 This is a field in need of development through wellconducted randomized clinical trials.

Immune-mediated neuropathies A milestone in oncology is the development of checkpoint immunotherapy. Tumor cells effectively evade the immune surveillance system by activating checkpoint pathways. ICI are now part of the standard treatment for metastatic melanoma, lung cancer, renal cancer, and some head and neck neoplasms. ICI are associated with a myriad of immune-related adverse events (irAE). Although uncommon (1–2%),4,23,24 neurological irAE may appear as early as 4 weeks after the first ICI administration. The most frequent immunemediated neuropathies are an axonal sensory neuropathy, a myasthenic syndrome, or the Guillain–Barre syndrome (GBS), with acute ascending sensory impairment associated with severe weakness and risk of respiratory failure.25 In this instance, electromyogram and nerve conduction studies, and MRI of the lumbar spine are necessary tests for diagnosis. The management tenets include the following: • • • •

Stopping ICI. IV corticosteroids. Intravenous immunoglobulin. Plasma exchange. Early recognition and initiation of the treatment for GBS can reduce the mortality and morbidity.

Paraneoplastic neuropathy26,27

Paraneoplastic neuropathies clinically develop before or during a diagnosis of cancer or its treatment. The neuropathy is not due to infiltration, treatment, infectious or metabolic complications. It affects 50% of deaths in HIV-infected individuals are from “non-AIDS” conditions. 85,86 The prevalence of comorbidities in HIV-infected individuals depends on a number of factors, including age, health behaviors, CD4 count, and HIV treatment history. 85 Comorbid cardiovascular disease, lung disease, liver disease, and renal disease as well as non-AIDS-defining malignancies and substance abuse are important contributors to the overall morbidity and decreased health-related quality of life and physical functioning in the HIV-infected population (Table 89.2). 69,84–89 Polypharmacy is a particular problem for HIV-infected patients with multiple comorbidities, and there is little data to help clinicians weigh risks and benefits of multiple therapies in these patients.90 Cardiovascular disease is prevalent in the HIV-infected population due to normal aging, established risk factors such as smoking and hypertension,91 and disease-specific risks. HIV infection itself is a proinflammatory state that leads to increased risk for cardiovascular events, and controlling HIV infection may be an

TABLE 89.2 Comorbidities by Age in Cohort of Patients in US Veteran Administration System with Chronic HIV Infection (from Ref. [84], with Permission) Age 40–49 Years

Age 50–59 Years

Age ≥60 Years

n = 14,561

n = 7225

n = 3112

(%)

(%)

(%)

(%)

Any medical disease Hypertension Diabetes Vascular disease Pulmonary disease Liver disease Renal disease

39 20 8 6 8 13 3

53 30 12 11 11 17 4

66 45 21 23 16 7 6

Comorbidity

Supportive and Palliative Care for Patients with HIV Infection important risk-modifying intervention.92 A recent study showed that HIV infection conferred a 50% increase in the risk of acute myocardial infarction even when controlling for traditional risk factors.93 Although controlling HIV infection is an important preventive measure, choice of antiretrovirals is also important. Protease inhibitor treatment is associated with elevated lipid levels, insulin resistance, and increased risk for cardiovascular events.94,95 Abacavir use increases the risk of cardiovascular events, most likely through a proinflammatory mechanism.89 Further research should focus on optimizing preventive measures for patients with HIV. Controlling risk factors such as hyperlipidemia and smoking are likely at least as important in HIV-infected people as in uninfected people96; however, there may be nuances to treatment that must be worked out for the HIV-infected population. For example, statin use may be associated with the increased risk of peripheral neuropathy in HIV-infected individuals, and this may have important implications for adherence.97 In addition to opportunistic lung infections such as Pneumocystis jirovecii pneumonia, bacterial pneumonia and TB can cause respiratory disease in patients with higher CD4 counts while on HAART. HIV infection in both the pre- and postHAART eras also poses an independent risk for the development of COPD and emphysema.98 HIV-infected people have higher rates of smoking, and the deleterious effects of smoking appear to be synergistic with HIV disease itself, causing even greater mortality and morbidity in smokers with HIV compared to smokers without HIV.99 HIV-infected adults commonly have comorbid liver disease, partly because of high rates of hepatitis C in the population of IV drug users in developed countries and higher rates of heavy alcohol use in HIV-infected populations. Risk for liver disease is further exacerbated by HIV infection itself. Coinfected individuals progress more rapidly to fibrosis, increased HCV viral load and persistence, end-stage liver disease, and death.89,100 In fact, endstage liver disease is a major cause of death in HIV-infected individuals. Consistent use of HAART can have a protective effect, and screening for and the treatment of HCV in HIV-infected individuals should be part of routine HIV care. Coinfection is associated with increased symptom burden, including abdominal pain, mental status change, and bleeding risk, which are all important areas for palliative intervention. HIV infection is linked to renal disease, particularly in AfricanAmerican patients, through an unknown mechanism.89 In the pre-HAART era, HIV-associated nephropathy, HIV-associated immune complex kidney disease, and thrombotic microangiopathy were common. In the HAART era, treatment-related nephrotoxicity, particularly from the use of tenofovir and indinavir, has become an issue. There is evidence that even in the HAART era, the risk of renal disease persists.101 The risk of progressing to chronic renal disease over time is similar in HIV-infected patients to patients with diabetes.102 Lessons learned from the experiences of palliative providers can assist in open and sensitive discussion about when to initiate and stop hemodialysis. The HAART era has changed the spectrum of malignancy in patients living with HIV infection. Although AIDS-defining cancers such as Kaposi’s sarcoma and non-Hodgkin lymphoma remain important, many patients are now also developing cancers not traditionally associated with AIDS, such as lung cancer, skin cancer, hepatocellular cancer, Hodgkin’s lymphoma, and HPV-related cancers such as anal cancer, penile cancer, cervical cancer, and vulvar and vaginal cancer.103 The elevated risk for HCV-, EBV-, and HPV-related cancers appears to be related to

835

immune deregulation in addition to behavioral risk factors.103,104 Lower CD4+ T cell count is strongly associated with the risk of developing non-AIDS-associated cancer, and a similar risk for cancer is present in chronically immunosuppressed transplant recipients, suggesting immune dysfunction as an important part of the pathogenesis.89 Although many PLWH are current or former smokers, HIV infection itself seems to act synergistically to elevate the risk of lung cancer. Anal cancer is a particularly prevalent cancer in PLWH105,106 and can present specific challenges to patients and clinicians. Anal cancer tends to be very painful and to require high-level symptom management, particularly as the disease progresses. Pain can be related to both tumor burden and to radiation therapy for the disease. Stigmatization of sexual behavior and vulnerable patient groups (e.g., transgendered people) add particularly to the emotional burden of living with anal cancer. In developed nations, injection drug use remains an important risk factor for contracting HIV. Continued misuse of opioids can place patients at greater risk for hepatitis B and C coinfection, hypogonadism, osteoporosis, malnutrition, and decreased physical activity.78 Substance abuse is also linked to poor adherence to HAART and greater mortality.107 In addition to substance use, other psychiatric conditions are among the most common comorbidities in the population of PLWH, with a prevalence of anxiety and depression of almost 50% in this group. Anxiety and depression are strong predictors of poor adherence to HAART,107 and treatment with psychotropic medication can improve adherence.108 Although HAART treatment itself may improve psychiatric comorbidities, it is imperative and in fact lifesaving to adequately treat underlying mood disorders in this population. Integration of palliative care principles throughout the life course The chronic phase of HIV infection is now characterized by complex interactions between HIV infection, multiple comorbid conditions, and aging (Table 89.3). As HIV-infected patients live longer, the field of HIV medicine must expand beyond the traditional focus on markers of HIV disease such as CD4 count and viral load.85 This will be a particular challenge in developing countries where clinics created for the treatment of HIV lack access to resources to diagnose and treat other comorbid conditions, such as lipid-lowering drugs for cardiovascular disease or rehabilitative services for patients with functional decline.109 In addition to improvements in infrastructure, adoption of principles of palliative care, including holistic patient care, an interdisciplinary approach and care coordination can be applied to the field of HIV medicine to help one to meet these new challenges. The principles of person centeredness demonstrated by palliative care have enormous potential to achieve the proposed “fourth 90” for the UNAIDS strategy to end the HIV epidemic [Ref. C]. The fourth 90 states that HIV care should move beyond viral suppression and that PLWH should have good quality of life.110 Models of care have been developed to achieve this. Training of HIV treatment nurses in the principles and practice of palliative care, provision of a person-centered assessment tool, a care plan and mentorship form specialist palliative care, resulted in better quality of life, mental health, and psychosocial well-being.16 The active components of the intervention were identified as greater receipt of weak opioid, laxatives, discussion about spiritual worries, emotional support from staff for themselves and their families, time to talk about worries, discussion about future, and planning ahead.22 An unintended outcome of the person-centered intervention was patient empowerment and stigma reduction.15 A further model of HIV

Textbook of Palliative Medicine and Supportive Care

836 TABLE 89.3 Interrelated Challenges of Chronic HIV Infection in the HAARTa Era: Biologic, Clinical, and Social Factors

TABLE

89.4  Evidence-Based Recommendations from Systematic Reviews on the Management of Mental Health Among PLWH

Biologic/pathophysiologic factors Chronic inflammation Oxidative stress Immune dysfunction Microbial translocation Hypercoagulability Immune senescence Clinical factors/comorbidities Cumulative medication toxicity Polypharmacy Accelerated aging/frailty Comorbidities Cardiovascular Renal Hepatic Metabolic Pulmonary Neurocognitive Coinfections hepB, hepC, HPV Malignancies Social/behavioral factors Psychosocial distress Social isolation Marginalized populations Unsafe environments Stigma

Outcome

Interventions with Strongest Evidence

Coping

Cognitive behavioral therapy Stress management Cognitive behavioral therapy Stress management Cognitive behavioral therapy Coping skills training

a

HAART, highly active antiretroviral therapy.

person-centered community care focused on whole-team staff skills training on the principles of palliative and person-centered care, which comprised the following: first, a three-session training program on person-centered care and communication; second, the use of holistic assessment tool to assess symptoms and concerns in the domains of physical, psychological, social, and spiritual well-being; third, collaborative care planning and delivery; and fourth, twice-weekly ongoing clinical supervision and mentorship. Preliminary evidence suggests that patients felt that they entered a partnership with staff, who, in turn, felt greater satisfaction with their work and that they better understood their patients’ problems through improved communication.111

Psychosocial distress The aging HIV-infected cohort is also at increased risk for psychosocial distress.112 In the United States, many HIV-infected individuals face the dual stigma associated with both HIV disease and homophobia. Some HIV-infected older gay men may have withdrawn from their biological families and may be lacking this support during the aging process. Many of these individuals have created families of choice or supportive social networks; however, those infected early in the epidemic may have lost many friends and their partners to AIDS. Support groups and outreach programs may be geared more toward LGBT youth, and some older HIV-infected patients may find their support systems shrinking

114

Anxiety115 Depression116 Post-traumatic stress117

at a time when they are in need of material and emotional assistance. In the United States, the bulk of custodial care for older adults is performed by informal (i.e., unpaid) caregivers, who are often family members. The lack of informal caregivers for patients aging with HIV is likely to become a pressing issue in the near future.113 In HIV-infected patients with injection drug use, support networks and family relationships may be strained due to the behaviors accompanying addiction. HIV-infected individuals also still experience significant discrimination from health-care providers within the health-care system. Similar stigma is an important isolating factor in developing countries as well. As these individuals near the end of life, specific problems may arise. Many patients may have never disclosed their HIV status to their biological families,113 making end-of-life decision-making strained and difficult. Important interventions include clarifying advanced directives and naming health-care agents well in advance of terminal illness and providing support and counseling to patients who may be interested in reconciling with family members prior to the terminal phase of illness. Psychosocial support can help patients come to terms with emotional rifts caused by prior traumatizing societal rejections and ease the transition toward end of life. Encouraging self-acceptance, generativity or giving back to the community and society, and rational living through engaging formal and informal support systems may improve resilience.112 Patients may be encouraged to reconnect with faith communities or explore spirituality. Those who were rejected by their childhood faith communities may be able to find similar faith communities that have a more accepting view of same-sex partnerships and people living with AIDS. A sensitive exploration of spiritual beliefs may aid patients in finding support and fulfillment prior to terminal illness. Evidence for most effective management of mental health is summarized from systematic review evidence in Table 89.4, although it should be noted that the evidence was largely generated among Caucasian men who have sex with men in high-income countries.

HIV infection at the end of life Prognostication in HIV has traditionally rested on markers of HIV disease such as CD4 count, viral load, and AIDS-defining conditions. However, given that many HIV-infected individuals will die of other causes, a broader approach to prognostication near the end of life is needed.85 The Veterans Aging Cohort Study risk index is the first attempt at improving prognostication in the increasingly complex HIV-infected population.85 HIVinfected patients with malignancies or cardiovascular disease may have poorer prognosis compared with non-HIV-infected individuals.9,10 For patients with serious comorbidities such as

Supportive and Palliative Care for Patients with HIV Infection non-HIV-associated malignancies or COPD, use of prognostic indicators for these diseases may be more appropriate. As patients near the end of life, weighing the continued use of HAART is an important clinical problem. If a patient’s life, expectancy is limited to weeks to months from comorbid cancer, cardiovascular, pulmonary, liver, or renal disease, clinicians must weigh the benefits and burdens of continuing HAART carefully. Pill burden and side effects may outweigh any benefit that can be expected in this case. However, discontinuing HAART may have its own risks even in patients nearing the end of life. If patients are at imminent risk for developing uncomfortable infectious complications such as oral candidiasis, HSV, or infectious lung disease, for example, continuation of HAART may maintain a better quality of life. Continuing HAART in patients with MDR TB may also help one to prevent the spread of the disease to others. Finally, clinicians must remain aware of the “Lazarus effect.” For patients who appear to be imminently dying from AIDS-related causes who have not had an adequate trial of HAART, initiating antiretrovirals may cause a rapid reversal of the disease process, allowing them years of additional life. This has important implications for prognostication and discussions pertaining to goals of care—careful attention to patient preference and anticipating the possibility of death despite clinical uncertainty. International comparison on the place of death in 11 countries across 3 continents found age-standardized relative risks, those with HIV less likely to die at home and more likely to die in hospital compared with cancer patients. Hospital was the most common place of death in all 11 countries, ranging from 56.6% of death in the Netherlands to 90.9% in Korea.118

Conclusions The reintroduction of palliative care as part of HIV treatment and care provision can be achieved. In the United Kingdom, a partnership between health-care professionals and PLWH has resulted in national quality standards for HIV care that include an auditable right of access to appropriate palliative care. We present three recommendations for palliative care as an essential component of the HIV care continuum, based on a detailed review of the evidence.119 First, palliative care should be integrated appropriately for PLWH according to need not prognosis. Early integration of palliative care is highly relevant for the wide range of progressive and incurable comorbidities seen among PLWH. Second, early identification of preferences and advance care plans should enable professionals support patients where there is clinical uncertainty. Third, HIV-specific palliative care services may not be necessary if good teamwork between HIV physicians and palliative care teams can determine optimal treatment plans while minimizing polypharmacy. This requires continuing professional education programs for HIV clinical teams to include palliative and end-of-life care.

References

1. Selwyn PA. Palliative care for patient with human immunodeficiency virus/acquired immune deficiency syndrome, (in eng). J Palliat Med 2005; Dec;8(6):1248–1268. 2. Simms V, Higginson IJ, Harding R. Integration of palliative care throughout HIV disease, (in eng). Lancet Infect Dis 2012; Jul;12(7):571–575. 3. Centers for Disease Control and Prevention. HIV Surveillance Report, Vol. 23, 2011. [Online]. Available from: https://www.cdc.gov/hiv/ library/reports/hiv-surveillance-archive.html.





837

4. Chu C, Selwyn PA. An epidemic in evolution: the need for new models of HIV care in the chronic disease era, (in eng). J Urban Health 2011; Jun;88(3):556–566. 5. Shepherd L, et al. Infection-related and -unrelated malignancies, HIV and the aging population, (in eng). HIV Med 2016; Sep;17(8);590–600. 6. Cingolani A, et al. Survival and predictors of death in people with HIVassociated lymphoma compared to those with a diagnosis of lymphoma in general population, (in eng). PLOS ONE 2017;12(10):e0186549. 7. Smith CJ, et al. Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration, (in eng). Lancet 2014; Jul;384(9939):241–248. 8. Smit M, et al. Future challenges for clinical care of an ageing population infected with HIV: a modelling study, (in eng). Lancet Infect Dis 2015; Jul;15(7):810–818. 9. Losina E, et al. Projecting 10-year, 20-year, and lifetime risks of cardiovascular disease in persons living with human immunodeficiency virus in the United States, (in eng). Clin Infect Dis 2017;65(8):1266–1271. 10. Jeon C, et al. Mortality and health service use following acute myocardial infarction among persons with HIV: a population-based study, (in eng). AIDS Res Hum Retroviruses 2017; Dec;33(12)1214–1219. 11. Eti S. Palliative care: an evolving field in medicine, (in eng). Prim Care 2011; Jun;38(2):159–171. 12. Kelley AS, Meier DE. Palliative care—a shifting paradigm, (in eng). N Engl J Med 2010; Aug;363(8):781–782. 13. Temel JS, et al. Early palliative care for patients with metastatic nonsmall-cell lung cancer, (in eng). N Engl J Med 2010; Aug;363(8):733–742. 14. Bekelman DB, et al. Giving voice to patients’ and family caregivers’ needs in chronic heart failure: implications for palliative care programs, (in eng). J Palliat Med 2011; Dec;14(12):1317–1324. 15. Lowther K, et al. Effect of participation in a randomised controlled trial of an integrated palliative care intervention on HIV-associated stigma, (in eng). AIDS Care 2018; Apr;1–9. doi: 10.1080/09540121.2018.1465176. 16. Lowther K, et al. Nurse-led palliative care for HIV-positive patients taking antiretroviral therapy in Kenya: a randomised controlled trial, (in eng). Lancet HIV 2015; Aug;2(8):e328–e334. 17. Wenger NS, et al. End-of-life discussions and preferences among persons with HIV, (in eng). JAMA 2001; Jun;285(22):2880–2887. 18. Croxford S, et al. Cause of death among HIV patients in London in 2016, (in eng). HIV Med 2019; Jul. doi: 10.1111/hiv.12761. 19. Harding R, Easterbrook P, Higginson I, Karus D, Raveis V, Marconi K. Access and equity in HIV/AIDS palliative care: a review of the evidence and responses, Palliat Med 2005;19(3):251–258. 20. Harding R, Karus D, Easterbrook P, Raveis VH, Higginson IJ, Marconi K. Does palliative care improve outcomes for patients with HIV/AIDS? A systematic review of the evidence, Sex Transm Infect 2005;81(1):5–14. 21. Sleeman KE, et al. The escalating global burden of serious health-related suffering: projections to 2060 by world regions, age groups, and health conditions, (in eng). Lancet Global Health 2019; Jul;7(7):e883–e892. 22. Lowther K, et al. Active ingredients of a person-centred intervention for people on HIV treatment: analysis of mixed methods trial data, (in eng). BMC Infect Dis 2018;18(1):27. 23. Harding R, et al. What factors are associated with patient self-reported health status among HIV outpatients? A multicentre UK study of biomedical and psychosocial factors, AIDS Care 2012. In Press. 24. Harding R, et al. Behavioral surveillance study: sexual risk taking behaviour in UK HIV outpatient attendees, (in eng). AIDS Behav 2012; Aug; 16(6):1708–1715. 25. Harding R, et al. Behavioral surveillance study: sexual risk taking behaviour in UK HIV outpatient attendees, AIDS Behav 2012; Aug;16(6):1708–1715. 26. Clucas C, et al. Doctor-patient concordance during HIV treatment switching decision-making, HIV Med 2010. doi: 10.1111/j. 1468-1293.2010.00851.x. 27. Harding R, et al. Symptoms are highly prevalent among HIV outpatients and associated with poor adherence and unprotected sexual intercourse, Sex Transm Infect 2010;86(7):520–524. 28. Lampe FC, Harding R, Smith CJ, Phillips AN, Johnson M, Sherr L. Physical and psychological symptoms and risk of virologic rebound among patients with virologic suppression on antiretroviral therapy. J Acquir Immune Defic Syndr 2010. doi: 10.1097/ QAI.0b013e3181ce6afe. 29. Sherr L, et al. Adherence to antiretroviral treatment in patients with HIV in the UK: a study of complexity, AIDS Care 2008;20(4): 442–448.

838 30. Lowther K, Selman L, Harding R, Higginson IJ. Experience of persistent psychological symptoms and perceived stigma among people with HIV on antiretroviral therapy (ART): a systematic review, (in eng). Int J Nurs Stud 2014; Aug;51(8):1171–1189. 31. Hunt J, Bristowe K, Chidyamatare S, Harding R. ‘So isolation comes in, discrimination and you find many people dying quietly without any family support’: accessing palliative care for key populations – an in-depth qualitative study, (in eng). Palliat Med 2019; Jun;33(6):685–692. 32. Bristowe K, et al. Recommendations to reduce inequalities for LGBT people facing advanced illness: ACCESSCare national qualitative interview study, (in eng). Palliat Med 2017; Apr. doi: 10.1177/0269216317705102. 33. Greenberg B, McCorkle R, Vlahov D, Selwyn PA. Palliative care for HIV disease in the era of highly active antiretroviral therapy, (in eng). J Urban Health 2000; Jun;77(2):150–165. 34. Bristowe K, et al. Towards person-centred care for people living with HIV: what core outcomes matter, and how might we assess them? A cross-national multi-centre qualitative study with key stakeholders, (in eng). HIV Med 2019; Jun. doi: 10.1111/hiv.12758. 35. Abboah-Offei M, et al. How can we achieve person-centred care for people living with HIV/AIDS? A qualitative interview study with healthcare professionals and patients in Ghana, (in eng). AIDS Care 2019; Dec;1–10. doi: 10.1080/09540121.2019.1698708. 36. Harding R, Molloy T. Positive futures? The impact of HIV infection on achieving health, wealth and future planning, AIDS Care 2008;20(5):565–570. 37. Meintjes G, Scriven J, Marais S. Management of the immune reconstitution inflammatory syndrome, (in eng). Curr HIV/AIDS Rep 2012; Sep;9(3):238–250. 38. Martin-Blondel G, Mars LT, Liblau RS. Pathogenesis of the immune reconstitution inflammatory syndrome in HIV-infected patients, (in eng). Curr Opin Infect Dis 2012; Jun;25(3):312–320. 39. Huis in ’t Veld D, Sun HY, Hung CC, Colebunders R. The immune reconstitution inflammatory syndrome related to HIV co-infections: a review, (in eng). Eur J Clin Microbiol Infect Dis 2012; Jun;31(6):919–927. 40. Lorent N, Conesa-Botella A, Colebunders R. The immune reconstitution inflammatory syndrome and antiretroviral therapy, (in eng). Br J Hosp Med 2010; Dec;71(12):691–697. 41. Grant PM, Zolopa AR. When to start ART in the setting of acute AIDS-related opportunistic infections: the time is now!, (in eng). Curr HIV/AIDS Rep 2012; Sep;9(3):251–258. 42. Marais S, Wilkinson RJ, Pepper DJ, Meintjes G. Management of patients with the immune reconstitution inflammatory syndrome, (in eng). Curr HIV/AIDS Rep 2009; Aug;6(3):162–171. 43. Merlin JS, et al. Pain and physical and psychological symptoms in ambulatory HIV patients in the current treatment era, (in eng). J Pain Symptom Manage 2012; Mar;43(3):638–645. 44. Peltzer K, Phaswana-Mafuya N. The symptom experience of people living with HIV and AIDS in the Eastern Cape, South Africa, (in eng). BMC Health Serv Res 2008; Dec;8:271. 45. Harding R, Molloy T, Easterbrook P, Frame K, Higginson IJ. Is antiretroviral therapy associated with symptom prevalence and burden?, (in eng). Int J STD AIDS 2006; Jun;17(6):400–405. 46. Lee KA, et al. Symptom experience in HIV-infected adults: a function of demographic and clinical characteristics, (in eng). J Pain Symptom Manage 2009; Dec;38(6):882–893. 47. Silverberg MJ, Jacobson LP, French AL, Witt MD, Gange SJ. Age and racial/ethnic differences in the prevalence of reported symptoms in human immunodeficiency virus-infected persons on antiretroviral therapy, (in eng). J Pain Symptom Manage 2009; Aug;38(2):197–207. 48. Farrant L, Gwyther L, Dinat N, Mmoledi K, Hatta N, Harding R. The prevalence and burden of pain and other symptoms among South Africans attending highly active antiretroviral therapy (HAART) clinics, (in eng). S Afr Med J 2012; Mar;102(6):499–500. 49. Harding R, et al. Prevalence, burden, and correlates of physical and psychological symptoms among HIV palliative care patients in subSaharan Africa: an international multicenter study, (in eng). J Pain Symptom Manage 2012; Jul;44(1):1–9. 50. Namisango E, et al. Pain among ambulatory HIV/AIDS patients: multicenter study of prevalence, intensity, associated factors, and effect, (in eng). J Pain 2012; Jul;13(7):704–713. 51. Bhengu BR, et al. Symptoms experienced by HIV-infected Individuals on antiretroviral therapy in KwaZulu-Natal, South Africa, (in eng). Appl Nurs Res 2011; Feb;24(1):1–9.

Textbook of Palliative Medicine and Supportive Care 52. Moens K, Higginson IJ, Harding R, Impact E. Are there differences in the prevalence of palliative care-related problems in people living with advanced cancer and eight non-cancer conditions? A systematic review, (in eng). J Pain Symptom Manage 2014; May;48(4):18. 53. Breitbart W, McDonald M, Rosenfeld B, Monkman N, Passik S. Fatigue in ambulatory AIDS patients. J Pain Symptom Manage 1998;15(3):159–167. 54. Norval D. Symptoms and sites of pain experienced by AIDS patients. SAMJ 2004;94(6):450–454. 55. Vincent I, et al. Modalities of palliative care in hospitalized patients with advanced AIDS, AIDS Care 2000;12(2):211–219. 56. Vogl D, et al. Symptom prevalence, characteristics, and distress in AIDS outpatients. J Pain Symptom Manage 1999;18(4):253–262. 57. Karus D, et al. Patient reports of symptoms and their treatment at three palliative care projects servicing individuals with HIV/AIDS. J Pain Symptom Manage 2005;30(5):408–417. 58. Kimball L, McCormick W. The pharmacologic management of pain and discomfort in persons with AIDS near the end of life: use of opioid analgesia in the hospice setting. J Pain Symptom Manage 1996;11(2):88–94. 59. Schreiner R, McCormick W. Challenges in pain management among persons with AIDS in a long-term-care facility. J Am Med Dir Assoc 2002;3:51–56. 60. Karus D, et al. Patient reports of symptoms and their treatment at three palliative care projects servicing individuals with HIV/AIDS, J Pain Symptom Manage 2005;30(5):408–417. 61. Rabkin J, Ferrando S, Jacobsberg L, Fishman B. Prevalence of axis I disorders in an AIDS cohort: a cross-sectional, controlled study. Compr Psychiatry 1997;38(3):146–154. 62. Gonzalez JS, et al. Physical symptoms, beliefs about medications, negative mood, and long-term HIV medication adherence, (in eng). Ann Behav Med 2007; Aug;34(1):46–55. 63. Gay C, et al. Self-reported medication adherence and symptom experience in adults with HIV, (in eng). J Assoc Nurses AIDS Care 2011; Jul-Aug;22(4):257–268. 64. Gonzalez JS, Batchelder AW, Psaros C, Safren SA. Depression and HIV/ AIDS treatment nonadherence: a review and meta-analysis, (in eng). J Acquir Immune Defic Syndr 2011; Oct;58(2):181–187. 65. Al-Dakkak I, Patel S, McCann E, Gadkari A, Prajapati G, Maiese EM. The impact of specific HIV treatment-related adverse events on adherence to antiretroviral therapy: a systematic review and meta-analysis, (in eng). AIDS Care 2013;25(4):400–414. 66. Ammassari A, et al. Self-reported symptoms and medication side effects influence adherence to highly active antiretroviral therapy in persons with HIV infection, (in eng). J Acquir Immune Defic Syndr 2001; Dec;28(5):445–449. 67. Willard S, et al. Does “asymptomatic” mean without symptoms for those living with HIV infection?, (in eng). AIDS Care 2009; Mar;21(3):322–328. 68. Edelman EJ, Gordon K, Rodriguez-Barradas MC, Justice AC. Patient-reported symptoms on the antiretroviral regimen efavirenz/ emtricitabine/tenofovir, (in eng), AIDS Patient Care STDS 2012; Jun;26(6):312–319. 69. High KP, et al., HIV and aging: state of knowledge and areas of critical need for research. A report to the NIH Office of AIDS Research by the HIV and Aging Working Group, (in eng). J Acquir Immune Defic Syndr 2012; Jul;60(Suppl 1):S1–S18. 70. Capeau J. Premature aging and premature age-related comorbidities in HIV-infected patients: facts and hypotheses, (in eng). Clin Infect Dis 2011; Dec;53(11):1127–1129. 71. Wendelken LA, Valcour V. Impact of HIV and aging on neuropsychological function, (in eng). J Neurovirol 2012; Aug;18(4):256–263. 72. Sabin CA, et al. Pain in people living with HIV and its association with healthcare resource use, well being and functional status, (in eng). AIDS 2018; Nov;32(18):2697–2706. 73. Walston J, et al. Research agenda for frailty in older adults: toward a better understanding of physiology and etiology: summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults, (in eng). J Am Geriatr Soc 2006; Jun;54(6):991–1001. 74. Onen NF, Overton ET. A review of premature frailty in HIV-infected persons; another manifestation of HIV-related accelerated aging, (in eng). Curr Aging Sci 2011; Feb;4(1):33–41. 75. Desquilbet L, et al. HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty, (in eng), J Gerontol A Biol Sci Med Sci 2007; Nov;62(11):1279–1286.

Supportive and Palliative Care for Patients with HIV Infection 76. Erlandson KM, Allshouse AA, Jankowski CM, MaWhinney S, Kohrt WM, Campbell TB. Functional impairment is associated with low bone and muscle mass among persons aging with HIV infection, (in eng). J Acquir Immune Defic Syndr 2013; Jun;63(2):209–215. 77. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review, (in eng). AIDS 2006; Nov;20(17):2165–2174. 78. Sharma A, Flom PL, Weedon J, Klein RS. Prospective study of bone mineral density changes in aging men with or at risk for HIV infection, (in eng). AIDS 2010; Sep;24(15):2337–2345. 79. Triant VA, Brown TT, Lee H, Grinspoon SK. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus nonHIV-infected patients in a large U.S. healthcare system, (in eng). J Clin Endocrinol Metab 2008; Sep;93(9):3499–3504. 80. Womack JA, et al. Increased risk of fragility fractures among HIV infected compared to uninfected male veterans, (in eng). PLOS ONE 2011; Feb;6(2):e17217. 81. Mateen FJ, Mills EJ. Aging and HIV-related cognitive loss, (in eng). JAMA 2012; Jul;308(4):349–350. 82. Ances BM, et al. HIV infection and aging independently affect brain function as measured by functional magnetic resonance imaging, (in eng). J Infect Dis 2010;201(3):336–340. 83. Cruse B, Cysique LA, Markus R, Brew BJ. Cerebrovascular disease in HIV-infected individuals in the era of highly active antiretroviral therapy, (in eng). J Neurovirol 2012; Aug;18(4):264–276. 84. Goulet JL, et al. Do patterns of comorbidity vary by HIV status, age, and HIV severity?, (in eng). Clin Infect Dis 2007; Dec;45(12):1593–1601. 85. Justice AC. HIV and aging: time for a new paradigm, (in eng). Curr HIV/AIDS Rep 2010; May;7(2):69–76. 86. Marin B, et al. Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy, (in eng). AIDS 2009; Aug;23(13):1743–1753. 87. Oursler KK, et al. Association of age and comorbidity with physical function in HIV-infected and uninfected patients: results from the Veterans Aging Cohort Study, (in eng). AIDS Patient Care STDS 2011; Jan;25(1):13–20. 88. Rodriguez-Penney AT, et al. Co-morbidities in persons infected with HIV: increased burden with older age and negative effects on health-related quality of life, (in eng). AIDS Patient Care STDS 2013; Jan;27(1):5–16. 89. Deeks SG, Phillips AN. HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity, (in eng). BMJ 2009; Jan;338:a3172. 90. Justice AC, Braithwaite RS. Lessons learned from the first wave of aging with HIV, (in eng). AIDS 2012; Jul;26(Suppl 1):S11–S18. 91. Glass TR, et al. Prevalence of risk factors for cardiovascular disease in HIV-infected patients over time: the Swiss HIV Cohort Study, (in eng). HIV Med 2006; Sep;7(6):404–410. 92. Guaraldi G, et al. Coronary aging in HIV-infected patients, (in eng). Clin Infect Dis 2009; Dec;49(11):1756–1762. 93. Freiberg MS, et al. HIV infection and the risk of acute myocardial infarction, (in eng) JAMA Intern Med 2013; Apr;173(8):614–622. 94. Kuritzkes DR, Currier J. Cardiovascular risk factors and antiretroviral therapy, (in eng). N Engl J Med 2003; Feb;348(8):679–680. 95. Friis-Moller N, et al. Class of antiretroviral drugs and the risk of myocardial infarction, (in eng). N Engl J Med 2007; Apr;356(17):1723–1735. 96. Petoumenos K, et al. Rates of cardiovascular disease following smoking cessation in patients with HIV infection: results from the D:A:D study(*), (in eng). HIV Med 2011; Aug;12(7):412–421. 97. Evans SR, et al. Peripheral neuropathy in HIV: prevalence and risk factors, (in eng). AIDS 2011; Apr;25(7):919–928. 98. Madeddu G, et al. Chronic obstructive pulmonary disease: an emerging comorbidity in HIV-infected patients in the HAART era?, (in eng). Infection 2013; Apr;41(2):347–353. 99. Crothers K, et al. Impact of cigarette smoking on mortality in HIVpositive and HIV-negative veterans, (in eng). AIDS Educ Prev 2009; Jun;21(3 Suppl):40–53. 100. Operskalski EA, Kovacs A. HIV/HCV co-infection: pathogenesis, clinical complications, treatment, and new therapeutic technologies, (in eng). Curr HIV/AIDS Rep 2011; Mar;8(1):12–22. 101. Izzedine H, Deray G. The nephrologist in the HAART era, (in eng). AIDS 2007; Feb;21(4):409–421. 102. Medapalli RK, et al. Comorbid diabetes and the risk of progressive chronic kidney disease in HIV-infected adults: data from the Veterans Aging Cohort Study, (in eng). J Acquir Immune Defic Syndr 2012; Aug;60(4):393–399.

839

103. Dubrow R, Silverberg MJ, Park LS, Crothers K, Justice AC. HIV infection, aging, and immune function: implications for cancer risk and prevention, (in eng). Curr Opin Oncol 2012; Sep;24(5):506–516. 104. Silverberg MJ, et al. HIV infection and the risk of cancers with and without a known infectious cause, (in eng). AIDS 2009; Nov;23(17):2337–2345. 105. Bedimo RJ, McGinnis KA, Dunlap M, Rodriguez-Barradas MC, Justice AC. Incidence of non-AIDS-defining malignancies in HIVinfected versus noninfected patients in the HAART era: impact of immunosuppression, (in eng). J Acquir Immune Defic Syndr 2009; Oct;52(2):203–208. 106. Piketty C, et al., Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy, (in eng). AIDS 2008; Jun;22(10):1203–1211. 107. Ammassari A, et al. Depressive symptoms, neurocognitive impairment, and adherence to highly active antiretroviral therapy among HIV-infected persons, (in eng). Psychosomatics 2004; Sep-Oct;45(5):394–402. 108. Dalessandro M, et al. Antidepressant therapy can improve adherence to antiretroviral regimens among HIV-infected and depressed patients, (in eng). J Clin Psychopharmacol 2007; Feb;27(1):58–61. 109. Mills EJ, Barnighausen T, Negin J. HIV and aging–preparing for the challenges ahead, (in eng). N Engl J Med 2012; Apr;366(14):1270–1273. 110. Lazarus JV, et al. Beyond viral suppression of HIV – the new quality of life frontier, (in eng). BMC Med 2016;14(1):94. 111. Abboah-Offei M, et al. Phase II mixed methods’ feasibility cluster randomised controlled trial of a novel community-based enhanced care intervention to improve person-centred outcomes for people living with HIV in Ghana, (in eng). AIDS Care 2020; Mar;1–12. doi: 10.1080/09540121.2020.1739217. 112. Emlet CA, Tozay S, Raveis VH. I’m not going to die from the AIDS: resilience in aging with HIV disease, (in eng). Gerontologist 2011; Feb;51(1):101–111. 113. Shippy RA, Karpiak SE. The aging HIV/AIDS population: fragile social networks, (in eng). Aging Ment Health 2005; May;9(3):246–254. 114. Harding R, Liu L, Catalan J, Sherr L. What is the evidence for effectiveness of interventions to enhance coping among people living with HIV disease? A systematic review, (in eng). Psychol Health Med 2011; Oct;16(5):564–587. 115. Clucas C, Sibley E, Harding R, Liu L, Catalan J, Sherr L. A systematic review of interventions for anxiety in people with HIV, (in eng). Psychol Health Med 2011; Oct;16(5):528–547. 116. Sherr L, Clucas C, Harding R, Sibley E, Catalan J. HIV and depression – a systematic review of interventions, Psychol Health Med 2011;16(5):493–527. 117. Sherr L, Nagra N, Kulubya G, Catalan J, Clucas C, Harding R. HIV infection associated post-traumatic stress disorder and posttraumatic growth – a systematic review, Psychol Health Med 2011;16(5):612–629. 118. Harding R, et al. Place of death for people with HIV: a population-level comparison of eleven countries across three continents using death certificate data, (in eng). BMC Infect Dis 2018;18(1):55. 119. Harding R. Palliative care as an essential component of the HIV care continuum, (in eng). Lancet HIV 2018; Sep;5(9):e524–e530. A Centers for Disease Control and Prevention. MMWR, 60, 689, 2011. Accessed at: http://www.cdc.gov/mmwr/pdf/wk/mm6021.pdf. B WHO, Update of Recommendations On First- and Second-Line Antiretroviral Regimens: HIV Treatment, Policy Brief WHO/CDS/ HIV/19.15 WHO, 2019. Accessed at: https://apps.who.int/iris/bitstream/handle/10665/325892/WHO-CDS-HIV-19.15-eng.pdf?ua=1. C 90-90-90: Treatment for All. https://www.unaids.org/en/resources/ 909090. D Samji H, Cescon A, Hogg RS, et al. Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada. PLOS ONE 2013;8:e81355. E Losina E, Schackman BR, Sadownik SN, et al. Racial and sex disparities in life expectancy losses among HIV-infected persons in the United States: impact of risk behavior, late initiation, and early discontinuation of antiretroviral therapy. Clin Infect Dis 2009;49:1570–1578. F Mills EJ, Bakanda C, Birungi J, et al. Life expectancy of persons receiving combination antiretroviral therapy in low-income countries: a cohort analysis from Uganda. Ann Intern Med 2011;155:209–216.

90

IMPLANTABLE CARDIAC DEVICES

Laura J. Morrison

Contents Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������841 Heart failure�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������842 Cardiovascular disease burden���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������842 Pacemakers�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������842 Worldwide access��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������842 Pacemaker indications, advances, and CRT����������������������������������������������������������������������������������������������������������������������������������������������������843 ICDs�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������845 ICD indications and advances����������������������������������������������������������������������������������������������������������������������������������������������������������������������������845 Pacemaker and ICD costs and complications�������������������������������������������������������������������������������������������������������������������������������������������������846 Palliative care role for pacemaker and ICD management�����������������������������������������������������������������������������������������������������������������������������������846 Communication�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������846 Pacemaker and ICD deactivation����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������847 Practical concerns�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������849 Practices and attitudes in pacemaker and ICD deactivation������������������������������������������������������������������������������������������������������������������������������850 Ethical and legal considerations�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������850 VADs������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������851 VAD indications and advances���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������853 VAD costs and complications�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������853 Palliative care role for VAD management��������������������������������������������������������������������������������������������������������������������������������������������������������������854 Communication�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������854 Focused support for caregivers���������������������������������������������������������������������������������������������������������������������������������������������������������������������������854 VAD withdrawal����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������854 Practical concerns�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������855 Practice and attitudes in VAD withdrawal�������������������������������������������������������������������������������������������������������������������������������������������������������������855 Ethical and legal considerations�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������855 Conclusion��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������855 References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������856

Introduction For an expanding number of patients with advanced or end-stage heart failure (HF), new technology in the form of implantable cardiac devices can be lifesaving and increase quality of life. Device therapy indications continue to increase.1–3 This chapter will discuss implantable cardiac devices, including standard pacemakers or those with cardiac resynchronization therapy (CRT), implantable cardioverter defibrillators (ICDs), and ventricular assist devices (VADs). Survival and quality of life may improve significantly for years in many patients receiving an implantable cardiac device through improved symptom management and function. However, all HF patients will eventually die of either their cardiac disease or another terminal condition. Mortality rates for patients with pacemakers and ICDs are 5–20% per year translating to tens of thousands of deaths annually.4,5 Similarly, while survival continues to improve for VAD patients, mortality rates remain high.6,7 Implantable devices can also change the character of a patient’s dying and death to include painful shocks8 or a more prolonged course of symptoms and morbidity before death.9,10 In other words, these devices can both play a palliative role in advanced HF and alter life in unpleasant ways. A patient

may become dependent on a device for survival or symptom relief, become immobile or unable to leave an institutional setting due to debility or complications, and require surgery for upgrades or replacements of devices and parts. In summary, depending on a patient’s clinical picture and goals, the prolonged HF course with an implanted device may be for better or worse. Compared to new advances and indications for implantable cardiac devices, device management for patients experiencing clinical decline or approaching death has received little attention, leaving many unanswered questions.11,12 Despite more than 35 years of ICD use in higher income countries, 2005 United States (US) practice guidelines for HF were the first to encourage consideration of deactivation for end-stage HF patients.13 Taking time to educate and consider possible outcomes for these devices can be challenging when an HF patient deteriorates rapidly and VAD implantation means life or death. Patients, families, and healthcare providers may find themselves in very complex situations if goals or quality of life later changes. They may question whether and how to discontinue one or more of these devices. Clarifying expectations, goals, and treatment options as a person’s course evolves is one potential role for palliative care. Another is to advocate with and on behalf of the patient and family for goal 841

Textbook of Palliative Medicine and Supportive Care

842 concordant care. This chapter aims to fill the information void in this area by describing the course of advanced HF and the role of pacemakers, CRT, ICDs, and VADs. The management and deactivation of these devices are highlighted with practical and ethical considerations to emphasize a palliative care framework.

Heart failure HF refers to a decrease in the heart’s ability to pump enough blood to meet the metabolic demands of the body. The failure may be due to structural or functional abnormalities leading to impaired contraction (HF with reduced ejection fraction), relaxation (HF with preserved ejection fraction), or both. An advanced state of HF implies that an individual experiences fatigue, dyspnea, or other symptoms at rest due to hypoperfusion despite maximal medical therapy.

Cardiovascular disease burden

The US 2018 statistics indicate that the prevalence of HF will increase 46% from 2012 to 2030 affecting more than 8 million adults, with total HF costs projected to be 69.7 billion.14 Moreover, the annual incidence of HF approaches 21 per 1000 for those older than 65.14 Globally, HF affects more than 26 million people and has an approximate prevalence of 1–2% in higher income countries.15 Nearly half of all people diagnosed with HF will die within 5 years.14 This mortality rate is similar to, if not higher than, that for many common cancers combined.16 As new treatments in higher income nations have slowed disease progression and demographics have shifted to an older population, the prevalence of patients with advanced disease continues to increase.14,17 Similar figures for HF are more difficult to identify for lower income countries as population studies are lacking,15,18–20 particularly in Africa.15 Worldwide, cardiovascular disease, specifically ischemic cardiomyopathy, is becoming more prevalent as countries progress with socioeconomic development and control infectious causes of death.18,20,21 In 2013, cardiovascular disease accounted for 31% of deaths globally and approximately 70% of these deaths occurred in low- to middle-income countries.14 In Africa and Asia, rheumatic heart disease continues to be a prominent cause of HF, often manifested by valvular disease,15,21,22 but ischemic causes are increasing in Asia.14,15 Along with hypertension, dilated and peripartum cardiomyopathies are also prevalent in Africa where HF is diagnosed at a younger age.14,15,20,21 Chagas disease remains a significant cause of HF in South and Central America, largely through conduction system abnormalities.20 HF severity is categorized with different systems of classification. The New York Heart Association (NYHA) Classes I–IV categorize HF based on symptom severity and functional level. Class I indicates no symptoms or functional impairment, while Class IV reflects significant symptoms at rest with severe limitations. The American College of Cardiology (ACC)/American Heart Association (AHA) system stages HF based on disease burden and severity (Figure 90.1). Stage A is high risk without disease or symptoms, and Stage D is advanced disease with refractory symptoms requiring specialized interventions or hospice care. Figure 90.1 represents an overlap of these classifications with a sequential approach to therapeutic options.23 The NYHA classification is the more widely used and the basis for many randomized study designs. Although HF survival and symptom severity have a direct relationship, the correlation between symptoms and ventricular function is less clear.24

Clinical guidelines from higher income countries provide an evidence-based approach to HF management.23,25–27 These now consistently support discussions of end-of-life care options for Stage D HF patients and suggest varied triggers for palliative care involvement.23,25–27 As well, increasing numbers of expert publications on the role of palliative care in HF are further strengthening the evidence base.28,29 Over the last two decades, palliative care has become a recognized component of high-quality care for HF. The use of implantable cardiac devices creates potential challenges in the provision of palliative care for HF patients. These devices represent significant advances in technology that go beyond routine medical therapy for HF. As HF progresses, patients may face increasing symptom burdens and/or increased risk for sudden cardiac death (SCD). Ideally, all these devices improve quality of life and extend survival for a given HF patient. However, a lack of clarity around patient goals and an evolving landscape of illness with exacerbations, complications, and progression of disease may eventually result in a device becoming less appropriate for someone. Repeated assessments of therapeutic benefits versus burdens are critical for high-quality HF care. Additional challenges for palliative care providers working with implantable cardiac devices include screening for the presence of pacemakers and ICDs (e.g., an ICD or pacemaker may not be readily apparent on exam or history taking) and keeping up to date as new technologies evolve. Research on these devices has begun to focus to a limited extent on how best to manage deactivation or withdrawal when this is indicated. The available expertise and education in this area are slowly expanding. Similarly, collaboration between clinicians involved in the management of patients with devices is recommended; however, clarification of roles and responsibilities can be difficult, especially with differing views on who should initiate discussions and actual deactivation. 30

Pacemakers

A pacemaker is an implantable pulse generator powered by a battery that senses a heart’s native rhythm and sends out appropriate pacing impulses through a lead. The first pacemaker was implanted in the 1950s. Early devices were large, requiring extended surgery and recovery. Today, smaller devices are implanted in the anterior chest or upper abdomen during outpatient procedures (see Figure 90.2b). Pacemakers and ICDs both run on lithium batteries, lasting a median of 4.6 years.5 Approximately 900,000 pacemakers were implanted, and 330,000 replaced worldwide in 2009 with 61 countries contributing data to this most recent published world survey. 31 Of note, most countries increased implantations over 2005 figures with the US at more than 225,000 implantations, 31 and most pacemakers were implanted in people 65 and older. 31,32 For 2014, more than 350,000 in hospital pacemaker implantations were performed in the US. 32

Worldwide access

Although pacemakers are implanted in many countries, poor access to pacemakers for the underserved in lower income countries contributes to health disparities. 33,34 The need is clear. Estimates indicate more than 1 million people die annually due to lack of access to a pacemaker. 35 Pacemaker reuse initiatives, shifting previously used, resterilized and tested devices from higher income countries for use in lower income countries, have been implemented in different parts of the world over many years with some success. 34–38 Legal, ethical, logistical, and safety concerns

Implantable Cardiac Devices

843

FIGURE 90.1  Stages in the development of HF and recommended therapy by stage. (From Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e193 with permission.)

continue to challenge these programs, 33,36,38,39 though infection rate data seems promising. 38,39 Palliative care providers in developing countries may, thus, find themselves advocating for someone to receive a pacemaker or face device management issues near the end of life.

Pacemaker indications, advances, and CRT

Early pacemakers helped people with complete heart block continue living and with symptomatic bradyarrhythmias increase function. Today, patients in these groups are considered pacemaker dependent if they have an absolute need for a pacemakergenerated heartbeat (atrial or ventricular) to prevent symptoms or prolong life. Although the majority of pacemakers are still placed for bradyarrhythmias, pacemakers can also be used to address tachyarrhythmias with antitachycardia pacing and advanced HF with resynchronization therapy. Over time, pacemakers have progressed from fixed rate, single-chamber devices to dual chamber and now biventricular devices. Biventricular pacing technology has opened the way to the development of CRT. CRT devices may be implanted with

(CRT-D) or without (CRT-P) ICD capability. Many people with HF have left ventricular dyssynchrony, or delayed interventricular electrical activation and ventricular coordination, which further decreases the mechanical efficiency of an already challenged heart. Left bundle branch block is a prominent example of such a ventricular conduction delay. CRT allows for the right and left ventricles to be better coordinated for optimal contraction to create improved hemodynamic heart function and perfusion. In landmark randomized controlled trials, CRT has been shown to increase functional status, exercise capacity, and quality of life in NYHA Class III and IV HF patients while decreasing allcause morbidity, mortality, and hospitalizations.2,40,41 Mortality may decrease further when CRT is combined with ICD therapy41; however, studies are still defining which patients can benefit.42 Some studies have shown structural remodeling from CRT with improved ejection fractions and left ventricular volumes.43,44 Thus, for many patients with moderate-to-severe HF, CRT may serve a distinctly palliative role in improving quality of life while also increasing survival. Interestingly, the literature also documents a lack of CRT efficacy for approximately 30% of those receiving CRT.2

844

Textbook of Palliative Medicine and Supportive Care

FIGURE 90.2  An implantable cardioverter defibrillator (ICD) and pacemaker. (a) ICD in the upper chest. (b) Pacemaker in the upper chest. To the untrained eye, a single, dual-chamber, or CRT pacemaker will grossly appear the same as an ICD in a patient. New models continue to advance technically with decreasing size and increasing function. Most devices today have potential for myriad pacing and defibrillation functions, requiring interrogation to reveal settings and therapeutic capacity. Nonetheless, a chest radiograph could suggest the presence of traditional or biventricular lead placement. For any device, regular follow-up with an electrophysiologist to monitor device function and delivered therapy is optimal.45 It is also standard practice to give a device recipient a wallet identification card that indicates the make, model, and implanting physician. This helps a health-care provider more quickly identify necessary equipment for interrogation or reprogramming of a device. Cardiology organizations in higher income countries provide intermittently updated device-based guidelines for pacemaker implantation.46,47 The ACC/AHA/Heart Rhythm Society 2018 adult guidelines for bradycardia and conduction delay describe pacemaker indications for sinus node dysfunction, atrioventricular and chronic bifascicular block, and neurocardiogenic syncope.47 The broader European Society of Cardiology (ESC) 2013 adult pacing guidelines add support for CRT with or without defibrillator therapy for those with severe systolic HF (left ventricular

ejection fraction [LVEF] ≤35% and QRS interval ≥120 ms) and provide evolving recommendations for CRT in those with NYHA Classes II and III.46 On a global level, 2009 survey data indicates high-degree atrioventricular block and sick sinus syndrome as the most common pacemaker indications. 31 At present, CRT is mostly limited to higher income countries due to cost, lack of trained professionals and cardiology centers, and less access to newer technology in lower income countries. In summary, pacemakers may have a role in improving troublesome symptoms and function in advanced HF, especially when CRT is indicated and available. This palliative role may be accompanied by prolonged survival in those with complete heart block or receiving CRT. As a health-care provider follows an HF patient over time, a core focus should be to reassess whether the pacemaker continues to match that patient’s unique goals. Complex issues can arise, and educating patients, family members, and health-care providers from the beginning is important. In examining the risk/benefit profile for a pacemaker/CRT, the potential burdens include device complications, regular followup, and eventual battery replacement. Aside from these standard elements, the burden is less clear. Studies show that health-care providers perceive a relatively low burden of this device, especially when compared to an ICD and potential shocking.48–50

Implantable Cardiac Devices As a result, there is often less acknowledgment of the option to deactivate a pacemaker later in a patient’s course. In some cases, however, a patient or legal surrogate may perceive a burden of suffering from a prolonged poor, undesirable quality of life. Late-stage dementia is an increasingly common scenario where goals may change as a person’s function declines with or without HF. 51,52 Patients judged to be pacemaker dependent with complete heart block may even decide for device deactivation with anticipation of SCD. 53 Thus, even with a low physical device burden, a patients’ perceived burden may vary dramatically. Recent consensus guidelines identify fear of prolonged dying, loss of control and dignity, and existential suffering as other potentially relevant considerations.9 Whether pacemakers prolong life during dying has been debated. Berger54 suggested pacemakers may stand in the way of the natural dying process. Others indicate that physiologic changes during the dying process eventually overwhelm individual organs like the heart, creating a nonfunctioning pacemaker.55,56 This is supported by a study that found participants who had ICDs deactivated near the end of life had similar survival whether pacing was turned off or left intact.11 Importantly, the effect of pacemaker deactivation on symptoms remains a concern. Unless someone has complete heart block, deactivation is unlikely to lead to painless SCD.52 Experts indicate that a symptomatic bradycardia is the most likely result with potential worsening of HF symptoms.55,57 Although palliative care measures can manage these symptoms, experts recommend pacemaker continuation,11,55 specifically antibradycardic and CRT pacing.58 Research is needed in this domain, especially for those receiving CRT and the 30% for whom CRT is less effective, as use expands.

ICDs

The first ICD was successfully implanted in 1980, an extension of the original battery-powered generator and lead pacemaker technology. ICDs are designed to prevent SCD by using defibrillation, delivery of a high-energy shock, to convert a lethal tachyarrhythmia to a stable normal rhythm. Modern ICD devices include pacing functions and are almost indistinguishable from a pacemaker device on physical examination (ICDs are slightly larger) (see Figure 90.2a). When a tachyarrhythmia is sensed, the device will either provide antitachycardia pacing, cardioversion, or defibrillation. Only device interrogation will reveal its programming and recent activity. ICD use has expanded rapidly as new populations who benefit from this technology are identified. 59,60 As of 2013, the US had approximately 120,000 new implants and 30,000 replacements annually. 5 The majority of ICDs were also placed in those 65 and older. 32 In 2009, approximately 278,000 ICDs were implanted, and 132,000 replaced worldwide. 31 Compared to the 2005 survey data, almost all countries had an exponential rate of implant increase, and the use of biventricular ICDs increased. 31 Like pacemakers, ICDs are far underutilized in developing countries, 31,34 and logistical, legal, ethical, and safety issues exist around potential ICD reuse. 33,38 Initiatives to facilitate ICD reuse exist34,38,61 but lag behind those promoting pacemakers as the most basic, needed electrophysiological intervention for symptomatic bradycardia. 35

ICD indications and advances

ICDs have a role in both primary and secondary prevention of SCD. Attention to secondary prevention led the initial technology

845 push as physicians aimed to prevent SCD in those already suffering a prior cardiac arrest or sustained ventricular tachycardia (VT). More recently, however, efforts to prevent a first cardiac arrest have identified expanded “at-risk” groups that may benefit from defibrillator therapy. In particular, ICDs have been shown to significantly increase survival in those with LVEF 30–35% with prior myocardial infarction or nonischemic cardiomyopathy.59,62,63 Compared to standard antiarrhythmic pharmacotherapy, mortality reductions with ICDs have been in the range of 23–55%.64 Per US guidelines, ICDs are indicated for secondary prevention in prior cardiac arrest, sustained VT, or syncope with significant ventricular arrhythmia.65 For a primary prevention indication, ESC and US guidelines recommend that a person having a predicted 1-year survival should be on optimal medical management and be ambulatory.65,66 An ICD should be considered for someone with NYHA Classes II, III, or IV with ejection fraction ≤35% and mainly combined with CRT.65,66 Of note, a wearable cardioverter defibrillator (WCD) is available in the US, Europe, Japan, and gradually, other countries. The US Food and Drug Administration (FDA) approved the first device for adults in December 2001 with advancing models and pediatric indications since 2015. The device consists of two parts: a lightweight vest garment that detects arrhythmias and delivers shocks and a monitor with battery pack worn at the waist or by shoulder strap that records the cardiac rhythm. It is a self-contained device designed for 24-hour wear aside from brief bathing. Guidelines indicate WCDs should be considered for temporary use in individuals at high risk of SCD who require ICD removal or those who are ineligible for ICD placement, e.g., awaiting heart transplant.65 Studies show similar survival to ICDs and favorable patient tolerability for adults and children.67,68 Although WCDs are not implanted devices, similar management challenges may arise for palliative care clinicians taking care of patients with them. In contrast to pacemakers, the burden versus benefit breakdown for ICDs is better defined. In advanced HF, an ICD may transition a patient’s course from SCD to a prolonged course of HF. At a basic level, when preventing SCD no longer aligns with a person’s goals or device burdens outweigh benefits, consideration for deactivation should occur. Potential device complications, routine care and monitoring, and battery replacement are also standard burdens for ICDs. From a palliative perspective, it is significant that the intended effect of the ICD, defibrillation, can become a clear source of suffering.69 ICD shocks can cause patient and family distress and are not consistent with dignity or comfort care near the end of life.8,55,70,71 A person touching the patient at the time of shocking may experience mild discomfort from a small current. For some patients, even appropriate shocks produce suffering through pain,72,73 anxiety,74 fear, and depression.72,75,76 More shocks may negatively impact quality of life measures.77 Our ability to predict whether a dying patient with comfort-oriented goals will receive ICD shocks is limited, and our accuracy poorly defined,78 but dying patients may experience arrhythmias from electrolyte disturbances, hypoxia, and sepsis.11 In case a dying patient develops an arrhythmia, ICD deactivation may allow for a painless SCD and avoid any chance of unwanted shocks.55,57 Clarifying the goal of a peaceful, natural death ahead of time is, thus, important for patients who have an ICD in the setting of life-limiting illness. Ideally, all patients receiving an ICD will undergo a comprehensive informed consent process with end-of-life considerations and have intermittent opportunities to reevaluate the appropriateness of the device over time.69

846 Pacemaker and ICD costs and complications

Cost is an important consideration with implantable cardiac devices as it pertains to the benefit versus harm analysis for patients in different settings. Kirkpatrick et al. 33 indicated estimated device costs in 2009 as follows: pacemaker pulse generator $2500–$3000 with leads at $800–$1000 each compared to ICD generator $20,000–$40,000 with leads at $10,000 or more. Baman et al.79 state that with associated costs, a device implantation may cost as much as $55,000. More recent, US 2014 annual statistics indicate mean hospital charges for pacemaker and ICD implantation at $84,000 and $171,000, respectively. 32 Pacemaker and ICD complications, while decreasing markedly over time, are similar and add an additional consideration for patient decision-making. ICDs have more complexity with defibrillation therapy and thus additional complications. Implant mortality is low, usually measured as death at 30 days after procedure.80 One study of resuscitated patients showed 2.4% 30-day mortality for those with ICDs compared to 3.5% for those on antiarrhythmic medication instead.81 Surgical device complications, including infection rates of 1–2%, may lead to additional surgery.45 Hematoma, seroma, pneumothorax, hardware connection problems, and device erosion within cardiac or soft tissue, especially with cachexia, are other potential complications.45 Lead dislodgment, malfunction, or fracture may lead to ineffective pacing therapy and inappropriate shocking from ICDs and again additional surgery. Frequent, and inappropriate, shocks are the most common complication of ICD implantation.45 In the MADIT trial,59 patients in the ICD group had lead problems and nonfatal infections requiring surgery at a combined rate of 2.5% and a slightly higher rate of new or worsened HF than those in the conventional therapy group. Though less likely with newer devices, persons with either device may also experience malfunctions from electric current or magnetic field exposures (e.g., MRI testing, cell phone use near device), thus potentially limiting these activity and procedural options.45 Finally, leading device manufacturers have released multiple advisories and recalls for pacemakers and ICDs malfunctions since 2005, affecting well over 100,000 devices in 2005 alone.82 It can be difficult for patients and clinicians to determine whether the risk of device malfunction or complication from device replacement is higher.1 One study suggests these can be high-stakes decisions as complications occur even when replacements are performed by experienced hands.82

Palliative care role for pacemaker and ICD management

National medical organizations have begun to provide more guidance around pacemaker and ICD management and deactivation. Publications from the US7, Europe, 58 and the United Kingdom83 provide overlapping consensus on the management of implantable cardiac devices in patients near the end of life or requesting withdrawal of device therapy. These are comprehensive with input from palliative care clinicians and serve as a detailed road map for a palliative care approach to device management. In addition, earlier US and European guidelines on implantable cardiac device monitoring include a detailed section on device management and ethical issues.56 Lastly, a 2012 US scientific statement details the role of shared decision-making in device management.6

Communication

Widespread agreement exists on the importance of an ongoing conversation about goals of care between clinicians and patients

Textbook of Palliative Medicine and Supportive Care with pacemakers and ICDs. The complexity of the prolonged course of advanced HF and these devices makes this imperative. The discussion ideally starts at preimplantation with a robust informed consent process that includes advance care planning (ACP) and education about current and future therapeutic options like device deactivation.9,11,49,50,54,58 Evidence indicates that device deactivation and other end-of-life implications are not routinely included in implantation informed consent.84 The shared decision-making model, one grounded in patient autonomy, patient centeredness, and informed consent where both patient and clinician share information, has been suggested to guide this communication.6,85 This model emphasizes the clinician role in making sure patients and families have adequate understanding of the medical context86 and complexity of potential trade-offs.87 For example, if a patient is receiving a device with both pacing and ICD functions, an understanding of the benefits and burdens and potential consequences of each function would need to be achieved. This is a proactive approach that empowers the patient’s examination of benefits and harms, options, and consequences, along the continuum of device management, to arrive at the best decision for the patient. Since patient preferences can change over time with disease progression, 88 the serial and iterative aspect is key. Effective communication is timely and overall focused on patient’s goals and values, allowing informed consent to be optimized and undesirable outcomes minimized. Clinician consultation with colleagues may define specific facts or options and promote clarity. Goal discussions should focus on symptoms, function, and quality of life, as well as aspects of dependency, control, and dignity. Once goals are clarified, treatment options can be negotiated to find the best patient fit for goal concordant care. Evidence suggests such proactive communication can benefit patients and their families.89 The ultimate outcome of shared decision-making for an advanced HF patient would be a patientdriven, comprehensive end-of-life plan, including preferences for device management.6 ACP is a process widely accepted in the US that promotes patient identification of goals and preferences for future health needs and a legal surrogate for decision-making in case of incapacitation.90 It ideally includes completion of written advance directives, a living will (for personal health-care goals and preferences), and durable power of attorney for health care. Perhaps more importantly, with or without written document completion, it should encourage directed discussions of identified patient goals, values, and preferences with family members and/or a legal surrogate. ACP should be included as a key part of communication for implantable cardiac device management from preimplantation counseling onward. This discussion could be triggered by the acknowledgment that device deactivation may be appropriate at a future point, and the course ahead is uncertain. Given the most ICD patients have never considered the role of their device at end of life, 33,91 ACP for this population appears limited at present. Nonetheless, those ICD patients engaged in ACP and those with earlier device deactivation have received fewer shocks at the end of life.11 A specific statement about device deactivation in a living will is encouraged9 but is rare in practice, even among ICD patients with advance directives.92,93 Many experts recommend event triggers for clinicians to initiate these serial conversations with patients so that opportunities for updating patient wishes and preferences are not missed9 (see Table 90.1). In addition to preimplantation, increased ICD firing, progression of cardiac disease with repeated hospitalizations, consideration of a new therapy, major change in

Implantable Cardiac Devices

847

TABLE 90.1  Goals of Care Conversations for Implantable Cardiac Devices—Triggers, Content, and Phrasing Timing of Conversation Prior to implantation

After an episode of increased or repeated firings from ICD Progression of cardiac disease and/ or secondary disease process When patient/ surrogate chooses a do-not-resuscitate order

Patients at end of life

Points to Be Covered

Helpful Phrases to Consider

Clear discussion of the benefits and burdens of the devices Brief discussion of potential future limitations or burdensome aspects of device therapy Encourage patients to have some form of advanced directive Inform of options to deactivate in the future Discussion of possible alternatives, including adjusting medications, adjusting device settings, and cardiac procedures to reduce future shocks in the context of goals of care Reevaluation of benefits and burdens of device Assessment of functional status, quality of life, and symptoms Referral to palliative and supportive care services Reevaluation of benefits and burdens of device Exploration of patient’s understanding of device and how he or she conceptualizes it with regard to external Defibrillation Referral to palliative care or supportive services Reevaluation of benefits and burdens of devices Discussion of option of deactivation addressed with all patients, though deactivation not required

“It seems clear at this point that this device is in your best interest, but you should know at some point if you become very ill, from your heart disease or another process you develop in the future, the burden of this device may outweigh its benefit. While that point is hopeful a long way off, you should know that turning off your defibrillator is an option.”

“I know that your device caused you some recent discomfort and that you were quiet distressed. Let’s see if we can find a correctable reason why this may be happening and discuss options to decrease the number of firings.” “It appears as though your heart disease is worsening. We should really talk about your thoughts and questions about your illness at this point and see if your goals have changed at all.” “Now that we’ve established that you would not want resuscitation in the event your heart was to go into an abnormal pattern of beating, we should reconsider the role of your device. In many ways, it is also a form of resuscitation. Tell me your understanding of the device and let’s talk about how it fits into the larger goals for your medical care at this point.” “I think at this point, we need to reevaluate what your [device] is doing for you, positively and negatively. Given how advanced your disease is, we need to discuss whether to make sense to keep it active. I know this may be upsetting to talk about, but can you tell me your thoughts at this point?”

Sources: Adapted from Lampert R, Hayes DL, Annas GJ, et al. Expert Consensus Statement on the Management of Cardiovascular Implantable Electronic Devices (CIEDs) in patients nearing end of life or requesting withdrawal of therapy. Heart Rhythm 2010;7(7):1008–1026.

medical condition or diagnosis of another terminal disease, battery replacement, transition to do not attempt resuscitation (DNAR) status, and imminent death are possible triggers. An annual HF visit should also have a structured review of all current and potential therapies for anticipated or unanticipated events.6 More general discussion triggers for advanced HF may also be relevant for those with devices.6,83

Pacemaker and ICD deactivation Experts suggest two potential scenarios for pacemaker or ICD withdrawal56: (1) patient’s quality of life has diminished or is poor due to ICD shocking or decline of overall condition due to coexisting diseases or (2) patient’s death is approaching and the device is no longer of benefit. Given these provide only a general framework, decisions for device deactivation should be tailored in all cases to the individual patient and relevant circumstances. Table 90.2 suggests a general stepwise approach for pacemakers, ICDs, and VADs. Again, this is ideally a shared decision-making process with the clinician providing directive guidance based on the patient’s expressed goals and the patient and physician arriving at a mutual decision.6 Deactivation is to be undertaken only after careful planning and thorough investigation of a patient’s clinical circumstance is completed, all other options are considered, verbal informed consent is obtained from the patient or legal surrogate with family involvement, and, ideally, all those involved in active medical care, including the interdisciplinary team, are informed. Coordination and communication of responsibilities

between all team members is crucial to facilitate a smooth process for everyone. Anticipatory symptom assessment and management should also be in place. Continuation of prior symptom-related medications may or may not be appropriate. Premedication for symptoms such as pain or dyspnea (opioids), anxiety (anxiolytics), or delirium (neuroleptics) should be considered.9 If SCD is predicted (pacemaker with complete heart block most likely) or if painful, unwanted shocks are already happening (ICD), sedation prior to discontinuation may be indicated and desired by patient or legal surrogate. Nonpharmacologic interventions should always be optimized (e.g., fan for dyspnea). In all cases, clinicians will want to continue to assess the patient before, during, and after deactivation for symptoms or distress with the ability to quickly administer medications. Prior to deactivation, clearly labeled syringes of opioids or sedatives can be prepared for urgent administration and dose titration as needed. For example, three syringes containing morphine 10 mg each and three syringes containing midazolam 10 mg each might be individually labeled and on a bedside table. If the patient is already receiving opioids, equianalgesic calculations should be made, and appropriate bolus doses determined beforehand. If the patient has been taking benzodiazepines, an alternative sedative such as a barbiturate or propofol may be considered because of tolerance. If available, involvement of an interdisciplinary palliative care team is ideal. This can provide additional support for clinicians, patient, and family and expertise in complex communication and symptom management for therapy withdrawal or end-of-life

Textbook of Palliative Medicine and Supportive Care

848

TABLE 90.2  Implantable Cardiac Device Deactivation—A Stepwise Approach for Clinicians Key Potential Time Points



Stakeholders for Discussions

1. Preimplantation or early planning discussion 2. Decline in patient’s clinical condition: a. Progressive cardiac dysfunction b. Progressive secondary disease (e.g., malignancy, dementia) c. Poor quality of life d. Catastrophic device complications

Patient, legal surrogate, family members, and caregivers Patient, legal surrogate, family members, and caregivers Other physicians and members of interprofessional team

3. Patient or legal surrogate desires device deactivation

Patient, legal surrogate, family members, and caregivers Other physicians and members of interprofessional team

4. (a). Deactivation—immediate death (death in seconds to minutes) unlikely

Patient, legal surrogate, family members, and caregivers Onsite interprofessional team

(b). Deactivation—immediate death anticipated 5. Device deactivated—first hours-days

Patient, legal surrogate, family members, and caregivers Onsite interprofessional team Patient, legal surrogate, family members, and caregivers Onsite interprofessional team

Potential Communication/Care Details • Present deactivation option as part of informed consent or early advance care planning after implantation • Optimize symptom management • Revisit/introduce option/benefits/risks of deactivation • Explore medical, ethical, legal, spiritual, and cultural aspects • Discuss deactivation details for the specific device: • Pacemaker functions • ICD therapies • Alert and/or remote monitoring • VAD functions • Assess symptoms, including mental health and coping • Consider ethical or legal consultation in some cases • Discuss and document in chart: • Clinician’s perception of patient’s cognitive and psychological state, including patient’s decision-making capacity • Informed consent of patient or legal surrogate, including uncertainty in course and timing after deactivation • Resuscitation status • Communication with the patient’s family • Clarify optimal timing, sequence of events, and presence of supportive individuals for deactivation based on patient or legal surrogate preferences and practical considerations • Details of device reprogramming should always be reviewed and documented by physician • A suitably trained person performs deactivation upon the express, written order of a physician • Provide active symptom management • Optimally performed by physician • Perform active symptom management and care for imminent death, if occurs • Patient and/or others: provide regular updates, education, support as appropriate • Team: debrief deactivation event to optimize process and support, immediately or soon thereafter

Practical points: pacemaker • Consider device interrogation in advance to determine function and likely deactivation outcome • Determine approach to continuation or discontinuation of other life-sustaining therapies (e.g., vasopressors), including resuscitation status Practical points: ICD • Consider device interrogation in advance to determine function and likely deactivation outcome • Determine approach to continuation or discontinuation of other life-sustaining therapies, including resuscitation status • Use magnet if inappropriate shocks and not able to deactivate Practical points: VAD • Consider VAD deactivation to be analogous to ventilator withdrawal • Determine approach to continuation or discontinuation of other life-sustaining therapies as they relate to timing and goals around VAD deactivation (VAD is often the last therapy to be stopped) • If active ICD is present, deactivate in advance of VAD deactivation • Confirm do not attempt resuscitation status • Discuss palliative sedation, as indicated by circumstances, with patient and/or family/legal surrogate • Have pre-deactivation meeting to specify team roles and responsibilities, in detail, and to clarify expectations and concerns with bedside RN, respiratory therapist, perfusionist, clergy, social worker, and all other involved staff • Have pre-deactivation meeting with patient or legal surrogate and involved family to clarify plan, expectations, and concerns • Confirm needed expertise is present for deactivation of specific VAD device (mechanism for deactivation and silencing of alarms with appropriate sequence of events) to minimize anxiety for all present • If premedication appropriate, administer prior to deactivation with reassessment to ensure adequate circulation and efficacy • Silence alarms and discontinue all non-symptom-directed monitoring • Have a backup “quiet container” in case alarm will not silence (e.g., large hazard box with foam or pillows)

Implantable Cardiac Devices situations. Psychiatry, ethics consultation, and legal counsel are not required unless there is an institutional policy or a clinical question. Deactivation is an accepted medical procedure. Pacemaker deactivation implies the device is turned off or reprogrammed to be nonfunctional in treating bradycardia. ICD, or defibrillator, deactivation, by contrast, means the device is reprogrammed to no longer treat tachyarrhythmias; pacing activity may continue or not depending on the clinical decision. Documentation in the medical record is standard of care in all cases. Details of expert recommendations for this vary but may include confirmation of the decision and decision-making capacity, components of informed consent, therapies to be deactivated, and family notification. Patient, surrogate, or witness signatures may be required by institutional policies but are not legal requirements.9,56,94,95 The presence of the physician, or another clinician with appropriate expertise, at the bedside during a device withdrawal is encouraged and may be required for deactivation in a patient with complete heart block.56,95 In any case, continued clinician involvement and caring is critical following device deactivation to avoid any sense of abandonment. Depending on the patient and resource situation, device deactivation may occur in a hospital or residential setting; prior to or thereafter, a transition to another level of care, like hospice, may be appropriate and should be made as smoothly as possible. The withdrawal of an ICD or pacemaker can be carried out painlessly with the device undisturbed in the patient. With time to plan, the patient’s device identification card can facilitate the arrival of the correct manufacturer-specific computer. Contacting the implanting physician and/or obtaining an overpenetrated anteroposterior chest radiograph to see the identification code on the device are other means to discover the specific manufacturer. In an emergency situation, all devices will stop functioning if a circular magnet is placed or taped directly over the device (see more detail on this situation in the following). When possible, prior to device deactivation, it can be helpful to know the original device indication and to interrogate the device with the same computer for the current function to anticipate the deactivation outcome. In the case where a patient may have complete heart block (pacemaker), this is especially important. Counseling, education, support, and medication can then be in place for a sudden death. Otherwise, as with discontinuation of ventilators, it is not wise to predict certain death following deactivation (pacemaker or ICD). Unanticipated escape rhythms may emerge that sustain enough cardiac contractility and blood pressure to sustain life (pacemaker). Specific counseling around uncertainty in the deactivation outcome is critical; moreover, standardization in the determination of device functioning, especially for pacemaker dependency, is lacking and may result in variable outcomes.53,95 In almost all settings, a medical order for device deactivation will be required. The order and medical record should reflect which therapies are to be withdrawn or continued (e.g., “discontinue all tachyarrhythmia therapies” for an ICD95). Most commonly, a physician or industry-employed allied professional (IEAP) uses a manufacturer-specific computer transdermally over the device to reprogram it. If present, it is often appropriate to discontinue rhythm monitoring at this time. If an IEAP is involved, this person works directly under physician supervision.9

Practical concerns

Once device deactivation has been performed, the patient and family will need support adjusting to the outcome. Whether this

849 is death, continued uncertainty or slow decline, or no tangible physical change, attentive care with tailored updates and interdisciplinary team support is appropriate. If death occurs, in addition to compassionate death care, education to families about device function may be helpful, namely, that pacemakers do not continue to function after death. Family members, friends, and other formal caregivers can safely touch an ICD patient without being shocked. In the case of cremation, both devices will be removed after death to prevent battery explosion. While technically possible, scheduling device therapy withdrawal may be difficult to coordinate for a patient at home, in a hospice unit,96 or even in a hospital,70,71 due to lack of equipment and expertise availability or infrequency with which this occurs. Clinician continuity and responsibility may be hard to define with multiple physicians involved, lack of training and research around these scenarios, and lack of facilitating protocols or institutional memory. This fragmented care is a potential challenge for patients with a device near the end of life. Physician advocacy is frequently able to overcome such barriers if there are time and confidence. No matter the scenario, the physician in charge of a patient’s care will want to contact clinicians or IEAPs to organize a device withdrawal. Whether medical staff or IEAPs perform the actual deactivation can vary; a European survey 97 indicates medical staff predominate, while US surveys48,95 suggest a dominant role for IEAPs. The same European survey explored the idea of safe remote deactivation with high physician disapproval.97 Increased research, innovation, and education are needed to create optimal facilitation of device withdrawals for patients who have made this decision. If urgent deactivation of an ICD is needed in a dying patient, a strong doughnut-shaped magnet placed transdermally over the device should stop the shocking and/or specifically programmed pacing immediately. In many hospice and palliative care settings, such magnets are available and specifically carried by home visit nurses. The default bradycardic pacing function (typically HR < 60) will continue. If the magnet is removed, the tachyarrhythmia sensing and shocking may resume. Some investigators suggest that household objects with magnetic fields, like cell phones, refrigerator magnets, speakers, and laptop computers, may also be effective in stopping shocks from earlier model ICDs in an emergency.96 A different approach to deactivation of either device is the decision to not replace a battery or defective part. More than 30,000 ICD replacement procedures alone occur in the US annually.98 Experts recommend a triggered reevaluation of a patient’s projected survival, quality of life, and goals prior to any replacement procedure.99,100 In a resource-poor setting, achieving part replacement may be more challenging, and the option to forego replacement may be more prominent. Consideration of pacemaker and ICD deactivation can also arise in the pediatric realm. Though increasing in number, most recent statistics suggest that less than 1% of all pacemaker and 3% of ICD implantations occur in minors. 32 In general, ethical principles and considerations for the clinical approach are similar to the situation for adults. However, the added challenge is determining the minor’s degree of autonomy and decisional capacity. While the child’s relevant prior experience and the developmental stage will contribute to this determination,9 the guiding concern must always be the best interest of the child.101 Authors, IEAPs, and clinicians have called for institutional protocols and guidelines for pacemaker and ICD deactivation in order to improve quality and standardization.8,11,49,50,95 Hospice and palliative care clinicians indicate a dearth of protocols in

850

Textbook of Palliative Medicine and Supportive Care

their institutions. 50 Any health-care setting that may have a patient with a pacemaker or ICD with comfort care goals or nearing the end of life should have a device management policy.9 Hospices, where dying is more likely, need to ensure devices are identified on patient admission, and conversations occur to identify patient’s goals and allow appropriate management. One study indicates that most hospices are receiving patients with ICDs, and almost 60% report a patient being shocked within the last year, but only 10% of hospices have protocols.102 Comprehensive device management includes coordinated care across all settings, including hospice, that communicates and supports patient care goals.

burden information, 70% of patients would request deactivation in at least one of five common end-of-life scenarios.114 Fortunately, our experience is growing, and the medical literature continues to expand. New consensus statements on pacemaker and ICD end-of-life management now exist.58,65,83 Experts and clinicians emphasize the need for clinician and patient education and earlier discussions.65,83,92,93 Despite this expanding base of support, a systematic approach to device deactivation is a reach in many settings around the world. Even where one exists, ongoing monitoring and advocacy will be important to best meet patient and family needs.

Practices and attitudes in pacemaker and ICD deactivation

The deactivation of pacemaker and ICD continues to trigger ongoing discussion as evidenced by a steady flow of literature on this topic. There is broad medical and legal consensus in the US and many Western countries for the right of a patient with decisionmaking capacity, terminal or not, or a legal surrogate, to request the withdrawal of any life-sustaining therapy, implantable cardiac device or other, and for the physician obligation to respect these wishes.9,56,90,115–117 This extends to support for a patient’s ability to determine one’s own acceptable quality of life as a result or in spite of possible medical therapies.118 No specific medical therapy has a unique ethical or legal status,9 and withholding or withdrawing a therapy is ethically equivalent.48 Moreover, when a patient dies after device deactivation, the death is attributed to the underlying disease process, or lethal pathophysiology, not device withdrawal.9 The death certificate should be completed in accordance with this approach. This consensus is derived from a Western tradition of medical ethics where patient autonomy (the patient’s right to self-determination), beneficence (promoting good to a patient), and nonmaleficence (avoiding harm to a patient) are central.119 In this paradigm, when a clinician deactivates a device, the intent is to relieve or prevent the patient’s burden and suffering, not to achieve death (assisted death). Of note, although years of case law in the US generally support this consensus approach to device deactivation, the particular case of implantable cardiac device withdrawal has not yet come before the US courts.94,105,117 Informed consent is a critical process that allows a patient with decision-making capacity to weigh benefits and burdens, understand options and consequences, and make a decision in line with personal goals and values.90,115 Ethically and legally, clinicians are bound to ensure patients are informed participants in clinical decision-making.7,104 In the case of a patient without decision-making capacity, a legal surrogate, as determined by an advance directive or legal hierarchy, is encouraged to use substituted judgment to act on a patient’s known wishes (these wishes may come from an advance directive) or, if unknown, to make a decision based on the patient’s best interest. A surrogate has the legal status of a capacitated patient but is never to base a decision solely on one’s own preferences. Knowing that an option is considered ethical in principle is different from actually writing an order or reprogramming a device with one’s own hand. For some, device deactivation brings up concerns about euthanasia and physician-assisted suicide even though this association is unambiguously rejected by experts.9,56 Nevertheless, different perceptions persist. Euthanasia is defined as intentionally causing the death of someone very sick or dying; physician-assisted suicide, or medical aid in dying, occurs when a physician helps a patient take his or her own life, most commonly by prescribing a lethal

In the realm of implantable cardiac devices, most attention to date has focused on device development, indications, and implantation training. The ethics and practices of device deactivation have received less.9,48,50,54,103 However, decisions about continuing or deactivating these devices near the end-of-life arise8,48,51,53,70,71,104 and will become more common globally with the aging population and expanding indications for device implantation. Multiple US surveys demonstrate that clinicians display attitudinal and practice differences for pacemaker and ICD deactivation, feeling less comfortable with pacemaker deactivation.4,48–50,105–107 IEAPs95 and cardiology society consensus statements also express this.9,53,58 Cardiology nurses also describe a perceived difference between withholding and withdrawing these devices.106 Most clinicians agree that ICD deactivation in terminally ill patients with informed consent is ethical.97,106 However, clinicians report low rates of personal experience in the actual procedure of deactivating a device.48,50,97 When performed, ICD deactivation occurs very late in the clinical course, hours to days before death.8 Despite the overall consensus on ethics and procedure, clinicians still struggle emotionally with this issue.4 In one study of HF professionals, 22% had refused requests for pacemaker deactivation and 6% for ICD deactivation.48 Clinicians appear more comfortable with deactivation as a patient’s death appears more imminent.49,97 Physicians acknowledge that although discussions of the deactivation option should occur, they rarely do. 30,97,108 These attitudes and practices cross physician specialties, representing primary care doctors and even electrophysiologists, as do the multiple potential obstacles to discussions. Inadequate knowledge is one potential barrier.4,49,103 A surprising number of physicians are unaware that ICD shocks can be painful, 38% in one study49 and 41% in another.103 Some appear overconfident in their ability to predict which patients will be shocked.78 Other known obstacles are the internal nature of the ICD (less visible reminder), less developed patient–physician relationships, discomfort with discussing death, and ethical concerns.8,108 Some doctors believe that this discussion is not their responsibility and should be initiated by another physician or the patient instead.109 It is clearly problematic when subspecialists defer responsibility to generalists who may have limited knowledge and experience. 36 Doctors also assume that patients are aware of the deactivation option.78,109 In fact, research suggests most patients are not aware; instead, they report few prior discussions, have mixed responses to these discussions, and may desire a guiding physician role in deactivation decisions.74,91,110–112 While prior studies have suggested patient reluctance to consider ICD deactivation even with frequent shocking111 or terminal cancer,113 a more recent study suggests that after receiving ICD benefit and

Ethical and legal considerations

Implantable Cardiac Devices medication the patient then takes.119 One study reports 11 and 1% of clinicians, respectively, indicate the deactivation of pacemaker and ICD is euthanasia with similar, slightly lower figures for physician-assisted suicide.48 In one group of ICD patients, 26% equated deactivation with assisted suicide.110 When deactivation will likely lead to immediate death, that is, a pacemaker patient has complete heart block, these actions can seem more active in assisting the path to dying. In one group of medical and legal professionals and patients, 30% considered deactivation in a pacemaker-dependent patient to be physician-assisted death or euthanasia.105 Most device IEAPs and cardiology nurses106 report much greater discomfort with deactivation in a pacemaker-dependent patient, and some device companies prevent technician participation in these cases.108 IEAPs report feeling uncomfortable, experiencing moral distress, and needing training around emotional aspects of deactivation.95 For these clinicians and technicians, the support of a responsible physician, interdisciplinary team members, an ethics committee, or palliative care team may be helpful.9 Conscientious objection is a well-accepted ethical concept and relevant option in this situation. Any clinician or IEAP in this situation has the option to not participate in deactivation. However, he or she or their supervisor is obligated to provide another able clinician to perform the task in a timely fashion.9,90,120 For instance, IEAPs report often setting up the reprogramming of a device for deactivation but having a physician or nurse push the button.95 Individual clinicians, patients, or family members may disagree with this widespread acceptance of device deactivation or follow a different ethical framework. Varied viewpoints, religious precepts, cultures, and values will be encountered and should be explored and respected.105 The authors in Ref. [121] have argued that by replacing a native body function, pacemakers and VADs create a new lethal pathophysiology when withdrawn, not a return to the underlying one. For them, withdrawal in these cases is not equivalent to withholding therapy and represents assisted suicide. Natural death comes only when a noncardiac lethal pathophysiology intervenes. Specific opposition to this viewpoint has been expressed with questioning of an ethical framework that would create an even larger population of those dying a prolonged death from HF.122 Above all, this alternative viewpoint highlights the importance of preimplantation counseling and informed consent for patients receiving these devices. In another example, two groups have expressed concerns about physicians making unilateral decisions to deactivate ICDs without appropriate consideration of circumstances (e.g., interpreting a DNAR status to mean ICD deactivation). Both suggest that implantation changes the nature of a device to a status between body part and medical device, implying a greater emphasis toward patient decisional ownership.123,124 Legal and ethical precedents support that all life-sustaining therapies, whether of longer or shorter duration, integrated into the body, or permanently taking over a vital function, are of equal status and may be withdrawn, emphasizing the patient’s decisional role.125 Globally, wherever one is, it is imperative to be aware of local palliative and end-of-life care practices, culture, faiths, viewpoints, etc., as they potentially bear on device deactivation. Both US and European experts emphasize the pluralistic traditions encountered by clinicians in their settings and the need for sensitivity and awareness.9,58 For example, legal practices and politics of advance directives vary greatly by culture, country, and within countries. Not all countries, including some in Europe,9

851 have advance directive legislation or pursue this framework of expression. In the US, 95% of patients in one study supported the concept of a device-specific advance directive.110 Even if advance directives exist, the interpretation or application may vary.9 As a result, accepted palliative care practices in the literature, or in higher income countries, may be more or less relevant and accepted in other parts of the world. Not surprisingly, pacemaker deactivation is less consistently supported in Europe than in the US and less so than ICD deactivation.48 In fact, pacemaker deactivation is illegal in some European countries.9 Ideally, an ethical consensus can prevail. The manner in which decisions around patient cardiopulmonary resuscitation are handled at the end of life should also be expected to vary globally. The presence of an ICD creates further complexity. Some espouse that a patient’s transition to DNAR status should imply ICD deactivation—equating both types of defibrillation.92,117,126 Clinician opinion on this varies greatly as demonstrated by three surveys with combined agreement and disagreement at 19–63% and 25–66%, respectively.48,49,103 A study of ICD patients also indicated a lack of consensus with 22% disagreement.110 Wilkoff et al.56 agree with ICD deactivation for DNAR status in most cases, but specify patients may benefit from continued ICD therapy if (1) the arrhythmias reflect the primary cardiac condition (vs. a different irreversible process) and (2) the patient agrees that ICD therapy confers meaningful improved survival and quality of life. Lack of consensus also exists around ICD management in hospice. In one study, 46% of ICD patients supported deactivation in hospice and 32% did not.110 Thirty percent of HF professionals agreed that hospices should require ICD deactivation on admission.48 Many advocate that a patient’s transition to DNAR status49,126 or hospice102 should be a trigger to consider deactivation of an ICD.

VADs

With the increasing prevalence of HF, technological innovation has focused on mechanical and surgical approaches to complement medical management. The first human heart transplant was performed in 1967. With further advances, survival rates have increased to nearly 50% at 10 years for heart recipients.127 This is the best overall treatment option for advanced HF patients who are eligible for transplant. However, many patients will die waiting for a heart. Less than 1% of those eligible will receive a heart transplant since available organs remain scarce.128 Thus, other efforts have focused on developing a total artificial heart (TAH). The first human TAH was implanted in 1984, but poor survival and prevalent safety issues were barriers.129 TAH technology continues to advance but remains limited clinically. In this realm of mechanical circulatory support (MCS) technology, VADs were developed as a temporary bridge for survival to more advanced HF therapies like transplant. A VAD is a mechanical pump that does the work of the left or right ventricle or both to restore normal hemodynamic parameters and perfusion for the body in advanced HF. Early VADs were transcutaneous, or extracorporeal. Most modern devices are now surgically implanted, or intracorporeal, aside from the power source, but percutaneous models have also been developed for short-term use. The pump mechanism in early models generated pulsatile flow with an eventual shift to continuous flow. More recently, further delineation has occurred between centrifugal or axial flow models. Left VADs (LVADs) pull blood from the left ventricle into the ascending aorta via two surgical conduits

852 and the pumping device that sits within the abdominal wall to increase cardiac output. A third conduit, the driveline, attaches the LVAD to an external power source through a person’s abdominal wall (see Figure 90.3), also an important potential source of infectious complications.

Textbook of Palliative Medicine and Supportive Care Right VADs (RVADs) are used less often and more for shortterm support after cardiac surgery or to treat increased pulmonary pressures. Blood is pumped from the right ventricle to the pulmonary artery. A biventricular assist device (BIVAD) combines an LVAD and RVAD but is distinctly different from a TAH.

FIGURE 90.3  A left ventricular assist device (LVAD). (a) LVAD in mobile patient. (b) Heart in cross section with LVAD. (Adapted from http://www.nhlbi.nih.gov/health/health-topics/topics/vad/.)

Implantable Cardiac Devices VAD indications and advances

Indications for VAD therapy have expanded since the early 1990s due to improving outcomes. Prior to the emergence of VADs, medical management, CRT, and ICDs were the maximal interventions short of transplant or TAH for those symptomatic and dying of advanced HF. VADs can be used in short-term management of acutely decompensated HF with preserved ejection fraction to allow time for consideration of the next steps.23 Percutaneous or implanted devices might be used for days or days to weeks, respectively. For long-term management in chronic Stage D HF, three VAD strategies are defined: bridge to transplantation (BTT), bridge to candidacy (BTC), and destination therapy (DT).23 Survival and duration of VAD use depend on the strategy of support at time of VAD implantation, timing of implantation, medical comorbidities, and patient age, among other factors.130 BTT indicates a person who is a heart transplant candidate but is not likely to survive to receive a transplant without VAD support. BTC indicates a person in whom LVAD support may allow a transition to becoming a transplant candidate (e.g., reversal of pulmonary hypertension), while DT is for someone with advanced HF who is not a transplant candidate and is likely to die without VAD support. In 1994, the US FDA approved an LVAD for BTT, and the first wearable device was used.129 In 2002, the US FDA approved LVADs for DT.129 The 2001 REMATCH study131 drew increased attention to this category. It demonstrated dramatically improved survival and quality of life in patients with LVADs when compared to medical therapy for those not transplant eligible.131 Average 1- and 2-year survival rates were 52 and 23% for those with LVADs compared to 25 and 8%, respectively, for those receiving medical management; health-related quality of life was also superior at 1 year for the LVAD group.131 More recent LVAD studies report an average 1-year survival figure of 74%130 and a predicted 2-year survival of 87%.132 Overall, VAD patients have survival rates of 80% at 1 year and 70% at 2 years per US and international registries.7,133 VADs can also rarely create a bridge to recovery (BTR) pathway. The native heart recovers adequate function to have VAD explantation and survival without heart transplant. Despite the compelling evidence of recovery in some cases, overall rates for achieving successful VAD explantation are low at 5–24% in different case series.134 Interestingly, one study reports comparable outcomes for BTR and BTT VAD pathways with a suggestion that a portion of transplants may be avoidable in the future.135 As with other cardiac technologies, VAD use is primarily limited to higher income countries. The high costs and need for tertiary HF centers, and ideally, cardiac transplant programs, remain barriers to global VAD access.136 Despite access limitations, growing efforts have led to established registries of mechanical support device use at national and international levels. In the US, FDA-approved VAD use has been prospectively monitored by the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) since 2005.137 The Pediatric Interagency Registry for Mechanically Assisted Circulatory Support (PEDIMACS)138 was created in late 2012 to capture similar data unique to those younger than 19 years old. In early 2013, the International Registry for Mechanical Assist Circulatory Support (IMACS) was established, building on prior efforts to create a worldwide data repository to monitor mechanical support device implantations and patient outcomes.139 IMACS data continues to expand, currently representing 35 countries, including 24 individual hospitals and 4 multicenter collectives: the United Kingdom’s UK Registry, Japan’s JMACS, Europe’s EUROMACS, and INTERMACS.140 The third IMACS annual report analyzing

853 data through 2017 revealed a trend toward DT as a growing, now dominant LVAD pathway in the US.140 This shift toward MCS for a predicted terminal pathway was not seen in data for Europe or the Asia Pacific region.140 In line with this trend suggesting significant medical acuity in patients, an earlier IMACS report indicated that more than half of LVAD recipients were in cardiogenic shock or rapid decline when implanted and that 28, 29, and 41% were in the BTT, BTC, and DT pathways, respectively.133 INTERMACS reports data from 185 US hospitals with more than 2500 new implants reported annually as of December 2016.7 Similar to the IMACS trend above, INTERMACS data shows almost 50% of LVADs implanted for DT, with 25 and 23% for BTT and BTC, respectively, as of 2015.7 TAH represented 2% and biventricular VAD support 5% of total implants.7 PEDIMACS reports 508 device implants for 30 US hospitals from 2012 to 2017.141 Implants were 81, 15, and 1% for LVAD, biventricular support, and TAH, respectively.141 Showing quite different trends in the pediatric population, indications were 55, 34, 6, and 2% for BTT, BTC, BTR, and DT, respectively.141 Multiple different guidelines representing higher income countries support VAD use for BTT and DT with an emphasis on appropriate patient selection.25–27 Importantly, even though device indications and guidelines are expanding in some countries, access to devices varies even among higher income countries. For instance, the National Health Service has limited the use of VADs in the United Kingdom to BTT or BTR while debating payment extension to DT.142 Early INTERMACS data was used to define seven clinical patient profiles of those being considered for VAD therapy.143 These profiles reflect the subsets of patients in NYHA Classes III and IV, spanning the spectrum of Profile 1, critical cardiogenic shock, and Profile 2, progressive decline, to Profile 7, advanced NYHA Class III symptoms. INTERMACS and other data show patient outcomes to be better when LVADs are implanted earlier, at times when patients are less severely ill.144,145 Over time, VAD innovation has led to smaller devices, improved safety, more dependable access to a power source, more advanced surgical approaches, and the transition from pulsatile to continuous-flow devices. Studies show VADs can increase functional status and quality of life and decrease pain,146 depression, and anxiety.147 Advances leading to smaller devices have led to a wave of new implantable, continuous-flow VADs that are currently in pediatric trials.148 Today, LVADs are helping more patients achieve mobility and independence at home.

VAD costs and complications

Few publications address LVAD costs, and methods vary when they do. Figures from Norway indicate two device costs of $32,000 (2005–2009) and $58,000 (2009–2011) and average costs from implantation to hospital discharge of $378,450 and $346,403, respectively.149 Other single-center studies show variable figures, suggesting LVAD and heart transplant costs are comparable at 1 year, $369,519 and $329,648, respectively,150 and that LVAD costs are double transplant cost at 1 year.151 VADs can clearly have a palliative role in advanced HF. Survival can usually be extended and quality of life improved. If all goes well, the palliative framework may even shift to one of survivorship with DT as permanent palliation. However, these gains are often balanced by potential serious complications, treatment burden, and persistently high mortality rates, even above 20% at 30–90 days in some studies.167 For early complications, bleeding is the most common, surgical initially and thereafter GI, followed

854 by infection, sometimes involving the driveline; then, infection becomes most common after 3 months.7 Seventy-five percent of patients will have infection, bleeding, stroke, LVAD thrombosis, or right ventricular failure in the first year,153 including rehospitalization for some. In one trial, 35% of LVADs had a malfunction at 2 years.131 Intensive care, including chronic renal replacement and ventilator support, may be necessary and results in an extended course with critical illness.154 If death occurs, sepsis, multi-organ system failure, stroke, and right HF are common causes.155 In less acute circumstances, the burden of device alarms, reliance on a power supply, increased anxiety, early satiety and anorexia from device size in the abdomen,156 altered mobility, and other medical complications, like pressure ulcers, may be central for a patient and family.

Palliative care role for VAD management Communication

As with pacemakers and ICDs, communication and the shared decision-making model6 are critical and recommended for clinicians and patients starting at preimplantation for VAD.6,10 Many experts are now recommending early involvement of palliative care teams in the VAD course to optimize patient care in all interdisciplinary domains.6,10,152,157,158 The clinician role in facilitating patient understanding around this high level of medical complexity is challenging but crucial for all device strategies (BTT, DT, etc.), especially for introducing alternative treatment pathways and the possibility of future VAD withdrawal. Ideally, patients clarify for their clinicians and loved ones what matters most to them about living and dying. Clinicians can then make recommendations that help patients to better align goals and values with treatment options. Achieving adequate informed consent for implantation may be a true test,154 especially when emergent events remove or challenge a patient’s decision-making capacity. Although VAD programs have structured processes for patient selection and implantation, the steps may blur when all want an imminently dying patient to live.152,159 The value of longitudinal communication and shared decision-making upstream for all advanced HF patients in just this situation cannot be overemphasized. Serial communications to revisit VAD patient goals, values, and preferences in alignment with cardiac disease status, current and potential therapies, and other medical conditions should occur regularly and address ACP. One study found that less than 50% of patients with LVADs had advance directives, and of those, none specifically mentioned LVAD end-of-life wishes.160 ACP should thus be fully integrated, potentially using the “hope for the best, plan for the worst” approach and emphasizing clinician continuity.6 Triggers for these discussions, similar to those previously mentioned (see Table 90.1), are also suggested. For VADs, new serious complications like stroke or renal failure, the need for additional life support measures, and loss of eligibility for heart transplantation could be other potential triggers for proactive communication. Research has suggested improved ACP, end-of-life planning, symptom management, and holistic care with palliative care team involvement for potential or current VAD patients.161 “Preparedness planning”10 is a proposed term in use describing a model of proactive palliative medicine consultation for VAD patients and families. It begins prior to implantation and continues with serial discussions over time, using proposed strategies to define patient goals in line with the disease course.162 Others have emphasized the need for a detailed informed consent process specific to VADs with similar emphasis.,159,163 More recently,

Textbook of Palliative Medicine and Supportive Care a group of investigators has created decision support materials for patients and their families considering DT LVAD therapy.164,165 In this study, those patients receiving clinician education using the LVAD decision-aid video and booklet had increased knowledge and better decision quality (higher concordance with stated values and treatment choice) early on in their course.164

Focused support for caregivers

In the US, a designated caregiver is usually required prior to eligibility for LVAD implantation. Caregivers go through a parallel process to patients in adapting to life with an LVAD and need specific focused education and guidance, again, even moreso due to the high medical complexity around device use.166 The potential for fear, anxiety, and guilt is high due to responsibility for multiple aspects of device management and daily care of someone with increased care needs.166 Palliative care clinicians have the potential to augment LVAD management teams in addressing unmet caregiver needs across settings. Respite options, support networks and materials, and caregiver rotation for a specific patient may be useful. A more specific area of often unmet need for caregivers is how to understand advancing illness and complications for a loved one with a VAD. A study of bereaved caregivers indicates they can be very surprised and confused when the end of life is nearing for the person with an LVAD.167 As well, they report not knowing what to expect in dying process with an LVAD and who to contact for help in the EMS to hospice spectrum.167 Caregivers may question the permissibility of deactivating a device and experience anxiety at the time near dying.167 Palliative care has the potential to fill in many of these gaps in care. Palliative care clinicians and teams can provide caregiver support and education and facilitate needed communication while also facilitating other domains of patient-centered care for LVAD patients and their families.

VAD withdrawal

When VAD benefits no longer outweigh burdens for a patient or meet a patient’s goals, withdrawal of the VAD should be considered. Whether the VAD is BTT or DT, the poor prognosis of advanced HF has worsened. Routine VAD withdrawal is not invasive and does not require surgery. Though, as with pacemakers and ICDs, great preparation and coordination is required. Decisionmaking and planning should be clearly documented in the medical record; it should outline decision-making capacity and symptom assessment and management, including anxiety and depression.168 Consultation with ethical and legal support may be appropriate in some cases. Beyond appropriate clarification of the goals of care, if the choice for deactivation is made, technical aspects should be clarified with the whole team, including technicians or perfusionists, in line with an optimal end-of-life setting for the patient and family. Involvement of an interdisciplinary palliative care team is ideal to address whole-person care for the patient and family and may improve the experience around VAD withdrawal for all involved.168 Education for all involved about expectations for the order and flow of events is important. Average time to death after VAD withdrawal was about 20 minutes in one study157 and 1 day or less in another.158 Comparison has been made to an endotracheal ventilator withdrawal scenario.6 Thus, families should be counseled to prepare for a very short timeframe of minutes with the caveat that one of the hours or longer is possible. Very rarely, a patient’s native heart function may be stronger than anticipated and allow

Implantable Cardiac Devices for brief stabilization, perhaps even transition to another site of care. VAD patients may be receiving other life-prolonging therapies, like mechanical ventilation, vasopressors, or hemodialysis, and the potential for deactivation of these interventions needs to be clarified and prioritized. ICDs, if present, should be deactivated in preparation for VAD withdrawal. Resuscitation status will likely need clarification with updating of paperwork to allow natural death during VAD withdrawal. Symptom assessment before, during, and after the withdrawal will focus on dyspnea, anxiety, and pain from the anticipated decrease in cardiovascular support. The medications to be ordered and immediately available at the bedside do not differ from those needed for pacemakers and ICDs. Premedication with opioids and anxiolytics before VAD withdrawal should be strongly considered to ensure adequate circulation of medications prior to decreased cardiac function. Dosing is based on medications already in use and symptoms prior to withdrawal. This planning will ideally be discussed with the patient or family based on anticipated distress and medication effects. Some patients may request sedation during the procedure, while others may not. A recommended checklist of steps for VAD withdrawal is provided for guidance (see Table 90.2) with other examples accessible.169 Of note, guidelines and checklists for withdrawal of VADs in children are lacking and needed.170 Once family members are present and ready, a device technician can plan for alarm silencing. Heart, blood pressure, and pulse oximetry monitors should be turned off. The technician can then turn off the device; this is generally an act of unplugging the power source. The presence of physician is needed for the duration if the timeframe is short, or until the patient appears clinically stable, particularly for continued assessment, reassurance, and education. When a last breath is taken, standard death pronouncement and postdeath care are conducted with the device left in place. The VAD may be removed later during the preparation of the body depending on chosen rituals.

Practical concerns

When patients have a good functional outcome with VAD therapy, they can often transition from the hospital setting to home or a nursing facility with their devices. If their medical status changes and the decision is made for VAD withdrawal, patients may also wish to die in these settings.6,171 While there is no medical, ethical, or legal barrier to this, practical considerations, like physician expertise, may be a challenge. As with pacemakers and ICDs, physician leadership in coordinating events and achieving the technical support and appropriate interdisciplinary team may be difficult to organize outside a hospital.

Practice and attitudes in VAD withdrawal

Training in end-of-life VAD management has been limited to date,172 though HF specialists are expected to be competent in VAD withdrawal.173 Cardiologists are more likely than hospice and palliative medicine physicians to believe that VAD withdrawal should only occur in an imminently dying person.174 Cases of VAD withdrawal occur and are becoming more common.163,175 In two groups of nearly 70 VAD patients, 24157 and 21%158 requested device withdrawal. Evidence suggests that new or worsening comorbidities serve as a primary trigger for patient or clinician consideration of LVAD withdrawal, specifically sepsis, stroke, cancer, renal failure, and pump failure.157 Research is needed to better document current practices and attitudes among clinicians, patients, and families and to define

855 standards of practice. In one survey, 61% of hospices reported accepting patients with LVADs, though lack of experience with the devices was noted as the most common barrier; hospices requested training from experts.176 Some institutions have a more structured, proactive approach to defining VAD patient wishes and decisions near the end of life and facilitating a smooth withdrawal process.10,157 Many do not. In one program review of 20 VAD patients who died,157 11 died at home, 8 in the hospital, and 1 in a nursing home. All were offered hospice and/or palliative care support and noted to have appropriate symptom management at time of death. Seventeen chose to turn off their device, while 3 continued the VAD until death, another 2–5 months. In another review of 14 VAD patients,158 12 died in the hospital and 2 in hospice units. Two patients made their own decisions for withdrawal, and surrogates acted for the other 12.

Ethical and legal considerations

Despite some who disagree, broad consensus supports decisions for VAD withdrawal in the same way that other life-sustaining measures may be discontinued.6,117,157,159,163 Informed consent and symptom control to prevent physical suffering are part of this ethical framework. For some, the newness of the technology may lead to questioning the ethics of VAD withdrawal. As with the aforementioned discussion of pacemakers and ICDs, some may object to VAD withdrawal based on characteristics of the device (being surgically implanted and taking over an essential physiologic function) or a perceived overlap with assisted suicide and euthanasia.158 Some specifically struggle with the extent to which the LVAD changes the physiology of the dying process once turned off.117,163 Personal beliefs and emotions may also differ from the ethical consensus. Conscientious objection is always an option for clinicians and technicians. Cultural, religious, and legal differences around the world may also affect the option of VAD withdrawal. Palliative care and ethics committee involvement is encouraged when clinicians, patients, or families struggle with these dilemmas.157,159 Ethical concerns may also arise before VAD withdrawal, or if withdrawal is not pursued, when a patient is judged to be receiving more burden than benefit from a VAD. Of course, this is the common situation for those considering VAD withdrawal, as discussed earlier. Some have termed this condition “destination nowhere” reflecting prolonged suffering without improvement in a DT VAD course.177 All involved may develop distress over the ongoing VAD support if patient suffering continues. The recognition of this ethically complex endpoint has led some to advocate for more stringent processes for the selection of and communication with potential DT VAD patients.159,177 Excluding patients from DT who do not have the capacity to voluntarily consent and those in whom implantation would be rushed to prevent imminent death has been proposed.159

Conclusion The landscape of advanced HF management continues to evolve rapidly with advancing technology. Implantable cardiac devices, pacemakers, ICDs, and VADs, in particular, have created exciting opportunities for improved patient quality of life, function, and survival. These devices have a clear role in the palliative realm. However, they do not prevent death or disability. Although they may change the course of a patient’s illness in a positive way, they may also adversely affect a patient with significant complications and adverse events, prolonging dying and

Textbook of Palliative Medicine and Supportive Care

856 increasing suffering. Even in the best scenario, the role of a given device will be temporary as that person ages and eventually dies, often with the device in place. Palliative care clinicians and teams can collaborate with HF colleagues to address many of the unmet care needs around implantable cardiac devices for HF patients and their families. A palliative approach includes shared decision-making with attention to informed consent and ACP processes starting at preimplantation. Ideally, this preparedness planning process also integrates (1) specific attention to the caregiver role with focused education and support around the implantable device and (2) serial points of continued communication and reassessment of device appropriateness over a patient’s lifetime. Routine checkups and specific events, like a new terminal diagnosis, progressing noncardiac illness, progression of HF with increasing symptom burden, or the need for battery replacement, should trigger such reviews. If and when the decision is made to deactivate or withdraw a device, a structured palliative approach to informed consent, communication, education, coordination, symptom management, and the spiritual, social, and emotional needs of the patient/family/team is essential. Palliative care specialty level expertise is expanding in this area along with the literature. It has an increasingly defined and valued role for HF patients with implantable devices and their families. Helpful resources are available.

References











1. Goldberger Z, Lampert R. Implantable cardioverter-defibrillators: expanding indications and technologies. J Am Med Assoc 2006;295(7): 809–818. 2. Linde C, Ellenbogen K, McAlister FA. Cardiac resynchronization therapy (CRT): clinical trials, guidelines, and target populations. Heart Rhythm 2012;9(Suppl. 8):S3–S13. 3. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147–e239. 4. Kramer DB, Kesselheim AS, Brock DW, Maisel WH. Ethical and legal views of physicians regarding deactivation of cardiac implantable electrical devices: a quantitative assessment. Heart Rhythm 2010;7: 1537–1542. 5. Kramer DB, Kennedy KF, Noseworthy PA, et al. Characteristics and outcomes of patients receiving new and replacement implantable cardioverter defibrillators: results from the NCDR. Circ Cardiovasc Qual Outcomes 2013;6:488–497. 6. Allen LA, Stevenson LW, Grady KL, et al. Decision making in advanced heart failure: a scientific statement from the American Heart Association. Circulation 2012;125(15):1928–1952. 7. Kirklin JK, Paganini FD, Kormos RL. Eighth annual INTERMACS report: special focus on framing the impact of adverse events. J Heart Lung Transplant 2017;36:1080–1086. 8. Goldstein NE, Lampert R, Bradley E, et al. Management of implantable cardioverter defibrillators in end-of-life care. Ann Intern Med 2004;141(11):835–838. 9. Lampert R, Hayes DL, Annas GJ, et al. Expert Consensus Statement on the Management of Cardiovascular Implantable Electronic Devices (CIEDs) in patients nearing end of life or requesting withdrawal of therapy. Heart Rhythm 2010;7(7):1008–1026. 10. Swetz KM, Freeman MR, Abou Ezzeddine OF, et al. Palliative medicine consultation for preparedness planning in patients receiving left ventricular assist devices as destination therapy. Mayo Clin Proc 2011;86(6):493–500. 11. Lewis WR, Luebke DL, Johnson NJ, et al. Withdrawing implantable defibrillator shock therapy in terminally ill patients. Am J Med 2006;119(10):892–896. 12. Desai AS, Schaefer KG, Tulsky JA, et al. Quality of death after left ventricular assist device implantation: more questions than answers. J Heart Lung Transpl 2019:38(4); 382–384.

13. Hunt SA, Abraham WT, Casey DE Jr., et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2005;46:e1–e82. 14. Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics-2018 update: a report for the American Heart Association. Circulation 2018;137(12):e67–e492. 15. Savarese G, Lund LH. Global public health burden of heart failure. Card Fail Rev 2017;3(1):7–11. 16. Stewart S, Ekman I, Ekman T, et al. Population impact of heart failure and the most common forms of cancer: a study of 1,162,309 hospital cases in Sweden (1988 to 2004). Circ Cardiovasc Qual Outcomes 2010;3:573–580. 17. Cubbon RM, Gale CP, Kearney LC, et al. Changing characteristics and mode of death associated with chronic heart failure caused by left ventricular systolic dysfunction: a study across therapeutic eras. Circ Heart Fail 2011;4:396–403. 18. Ponikowski P, Anker SD, Al Habib KF, et al. Heart failure: preventing disease and death worldwide. ESC Heart Fail 2014:1(1):4–25. 19. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart 2007;93:1137–1146. 20. Mendez GF, Cowie MR. The epidemiological features of heart failure in developing countries: a review of the literature. Int J Cardiol 2001;80:213–219. 21. Sliwa K, Damasceno A, Mayosi BM. Epidemiology and etiology of cardiomyopathy in Africa. Circulation 2005;112(23):3577–3583. 22. Marijon E, Mirabel M, Celermajer DS, Jouven X. Rheumatic heart disease. Lancet 2012;379:953–964. 23. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2017;70:776–803. 24. Chen J, Normand SL, Wang Y, Krumholz HM. National and regional trends in heart failure hospitalization and mortality rates for Medicare beneficiaries, 1998–2008. J Am Med Assoc 2011;306:1669–1678. 25. Ezekowitz JA, O’Meara E, McDonald MA, et al. 2017 Comprehensive update of the Canadian cardiovascular society guidelines for the management of heart failure. Can J Cardiol 2017;33(11):1342–1433. 26. Atherton JJ, Sindone A, De Pasquale CG, et al. National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Australian clinical guidelines for the management of heart failure 2018. Med J Aust 2018;209(8):363–369. 27. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016;37:2129–2200. 28. Kavalieratos D, Gelfman LP, Tycon LE, et al. Palliative Care in Heart Failure: rationale, evidence, and future priorities. J Am Coll Cardiol 2017; Oct;70(15):1919–1930. 29. Kaufman BD, Cohen HJ. Palliative care in pediatric heart failure and transplantation. Curr Opin Pediatr 2019; Oct;31(5):611–616. 30. Hauptman PJ, Swindle J, Hussain Z, Biener L, Burroughs TE. Physician attitudes toward end-stage heart failure: a national survey. Am J Med 2008;121(2):127–135. 31. Mond HG, Proclemer A. The 11th world survey of cardiac pacing and implantable cardioverter-defibrillators: calendar year 2009—A World Society of Arrhythmia’s Project. Pacing Clin Electrophysiol 2011;34:1013–1027. 32. Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke statistics—2020 update: a report from the American Heart Association. Circulation 2020;141(19):e139–e596. 33. Kirkpatrick JN, Papini C, Baman TS, et al. Reuse of pacemakers and defibrillators in developing countries: logistical, legal, and ethical barriers and solutions. Heart Rhythm 2010;7:1623–1627. 34. Bonny A, Ngantcha M, Yuyun M, et al. Cardiac arrhythmia services in Africa from 2011–2018: the second report from the Pan African Society of Cardiology Working Group on Cardiac Arrhythmias and Pacing. Europace 2020;22(3):420–433. 35. Baman TS, Kirkpatrick JN, Romero J, et al. Pacemaker reuse: an initiative to alleviate the burden of symptomatic bradyarrhythmia in impoverished nations around the world. Circulation 2010;122:1649–1656. 36. Groh WJ. You shouldn’t take it with you: postmortem device reuse. Heart Rhythm 2012;9:215–216.

Implantable Cardiac Devices 37. Bogáts G, Kovács G, Rudas L. Postmortem device reuse. Heart Rhythm 2012;9(6):e15. 38. Khairy TF, Lupien MA, Nava S, et al. Infections associated with resterilized pacemakers and defibrillators. N Engl J Med 2020;382:1823–1831. 39. Baman TS, Meier P, Romero J, et al. Safety of pacemaker reuse: a metaanalysis with implications for underserved nations. Circ Arrhythm Electrophysiol 2011;4:318–323. 40. Cleland JGF, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–1549. 41. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350(21):2140–2150. 42. Laish-Farkash A, Bruoha S, Katz A, et al. Morbidity and mortality with cardiac resynchronization with pacing vs. with defibrillation in octogenarian patients in a real world setting. Europace. 2017;19(8):1357–1363. 43. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–1853. 44. Ghio S, Freemantle N, Scelsi L, et al. Long-term left ventricular reverse remodeling with cardiac resynchronization therapy: results from the CARE-HF trial. Eur Heart J 2009;22:480–488. 45. DiMarco JP. Implantable cardioverter-defibrillators. N Engl J Med 2003;349:1836–1847. 46. Brignole M, Auricchio A, Baron-Esquivias G, et al. 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the taskforce on cardiac pacing and resynchronization therapy of the ESC. Eur Heart J 2013;34(29):2281–2329. 47. Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS Guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation 2019;140(8):e382–e482. 48. Mueller PS, Jenkins SM, Bramstedt KA, and Hayes DL. Deactivating implanted cardiac devices in terminally ill patients: practices and attitudes. Pacing Clin Electrophysiol 2008;31(5):560–568. 49. Kelley AS, Reid MC, Miller DH, et al. Implantable cardioverter defibrillator at end-of-life: a physician survey. Am Heart J 2009;157:702–708. 50. Morrison LJ, Calvin AO, Nora H, Storey PC Jr. Managing cardiac devices near the end of life: a survey of hospice and palliative care providers. Am J Hosp Palliat Care 2010;8:545–551. 51. Rhymes JA, McCullough LB, Luchi RJ, et al. Withdrawing very lowburden interventions in chronically ill patients. J Am Med Assoc 2000;283(8):1061–1063. 52. Harrington MD, Luebke DL, Lewis WR, et al. Cardiac pacemakers at the end of life #111. Palliative Care Fast Facts. 2017. https://www. mypcnow.org/fast-fact/cardiac-pacemakers-at-end-of-life/ (Accessed: June 2, 2020). 53. Whitlock SN, Goldberg IP, and Singh JP. Is pacemaker deactivation at the end of life unique? A case study and ethical analysis. J Palliat Med 2011;14(10):1184–188. 54. Berger JT. Ethics of deactivating implanted cardioverter defibrillators. Ann Intern Med 2005;142(8):631–634. 55. Braun TC, Hagen NA, Hatfield RE, & Wyse DG. Cardiac pacemakers and implantable defibrillators in terminal care. J Pain Symptom Manage 1999;18(2):126–131. 56. Wilkoff BL, Auricchio A, Brugada J, et al. HRS/EHRA Expert Consensus on the Monitoring of Cardiovascular Implantable Electronic Devices (CIEDs): description of techniques, indications, personnel, frequency, ethical considerations: developed in partnership with the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA); and in collaboration with the American College of Cardiology (ACC), the American Heart Association (AHA), the European Society of Cardiology (ESC), the Heart Failure Association of ESC (HFA), and the Heart Failure Society of America (HFSA). Endorsed by the Heart Rhythm Society, the European Heart Rhythm Association (a registered branch of the ESC), the American College of Cardiology, the American Heart Association. Europace 2008;10:707–725. 57. Ballentine JM. Pacemaker and defibrillator deactivation in competent hospice patients: an ethical consideration. Am J Hosp Palliat Care 2005; (1):14–19. 58. Padeletti L, Arnar DO, Boncinelli L, et al. EHRA Expert consensus statement on the management of cardiovascular implantable electronic devices in patients nearing end of life or requesting withdrawal of therapy. Europace 2010;12(10):1480–1489.

BK-TandF-BRUERA_9780367642037-200160-Chp90.indd 857

857 59. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:83–87. 60. CMS. National Coverage Determination for Implantable Automatic Defibrillators (20.4) document. http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=110&ncdver=3&CAId =39&ver=11&NcaName=Implantable+Cardioverter+Defibrillators+( ICDs)&CoverageSelection=National&KeyWord=ICD&KeyWordLook Up=Title&KeyWordSearchType=And&bc=gAAAABAACAAAAA%3 d%3d& (Accessed June 2, 2020). 61. Pavri BB, Lokhandwala Y, Kulkarni GV, et al. Reuse of explanted, resterilized implantable cardioverter-defibrillators: a cohort study. Ann Intern Med 2012;157(8):542–548. 62. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic cardiomyopathy. N Engl J Med 2004;350:2151–2158. 63. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–237. 64. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol 2006;48(5):e247–e346. 65. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018;72:e91–220. 66. Priori SG, Blomstrom-Lundqvist C, Mazzanti F, et al. 2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Euro Heart J 2015;36:2793–2867. 67. Klein HU, Meltendorf U, Reek S, et al. Bridging a temporary high risk of sudden arrhythmic death. Experience with the wearable cardioverter defibrillator. Pacing Clin Electrophysiol 2010;33(3): 353–367. 68. Spar DS, Bianco NR, Knilans TK, et al. The US experience of the wearable cardioverter-defibrillator in pediatric patients. Circ Arrhythm Electrophysiol 2018;11(7):e006163. 69. Withell B. Patient consent and implantable cardioverter defibrillators: some palliative care implications. Int J Palliat Nurs 2006;12(10):470–475. 70. Nambisan V, Chao D. Dying and defibrillation: a shocking experience. Palliat Med 2004;18(5):482–483. 71. Looi YC. And it can go on and on and on. J Pain Symptom Manage 2006;31:1–2. 72. Sears SF, Shea JB, Conti JB. How to respond to an ICD shock. Circulation 2005;111(23):e380–e382. 73. Ahmad M, Bloomstein L, Roelke M, et al. Patients’ attitudes toward implanted defibrillator shocks. Pacing Clin Electrophysiol 2000;23(6):934–938. 74. Goldstein NE, Mehta D, Siddiqui S, et al. “That’s like an act of suicide”: patients’ attitudes toward deactivation of implantable defibrillators. J Gen Intern Med 2008;23(Suppl. 1):7–12. 75. Eckert M, Jones T. How does an implantable cardioverter defibrillator (ICD) affect the lives of patients and their families? Int J Nurs Pract 2002;8(3):152–157. 76. Freedenberg V, Thomas SA, Friedmann E. Anxiety and depression in implanted cardioverter-defibrillator recipients and heart failure: a review. Heart Fail Clin 2011;7(1):59–68. Review. 77. Irvine J, Dorian P, Baker B, et al. Quality of life in the Canadian implantable defibrillator study (CIDS). Am Heart J 2002;144: 282–289. 78. Goldstein NE, Bradley E, Zeidman J, et al. Barriers to conversations about deactivation of implantable defibrillators in seriously ill patients: results of a nationwide survey comparing cardiology specialists to primary care physicians. J Am Coll Cardiol 2009;54(4):371–373. 79. Baman TS, Crawford T, Sovitch P, et al. Feasibility of postmortem device acquisition for potential reuse in underserved nations. Heart Rhythm 2012;9:21–214.

24/06/21 11:57 AM

858 80. Glikson M, Friedman PA. The implantable cardioverter defibrillator. Lancet 2001;357(9262):1107–1117. 81. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias: the Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. N Engl J Med 1997;337:1576–1583. 82. Costea A, Rardon DP, Padanilam BJ, et al. Complications associated with generator replacement in response to device advisories. J Cardiovasc Electrophysiol 2008;19(3):26–269. 83. Pitcher D, Soar J, Hogg K, et al. Cardiovascular implanted electronic devices in people towards the end of life, during cardiopulmonary resuscitation and after death: guidance from the Resuscitation Council (UK), British Cardiovascular Society and National Council for Palliative Care. Heart 2016;102:A1–A17. 84. Niewald A, Broxterman J, Rosell T, et al. Documented consent process for implantable cardioverter-defibrillators and implications for end-oflife care in older adults. J Med Ethics 2013;39(2):94–97. 85. Lampert R. Quality of life and end-of-life issues for older patients with implanted cardiac rhythm devices. Clin Geriatr Med 2012;28(4):693–702. 86. Frosch DL, Kaplan RM. Shared decision making in clinical medicine: past research and future directions. Am J Prev Med 1999;17:285–294. 87. Elwyn G, Edwards A, Kinnersley P, Grol R. Shared decision making and the concept of equipoise: the competences of involving patients in healthcare choices. Br J Gen Pract 2000;50:892–899. 88. Fried TR, Byers AL, Gallo WT, et al. Prospective study of health status preferences and changes in preferences over time in older adults. Arch Intern Med. 2006;166(8):890–895. 89. Wright AA, Zhang B, Ray A, et al. Associations between end-of-life discussions, patient mental health, medical care near death, and caregiver bereavement adjustment. J Am Med Assoc 2008;300(14):1665–1673. 90. Sulmasy LS, Bledsoe TA. American college of physicians ethics manual: seventh edition. Ann Intern Med 2019;170:S1–S32. 91. Haugaa KH, Potpara TS, Boveda S, et al. Patients’ knowledge and attitudes regarding living with implantable electronic devices: results of a multicentre, multinational patient survey conducted by the European heart rhythm association. Europace 2018;20(2):386–391. 92. Berger JT, Gorski M, Cohen T. Advance health planning and treatment preferences among recipients of implantable cardioverter defibrillators: an exploratory study. J Clin Ethics 2006;17(1):72–78. 93. Tajouri TH, Ottenberg AL, Hayes DL, Mueller PS. The use of advance directives among patients with implantable cardioverter defibrillators. Pacing Clin Electrophysiol 2012;35(5):567–573. 94. McGeary A, Eldergill A. Medicolegal issues arising when pacemaker and implantable cardioverter defibrillator devices are deactivated in terminally ill patients. Med Sci Law 2010;50:40–44. 95. Mueller PS, Ottenberg AL, Hayes DL, Koenig BA. “I felt like the angel of death”: role conflicts and moral distress among allied professionals employed by the U.S. cardiovascular implantable electronic device industry. J Interv Card Electrophysiol 2011; 32(3): 253–261. 96. Beets MT, Forringer E. Urgent implantable cardioverter defibrillator deactivation by unconventional means. J Pain Symptom Manage 2011;42(6):941–945. 97. Marinskis G, van Erven L, EHRA Scientific Initiatives Committee. Deactivation of implanted cardioverter-defibrillators at the end of life: results of the EHRA survey. Europace 2010;12:1176 98. Hammill SC, Kremers MS, Stevenson LW, et al. Review of the registry’s fourth year, incorporating lead data and pediatric ICD procedures, and use as a national performance measure. Heart Rhythm 2010;7:1340–1345. 99. Kramer DB, Buxton AE, Zimetbaum PJ. Time for a change—a new approach to ICD replacement. N Engl J Med 2012;366(4):291–293. 100. Merchant FM, Quest T, Leon AR, et al. Implantable cardioverter-­ defibrillators at end of battery life opportunities for risk (Re)stratification in ICD recipients. J Am Coll Cardiol. 2016:67(4):435–44. 101. United Nations. Convention on the Rights of the Child. No. GA res.44/25, annex, 44 UN GAOR Supp.(No.49) at 167, U.N. Doc. A/44/49 (1989). 1989. 102. Goldstein N, Carlson M, Livote E, Kutner JS. Brief communication: management of implantable cardioverter-defibrillators in hospice: a nationwide survey. Ann Intern Med 2010;152(5):296–299. 103. Sherazi S, Daubert JP, Block RC, et al. Physicians’ preferences and attitudes about end-of-life care in patients with an implantable cardioverter-defibrillator. Mayo Clin Proc 2008;83:1139–141. 104. Powell T. Life imitates work [A Piece of My Mind]. J Am Med Assoc 2011;305(6):542–543.

Textbook of Palliative Medicine and Supportive Care 105. Kapa S, Mueller PS, Hayes DL, Asirvatham SJ. Perspectives on withdrawing pacemaker and implantable cardioverterdefibrillator therapies at end of life: results of a survey of medical and legal professionals and patients. Mayo Clin Proc. 2010;85:981–990. 106. Kramer DB, Ottenberg AL, Gerhardson S, et al. “Just because we can doesn’t mean we should”: views of nurses on deactivation of pacemakers and implantable cardioverter-defibrillators. J Interv Card Electrophysiol 2011;32(3):243–252. 107. Daeschler M, Verdino RJ, Caplan AL, et al. Defibrillator deactivation against a patient’s wishes: perspectives of electrophysiology practitioners. Pacing Clin Electrophysiol 2015;38(8):917–24. 108. Goldstein NE, Mehta D, Teitelbaum E, et al. “It’s like crossing a bridge”: complexities preventing physicians from discussing deactivation of implantable defibrillators at the end of life. J Gen Intern Med 2008;23(Suppl. 1):2–6. 109. Kelley AS, Mehta SS, Reid MC. Management of patients with ICDs at the end of life (EOL): a qualitative study. Am J Hosp Palliat Care. January 2008–December 2009;25(6):440–46. 110. Kirkpatrick JN, Gottlieb M, Sehgal P, et al. Deactivation of implantable cardioverter defibrillators in terminal illness and end of life care. Am J Cardiol 2012;109(1):91–94. 111. Raphael CE, Koa-Wing M, Stain N, et al. Implantable cardioverter-defibrillator recipient attitudes towards device deactivation: how much do patients want to know? Pacing Clin Electrophysiol. 2011;34(12):1628–1633. 112. Herman D, Stros P, Curila K, et al. Deactivation of implantable cardioverter-defibrillators: results of patient surveys. Europace 2013;15(7):963–969. 113. Kobza R, Erne P. End-of-life decisions in ICD patients with malignant tumors. Pacing Clin Electrophysiol. 2007;30(7):845–849. 114. Dodson JA, Fried TR, Van Ness PH, et al. Patient preferences for deactivation of implantable cardioverter-defibrillators. JAMA Intern Med. 2013;173(5):37–379. 115. Annas GJ. The Rights of Patients: The Authoritative ACLU Guide to the Rights of Patients, 3rd edition. New York, NY: New York University Press; 2004. 116. Pellegrino ED. Decisions to withdraw life-sustaining treatment: a moral algorithm. J Am Med Assoc 2000;283:1065–1067. 117. Noah L. Turn the beat around: deactivating implanted cardiac-assist devices. William Mitchell Law Rev. 2013;30(4); Article 7. 118. Gostin LO. Deciding life and death in the courtroom. From Quinlan to Cruzan, Glucksberg, and Vacco—a brief history and analysis of constitutional protection of the “right to die”. J Am Med Assoc 1997;278:1523–1528. 119. Beauchamp TL, Childress JF. Principles of Biomedical Ethics, 7th ed. New York, NY: Oxford University Press; 2012. 120. AMA Council on Ethical and Judicial Affairs. Physician Objection to Treatment and Individual Patient Discrimination: CEJA Report 6-A07. Chicago, IL: AMA Press; 2007. 121. Rady MY, Verheijde JL. When is deactivating an implanted cardiac device physician-assisted death? Appraisal of the lethal pathophysiology and mode of death. J Palliat Med 2011;14(10):1086–1088. 122. Stuart B. On deactivating cardiovascular implanted electronic devices: let our people go. J Palliat Med 2001;14(10):1089–1090. 123. Paola FA, Walker RM. Deactivating the implantable cardioverter defibrillator: a biofixture analysis. South Med J 2000;93:20–23. 124. England R, England T, Coggon J. The ethical and legal implications of deactivating an implantable cardioverter-defibrillator in a patient with terminal cancer. J Med Ethics 2007;33:538–540. 125. Sulmasy DP. Within you/without you: biotechnology, ontology, and ethics. J Gen Intern Med 2008;23(Suppl. 1):69–72. 126. Morrison LJ, Sinclair CT. Next-of-kin responses and do-not-resuscitate implications for implantable cardioverter defibrillators [letter]. Ann Intern Med 2005;142(8):676–677. 127. Hertz MI, Taylor DO, Trulock EP, et al. The registry of the International Society for Heart and Lung Transplantation: nineteenth Official Report—2002. J Heart Lung Transplant 2002;21:950–970. 128. Swetz K, Matlock DD, Ferris H, et al. Palliative Care Fast Fact #205: Mechanical circulatory support in advanced heart failure. July 2015 Fast facts and concepts. Available at: http://https://www.mypcnow. org/fast-fact/mechanical-circulatory-support-in-advanced-heartfailure/ (Last accessed: June 2, 2020). 129. Goldstein DJ, Oz MC, Rose EA. Implantable left ventricular assist devices. N Engl J Med 1998;339(21):152–1533.

Implantable Cardiac Devices 130. Goldstein NE, May CW, Meier DE. Comprehensive care for mechanical circulatory support: a new frontier for synergy with palliative care. Circ Heart Fail 2011;4(4):519–527. 131. Rose EA, Gellins AC, Moskowitz AJ, et al. Long-term use of a left ventricular assist device for end stage heart failure. N Engl J Med 2001;345:1435–1443. 132. Pamboukian SV, Tallaj JA, Brown RN, et al. Improvement in 2-year survival for ventricular assist device patients after implementation of an intensive surveillance protocol. J Heart Lung Transplant 2011;30(8):879–887. 133. Kirklin JK, Xie R, Cowger J, et al. Second annual report from the ISHLT Mechanically Assisted Circulatory Support Registry. J Heart Lung Transplant 2018;37:685–691. 134. Birks EJ, Tansley PD, Hardy J, et al. Left ventricular assist device and drug therapy for the reversal of heart failure. N Engl J Med 2006;355(18):1873–1884. 135. Birks EJ, George RS, Firouzi A, et al. Long-term outcomes of patients bridged to recovery versus patients bridged to transplantation. J Thorac Cardiovasc Surg 2012;144(1):190–196. 136. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012;14(8):803–869. 137. Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). https://www.uab.edu/medicine/intermacs/ (Accessed June 2, 2020). 138. Pediatric Interagency Registry for Mechanically Assisted Circulatory Support (PEDIMACS) Registry. https://www.uab.edu/medicine/intermacs/pedimacs (Last accessed June 2, 2020). 139. International Registry for Mechanical Circulatory Support (IMACS) https://ishlt.org/registries/international-registry-for-mechanicallyassisted-c (Accessed June 2, 2020). 140. Goldstein DJ, Meyns B, Xie R, et al. Third annual report for the ISHLT Mechanically Assisted Circulatory Support Registry: a comparison of centrifugal and axial continuous-flow left ventricular assist devices. J Heart Lung Transplant 2019;38:352−363. 141. Morales DLS, Rossano JW, VanderPluym CV, et al. Third Annual Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) Report: preimplant characteristics and outcomes. Ann Thorac Surg 2019;107:993–1004. 142. Macgowan GA, Parry G, Schueler S, Hasan A. The decline in heart transplantation in the UK. Br Med J 2011;342:d2483. 143. Stevenson LW, Pagani FD, Young JB, et al. INTERMACS profiles of advanced heart failure: the current picture. J Heart Lung Transplant 2009;28(6):535–541. 144. Kirklin JK, Naftel DC, Pagani FD, et al. Seventh INTERMACS annual report: 15,000 patients and counting. J Heart Lung Transplant 2015;34:1495–1504. 145. Estep JD, Starling RC, Horstmanshof DA, et al. Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients: results from the ROADMAP study. J Am Coll Cardiol 2015;66:1747–1761. 146. Weerahandi H, Goldstein N, Gelfman LP, et al. Pain and functional status in patients with ventricular assist devices. J Pain Symptom Manage 2016;52:483–490. 147. Reynard AK, Butler RS, McKee MG, et al. Frequency of depression and anxiety before and after insertion of a continuous flow left ventricular assist device. Am J Cardiol 2014;114:433–440. 148. Burki S, Adachi I. Pediatric ventricular assist devices: current challenges and future prospects. Vasc Health Risk Manage 2017;13:177–185. 149. Mishra V, Fiane AE, Geiran O, et al. Hospital costs fell as numbers of LVADs were increasing: experiences from Oslo University Hospital. J Cardiothorac Surg 2012;7:76. 150. Patel SR, Sileo A, Bello R, et al. Heart transplantation versus continuous-flow left ventricular assist device: comprehensive cost at 1 year. J Card Fail 2015;21(2):160–166. 151. Marasco SF, Summerhayes R, Quayle M, et al.Current comparison of heart transplant vs. left ventricular assist device therapy at one year. Clin Transplant 2016:30:598–605. 152. Rizzieri AG, Verheijde JL, Rady MY, McGregor JL. Ethical challenges with the left ventricular assist device as a destination therapy. Philos Ethics Humanit Med 2008;3:20.

859 153. Warraich HJ, Maurer MS, Patel CB, et al. Top ten tips palliative care clinicians should now about caring for patients with left ventricular assist devices. J Palliat Med 2019:22(4);437–441. 154. Raiten JM, Neuman MD. If only I had known: on choice and uncertainty in the ICU. N Engl J Med 2012;367(19):1779–1781. 155. Lietz K, Long JW, Kfoury AG, et al. Outcomes of left ventricular assist device implantation as destination therapy in the post-REMATCH era: implications for patient selection. Circulation 2007;116(5): 497–505. 156. Stevenson LW, Shekar P. Ventricular assist devices for durable support. Circulation 2005;112:e111–e115. 157. Brush S, Budge D, Alharethi R, et al. End-of-life decision making and implementation in recipients of a destination left ventricular assist device. J Heart Lung Transplant 2010;29:1337–1341. 158. Mueller PS, Swetz KM, Freeman MR, et al. Ethical analysis of withdrawing ventricular assist device support. Mayo Clin Proc 2010;85(9):791–797. 159. Dudzinski DM. Ethics guidelines for destination therapy. Ann Thorac Surg 2006;81(4):1185–188. 160. Swetz KM, Mueller PS, Ottenberg AL, et al. The use of advance directives among patients with left ventricular assist devices. Hosp Pract (Minneap). 2011;39(1):78–84. 161. Schwarz ER, Baraghoush A, Morrissey RP, et al. Pilot study of palliative care consultation in patients with advanced heart failure referred for cardiac transplantation. J Palliat Med 2012;15(1):12–15. 162. Swetz KM, Kamal AH, Matlock DD, et al. Preparedness planning before mechanical circulatory support: a ‘‘how-to’’ guide for palliative medicine clinicians. J Pain Symptom Manage 2014;47(5):926–935. 163. Bramstedt KA, Wenger NS. When withdrawal of life-sustaining care does more than allow death to take its course: the dilemma of left ventricular assist devices. J Heart Lung Transplant 2001;20:544–548. 164. Allen LA, McIlvennan CK, Thompson JS, et al. Effectiveness of an intervention supporting shared decision making for destination therapy left ventricular assist device: the DECIDE-LVAD randomized clinical trial. JAMA Intern Med 2018;178:520–529. 165. Colorado Program for Patient Centered Decisions: LVAD decision aid. https://patientdecisionaid.org/lvad/ (Accessed June 2, 2019). 166. Adams EE, Wrightson ML. Quality of life with an LVAD: a misunderstaood concept. Heart Lung 2018;47:177–183. 167. McIlvennan CK, Jones J, Allen LA, et al. Bereaved caregiver perspectives on the end-of-life experience of patients with a left ventricular assist device. JAMA Intern Med 2016;176(4):534–539. 168. Slavin SS, Allen LA, McIlvennan CK, et al. Left ventricular assist device withdrawal: ethical, psychological, and logistical challenges. J Pall Med 2020;23(4):456–458. 169. Schaefer KG, Griffin L, Smith C, et al. An interdisciplinary checklist for left ventricular assist device deactivation. J Palliat Med 2014; 17(4):4–5. 170. Hollander SA, Axelrod DM, Bernstein D, et al. Compassionate deactivation of ventricular assist devices in pediatric patients. J Heart Lung Transplant 2016;35:564–567. 171. Panke JT, Ruiz GR, Elliott T, et al. Discontinuation of a left ventricular assist device in the home hospice setting. J Pain Symptom Manage 2016;52(2):313–317. 172. Dabbouseh NM, Kaushel S, Peltier W, et al. Palliative care training in cardiology fellowship: a national survey of the fellows. Amer J Hospice Palliat Med 2018;35(2):284–292. 173. Francis GS, Greenberg BH, Hsu DT, et al. ACCF/AHA/ACP/HFSA/ ISHLT 2010 clinical competence statement on management of patients with advanced heart failure and cardiac transplant: a report of the ACCF/AHA/ACP Task Force on Clinical Competence and Training. J Am Coll Cardiol 2010;56(5):424–453. 174. McIlvennan CK, Wordingham SE, Allen LA, et al. Deactivation of left ventricular assist devices: differing perspectives of cardiology and hospice/palliative medicine clinicians. J Card Failure 2017;23(9): 708–712. 175. Maclver J, Ross HJ. Withdrawal of ventricular assist device support. J Palliat Care 2005;21(3):151–156. 176. Groninger H, Gilhuly D, Walker KA. Getting to the heart of the matter: a regional survey of current hospice practices caring for patients with heart failure receiving advanced therapies. Am J Hosp Palliat Care 2019;36(1);55–59. 177. Bramstedt KA. Destination nowhere: a potential dilemma with ventricular assist devices. ASAIO J 2008;54(1):1–2.

91

SUPPORTIVE CARE FOR PATIENTS WITH ADVANCED CHRONIC KIDNEY DISEASE

Sara N. Davison

Contents Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������861 Which CKD patients need palliative/supportive care?���������������������������������������������������������������������������������������������������������������������������������������������861 Determining prognosis in patients with advanced CKD������������������������������������������������������������������������������������������������������������������������������������861 Decision-making regarding dialysis������������������������������������������������������������������������������������������������������������������������������������������������������������������������������863 Conservative kidney management (CKM)�������������������������������������������������������������������������������������������������������������������������������������������������������������863 Withdrawal of dialysis������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������864 Symptom management in advanced CKD�������������������������������������������������������������������������������������������������������������������������������������������������������������������866 Symptom prevalence and screening������������������������������������������������������������������������������������������������������������������������������������������������������������������������866 Epidemiology of pain in CKD�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������866 Pharmacologic management of pain in CKD��������������������������������������������������������������������������������������������������������������������������������������������������������866 WHO analgesic ladder�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������869 References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������870

Introduction Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function, present for a minimum of 3 months, with implications for health.1 It is classified on the basis of cause, glomerular filtration rate (GFR), and albuminuria category (Table 91.1). Stage 5 CKD is also known as end-stage kidney disease (ESKD), in which patients may need to consider whether renal replacement therapy in the form of either dialysis or a kidney transplant will prolong life or improve quality of life (QOL) versus conservative (non-dialysis) kidney management (CKM). Patients with advanced CKD are typically elderly: the average age of those starting chronic dialysis in most developed countries is approximately 65 years, and patients over the age of 75 are the fastest growing incident cohort of dialysis patients.2 As CKD advances, patients typically experience numerous, complex comorbidities (e.g., heart disease, diabetes, and geriatric syndromes), high symptom burden, and substantial emotional and spiritual suffering. Even for patients who elect to start dialysis, the mortality rate is extremely high at 20–25%/year, rivaling that of most cancers (Table 91.2). Incident dialysis patients aged 65–74 years have a survival probability of ∼55% at 2 years and patients aged ≥75 years have ∼45% at 2 years.2 In North America and several European countries, approximately 15–25% of the annual mortality results from decisions to discontinue dialysis, representing the second leading cause of death after cardiovascular disease. There is growing recognition that people with advanced CKD have tremendous palliative care needs throughout their illness trajectory. Early integration of palliative care into kidney care is essential to optimize symptom control, facilitate advance care planning, and ease transitions toward the end of life and has the potential to improve markedly patient outcomes. 3,4 However, kidney palliative care needs a systematic approach combined with relevant training and dedicated resources and is probably best delivered through the combined expertise of nephrology

professionals, family- or community-based professionals, and specialist hospice or palliative care providers.4,5

Which CKD patients need palliative/supportive care? Not all CKD patients require palliative care. However, most patients will transition eventually to a trajectory of progressive functional decline associated with complex clusters of physical and psychological symptoms. Predicting and understanding patients’ needs aid in timely and effective planning of palliative services. At a minimum, those at high risk for death within the next year or those experiencing significant suffering, whether physical, psychosocial, or spiritual, should have a palliative care assessment. Table 91.3 outlines CKD patients most likely to benefit from palliative and supportive care services.

Determining prognosis in patients with advanced CKD

Illness trajectories are particularly heterogeneous among CKD patients,6 and predicting survival and other important outcomes such as symptom burden is difficult. For this reason, regular symptom assessment is important, and symptom management challenges may well be good reasons to refer patients to palliative care (Refs. 6A, 6B). However, to facilitate informed decisions about ongoing care, especially starting, withholding, or withdrawing dialysis, current clinical guidelines recommend that all patients with ESKD receive patient-specific estimates of prognosis.4,5 Factors associated with poor prognosis are summarized in Table 91.3. Age is a powerful risk factor for death (Table 91.2), with incident dialysis patients in most developed countries having remaining lifetimes that are on average one-fourth as long as non-dialysis patients of the same age and gender. Serum albumin level, both at baseline and during the course of dialysis treatment, is a consistent and strong predictor of death.6,7 Poor functional status is highly predictive of early death and the inability to transfer and falls are particularly indicative of 861

Textbook of Palliative Medicine and Supportive Care

862 TABLE 91.1 Kidney Disease: Improving Global Outcomes (KDIGO) Classification of CKD

TABLE 91.3  Patients Most Likely to Benefit from Palliative and Supportive Care

GFR Category

Description

G1 G2 G3a G3b G4 G5

Normal or high Mildly decreased Mildly to moderately decreased Moderately to severely decreased Severely decreased Kidney failure

• High mortality risk within the next year. – Patient who have chosen conservative kidney management (CKM) with an estimated GFR ≤ 10 mL/minute/1.73 m2 over the past 3 months. – Advanced age. – Answer “no” to the question “Would you be surprised if the patient died within the next 12 months?” – Functional decline. – Serum albumin 8, associated with ∼50% 1-year mortality) (12). – Prognostic models may also be used. Experiencing significant suffering, whether physical, emotional, psychosocial, or spiritual. This should be assessed using clinical tools measuring symptoms, such as the Edmonton Symptom Assessment System—revised: Renal (ESAS-r: Renal)34,37 or the Palliative care Outcome Scale (POS)—which has dedicated renal versions. Symptom deterioration can indicate an overall deterioration in health (Ref. 37A). • Considering withdrawal from dialysis or CKM. – Whenever possible, referrals should be before withdrawal of dialysis as aspects of management such as care at home may need considerable advanced planning. • Difficulty with end-of-life decision-making and determining goals of care. • Patient request.

GFR (mL/minute/1.73 m2)a ≥90 60–89 45–59 30–44 15–29