Critical Care Obstetrics [7 ed.] 9781119820239, 9781119820246, 9781119820253

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Seventh Edition

Critical Care Obstetrics Editor- in- Chief Luis D . Pacheco Editors Jeffrey R Phelan • Torre L. Halscott Leslie A. Moroz • Arthur J. Vaught Antonio F. Saad • Amir A. Shamshirsaz

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Critical Care Obstetrics

本书版权归John Wiley & Sons Inc.所有 0005731744.INDD 1

Critical Care Obstetrics Seventh Edition

Edited by Luis D. Pacheco Jeffrey P. Phelan Torre L. Halscott Leslie A. Moroz Arthur J. Vaught Antonio F. Saad Amir A. Shamshirsaz

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This seventh edition first published 2024 © 2024 John Wiley & Sons Ltd Edition History John Wiley and Sons [6e, 2019; 5e, 2011] All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions. The right of Luis D. Pacheco, Jeffrey P. Phelan, Torre L. Halscott, Leslie A. Moroz, Arthur J. Vaught, Antonio F. Saad, and Amir A. Shamshirsaz to be identified as the authors of the editorial material in this work has been asserted in accordance with law. Registered Offices John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK For details of our global editorial offices, customer services, and more information about Wiley products, visit us at www.wiley.com. Wiley also publishes its books in a variety of electronic formats and by print-­on-­demand. Some content that appears in standard print versions of this book may not be available in other formats. Trademarks: Wiley and the Wiley logo are trademarks or registered trademarks of John Wiley & Sons, Inc. and/or its affiliates in the United States and other countries, and may not be used without written permission. All other trademarks are the property of their respective owners. John Wiley & Sons, Inc. is not associated with any product or vendor mentioned in this book. Limit of Liability/Disclaimer of Warranty The contents of this work are intended to further general scientific research, understanding, and discussion only, and are not intended and should not be relied upon as recommending or promoting scientific method, diagnosis, or treatment by physicians for any particular patient. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials, or promotional statements for this work. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. Library of Congress Cataloging-­in-­Publication Data Names: Pacheco, Luis D., editor. Title: Critical care obstetrics / edited by Luis D. Pacheco, Jeffrey P. Phelan, Torre L. Halscott, Leslie A. Moroz, Arthur J. Vaught, Antonio F. Saad, Amir A. Shamshirsaz. Other titles: Critical care obstetrics (Clark) Description: Seventh edition. | Hoboken, NJ : Wiley 2024. | Includes bibliographical references and index. Identifiers: LCCN 2023048998 (print) | LCCN 2023048999 (ebook) | ISBN 9781119820239 (cloth) | ISBN 9781119820246 (adobe pdf) | ISBN 9781119820253 (epub) Subjects: MESH: Pregnancy Complications | Critical Care–methods | Pregnancy Classification: LCC RG951 (print) | LCC RG951 (ebook) | NLM WQ 240 | DDC 618.2/0231–dc23/eng/20240112 LC record available at https://lccn.loc.gov/2023048998 LC ebook record available at https://lccn.loc.gov/2023048999 Cover Design: Wiley Cover Images: © Liliboas/Getty Images; Kieran Stone/Getty Images; Justin Paget/Getty Images Set in 9.5/12.5pt STIXTwoText by Straive, Pondicherry, India

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Contents Notes on Contributors  ix Foreword  xvii Preface  xix Part One  Basic Critical Care Clinical and Surgical Principles  1 1 Epidemiology of Critical Illness in Pregnancy  3 Cande V. Ananth and John C. Smulian 2 Organizing an Obstetrical Critical Care Unit: Care without Walls  17 Lilly Y. Liu and Leslie Moroz 3 Critical Care Obstetric Nursing  33 Nan H. Troiano and Suzanne McMurtry Baird 4 Pregnancy-­Induced Physiologic Alterations  49 Julian N. Robinson and Jeffrey P. Phelan 5 Maternal Blood Gas Physiology  77 Aaron B. Caughey 6 Fluid and Electrolyte Balance  95 William E. Scorza and Sharon Maynard 7 Interventional Radiology in Pregnancy  123 Arsalan Saleem, Sania Javed, Irfan Masood, and Eric M. Walser 8 Fetal Considerations in the Critically Ill Gravida  133 Jeffrey P. Phelan 9 Fetal Effects of Drugs Commonly Used in Critical Care  163 Anthony Kendle and Sarah Gloria Običan 10 Maternal–Fetal Oxygenation  189 Alfred D. Fleming and Marsha Henn 11 Cardiopulmonary Resuscitation (CPR) in Pregnancy  199 Terri–Ann Bennett  and Carolyn M. Zelop

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Contents

12 Neonatal Resuscitation in the Critical Care Setting  209 Jay P. Goldsmith and Gilbert I. Martin 13 Ventilator Management in Critical Illness  233 Luis D. Pacheco and Antonio F. Saad 14 Vascular Access  267 Eryn Hart, Gayle Olson, and Aristides P. Koutrouvelis 15 Nutritional Support  283 Bill Tang, Michael J. Tang, and Jeffrey P. Phelan 16 Acute Kidney Injury and Renal Replacement Therapy  291 Luis D. Pacheco and Chasey I. Omere 17 Cardiopulmonary Bypass  305 Erin G. Sreshta, Tris M. Miller, and Alexis L. McQuitty 18 ECMO in Obstetrics  323 Emily E. Naoum, Amir A. Shamshirsaz, and Luis D. Pacheco 19 Antibiotics, Antivirals, and Antifungals in Critical Care  335 Amir A. Shamshirsaz and Arthur J. Vaught 20 Noninvasive Monitoring in Critical Care  361 Sarah Rae Easter 21 Critical Care Drills in Obstetrics  381 Monica A. Lutgendorf and Shad H. Deering 22 Maternal–Fetal Transport in the High-­Risk Pregnancy  397 Joshua A. Makhoul, Albert P. Sarno, Jr., and John C. Smulian Part Two  Acute Emergencies  411 23 Seizure and Status Epilepticus  413 Amir Arain and Michael W. Varner 24 Acute Spinal Cord Injury  423 Lisa R. Wenzel, Angela Vrooman, and Hunter Hammill 25 Severe Acute Asthma  443 Dharani K. Narendra and Nicola A. Hanania 26 Acute Respiratory Distress Syndrome in Pregnancy  455 Dharani K. Narendra, Munish Sharma, David Muigai, and Kalpalatha K. Guntupalli 27 The Acute Abdomen During Pregnancy  475 Ibrahim A. Hammad 28 Acute Pancreatitis  487 Anna S. Leung and Jeffrey P. Phelan

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Contents

29 Pneumonia During Pregnancy (Bacterial and Viral)  503 M. Ashley Cain and Judette M. Louis 30 Acute Fatty Liver of Pregnancy  519 Ibrahim A. Hammad and T. Flint Porter 31 Disseminated Intravascular Coagulation  527 Martina Burn, Hillary Hosier, Nazli Hossain, and Michael J. Paidas 32 Endocrine Emergencies  541 Mary C. Tolcher, Heather S. Hoff, Kjersti M. Aagaard, and Jeffrey P. Phelan 33 Acute Psychiatric Conditions in Pregnancy: Critical Care Obstetrics  555 Kelly B. Zafman and Adina R. Kern-­Goldberger 34 Diabetic Ketoacidosis  571 Mark A. Curran Part Three  Shock in Pregnancy  585 35 Hypovolemic Shock  587 Jerasimos Ballas and Scott Roberts 36 Blood Component Therapy and Massive Transfusion  603 Shiu-­Ki R. Hui, Kjersti M. Aagaard, and Jun Teruya 37 Etiology and Management of Hemorrhage (Includes Accreta)  627 Irene A. Stafford, Karin A. Fox, Michael A. Belfort, and Gary A. Dildy 38 Septic Shock  665 Sonya S. Abdel-­Razeq 39 Cardiogenic Shock  697 Martha W. F. Rac and Mary C. Tolcher 40 Anaphylactic Shock in Pregnancy  707 Richard Burwick 41 Amniotic Fluid Embolism  719 Gary A. Dildy, Michael A. Belfort, and Steven L. Clark Part Four  Medical/Surgical Management  737 42 Pregnancy-­Related Stroke  739 Loralei L. Thornburg, Jamil ElFarra, and James N. Martin, Jr. 43 Cardiac Disease and Pregnancy  775 Abby Frederickson, Jordan D. Awerbach, Roxann Rokey, Michael A. Belfort, and Wayne J. Franklin 44 Anesthesia Considerations for the Critically Ill Gravida with Cardiac Disease  813 Yi Deng, Sanjna Tripathy , Lisa Mouzi Wofford, Vibha Mahendra, and Shoba Murugan

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45 Thromboembolic Disease  831 Martha Pritchett Mims and Arthur J. Vaught 46 Pulmonary Hypertension in Pregnancy  849 Mohammad Zaidan and Alexander G. Duarte 47 Sickle Cell Disease and Pregnancy  869 Mark M. Udden and Iberia Romina Sosa 48 Thrombotic Thrombocytopenic Purpura, Hemolytic–Uremic Syndrome, and HELLP  883 Kelty R. Baker 49 Complications of Preeclampsia  901 Mary C. Tolcher and Kjersti M. Aagaard 50 Systemic Lupus Erythematosus and Antiphospholipid Syndrome  939 Fawzi Saoud and Maged M. Costantine 51 Trauma in Pregnancy  959 Robert Rossi, Alfredo F. Gei, Arthur J. Vaught, and James W. Van Hook 52 Thermal and Electrical Injury  987 Cornelia R. Graves 53 Overdose, Poisoning, and Envenomation during Pregnancy  995 Alfredo F. Gei, Victor R. Suarez, Arthur J. Vaught, and James W. Van Hook 54 The Organ Transplant Patient in the Obstetric Critical Care Setting  1053 Calla Holmgren and James Scott 55 Fetal Surgery Procedures and Associated Maternal Complications  1065 Eyal Krispin, Amir A. Shamshirsaz, Ahmed A. Nass, and Alireza A. Shamshirsaz 56 Cancer in the Pregnant Patient  1075 Kristin Bixel, Kenneth H. Kim, and David M. O’Malley 57 Mass Casualties and the Obstetrical Patient  1093 Lisa M. Foglia and Peter E. Nielson 58 Biological, Chemical, and Radiological Exposures in Pregnancy  1099 Lisa M. Foglia and Peter E. Nielson Part Five  Ethical and Legal Considerations  1109 59 Ethics in the Obstetric Critical Care Setting  1111 Fidelma B. Rigby 60 Medical–Legal Considerations in Critical Care Obstetrics  1137 Jeffrey P. Phelan Index  1161

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Notes on Contributors Aagaard, Kjersti M. Department of Obstetrics and Gynecology Division of Maternal–Fetal Medicine Baylor College of Medicine and Texas Children’s Hospital Houston, TX, USA Abdel-­Razeq, Sonya S. Obstetrics, Gynecology, and Reproductive Sciences Yale University New Haven, CT, USA Ananth, Cande V. Division of Epidemiology and Biostatistics Department of Obstetrics, Gynecology and Reproductive Sciences Rutgers Robert Wood Johnson Medical School New Brunswick, NJ, USA Department of Biostatistics and Epidemiology Rutgers School of Public Health Piscataway, NJ, USA Cardiovascular Institute of New Jersey New Brunswick, NJ, USA Environmental and Occupational Health Sciences Institute Rutgers Robert Wood Johnson Medical School New Brunswick, NJ, USA Arain, Amir Department of Neurology University of Utah Health Sciences Center Salt Lake City, UT, USA Awerbach, Jordan D. Department of Internal Medicine University of Arizona College of Medicine Phoenix, AZ, USA Department of Child Health University of Arizona College of Medicine Phoenix, AZ, USA

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Center for Heart Care Phoenix Children’s Phoenix, AZ, USA Baird, Suzanne McMurtry Co-­Owner and Nursing Director Clinical Concepts in Obstetrics, LLC Brentwood, TN, USA Baker, Kelty R. Houston Methodist Hospital Houston, TX, USA Ballas, Jerasimos Division of Maternal-­Fetal Medicine UC San Diego Health San Diego, CA, USA Belfort, Michael A. Department of Obstetrics and Gynecology Division of Maternal–Fetal Medicine Baylor College of Medicine Houston, TX, USA Bennett, Terri–Ann Division of Maternal–Fetal Medicine Department of Obstetrics and Gynecology New York University Langone Hospital Brooklyn New York, NY, USA Department of Obstetrics and Gynecology New York University Grossman School of Medicine New York, NY, USA Bixel, Kristin Division of Gynecologic Oncology Department of Obstetrics and Gynecology James Cancer Hospital and Solove Research Institute The Ohio State University Columbus, OH, USA

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Notes on Contributors

Burn, Martina Department of Obstetrics, Gynecology, and Reproductive Sciences Division of Maternal-­Fetal Medicine Yale University New Haven, CT, USA Burwick, Richard Division of Maternal–Fetal Medicine San Gabriel Valley Perinatal Medical Group Pomona Valley Hospital Medical Center Pomona, CA, USA Cain, M. Ashley Department of Obstetrics and Gynecology Division of Maternal–Fetal Medicine The University of South Florida Morsani College of Medicine Tampa, Florida, USA Caughey, Aaron B. Department of Obstetrics & Gynecology Oregon Health & Science University Portland, OR, USA Clark, Steven L. Department of Obstetrics and Gynecology Baylor College of Medicine Houston, TX, USA Costantine, Maged M. Division of Maternal–Fetal Medicine Department of Obstetrics and Gynecology The Ohio State University Columbus, OH, USA Curran, Mark A. San Gabriel Valley Perinatal Medical Group, Inc. West Covina, CA, USA Deering, Shad H. Department of Obstetrics and Gynecology Baylor College of Medicine Children’s Hospital of San Antonio San Antonio, TX, USA Deng, Yi Cardiac Anesthesia and Critical Care Medicine Ben Taub General Hospital Baylor College of Medicine Houston, TX, USA

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Dildy, Gary A. Department of Obstetrics and Gynecology Baylor College of Medicine Houston, TX, USA Department of Obstetrics and Gynecology St. Louis University School of Medicine St. Louis, MO, USA Duarte, Alexander G. Division of Pulmonary, Critical Care and Sleep Medicine University of Texas Medical Branch Galveston, TX, USA Easter, Sarah Rae Division of Maternal–Fetal Medicine Division of Critical Care Medicine Brigham and Women’s Hospital Harvard Medical School Boston, MA, USA ElFarra, Jamil Maternal–Fetal Medicine Norton Healthcare Louisville, KY, USA Fleming, Alfred D. Department of Obstetrics and Gynecology Maternal–Fetal Medicine Saint Luke’s Regional Medical Center Sioux City, IA, USA Foglia, Lisa M. Uniformed Services University of the Health Sciences Medical Education and Research Womack Army Medical Center Fayetteville, NC, USA Fox, Karin A. Department of Obstetrics and Gynecology Baylor College of Medicine Houston, TX, USA Franklin, Wayne J. Department of Internal Medicine University of Arizona College of Medicine Phoenix, AZ, USA Department of Child Health University of Arizona College of Medicine Phoenix, AZ, USA

Notes on Contributors

Center for Heart Care Phoenix Children’s Phoenix, AZ, USA Department of Obstetrics and Gynecology University of Arizona College of Medicine Phoenix, AZ, USA Frederickson, Abby Department of Internal Medicine University of Arizona College of Medicine Phoenix, AZ, USA Department of Child Health University of Arizona College of Medicine Phoenix, AZ, USA Gei, Alfredo F. Department of Obstetrics and Gynecology Division of Maternal–Fetal Medicine Houston Center for Maternal Fetal–Medicine Houston, TX, USA Goldsmith, Jay P. Department of Pediatrics Division of Neonatal Medicine Tulane University New Orleans, LA, USA Graves, Cornelia R. Tennessee Maternal-­Fetal Medicine PLC Saint Thomas Health, and the University of Tennessee Nashville, TN, USA Guntupalli, Kalpalatha K. Division of Pulmonary, Critical Care, and Sleep Medicine Department of Medicine Baylor College of Medicine Houston, TX, USA Hammad, Ibrahim A. Maternal–Fetal Medicine Department of Obstetrics and Gynecology University of Utah and Intermountain Healthcare Salt Lake City, UT, USA Hammill, Hunter Department of Physical Medicine Spinal Cord Injury Attending at TIRR Memorial Herman Hospital Houston, TX, USA

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Hanania, Nicola A. Division of Pulmonary, Critical Care, and Sleep Medicine Department of Medicine Baylor College of Medicine Houston, TX, USA Hart, Eryn Department of Obstetrics and Gynecology Division of Maternal–Fetal Medicine Spectrum Health/Michigan State University College of Human Medicine Grand Rapids, MI, USA Henn, Marsha Director of Quality Saint Luke’s Regional Medical Center Sioux City, IA, USA Hoff, Heather S. University of North Carolina Department of Obstetrics & Gynecology Division of Reproductive Endocrinology and Infertility Chapel Hill, NC, USA Holmgren, Calla Department of Obstetrics and Gynecology University of Utah Medical Center Salt Lake City, UT, USA Hosier, Hillary Department of Obstetrics, Gynecology, and Reproductive Sciences Division of Maternal-­Fetal Medicine Yale University New Haven, CT, USA Hossain, Nazli Department of Obstetrics and Gynecology Dow University of Health Sciences Karachi, Pakistan Hui, Shiu-­Ki R. Department of Pathology & Immunology and Department of Pediatrics Baylor College of Medicine Houston TX, USA Division of Transfusion Medicine & Coagulation Texas Children’s Hospital Houston, TX, USA

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Notes on Contributors

Javed, Sania Department of Radiology Division of Interventional Radiology The John Sealy School of Medicine University of Texas Medical Branch Galveston, TX, USA

Louis, Judette M. Department of Obstetrics and Gynecology Division of Maternal–Fetal Medicine The University of South Florida Morsani College of Medicine Tampa, Florida, USA

Kendle, Anthony Department of Obstetrics and Gynecology Morsani College of Medicine University of South Florida Tampa, FL, USA

Lutgendorf, Monica A. Department of Gynecologic Surgery & Obstetrics Uniformed Services University of the Health Services Bethesda, MD, USA

Kern-­Goldberger, Adina R. Department of Obstetrics and Gynecology Perelman School of Medicine University of Pennsylvania Philadelphia, PA, USA

Mahendra, Vibha Obstetric Anesthesia Department of Anesthesiology St Mary Medical Center Long Beach, CA, USA

Kim, Kenneth H. Division of Gynecologic Oncology Department of Obstetrics and Gynecology Cedars-­Sinai Medical Center Los Angeles, CA, USA

Makhoul, Joshua A. Scottsdale Perinatal Associates Phoenix, AZ, USA

Koutrouvelis, Aristides P. Department of Anesthesiology The University of Texas Medical Branch Galveston, TX, USA Krispin, Eyal Boston Children’s Hospital Department of Surgery, Maternal–Fetal Care Center Boston, MA, USA

Martin Jr., James N. Department of Obstetrics and Gynecology Division of Maternal–Fetal Medicine University of Mississippi, Medical Center Jackson, MS, USA Martin, Gilbert I. Department of Pediatrics Loma Linda University Medical Center Loma Linda, CA, USA

Harvard University Harvard Medical School Boston, MA, USA

Neonatal Intensive Care Unit Emanate Health Queen of the Valley Campus West Covina, CA, USA

Leung, Anna S. Department of Obstetrics and Gynecology Emanate Health Queen of the Valley Hospital West Covina, CA, USA San Gabriel Valley Perinatal Medical Group, Inc. West Covina, CA, USA

Masood, Irfan Department of Radiology Division of Interventional Radiology The John Sealy School of Medicine University of Texas Medical Branch Galveston, TX, USA

Liu, Lilly Y. Maternal–Fetal Medicine Department of Obstetrics and Gynecology Columbia University Irving Medical Center New York, NY, USA

Maynard, Sharon Division of Nephrology Department of Medicine Lehigh Valley Health Network Allentown, PA, USA

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Notes on Contributors

McQuitty, Alexis L. Cardiac Anesthesiology The University of Texas Medical Branch Galveston, TX, USA Shriners Children’s Texas Galveston, TX, USA Miller, Tris M. Anesthesiology Critical Care Medicine The University of Texas Medical Branch Galveston, TX, USA Mims, Martha Pritchett Department of Medicine Division of Hematology and Oncology Baylor College of Medicine Houston, TX, USA Moroz, Leslie Maternal–Fetal Medicine Department of Obstetrics, Gynecology and Reproductive Health Sciences Yale School of Medicine New Haven, CT, USA Muigai, David Division of Pulmonary, Critical Care, and Sleep Medicine Department of Medicine Baylor College of Medicine Houston, TX, USA Murugan, Shoba Obstetric Anesthesia Department of Anesthesiology University of Texas Medical Branch Galveston TX, USA Naoum, Emily E. Harvard Medical School/Massachusetts General Hospital Boston, MA, USA Narendra, Dharani K. Division of Pulmonary, Critical Care, and Sleep Medicine Department of Medicine Baylor College of Medicine Houston, TX, USA

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Nass, Ahmed A. Department of Medicine Division of Pulmonary Critical Care Baylor College of Medicine Houston, TX, USA Department of Obstetrics and Gynecology Division of Fetal Intervention Texas Children’s Hospital Baylor College of Medicine Houston, TX, USA Nielson, Peter E. Department of Obstetrics and Gynecology Baylor College of Medicine San Antonio, TX, USA O’Malley, David M. Division of Gynecologic Oncology Department of Obstetrics and Gynecology James Cancer Hospital and Solove Research Institute The Ohio State University Columbus, OH, USA Običan, Sarah Gloria Department of Obstetrics and Gynecology Morsani College of Medicine University of South Florida Tampa, FL, USA Olson, Gayle Department of Obstetrics and Gynecology Division of Maternal–Fetal Medicine The University of Texas Medical Branch Galveston, TX, USA Omere, Chasey I. Department of Obstetrics and Gynecology Division of Maternal–Fetal Medicine The University of Texas Medical Branch Galveston, TX, USA Pacheco, Luis D. Department of Obstetrics and Gynecology, and Anesthesiology Division of Maternal–Fetal Medicine and Surgical Critical Care The University of Texas Medical Branch Galveston, TX, USA

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Notes on Contributors

Paidas, Michael J. Department of Obstetrics and Gynecology Division of Maternal–Fetal Medicine University of Miami Health System Miami, FL, USA Phelan, Jeffrey P. San Gabriel Valley Perinatal Medical Group, Inc. West Covina, CA, USA Childbirth Injury Prevention Foundation Glendora, CA, USA Department of Obstetrics and Gynecology Citrus Valley Medical Center West Covina, CA, USA Director of Clinical Research Childbirth Injury Prevention Foundation City of Industry, CA, USA Department of Obstetrics and Gynecology Division of Maternal–Fetal Medicine Emanate Health Queen of the Valley Hospital West Covina, CA, USA Porter, T. Flint Maternal–Fetal Medicine University of Utah Health Sciences and Maternal–Fetal Medicine Intermountain Medical Center and LDS Hospital Intermountain Healthcare Salt Lake City, UT, USA Rac, Martha W. F. Department of Obstetrics & Gynecology Division of Maternal–Fetal Medicine Baylor College of Medicine and Texas Children’s Hospital Houston, TX, USA Rigby, Fidelma B. Department of Obstetrics and Gynecology Division of Maternal–Fetal Medicine MCV Campus of Virginia Commonwealth University Richmond, VA, USA Roberts, Scott High-­Risk Obstetrical Unit Parkland Hospital Department of Obstetrics and Gynecology University of Texas Southwestern Medical Center Dallas, TX, USA

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Robinson, Julian N. Harvard Medical School Division of Maternal-­Fetal Medicine Department of Obstetrics, Gynecology and Reproductive Biology Brigham and Women’s Hospital Boston, MA, USA Rokey, Roxann Department of Cardiology Marshfield Clinic Marshfield, WI, USA Rossi, Robert Department of Obstetrics and Gynecology Division of Maternal–Fetal Medicine University of Cincinnati College of Medicine Cincinnati, OH, USA Saad, Antonio F. Director of the Perinatal Research Unit and Maternal Fetal Medicine Fellowship MFM and Critical Care Specialist Inova Health Inova Fairfax Medical Campus Falls Church, VA, USA Saleem, Arsalan Department of Radiology Division of Interventional Radiology The John Sealy School of Medicine University of Texas Medical Branch Galveston, TX, USA Saoud, Fawzi Division of Maternal–Fetal Medicine Department of Obstetrics and Gynecology The Ohio State University Columbus, OH, USA Sarno, Jr., Albert P. Department of Obstetrics and Gynecology Lehigh Valley Health Network Allentown, PA, USA Department of Obstetrics and Gynecology Morsani College of Medicine University of South Florida Tampa, FL, USA

Notes on Contributors

Scorza, William E. Division of Maternal–Fetal Medicine Department of Obstetrics Lehigh Valley Hospital Allentown, PA, USA Scott, James Department of Obstetrics and Gynecology University of Utah Medical Center Salt Lake City, UT, USA Shamshirsaz, Alireza A. Boston Children’s Hospital Department of Surgery Maternal–Fetal Care Center Boston, MA, USA Harvard University Harvard Medical School Boston MA, USA Shamshirsaz, Amir A. Department of Obstetrics and Gynecology Division of Maternal–Fetal Medicine Texas Children’s Hospital Baylor St. Lukes Medical Center Houston, TX, USA Department of Medicine Division of Pulmonary Critical Care Baylor College of Medicine Texas Children’s Hospital Houston, TX, USA Sharma, Munish Division of Pulmonary, Critical Care, and Sleep Medicine Department of Medicine Baylor College of Medicine Houston, TX, USA Smulian, John C. Department of Obstetrics and Gynecology Division of Maternal–Fetal Medicine University of Florida College of Medicine Gainesville, FL, USA Sosa, Iberia Romina The Department of Hematology/Oncology Fox Chase Cancer Center Philadelphia, PA, USA

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Sreshta, Erin G. Cardiac Anesthesiology The University of Texas Medical Branch Galveston, TX, USA Stafford, Irene A. Department of Obstetrics and Gynecology University of Texas Health Sciences Center Houston, TX, USA Suarez, Victor R. Maternal–Fetal Medicine Attending Advocate Christ Medical Center Chicago, IL, USA Tang, Bill Department of Obstetrics and Gynecology Citrus Valley Medical Center West Covina, CA, USA Tang, Michael J. Universidad Autonoma de Guadalajara School of Medicine Guadalajara, Mexico Teruya, Jun Division of Transfusion Medicine & Coagulation Texas Children’s Hospital Houston, TX, USA Department of Pathology & Immunology Department of Pediatrics, and Department of Medicine Baylor College of Medicine Houston TX, USA Thornburg, Loralei L. Department of Obstetrics and Gynecology Division of Maternal–Fetal Medicine University of Rochester Rochester, NY, USA Tolcher, Mary C. Department of Obstetrics & Gynecology Division of Maternal–Fetal Medicine Baylor College of Medicine and Texas Children’s Hospital Houston, TX, USA Department of Critical Care The University of Texas MD Anderson Cancer Center Houston, TX, USA

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Tripathy, Sanjna MS 2 UT McGovern School of Medicine Houston, TX, USA Troiano, Nan H. Director, Women’s and Infants’ Services Adventist HealthCare Shady Grove Medical Center Rockville, MD, USA Udden, Mark M. Section of Hematology and Oncology Department of Medicine Baylor College of Medicine Houston, TX, USA

Walser, Eric M. Department of Radiology Division of Interventional Radiology The John Sealy School of Medicine University of Texas Medical Branch Galveston, TX, USA Wenzel, Lisa R. Department of Physical Medicine and Rehabilitation Baylor College of Medicine Houston, TX, USA Department of Physical Medicine Spinal Cord Injury Attending at TIRR Memorial Herman Hospital Houston, TX, USA

Van Hook, James W. Department of Obstetrics and Gynecology Division of Maternal–Fetal Medicine University of Toledo College of Medicine and Life Sciences Toledo, OH, USA

Wofford, Lisa Mouzi Division of Trauma and Regional Anesthesia Ben Taub General Hospital Baylor College of Medicine Houston, TX, USA

Varner, Michael W. Department of Obstetrics and Gynecology University of Utah Health Sciences Center Salt Lake City, UT, USA

Zafman, Kelly B. Department of Obstetrics and Gynecology Perelman School of Medicine University of Pennsylvania Philadelphia, PA, USA

Vaught, Arthur J. Department of Gynecology and Obstetrics Division of Maternal–Fetal Medicine Department of Surgery, Division of Surgical Critical Care The Johns Hopkins Hospital Baltimore, MD, USA

Zaidan, Mohammad Division of Pulmonary, Critical Care and Sleep Medicine University of Texas Medical Branch Galveston, TX, USA

Department of Medicine, Division of Hematology and Oncology Baylor College of Medicine Houston, TX, USA Vrooman, Angela Department of Physical Medicine University of Texas Health Science Center San Antonia, TX, USA

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Zelop, Carolyn M. Department of Obstetrics and Gynecology New York University Grossman School of Medicine New York, NY, USA Division of Maternal–Fetal Medicine Program Department of Obstetrics and Gynecology The Valley Hospital Ridgewood, NJ, USA

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­Foreword Maternal mortality in the United States is on the rise. The causes behind this increase are complex and multifactorial and include difficulty in accessing proper prenatal care, lack of insurance, limited access to early pregnancy termination, obesity, increased prevalence of cardiovascular ­disease among women of reproductive age, and improved surgical care of congenital heart disease allowing patients to live well into adulthood, just to name a few. As the medical complexity of these patients is expected to increase, it is mandatory that us, as maternal–fetal medicine specialists, to redefine our role in the care of high-­ risk pregnancies coexisting with medical and/or surgical complications. The passive role commonly adopted within multidisciplinary teams assembled to care for complicated

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pregnant patients should be replaced with a more ­proactive role where high-­risk pregnancy specialists become leaders of such teams aiming for improved maternal and neonatal outcomes. Training programs should be revised to increase clinical time for residents and fellows guarantying participation in key specialties including cardiology, pulmonary, and critical care medicine. The present book is expected to serve as an updated resource for those embarking in this desperately needed change in practice to improve pregnancy and neonatal ­outcomes in the setting of a rapidly changing and more complex population of pregnant women.

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Preface The current 7th edition of Critical Care Obstetrics comes with significant changes in content and with a new generation of editors. We acknowledge the valuable contributions of previous editors including David Cotton, Jeff Phelan, Steve Clark, Gary DV Hankins, Michael Belfort, Gary Dildy, George Saade, and Michael Foley. They are the true “fathers” of obstetrical critical care and have influenced all of us to follow their passion. For the current edition, we have added five new editors with extensive training and knowledge in critical care

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medicine. Each chapter has been revised and updated, and new chapters covering exciting topics, such as extracorporeal membrane oxygenation, pneumonia, antibiotics, antivirals, and antifungals, have been added. We hope the book serves to improve care of seriously ill pregnant patients around the world and stimulate younger generations to pursue excellence in maternal medicine.

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Part One Basic Critical Care Clinical and Surgical Principles

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1 Epidemiology of Critical Illness in Pregnancy Cande V. Ananth1–4 and John C. Smulian5 1 Division of Epidemiology and Biostatistics, Department of Obstetrics, Gynecology and Reproductive Sciences, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA 2 Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, NJ, USA 3 Cardiovascular Institute of New Jersey, New Brunswick, NJ, USA 4 Environmental and Occupational Health Sciences Institute, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA 5 Department of Obstetrics and Gynecology, Division of Maternal–Fetal Medicine, University of Florida College of Medicine, Gainesville, FL, USA

Introduction The successful epidemiologic evaluation of any disease or condition has several prerequisites. Two of the most important prerequisites are that the condition should be accurately defined and that there should be measurable outcomes of interest. Another requirement is that there must be some systematic way of data collection or surveillance that will allow the measurement of the outcomes of interest and associated risk factors. The epidemiologic evaluation of critical illness associated with pregnancy has met with mixed success on all of these counts. Historically, surveillance of pregnancy-related critical illness has focused on the well-defined outcome of maternal mortality in order to identify illnesses or conditions that might have led to maternal death. Identification of various conditions associated with maternal mortality initially came from observations by astute clinicians. One of the best examples is the link described by Semmelweis between handwashing habits and puerperal fever. In most industrial and many developing countries, there are now population-based surveillance mechanisms in place to track maternal mortality. These are often mandated by law. In fact, the World Health Organization uses maternal mortality as one of the measures of the health of a population [1]. Fortunately, in most industrialized nations, the maternal mortality rates have fallen to very low levels. Unfortunately, recent statistics for the United States suggest that overall maternal mortality has been increasing, but it remains

unclear whether this is just due to improvements in surveillance [2]. Although maternal mortality is an important maternal health measure, tracking maternal deaths may not be the best way to assess pregnancy- related critical illnesses since the majority of such illnesses do not result in maternal death. As stated by Harmer [3], “death represents the tip of the morbidity iceberg, the size of which is unknown.” Unlike mortality, which is an unequivocal endpoint, critical illness in pregnancy as a morbidity outcome is difficult to define and, therefore, difficult to measure and study precisely. There are many common conditions in pregnancy – such as hypertensive diseases, intrapartum and postpartum hemorrhage, venous thromboembolism, diabetes, thyroid disease, asthma, seizure disorders, and infection and sepsis – that occur frequently and require special medical care, but do not actually become critical illnesses. Most women with these complications have relatively uneventful pregnancies that result in good outcomes for both mother and infant, but each of these conditions can be  associated with significant complications that have the potential for serious morbidity, disability, or death. The stage at which any condition becomes severe enough to be classified as a critical illness has not been clearly defined. However, it may be helpful to consider critical illness as impending, developing, or established significant organ dysfunction, which may lead to long-term morbidity or death. This allows some flexibility in the characterization of disease severity, since it recognizes conditions that can deteriorate rather quickly in pregnancy.

Critical Care Obstetrics, Seventh Edition. Edited by Luis D. Pacheco, Jeffrey P. Phelan, Torre L. Halscott, Leslie A. Moroz, Arthur J. Vaught, Antonio F. Saad, and Amir A. Shamshirsaz. © 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.

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Epidemiology of Critical Illness in Pregnancy

Maternal mortality data collection is reasonably well established in many places, but specific structured surveillance systems that track severe complications of pregnancy (without maternal mortality) are rare. It has been suggested that most women suffering a critical illness in pregnancy are likely to spend some time in an intensive care unit (ICU) [3–5]. These cases have been described by some as “near-miss” mortality cases  [6,7]. Therefore, examination of cases admitted to ICUs can provide insight into the nature of pregnancy-related critical illnesses and can complement maternal mortality surveillance. However, it should be noted that nearly two-thirds of maternal deaths might occur in women who never reach an ICU [5]. The remainder of this chapter reviews much of what is currently known about the epidemiology of critical illness in pregnancy. Some of the information is based on published studies; however, much of the data are derived from publicly available data that are collected as part of nationwide surveillance systems in the United States.

Pregnancy-related hospitalizations Pregnancy complications contribute significantly to maternal, fetal, and infant morbidity, as well as mortality  [8]. Many women with complicating conditions are hospitalized without being delivered. Although maternal complications of pregnancy are the fifth leading cause of infant mortality in the United States, little is known about the epidemiology of maternal complications associated with hospitalizations. Examination of complicating conditions associated with maternal hospitalizations can provide information on the types of conditions requiring hospitalized care. In the United States, between 1991 and 1992, it was estimated that 18.0% of pregnancies were associated with non-delivery-related hospitalization, with disproportionate rates between black (28.1%) and white (17.2%) women  [9]. This 18.0% hospitalization rate comprised 12.3% for obstetric conditions (18.3% among black women and 11.9% among white women), 4.4% for pregnancy losses (8.1% among black women and 3.9% among white women), and 1.3% for nonobstetric (medical or surgical) conditions (1.5% among black women and 1.3% among white women). The likelihood of pregnancy-associated hospitalizations in the United States declined between 1986–1987 and 1991–1992 [9,10]. More recent data about pregnancy-related hospitalization diagnoses can be found in the aggregated National Hospital Discharge Summary (NHDS) data for 2005–2009. These data are assembled by the National Center for Health Statistics (NCHS) of the US Centers for Disease Control and Prevention. The NHDS data are a survey of medical

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records from short-stay, nonfederal hospitals in the United States, conducted annually since 1965 [11]. Briefly, for each hospital admission, the NHDS data include a primary and up to six secondary diagnoses, as well as up to four procedures performed for each hospitalization. These diagnoses and procedures are all coded based on the International Classification of Diseases (9th rev., clinical modification). We examined the rates (per 100 hospitalizations) of hospitalizations by indications (discharge diagnoses) during 2005–2009  in the United States, separately for delivery-related (n = 20,862,592) and non-delivery-related (n = 2,225,243) hospitalizations. We also examined the mean hospital length of stay (LOS; with a 95% confidence interval [CI]). Antepartum and postpartum hospitalizations were grouped as non-delivery-related hospitalizations. During 2005–2009, nearly 8.8% of all hospitalizations were for hypertensive diseases associated with a delivery and 9.1% were for hypertensive diseases not delivered (Table  1.1). Mean hospital LOS, an indirect measure of acuity for some illnesses, was higher for delivery-related than for non-delivery-related hospitalizations for hypertensive diseases. Hemorrhage, as the underlying reason for hospitalization (as either a primary or secondary diagnosis), occurred with similar frequencies for delivery- and non-delivery-related hospitalizations. Non-delivery-related hospitalizations for genitourinary infections occurred over nine times more frequently (12.3%) than delivery-related ones (1.3%), although the average LOS was shorter for non-delivery-related hospitalizations. Hospitalizations for preterm labor occurred over twice as frequently for non-delivery-related hospitalizations (18.0%) than for delivery-related hospitalizations (8.0%). This is expected since many preterm labor patients are successfully treated for arrest of labor and some of these hospitalizations are for “false labor.” Liver disorders were uncommonly associated with hospitalization. However, the mean hospital LOS for liver disorders that occurred with non-delivery-related hospitalizations was 6.6  days, compared with a mean LOS of 3.7  days if the liver condition was delivery related. Coagulation-related defects required 4.6  days of hospitalization if not related to delivery compared with a mean LOS of 3.7  days if the condition  was  delivery related. Hospitalizations for embolismrelated complications were infrequent, but generally required  extended hospital stays during delivery-related hospitalizations. The top  10 conditions associated with hospital admissions, separately for delivery- and non-delivery-related events, are presented in Figure 1.1. The chief cause for hospitalization (either delivery or non-delivery related) was preterm labor. The second most frequent condition was hypertensive disease (8.8% for delivery related and 9.1% for

Pregnancy-related hospitalizations

Table 1.1 Rate (per 100 hospitalizations) of delivery- and non-delivery-related hospitalizations, and associated hospital length of stay by diagnosis: United States, 2005–2009. Delivery-related hospitalization (n = 20,862,592) Hospital admission diagnosisa

Rate (%)

Mean LOS (95% CI)

Non-delivery-related hospitalization (n = 2,225,243) Rate (%)

Mean LOS (95% CI)

Hypertensive diseases Chronic hypertension

4.6

3.0 (3.0, 3.1)

4.6

2.6 (2.4, 2.9)

Preeclampsia/eclampsia

3.8

4.0 (3.8, 4.1)

3.9

3.0 (2.7, 3.4)

Superimposed preeclampsia

0.4

5.7 (5.0, 6.3)

0.7

3.9 (2.1, 5.8)

1.0

4.0 (3.5, 4.4)

0.7

4.3 (3.3, 5.3)

Hemorrhage-related Placental abruption Placenta previa

0.6

4.5 (3.7, 5.3)

0.1

4.4 (2.9, 6.0)

Hemorrhage (undetermined etiology)

0.3

3.3 (2.9, 3.7)

1.4

2.0 (1.6, 2.4)

80%) can occur when oxygen delivery increases, oxygen consumption decreases (or some combination of the two), cardiac output increases, or the pulmonary artery catheter tip is in a pulmonary capillary instead of the artery. A  decrease in SvO2 (5 mL/kg Minute ventilation 10 mL/kg PaO2 >60 mmHg on FiO2 0.4 Negative inspiratory pressure >–25 cmH2O PaO2/FiO2 ratio >200 f/Vt ratio 57 breaths/L/ min [188]. Out of all these parameters, we rely more on the f/Vt ratio and the NIP than any others.

Weaning techniques A variety of options for weaning from mechanical ventilation have been proposed and used over the past 25 years [189]. With the intermittent mandatory ventilation method, spontaneous breathing by the patient is assisted by a preset number of ventilatory-delivered breaths each minute. The intermittent mandatory ventilation rate is usually reduced in steps until a rate of 4 or close to 4 is reached. If the patient tolerates breathing with a mandatory rate of 4 and minimal pressure support (usually 5–8 cmH2O) for a period of 30–120  min, she is extubated. In the PSV method of weaning, each breath is initiated by the patient but supported in part by positive pressure delivered by the ventilator. In this method, weaning involves a progressive decrease in the magnitude of the pressure support delivered with each patient’s breath. When the patient breathes comfortably with pressure support values of 5–8  cmH2O for a period of 30–120 min, she is extubated. Another technique for weaning mechanical ventilation is the once-daily trial of spontaneous breathing (SBT). In this technique, patients are either disconnected from the ventilator and allowed to breathe spontaneously through a T-tube circuit connected to the endotracheal tube or placed in CPAP with a PEEP of 5 cmH2O and pressure support of 5–8 cmH2O for 30–120 min. If the patient tolerates the test, she is extubated. This method allows for faster weaning. No evidence exists that “working the patient” for more than 2 h a day has any benefits. In fact, it may lead to respiratory muscle fatigue. If signs of intolerance develop, mechanical

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ventilation is reinstituted for 24 h, at which time another trial is attempted. After failure of an SBT, the clinician should actively look for reversible causes of the failure (e.g., development of pulmonary edema, electrolyte imbalances, metabolic acidosis, or overfeeding). Patients who tolerate an SBT of at least 30 min and no more than 2 h without signs of distress are extubated. These three methods of weaning were compared in a prospective, randomized, multicenter study [184]. The rate of success of weaning depended on the technique employed; a once-daily trial of spontaneous breathing led to extubation about three times faster than intermittent mandatory ventilation and about twice as quickly as PSV. There were no significant differences in the rate of success between a once-daily trial and the multiple daily trials (T-tube trial) of spontaneous breathing, or between intermittent mandatory ventilation and PSV. Patients who tolerate an SBT of 30–120 min are successfully extubated at least 77% of the time [186]. Evidence-based guidelines for weaning and discontinuation of mechanical ventilation published by American College of Chest Physicians, the American Association for Respiratory Care, and the American College of Critical Care Medicine concluded that the daily SBT is the ideal method for ventilatory support weaning  [186]. Recent guidelines recommend the use of CPAP with PS of 5–8 cmH2O over T-piece as the former may increase the number of patients successfully extubated without increasing the extubation failure rate [190].

Failed weaning The major underlying causes for ventilatory dependence are neurologic issues, respiratory system muscle/load/ gas exchange interactions, cardiovascular factors, and psychologic factors [186]. When a patient fails an SBT, she should be evaluated closely, and reversible causes should be corrected. If she is still a candidate for a weaning trial, it should be repeated in 24 h. In between trials, the patient should receive a comfortable stable ventilatory support. No evidence supports the idea that slowly decreasing the level of ventilatory support will accelerate mechanical ventilation discontinuation [67].

Respiratory system interactions Although mechanical ventilation is commonly instituted because of problems with oxygenation, this is rarely a cause of difficulty at the time that mechanical ventilation is being stopped. This is largely because ventilator discontinuation is not contemplated in patients who display significant problems with oxygenation. However, during a  weaning trial, hypoxemia may occur because of

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hypoventilation, impaired pulmonary gas exchange, or decreased oxygen content of venous blood [183]. Impaired pulmonary gas exchange can be distinguished from pure hypoventilation by the presence of an elevated alveolar– arterial oxygen tension gradient. If the patient displays evidence of hypoxemic respiratory failure during weaning attempts, mechanical ventilation should be reinstituted until the cause of the hypoxemic respiratory failure has been identified and addressed. Impaired pulmonary gas exchange may be evidence of continuation of the initial precipitating illness or of other pathologic pulmonary processes such as pneumonia or pulmonary edema. These conditions should be treated before additional weaning attempts. Hypoventilation may occur secondary to extensive sedation or respiratory muscle fatigue. As stated in this chapter, respiratory muscle pump failure is a common cause of failure to wean from mechanical ventilation. This may result from decreased neuromuscular capacity, increased respiratory muscle pump load, or both (see Table  13.11)  [183]. Evidence supports that in ventilator-dependent patients, ventilator muscles are weak, due to atrophy and remodeling from inactivity [186]. Decreased respiratory sensor output may result from neurologic structural damage, sedative agents, sleep deprivation, semistarvation, and metabolic alkalosis [183]. In addition, mechanical ventilation may decrease

Table 13.11

Causes of respiratory muscle pump failure.

Decreased neuromuscular capacity Decreased respiratory center output Phrenic nerve dysfunction Decreased respiratory muscle strength and/or endurance Hyperinflation Malnutrition Decreased oxygen supply Respiratory acidosis Mineral and electrolyte abnormalities (hypokalemia and hypophosphatemia) Endocrinopathy (hypothyroidism and adrenal insufficiency) Disuse muscle atrophy Respiratory muscle fatigue Increased respiratory muscle pump load Increased ventilatory requirements Increased CO2 production (overfeeding) Increased dead space ventilation Inappropriately increased respiratory drive Increased work of breathing Source: Reproduced by permission from Tobin and Yang [183].

Respiratory system interactions

respiratory center output by a number of mechanisms: lowering of arterial CO2 tension, with a consequent reduction in chemoreceptor stimulation; activation of pulmonary stress receptors; and stimulation of muscle spindles or joint receptors in the chest wall. Dynamic hyperinflation (e.g., asthma and COPD) poses a significant load to respiratory muscles and may be a cause of weaning failure. The increase in lung volume causes the inspiratory muscles to shorten with consequent decrease in  the force of contraction. In the hyperinflated chest, thoracic elastic recoil is directed inward, which poses an additional elastic load. Finally, increased diaphragmatic pressure secondary to lung overdistention may impair diaphragmatic blood supply. Adequate use of bronchodilators postextubation is of paramount importance in this population and in any patient who develops bronchospasm after mechanical ventilation is discontinued. Underfeeding has several adverse effects on the respiratory system [189]. These adverse effects can interfere with weaning. It predisposes to nosocomial pneumonia and causes a decrease in the ventilatory response to hypoxia, decrease in diaphragmatic mass in thickness, and decrease in respiratory muscle strength and endurance. Malnutrition may be accompanied by metabolic abnormalities such as hypophosphatemia, hypokalemia, hypocalcemia, or hypomagnesemia that may adversely affect respiratory muscle function [183]. Similarly, overfeeding should also be avoided. It may impair the ventilator withdrawal process by increasing CO2 production, which further increases ventilatory demands  [191]. Corticosteroid therapy [192] and thyroid disease [193] may also impair respiratory muscle function. Severe hypothyroidism impairs diaphragmatic function and blunts the brainstem response to hypoxia and hypercapnia [194]. Steroid use has been associated with an increased incidence of critical illness polyneuromyopathy. This entity is associated with prolonged periods of weaning from mechanical ventilation. However, adrenal insufficiency may also be a cause of suboptimal ventilatory muscle performance [195]. Another possibility is that respiratory muscle fatigue may be a primary cause of failure to wean. As discussed in this chapter, most evidence recommends that in between SBTs, the patient should receive comfortable stable ventilatory support to avoid muscle fatigue. Increased ventilatory requirements may also lead to weaning failure. Factors that cause an increase in ventilatory requirements include increased CO2 production (e.g., sepsis, fever, seizures, and overfeeding), increased dead space ventilation, and an inappropriately elevated respiratory drive. Patients with a metabolic acidosis may not be able to adequately compensate their acid–base disturbance by hyperventilating; correction of the primary disorder should be undertaken before starting the weaning process.

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Neurologic issues The ventilation pump controller is localized in the brainstem. This center receives feedback from cortical, chemoreceptive, and mechanoreceptive sensors. Ventilator dependence may be secondary to brainstem dysfunction due to structural damage (e.g., brainstem strokes) or metabolic conditions (e.g., electrolyte imbalances, sedation, and narcotics) [195].

Cardiovascular factors Patients with limited cardiac reserve (e.g., peripartum cardiomyopathy) may frequently fail attempts to withdraw mechanical ventilation secondary to heart failure and subsequent hydrostatic pulmonary edema. Spontaneous breathing generates negative intrathoracic pressure during inspiration; this translates into a significant increase in afterload for the left ventricle as well as preload as a pressure gradient develops between the abdomen and the thorax favoring venous return. The transition from mechanical ventilation to spontaneous breathing is associated with increased metabolic demands [183]. When performing an SBT in patients with limited cardiac reserve, attention should be directed at changes in vascular filling pressures like the PAOP (if available) and CVP, development of pulmonary edema, systemic blood pressure, and oxygen saturation. Bedside echocardiography during the breathing trial can provide valuable information regarding estimates of filling pressures. The use of diuretics and inotropes coupled with postextubation NPPV could assist in liberating these patients from the ventilator.

Psychologic problems Dependence on mechanical ventilation can be associated with feelings of insecurity, anxiety, fear, agony, and panic  [196]. Many patients develop a fear that they will remain dependent on mechanical ventilation and that discontinuation of ventilator support will result in sudden death. These psychologic factors are major determinants of outcome of weaning trials in some patients, especially those patients who require prolonged ventilator support [197]. Stress can be minimized by frequent communication with the patient and family members. One should always keep in mind that in postoperative patients, breathing may be impaired by pain associated with deep inspiration; pain control should always be adequate [67]. Patients who become severely agitated during the weaning/extubation process may benefit from the use of dexmedetomidine. The latter may be infused during the whole process (as it does not compromise the respiratory drive), allowing a controlled, calm SBT, and extubation.

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Conclusion In summary, management of the gravida with respiratory failure can be difficult. However, early recognition of respiratory failure and institution of ventilatory support, knowledge of the changes in the cardiorespiratory system

that occur in gestation, judicious therapy of underlying pathophysiologic aberrations, thoughtful measures to prevent known complications, and prudent attempts to release the patient from ventilator dependency may improve the outcome of pregnant patients who suffer respiratory failure.

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47 Lain DC, DiBenedetto R, Morris SL, et al. Pressure control inverse ratio ventilation as a method to reduce peak inspiratory pressure and provide adequate ventilation and oxygenation. Chest. 1989;95(5): 1081–1088. 48 Tharratt RS, Allen RP, Albertson TE. Pressure controlled inverse ratio ventilation in severe adult respiratory failure. Chest. 1988;94(4):755–762. 49 Douglass JA, Tuxen DV, Horne M, et al. Myopathy in severe asthma. Am Rev Respir Dis. 1992;146(2):517–519. 50 Segredo V, Caldwell JE, Matthay MA, et al. Persistent paralysis in critically ill patients after long-term administration of vecuronium. N Engl J Med. 1992;327(8):524–528. 51 Biddle C. AANA journal course: Update for nurse anesthetists: Advances in ventilating the patient with severe lung disease. AANA J. 1993;61(2):170–174, quiz 175. 52 Stock MC, Downs JB, Frolicher DA. Airway pressure release ventilation. Crit Care Med. 1987;15(5):462–466. 53 Habashi NM. Other approaches to open-lung ventilation: Airway pressure release ventilation. Crit Care Med. 2005;33(3 Suppl):S228–S240. 54 Frawley PM, Habashi NM. Airway pressure release ventilation: Theory and practice. AACN Clin Issues 2001;12(2):234–246, quiz 328–239. 55 Fredericks AS, Bunker MP, Gliga LA, et al. Airway pressure release ventilation: A review of the evidence, theoretical benefits, and alternative titration strategies. Clin Med Insights Circ Resp Pulm Med 2020;5(14):1179548420903297. 56 Cole DE, Taylor TL, McCullough DM, et al. Acute respiratory distress syndrome in pregnancy. Crit Care Med. 2005;33(10 Suppl.):S269–S278. 57 Chan KP, Stewart TE. Clinical use of high-frequency oscillatory ventilation in adult patients with acute respiratory distress syndrome. Crit Care Med. 2005;33(3 Suppl.):S170–S174. 58 Derdak S. High-frequency oscillatory ventilation for acute respiratory distress syndrome in adult patients. Crit Care Med. 2003;31(4 Suppl.):S317–S323. 59 Young D, Lamb SE, Shah S, et al. High-frequency oscillation for acute respiratory distress syndrome. N Engl J Med. 2013;368(9):806–813. 60 Papazian L, Gainnier M, Marin V, et al. Comparison of prone positioning and high-frequency oscillatory ventilation in patients with acute respiratory distress syndrome. Crit Care Med. 2005;33(10):2162–2171. 61 Sevransky JE, Levy MM, Marini JJ. Mechanical ventilation in sepsis-induced acute lung injury/acute respiratory distress syndrome: An evidence-based review. Crit Care Med. 2004;32(11 Suppl.):S548–S553.

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62 Suter PM, Fairley B, Isenberg MD. Optimum endexpiratory airway pressure in patients with acute pulmonary failure. N Engl J Med. 1975;292(6):284–289. 63 Shapiro BA, Cane RD, Harrison RA. Positive endexpiratory pressure therapy in adults with special reference to acute lung injury: A review of the literature and suggested clinical correlations. Crit Care Med. 1984;12(2):127–141. 64 Ralph DD, Robertson HT, Weaver LJ, et al. Distribution of ventilation and perfusion during positive end-expiratory pressure in the adult respiratory distress syndrome. Am Rev Respir Dis. 1985;131(1):54–60. 65 Tyler DC, Cheney FW. Comparison of positive endexpiratory pressure and inspiratory positive pressure plateau in ventilation of rabbits with experimental pulmonary edema. Anesth Analg. 1979;58(4):288–292. 66 Puybasset L, Cluzel P, Chao N, et al. A computed tomography scan assessment of regional lung volume in acute lung injury. The CT Scan ARDS Study Group. Am J Respir Crit Care Med. 1998;158(5 Pt. 1):1644–1655. 67 MacIntyre NR. Current issues in mechanical ventilation for respiratory failure. Chest. 2005;128(5 Suppl. 2):561s–567s. 68 Tobin MJ. Advances in mechanical ventilation. N Engl J Med. 2001;344(26):1986–1996. 69 Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004;351(4):327–336. 70 Talmor D, Sarge T, Malhotra A, et al. Mechanical ventilation guided by esophageal pressure in acute lung injury. N Engl J Med. 2008;359(20):2095–2104. 71 Beitler JR, Sarge T, Banner-Goodspeed VM, et al. Effect of titrating positive end expiratory pressure (PEEP) with an esophageal pressure guided strategy vs an empirical high PEEP-FiO2 strategy on death and days free from mechanical ventilation among patients with acute respiratory distress syndrome: A randomized clinical trial. JAMA. 2019;321(9):846-857. 72 The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301–1308. 73 Piehl MA, Brown RS. Use of extreme position changes in acute respiratory failure. Crit Care Med. 1976;4(1):13–14. 74 Douglas WW, Rehder K, Beynen FM, et al. Improved oxygenation in patients with acute respiratory failure: The prone position. Am Rev Respir Dis. 1977;115(4):559–566. 75 Gattinoni L, Tognoni G, Pesenti A, et al. Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med. 2001;345(8):568–573.

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76 Guerin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368(23):2159–2168. 77 McAuley DF, Giles S, Fichter H, et al. What is the optimal duration of ventilation in the prone position in acute lung injury and acute respiratory distress syndrome? Intensive Care Med. 2002;28(4):414–418. 78 Anzueto A, Guntapalli K. Adjunctive therapy to mechanical ventilation: Surfactant therapy, liquid ventilation, and prone position. Clin Chest Med. 2006;27(4):637–654, abstract ix. 79 Hill JD, O’Brien TG, Murray JJ, et al. Prolonged extracorporeal oxygenation for acute post-traumatic respiratory failure (shock–lung syndrome): Use of the Bramson membrane lung. N Engl J Med. 1972;286(12):629–634. 80 Pesenti A, Gattinoni L, Kolobow T, Damia G. Extracorporeal circulation in adult respiratory failure. ASAIO Trans. 1988;34(1):43–47. 81 ECMO. ECMO Registry of the Extracorporeal Life Support Organization (ELSO). Quarterly report. Ann Arbor, MI; ECMO; 1994. 82 Anderson HLI, Bartlett RH. Extracorporeal and intravascular gas exchange devices. In: Ayres SM, Grenvik A, Holbrook PR, Shoemaker WC, editors. Textbook of critical care. 3rd ed. Philadelphia: W.B. Saunders; 1995; p. 943–951. 83 Anderson HL 3rd, Delius RE, Sinard JM, et al. Early experience with adult extracorporeal membrane oxygenation in the modern era. Ann Thorac Surg. 1992;53(4):553–563. 84 Mols G, Loop T, Geiger K, et al. Extracorporeal membrane oxygenation: A ten-year experience. Am J Surg. 2000;180(2):144–154. 85 Saad AF, Rahman M, Maybauer DM, et al. Extracorporeal membrane oxygenation in pregnant and postpartum women with H1N1-related acute respiratory distress syndrome: A systematic review and meta-analysis. Obstet Gynecol. 2016;127(2):241–247. 86 Combes A, Hajage D, Capellier G, et al. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. N Engl J Med 2018;378:1965–1975. 87 McIntyre RC Jr., Pulido EJ, Bensard DD, et al. Thirty years of clinical trials in acute respiratory distress syndrome. Crit Care Med. 2000;28(9):3314–3331. 88 Lundin S, Mang H, Smithies M, et al. Inhalation of nitric oxide in acute lung injury: Results of a European multicentre study. The European Study Group of Inhaled Nitric Oxide. Intensive Care Med. 1999;25(9):911–919. 89 Griffiths MJ, Evans TW. Inhaled nitric oxide therapy in adults. N Engl J Med. 2005;353(25):2683–2695.

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134 Kalil AC, Metersky ML, Klompas M, et al. Executive summary: Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):575–582. 135 Shorr AF, Sherner JH, Jackson WL, Kollef MH. Invasive approaches to the diagnosis of ventilator-associated pneumonia: A meta-analysis. Crit Care Med. 2005;33(1):46–53. 136 Shorr AF, Kollef MH. Ventilator-associated pneumonia: Insights from recent clinical trials. Chest. 2005;128(5 Suppl. 2):583s–591s. 137 Rello J, Sonora R, Jubert P, et al. Pneumonia in intubated patients: Role of respiratory airway care. Am J Respir Crit Care Med. 1996;154(1):111–115. 138 Bernard EA, Weser E. Complications and prevention. In: Rombeau JL, Caldwell MD, editors. Enteral and tube feeding. Philadelphia: W.B. Saunders; 1984; p. 542. 139 Ang SD, Daly JM. Potential complications and monitoring of patients receiving total parenteral nutrition. In: Rombeau JL, Caldwell MD, editors. Parenteral nutrition. Philadelphia: W.B. Saunders; 1986; p. 331. 140 Rochester DF, Esau SA. Malnutrition and the respiratory system. Chest. 1984;85(3):411–415. 141 Kelly SM, Rosa A, Field S, et al. Inspiratory muscle strength and body composition in patients receiving total parenteral nutrition therapy. Am Rev Respir Dis. 1984;130(1):33–37. 142 Martin TR. The relationship between malnutrition and lung infections. Clin Chest Med. 1987;8(3):359–372. 143 Dickerson RN. Hypocaloric feeding of obese patients in the intensive care unit. Curr Opin Clin Nutr Metab Care. 2005;8(2):189–196. 144 Jeejeebhoy KN. Permissive underfeeding of the critically ill patient. Nutr Clin Pract. 2004;19(5): 477–480. 145 Baker JP, Detsky AS, Stewart S, et al. Randomized trial of total parenteral nutrition in critically ill patients: Metabolic effects of varying glucose–lipid ratios as the energy source. Gastroenterology. 1984;87(1):53–59. 146 Tehila M, Gibstein L, Gordgi D, et al. Enteral fish oil, borage oil and antioxidants in patients with acute lung injury (ALI) [Abstract]. Clin Nutr. 2003;22 (Suppl. 1):S20. 147 McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (ASPEN). JPEN J Parenter Enteral Nutr. 2016;40(2):159–211. 148 Artinian V, Krayem H, DiGiovine B. Effects of early enteral feeding on the outcome of critically ill

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14 Vascular Access Eryn Hart1, Gayle Olson2, and Aristides P. Koutrouvelis3 1 Department of Obstetrics and Gynecology, Division of Maternal–Fetal Medicine, Spectrum Health/Michigan State University College of Human Medicine, Grand Rapids, MI, USA 2 Department of Obstetrics and Gynecology, Division of Maternal–Fetal Medicine, The University of Texas Medical Branch, Galveston, TX, USA 3 Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX, USA

Introduction Placement and maintenance of vascular access comprise an important adjunct in the care of the critically ill obstetric patient. Arterial and venous access affords the clinician several diagnostic and therapeutic advantages (see Table 14.1). Long-term central intravenous (IV) access may also be indicated for gravidas with coexisting disease, such as those illustrated in Table  14.2, and for the administration of parenteral nutrition, drugs, or antibiotics [1–4]. This requires knowledge of catheter types, access routes, insertion techniques, and maintenance. Simulation training for central line catheterization and implementation of ultrasound is now well established in training and in clinical practice [5].

Catheter type There are various types of IV catheters, which can be classified according to the length of use as well as placement location (see Table 14.3). The use of the terms peripheral and central is based on the peripheral or central location of insertion and the location of the catheter tip. Central vein cannulation is required to accommodate large-bore catheters necessary for high-volume administration rates. When administering highly osmolar and sclerotic IV fluids, most clinicians agree that the catheter tip should be placed near the heart in the superior or inferior vena cava, although optimal placement has not been established in prospective human studies [6]. Choosing the venous catheter type and the site for insertion is influenced by indication (see Table 14.2), duration of use, urgency of administration, and composition of the

infusate (e.g., osmolarity, tonicity, and whether crystalloid or colloid). Catheters with shorter lengths and larger diameters allow for more rapid flow rates. For example, coupling of the tube diameter (0.71  mm or 22-gauge vs. 1.65  mm or 16-gauge) results in almost a quadrupling of the flow rate (25 mL/min vs. 96 mL/min) [7]. Multilumen catheters are routinely used for central venous cannulation (see Figure 14.1). The more commonly used triple-lumen catheter has an outside diameter of 2.3  mm (6.9-French) and provides three channels (three 18-gauge, or two 18gauge plus one 16-gauge) The opening of each channel is separated from the other by at least 1 cm in order to reduce mixing of infusates. Short-term (less than 2 weeks) transcutaneous catheters are constructed of polyethylene, polyurethane, polycarbonate, vinyl chloride, or silicone and are available in multiple lengths, diameters, and lumen numbers. Short-term transcutaneous catheters are suitable for most obstetric patients in the “difficult access” group (i.e., history of IV drug abuse, IV chemotherapy, and/or hypovolemia) and for others with rapidly resolvable clinical conditions. Because of the intended short duration of use, sites on the lower extremities, such as the pedal, saphenous, and femoral veins, might be selected; however, decreased mobility and increased risk of catheter dislodgement are among the disadvantages of lower-extremity access locations. Long-term (weeks to months) transcutaneous catheters are usually constructed of more flexible and less thrombogenic derivatives of silicone; they are passed through a subcutaneous tunnel between the points of venous insertion and exit from the skin  [8,9]. Frequently, these catheters incorporate a Dacron cuff just proximal to the skin exit site. Catheter tunneling and the Dacron cuff promote tissue

Critical Care Obstetrics, Seventh Edition. Edited by Luis D. Pacheco, Jeffrey P. Phelan, Torre L. Halscott, Leslie A. Moroz, Arthur J. Vaught, Antonio F. Saad, and Amir A. Shamshirsaz. © 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.

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Table 14.1 Advantages of vascular access in the critically ill obstetric patient. Vascular access site

Advantages

Artery

Continued access for blood pressure monitoring and frequent arterial blood sampling

Central

Rapid fluid and blood administration

Venous

Hemodynamic monitoring, total parenteral nutrition access

Table 14.2 Indications for prolonged venous access. Parenteral nutrition and drug therapy Hyperemesis gravidarum Inflammatory bowel disease Gastroparesis Pancreatitis Cystic fibrosis Short bowel syndrome Heparin (heart valves, deep vein thrombosis) Antibiotics (bacterial endocarditis, osteomyelitis) Chemotherapeutic agents for malignancy Need for plasmapheresis Lack of peripheral access Previous intravenous drug abuse Previous prolonged chemotherapy Hemodialysis

ingrowth and fixation, and they limit the spread of skin exit-site colonization or infection. Long-term catheters may incorporate a Groshong valve tip. Such catheters are blind-ended, but incorporate a side slit near the catheter tip. Positive pressure exerted through the catheter blows the slit walls open outwardly for fluid or medication administration, while negative pressure draws the slit walls inward for blood sampling. At rest, the catheter is closed, theoretically obviating the need for heparinization between periods of catheter use. Venous sites commonly used for long-term catheter use include the subclavian, external and internal jugular, basilic, and greater saphenous veins. When the femoral, greater saphenous, or basilic veins are used, the catheter is tunneled to allow for port placement onto the lower chest, abdominal wall, thigh, or forearm [10]. Peripherally inserted central venous catheters (PICCs), introduced in 1975  [11], are increasingly popular due to the  ease of insertion compared with traditionally placed

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surgical catheters (e.g., Hickman ports and central venous ports), with potentially fewer complications [12]. Totally implantable venous access systems (TIVAs), generically known as portacaths, utilize catheters attached to reservoirs placed into subcutaneous pockets. These systems are indicated for very long-term use (months to years), typically in patients requiring intermittent medications. During catheter use, the reservoir is accessed with the use of a special Huber-point needle that uses a noncoring tip. Although surgical insertion is required for implantable catheters, the early and late complications associated with venous access are reduced with implantable catheters  [13]. Ideally, reservoirs for implantable catheters should be placed in a secure, flat, nonmobile area, preferably overlying a rib. Arterial catheters should be used for specific purposes and for short time intervals. Arteries that are accessible to palpation and that can usually be cannulated include (in order of preference) the radial, dorsalis pedis, femoral, axillary, and brachial.

­Preparing for catheter insertion Before cannulation of any vessel, it is necessary to ensure the patency of the vessel. Contraindications to vessel cannulation include infection or inflammation at the site, arterial–venous or aneurysmal malformations, and the presence of arterial grafts. Coagulopathy is a relative contraindication to cannulation. In the presence of coagulopathy, the use of ultrasound to identify the location of vessels reduces complications. Catheter insertion has been demonstrated in 242 patients with corrected coagulopathy and 88  with uncorrected coagulopathy. In these cases, most bleeding after cannulation was controlled with a suture at the catheter insertion site, and the only variable significantly associated with a bleeding complication was a platelet count 10 g/dL. Hct >30%) Increased clotting factor production Retention of sodium (1000 mEq) and potassium (350 mEq) Increased cardiac output (50%), heart rate (20%), stroke volume (25–40%)

Facilitated diffusion

Sugars/carbohydrate

Active transport

Amino acids, some cations, water-soluble vitamins

Solvent drag

Electrolytes

Pinocytosis, breaks in membrane

Proteins

Source: Reproduced by permission from Martin and Blackburn [12].

Reduced systemic vascular resistance (20%) Increased renal blood flow (50%) and glomerular filtration rate (50%) Increased clearance of glucose, urea, and protein Creatinine clearance increased (100–180 mL/min) Increased serum lipids Increased total iron-binding capacity (40%), increased serum iron (30%)

Table 15.3 Factors responsible for the transport of substrates between the maternal-fetal units. Maternal-fetal concentration gradient Physical properties of the substrate Placental surface area Uteroplacental blood flow

Hypomotility of gastrointestinal tract

Nature of transport mechanism (passive vs active transport)

Delayed gastric emptying

Specific binding or carrier proteins in maternal and fetal circulation

Gastroesophageal reflux Constipation

density tissue, fat-soluble vitamins, and essential fatty acids necessary for brain growth and metabolism in the perinatal period. In contrast, amino acids are fundamental building blocks for organ development and enzyme synthesis. Any aberration of this process may affect fetal growth. The placenta plays a crucial role in fetomaternal nutrition and is more than a biologic pipeline passively directing nutrients from the mother to the fetus or fetuses. For example, placental human chorionic gonadotropin (HCG) is important for the maintenance of the corpus luteum in early pregnancy. Progesterone, produced from the corpus luteum, induces a glucose-sparing effect in the placenta and makes more glucose available to the developing embryo. HPL, by stimulating lipolysis, stimulates free fatty acid release into the maternal circulation to serve as a caloric source and thereby spare amino acids and glucose to be passed transplacentally to the actively growing fetus. Placental estrogen stimulates protein synthesis for uterine growth and systematic vasodilatation to help maintain uteroplacental blood flow. Additionally, the placenta has well-developed mechanism to control the passage of substrate to the fetus (see  Table  15.2). The effectiveness of the passage of any

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Placenta metabolism of the substance

substance across the syncytiotrophoblast depends on a number of factors listed in Table 15.3.

­Malnutrition in pregnancy Our knowledge of the effects of nutritional deprivation in pregnancy is based primarily on animal studies and unfortunate human circumstance. Although several welldesigned experiments studying the effects of starvation in pregnant rats are available, the suitability of using rodent model for studying the primate pregnancy has been questioned [13]. One would expect, intuitively, that the consequences of nutritional deprivation to the mother or fetus in a multifetal gestation of short duration (the typical rodent gestation) should differ from one of a singleton gestation of long duration (the typical human pregnancy). Pond  [14], following their experiments in swine, concluded the following: “All gravidas fed protein-deficient diets lost weight. The earlier the protein deficiency began, the more severe the adverse effects.” Protein deficiency during periods of fetal growth may affect DNA/RNA synthesis in vital organs, for example, brain and liver, or enzyme systems. Maternal prepregnant labile protein reserve may mitigate the effect

­Routes Ror ouorurR nal esouuRou

of protein deprivation in pregnancy. Riopelle [15] made the following observations of the rhesus monkey: “Although protein deficiency tends to increase fetal morbidity and mortality, the precise effect is dependent on several interacting factors. The improvement in metabolic efficiency in response to starvation is greater in the pregnant than the non-pregnant monkey.” Antonov [16] reported that birthweight was reduced by 400–600 g when pregestational nutrition was poor during the war in Leningrad. Reporting on undernourished women during a famine in Holland, Smith [17] and Stein and Susser [18] observed that birthweight declined 10% and placental weight 15% when poor nutrition and caloric intake less than 1500 g/day occurred in the third trimester. Generalized caloric intake reduction, as well as specific deficiencies like protein, zinc, folate, and oxygen, have been implicated in the etiology of fetal growth restriction [19,20]. Winick’s hypothesis is particularly helpful in understanding the effect of maternal malnutrition in fetal growth [21]. He suggests that there are three phases of fetal growth: cellular hyperplasia, followed by both hyperplasia and hypertrophy, and then predominantly hypertrophy. Fetal malnutrition early in pregnancy is likely to cause a decrease in cell size and number and result in symmetric growth failure. This difference is of prognostic importance because postnatal catch-up growth is more likely with asymmetric rather than symmetric intrauterine growth impairment. Even when low total fetal body weight suggests growth restriction, the severity varies with the organ system. The adrenal and heart are more severely affected than the brain or skeleton [22].

Table 15.4

Vitamins and minerals requirement.

Nutrient

Daily requirement

Folic acid

400–800 mcg

Iron

27 mg

Calcium

1000 mg (1300 mg if 18 or younger)

Vitamin A

770 mcg (750 mcg if 18 or younger)

Vitamin B12

2.6 mcg

A pregnant woman needs more of many important vitamins, minerals, and nutrients than she did before pregnancy. The daily requirements of vitamins and minerals are illustrated in Table 15.4.

­Weight gain during pregnancy In 2009, the Institute of Medicine (IOM)  [24] published revised gestational weight gain guideline that are based on pregnancy body mass index ranges from underweight, normal weight, overweight, and obese women and is reflected in Table 15.5. This information was updated in 2013 [25]. For twin pregnancy, the IOM recommended a gestational weight gain of 16.8–24.5 kg (37–54 lbs) for women of normal weight, 14.1–2.7 kg (31–50 lbs) for overweight women, and 13–19.1 kg (25–42 lbs) for obese women and supported by the work of Luke and associates [26]. At present, there are insufficient data to recommend the amount of maternal weight gain for triplet gestations or higher orders [24,25].

­Nutritional assessment during pregnancy Several protocols have been proposed to evaluate the nutritional status of women during pregnancy. Some are based on parameters including maternal morphometry, serum biochemistry, and provoked immune responses [12,23]. In practice, however, such techniques have limited utility for the following reasons:

­Routes for nutritional support

1) Normal values obtained in nonpregnant women cannot be readily extrapolated to the hemodiluted pregnant patient. 2) Immune function is impaired in normal pregnancy. 3) Nutritional supplementation is initiated in pregnant patients whose food intake is inadequate before these observations are made. 4) Although nitrogen balance and creatinine clearance may be effective methods to assess protein status in the  nonpregnant patient, both are altered markedly by  the increased glomerular filtration rate in normal pregnancy.

Table 15.5 Institute of Medicine weight gain recommendation for singleton pregnancies.

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The most common conditions treated with parenteral nutrition during pregnancy include hyperemesis gravidarum, cholecystitis, pancreatitis, and inflammatory

Range of Rate in second and Pregnancy Body mass total weight third trimester mean weight category index (BMI) (lbs) range [lbs/wk]

Underweight

28–40

1 (1–1.3)

Normal weight 18.5–24.9

< 18.5

25–35

1 (0.8–1)

Overweight

25–29.9

15–25

0.6 (0.5–0.7)

Obese

30 and greater

11–20

0.5 (0.4–0.6)

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Table 15.6 Possible criteria for consideration of pregnant patients for total parenteral nutrition.

Table 15.7 Nutritional contents of enteral feedings.

Inaccessible or inadequate gastrointestinal route for any reason

Product

kcal/ml

NP kcal/ml

Protein gm/L

CHO gm/L

Fat gm/L

Maternal malnutrition

Ensure

1.06

0.91

37.2

145.0

37.2

Weight loss greater than 1 kg/week for 4 weeks consecutively

Ensure Plus

1.50

1.28

54.9

200.0

53.3

Total weight loss of 6 kg or failure to gain weight

Glucerna

1.00

0.83

41.8

93.7

55.7

Underlying chronic disease that increases basal nutritional demands and/or precludes enteral feedings such as inflammatory bowel disease, unremitting pancreatitis

Jevity

1.06

0.73

44.4

152.0

36.9

Nepro

2.00

1.72

69.9

215.2

95.6

NutriHep

1.50

1.34

40.0

290.0

21.2

Osmolite

1.06

0.73

44.4

141.2

36.8

Pulmocare

1.50

1.25

62.6

106.0

92.1

Prepregnancy malnutrition Biochemical markers of malnutrition Severe hypoalbuminemia less than 2 g/dL Persistent ketosis Hypocholesterolemia Lymphocytopenia Macrocytic anemia: diminished folic acid Microcytic anemia and decreased serum iron Negative nitrogen balance Anthropometric markers of malnutrition Weight and height, growth rate, poor weight gain, delayed growth of adolescent, skin fold thickness, head chest, waist, and arm circumference Intrauterine growth restriction of the fetus Source: Reproduced from Lavin et al. [27]/with permission of American College of Obstetricians and Gynecologists.

bowel disease. The decision whether a given patient requires nutritional support is best determined by a multidisciplinary team composed of the obstetrician, intensivist, clinical nutritionist, clinical- pharmacist, and patient. Once the decision for nutritional support has been made, the goal of support must clearly be established. Two important issues relevant to this decision are the baseline nutritional status of the patient and whether the patient can ingest any “normal” nutrition. These determine whether the hyperalimentation goal will be to supplement, to maintain, or to build tissue (anabolic). This determination significantly influences the potential route and formulations that can or need to be used. Two routes of hyperalimentation are available: enteral and parenteral. Guidelines published by the American Society for Parenteral and Enteral Nutrition (ASPEN) recommend that total parenteral nutrition (TPN) should only be used if enteral nutrition (EN) is not feasible. When to start TPN is based on the nutritional status of the patient. The possible criteria for consideration of TPN are listed in Table  15.6. For example, if there is evidence of malnutrition, TPN may be initiated immediately if EN cannot be used. If a patient has no evidence of

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malnutrition, TPN should be reserved and initiated only after 7 days. Studies have shown a significant increase in mortality with the early use of TPN and a trend toward greater rate of complications in well-nourished patients. Enteral, in contrast with parenteral, helps maintain bowel function, causes fewer maternal metabolic derangements, is more cost effective, and makes it easier to monitor maternal health. When using EN, the delayed gastric emptying typical of pregnancy should be taken into account. The maternal risks of regurgitation and aspiration can be reduced by simply adjusting the feeding solution delivery rates. For your review, Table  15.7 illustrates the products available for EN and their nutritional contents. TPN may be given in peripheral or central lines [27–33]. Watson [28] reported favorably on the tolerance and efficacy of hypercaloric, hyperosmotic 3-in-1 (carbohydrates, protein, and lipid in same solution) PVN. While the precise indications and potential side effects had not been elucidated satisfactorily by 1990  [28], CVN does carry a greater risk than PVN. Most of the risks are related to the mechanical risks associated with central venous access. Nevertheless, PVN cannot be continued for more than 1–2 weeks because of the risk of phlebitis [29]. PVN has limitation on substrate capacities that can be delivered through a peripheral vein, and it requires administration of significant volumes to meet the total nutritional needs of the patient.

­Calculation of nutritional requirements To determine the nutritional need of a pregnant women, the first step is to determine the women’s total caloric needs. Maintenance needs, described as basal energy expenditure (BEE), can be calculated using Wilmore’s

Carbohydrates

Table 15.8 Sample calculation of total parenteral nutrition requirements for a 60-kg patient. Total protein requirements 1.5 g/kg = 1.5 × 60 = 90 g/day Total caloric requirements 36 kcal/kg = 36 × 60 = 2160 kcal/ day If calories are provided in a ratio of 70% dextrose: 30% lipid Daily dextrose requirement (2160 × 0.7)(3.4 kcal/g) = 445 g Daily lipid requirement (2160 × 0.3)(9 kcal/g) = 72 g Infusion is usually begun at about 50% of total estimated needs and increased gradually to target values at a rate that minimizes maternal metabolic derangement. Basal energy expenditure (BEE) in kcal = 655 + 9.563W + 1.85H − 4.766A where W is the weight in kilograms, H is the height in centimeters, and A is the age in years. During pregnancy, this value is then multiplied by the “stress factor” of 1.25 to account for the caloric demands of pregnancy [33]. The recommended dietary allowance is an additional 300 kcal/day in singleton or 500 kcal/day in twin pregnancies in the second and third trimesters. A nutritionally deficient pregnant woman may require more than 300 kcal/ day for supplementation in a singleton pregnancy. Therefore: Maintenance therapy BEE (kcal) × 1.25 + 300 kcal or 500 kcal (twin) Anabolic therapy Parenteral BEE (kcal) × 1.75 Enteral BEE (kcal) × 1.50

normogram  [30] or the Harris-Benedict equation for women [31] and adjusted slightly for pregnancy [32,33]. The estimation of caloric requirements should be individualized and tailored to the patient’s current metabolic rate (Table  15.8). Commercially available metabolic charts, which base estimation of caloric requirement on oxygen consumption and carbon dioxide production, have recently become available for clinical use. These systems are generally quite accurate except at very high FiO2 values (>60%). A useful but imprecise rule to help a patient maintain a positive nitrogen balance  [33,34] is 36 kcal/kg/day. Monitoring the effectiveness of maternal nutritional support is accomplished by plotting maternal weight gain against standard charts and serial sonographic estimates of fetal growth.

Amino acids When the intake of other nutrients is adequate, nitrogen and energy intake are the dominant factors influencing positive nitrogen balance. Protein catabolism rises with an

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increase in the maternal metabolic rate, whereas total protein need is additionally dependent on the patient’s previous nutritional status, the provision of the nonprotein energy, and the rate of desired replacement. With the expansion of the maternal circulating blood volume and growth of the uterus, fetus, and placenta, maternal requirements for protein intake are increased during pregnancy. The minimum daily protein requirement throughout pregnancy is approximately 1 g/kg to meet maternal and fetal nutritional needs. The adequacy of maternal protein intake can be assessed by measuring maternal serum protein levels and urea nitrogen excretion. In certain situations, such as maternal renal failure, protein and caloric requirements are increased significantly. Frequent dialysis may require even higher amounts. Under these circumstances, survival rates appear to correlate with the adequacy of maternal caloric and protein intake. For example, the protein requirement may reach 2 g/kg to maintain a normal nitrogen balance. Most commercially available amino acid products have been used successfully to maintain normal fetal growth.

­Carbohydrates Dextrose, the most common energy source, is easily metabolized, promotes nitrogen retention, is readily miscible with other additives, can be prepared in any relevant concentration, and is relatively inexpensive. The disadvantages may include increased oxygen consumption, increased carbon dioxide production, hyperglycemia, and its low caloric potency (3.4 kcal/kg) precluding its use as the sole source of energy. Dextrose in concentration greater than 10% (600 mosm) should not be administered peripherally in order to minimize osmolarity-induced phlebitis and venospasm. A small amount of amino acid and electrolytes can be added to the dextrose for peripheral solutions. Fat emulsions can also be added to increase caloric density and decrease the osmolarity. Aside from the concentration (osmolarity) limit, other limiting factors in the use of these solutions peripherally are the volume needed to meet patient’s needs, the time needed to infuse this volume, and the total fat limitations. To infuse hyperosmolar solutions of the dextrose utilizing more concentrated energy and protein substrates, central venous access is medically necessary. Although infusion rates of 4–6 mg/kg/min of dextrose may reduce the severity and the likelihood of maternal complications, insulin may be necessary to maintain maternal euglycemia. Assuming that maternal euglycemia can be maintained, no adverse fetal effects have been described.

287

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­Fat emulsions Lipids are an important component of the TPN in the pregnant patient for the following reasons:

Table 15.9 Recommended daily allowance for pregnant and nonpregnant women. Nutrients

Nonpregnant Pregnant % Increase

1) They are an excellent energy source (approximately 9 kcal/g). 2) Essential fatty acids are utilized for fetal fat depot formation, brain development and myelination, and lung surfactant synthesis. 3) Fatty acid metabolism requires less oxygen and produces less carbon dioxide than glucose metabolism.

Energy (kcal)

2200

Most commercially available solutions are a suspension of chylomicrons of arachidonic acid precursors and essential fatty acids in a base of safflower or soybean oil. Emulsions are available in concentrations of 10% and 20%. Infusion is usually limited to 12 h a day, because chylomicrons may remain in maternal circulation for up to 8–10 h after administration and because of concern about possible bacteria contamination of the emulsion when infusion “hang time” is prolonged. Since the placenta transport of fatty acids is primarily by passive diffusion, a high maternal-fetal concentration gradient is necessary to ensure adequate lipid transfer. Essential fatty acid efficiency usually requires 4 weeks or more of nutritional depletion to become clinically manifested  [32–37]. Maternal serum hypertriglyceridemia and ketosis are important complications of lipid use that should be sought and corrected. Initial concern about preterm labor and placental infraction from fat embolism have failed to materialize with the concentrations of the commonly used for TPN (i.e., 30–40% of total caloric requirements) [34].

­Fluid and electrolytes Maternal fluid requirements over the course of a singleton term pregnancy are increased dramatically as total body water increases by about 8–9 L. This 8–9 L requirement for water is to compensate for the expansion of extracellular and intravascular volumes, fetal needs, and amniotic fluid formation. Inadequate plasma volume expansion adversely affects fetal well-being  [35–39]. An additional 30  ml/day over standard maintenance fluids is considered sufficient to satisfy maternal fluid requirements [9]. Care should be taken to match any additional losses (e.g., gastrointestinal fluid from hyperemesis) with the appropriate solutions. Fluid replacement should be separate from the hyperalimentation solution to prevent complications due to changes in rate and content of the TPN delivered. Recommended dietary allowance for electrolytes and vitamins for pregnant and nonpregnant women is displayed in Table 15.9. These are based on estimates of oral recommended dietary allowances actually absorbed.

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2500

14

Protein (g)

44–45

60

20

Calcium (mg)

1200*

1200

50

800

1200

50

15

30

100

Phosphorus (mg) Iron (mg) Magnesium (mg)

280

320

14

Iodine (mg)

150

175

17

Zinc (mg)

12

15

25

Selenium (mg)

55

65

18

800

800

0

10

0

Vitamin A (mcg and RE) Vitamin D (mg) Vitamin E (mg and TE)

10^ 8

10

25

Vitamin K (mg)

55

55

0

Vitamin C (mg)

60

70

17

Thiamine (mg) Riboflavin (mg) Niacin (mcg and NE) Folate

1.1 1.3

1.5

36

1.6

23

15

17

13

180

400

122

Vitamin B6 (mg)

1.6

2.2

38

Vitamin B 12 (mg)

2.0

2.2

10

* Above age 24, RDA is 800 mg (no further bone growth) ^  Above age 24, RDA is 5 mg (no further bone growth) NE = Niacin equivalent; RDA = Recommended dietary allowance; RE = Retinol equivalent; TE + Tocopherol equivalent. Source: Adapted from Hamaoui and Hamoui [4].

Commercially available intravenous vitamin preparations are proven to be adequate for normal fetal growth.

­Monitoring and complications TPN, when properly adjusted for pregnancy, can provide adequate maternal nutrition resulting in a maternal anabolic state as well as support adequate fetal growth for extended periods. Serious complications are an expected but undesirable component of TPN. The introduction of the peripherally inserted central catheter instead of the conventional Broviac or Hickman catheter has significantly reduced the rate of catheter-related infection and other serious complications such as pneumothorax or cardiac tamponade. A suggested protocol for monitoring the pregnant patient receiving TPN is outlined in Table  15.10. Commonly encountered complications of nutritional therapy  [4,25] are detailed in Table 15.11.

References

Table 15.10 Monitoring during TPN. Daily weights Strict input/output Urine sugar/ketones Serum glucose (every 6–12 h) Daily electrolytes Liver function assessment and Calcium Phosphorous, magnesium, albumin (2–3 times/weeks) Weekly nitrogen balance Fetal growth assessment (every 2–4 weeks)

Table 15.11 Complications of TPN in obstetric patient. Catheter related: Pneumothorax, arterial laceration, mediastinal hematoma, malposition, brachial plexus/phrenic nerve palsy, catheter sepsis, subclavian vein thrombosis/right arterial thrombosis, hydro-/chylothorax Metabolic: Deficiencies of vitamins, minerals, electrolytes, trace metals, or essential fatty acids, hypoglycemia, hepatic dysfunction and fatty infiltration, carbon dioxide retention, over-/underhydration Other: Bowel atrophy, cholecystitis, Heparin-related complications (e.g., hemorrhage, thrombocytopenia, and osteopenia) Neonatal: Maternal diabetes syndrome (e.g., macrosomia and postnatal hypoglycemia), growth restriction

­References 1 Lakoff KM, Feldman JD. Anorexia nervosa associated with pregnancy. Obstet Gynecol. 1972;36:699. 2 Lee R, Roger B, Young C, et al. Total parenteral nutrition in pregnancy. Obstet Gynecol. 1986;68:563–571. 3 Smith C, Refleth P. Phelan J, et al. Long term hyperalimentation in the pregnant women with insulindependent diabetes: A report of two cases. Am J Obstet Gynecol. 1981;141:180–183. 4 Hamaoui E, Hamaoui M. Nutritional Assessment and support during pregnancy. Gastroenterol Clin N Am. 1998;27(1):89–121. 5 Taffell SM, National Center of Health Services. Maternal weight gain and the outcome of pregnancy: United States; 1980. Vital and Health Statistic Series 21-No.44. DHHS (PHS) 86, Public Health Service. Washington DC: US Government Printing Office; 1986. 6 Abrams B, Newman V, Key T, Parker J. Maternal weight gain and preterm delivery. Obstet Gynecol. 1989;74: 577–583. 7 Abrams B, Newman V. Small for gestational age birth: maternal predictors and comparison with risk factors of spontaneous preterm delivery in same cohort. Am J Obstet Gynecol. 1991;164:785. 8 Institute of Medicine, Committee on Nutritional Status During Pregnancy and Lactation. National Academy of Sciences. Nutrition During Pregnancy. Washington DC: National Academy Press; 1990. 9 National Research Council. Subcommittee on the Tenth Edition of the RDA’S Food and Nutrition Board. Commission on Life Sciences. Washington DC: National Academy Press, 1989. 10 Goodnight W, Newman R. Optimal nutrition for improved twin pregnancy outcome. Obstet Gynecol. 2009;114(5):1121–1134. 11 Dunnihoo D. Fundamentals of gynecology and obstetrics. Philadelphia: JB Lippincott; 1990; p. 164–176.

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12 Martin R, Blackburn G. Hyperalimentation in pregnancy. In: Berkowitz R. editor. Critical care of the obstetric patient. Edinburgh: Churchill Livingstone; 1983; p. 133–163. 13 Payne PR, Wheeler EF. Comparative nutrition in pregnancy and lactation. Proc Nutr Soc. 1968;27:129–138. 14 Pond WG, Strachan DN, Sinha YN, et al. Effect of protein deprivation of the swine during all or part of gestation on birth weight, postnatal growth rate, and nucleic acid content of brain and muscle of progeny. J Nutr. 1969;99:61. 15 Riopelle AJ, Hill CW, Li SC. Protein deprivation in primates versus fetal mortality and neonatal status in infant monkeys born of deprived mothers. Am J Clin Nutr. 1975;28:989–993. 16 Antonov AN. Children born during siege of Leningrad in 1942. J Pediatr. 1947;30:250–259. 17 Smith CA. Effects of maternal malnutrition upon newborn infants in Holland: 1944–1945. J Pediatr. 1947;30:229–243. 18 Stein Z, Susser M. The Dutch famine 1944–1945, and the productive process. Effects on six indices at birth. Pediatr Res. 1975;9:70. 19 Goldenberg RL, Tamura T, Cliver SP, et al. Serum folate and fetal growth retardation: A matter of compliance. Obstet Gynecol. 1992;79:719–722. 20 Neggars YH, Cutter GR, Alvarez JO, et al. The relationship between maternal serum zinc levels during pregnancy and birthweight. Early Hum Dev. 1991;25:75–85. 21 Winick M. Cellular changes during placental and fetal growth. Am J Obstet Gynecol. 1971;109:66–176. 22 Lafever HN, Jones CT, Rolph TP, et al. Some of the consequences of the intrauterine growth retardation. In: Visser HK, editor. Nutrition and metabolism of the fetus and infant. The Hague: Martinus Nijihoff; 1979.

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23 Wolk RA, Rayburn WF. Parenteral nutrition in obstetric patients. Nutr Clin. Pract. 1990;5:139–152. 24 Institute of Medicine of the National Academies. Report Brief. May 2009. 25 Weight gain during pregnancy. Committee Opinion No. 548. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2013;121:210–212. 26 Luke, B., Hediger, ML, Nugent, C, et al. Body weight index-specific weight gains associated with optimal birthweights in twin pregnancies. J. Reprod. Med. 2003;48:217–224. 27 Lavin JP, Gimmon Z, Miodovnik M, et al. Total parenteral nutrition in a pregnant insulin requiring diabetic. Obstet Gynecol. 1982;59:660–664. 28 Watson LA, Bermarilo AA, Marshall J, et al. Total peripheral nutrition in pregnancy. JPEN. 1990;14:485–489. 29 Turrentine MA, Smalling RW, Parisi V, et al. Right atrial thrombus as a complication of total parenteral nutrition in pregnancy. Obstet Gynecol. 1994;84:675–677. 30 Wilmore D. The metabolic management of the critically ill. New York: Plenum; 1980. 31 Harris J, Benedict F. Biometric studies of basal metabolism in man. Washington, DC: Carnegie Institute of Washington; 1991; publication no. 279. 32 Driscoll DF, Blackburn GL. Total parenteral nutrition 1990. A review of its current status in hospitalized

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33

34

35

36

37

38

39

patients and the needs for patient specific feeding. Drugs 1990;49:346–363. Badgett T, Feigold M. Total parenteral nutrition in pregnancy. Case review and Guidelines for calculating requirements. J Matern Fetal Med. 1997;6:215–217. Oldham H, Shaft B. Effect of caloric intake on nitrogen utilization during pregnancy. J Am Diet Assoc. 1957;27:847. Little G, Frigoletto F, Guidelines for perinatal care. 2nd ed. Washington DC: Am College of Obstetrics and Gynecology; 1988. Parenteral and Enteral Nutrition Team. Parenteral and enteral nutrition manual. 5th edn. Ann Arbor, MI: University of Michigan Hospitals; 1988. Heller L. Clinical and experimental studies in complete parenteral nutrition. Scand J Gastroenterol. 1968;4(Suppl.):5–7. Elphick MC, Filshie GM, Hull D, et al. The passage of fat emulsion across the human placenta. Br J Obstet Gynecol. 1978;85:610–618. Daniel SS, James LS, Stark RI, et al. Prevention of the normal expansion of maternal plasma volume: A model for chronic fetal hypoxemia. J Dev Physiol. 1989;11:225–228.

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16 Acute Kidney Injury and Renal Replacement Therapy Luis D. Pacheco1,2 and Chasey I. Omere1 1 2

Department of Obstetrics and Gynecology, Division of Maternal–Fetal Medicine, The University of Texas Medical Branch, Galveston, TX, USA Department of Anesthesiology, Division of Surgical Critical Care, The University of Texas Medical Branch, Galveston, TX, USA

While acute kidney injury (AKI) rarely affects pregnancy, it may be associated with significant morbidity and mortality [1]. Current definitions of AKI do not necessarily apply to pregnant individuals secondary to the physiologic increase in glomerular filtration rate and urine output seen during gestation [1,2]. Even though the incidence AKI during pregnancy is overall low in developed countries, the rate has recently increased in the United States [3]. As rates of AKI due to septic abortions and poor antenatal care are decreasing, the risk profile for AKI is changing. Women are conceiving at older ages, have higher body mass indices, and are more likely to have baseline comorbidities including hypertension, diabetes, and chronic kidney disease, predisposing them to renal injury. Hildebrand et al. [4] performed a retrospective cohort study in Ontario, Canada, between 1997 and 2011 that evaluated the number of pregnancies affected by renal disease and their outcomes. During that period, 1,918,789 pregnancies were evaluated with 188 being complicated by renal failure requiring dialysis, representing an incidence of approximately 1 in 10,000. Of those women, 11.2% had a preexisting comorbidity. In addition, 130  (69.2%) of women diagnosed with renal disease experienced a major antepartum complication including preeclampsia, thrombotic microangiopathies, heart failure, sepsis, or postpartum hemorrhage. Of those women requiring dialysis, less than 4% were dialysis-dependent by 12  weeks postpartum. This is a significant change from previously reported rates, where 50% of women with renal failure requiring dialysis remained dialysis-dependent. Mehrabadi et  al.  [5] also conducted a retrospective study of almost 11 million deliveries in the United States from 1999 to 2011. Of these deliveries, 4300  women

developed AKI, with a rise from 2.4 per 10,000 deliveries in 1999–2001 to 6.3 per 10,000 deliveries in 2010–2011. When examining the total number of AKI cases between the two halves of the studies (1999–2005, n = 1680; and 2006–2011, n = 2620), the proportion of patients requiring dialysis decreased from 9.5% to 7.2%. The authors concluded that the increase in AKI rates was the result of increased rates of pregnancies with chronic hypertension, baseline kidney disease, and other comorbidities predisposing them to AKI. The latter stresses the importance of preconception counseling in women at high risk of AKI, particularly those with chronic kidney disease. As expected, pregnancies affected by renal failure are more likely to result in fetal/neonatal complications such as low birth weight, fetal growth restriction, and premature delivery.

­Definition of acute renal failure The term acute renal failure has been standardized in non-pregnant individuals by the Acute Dialysis Quality Initiative Work Group into a severity continuum, the Risk– Injury–Failure–Loss–End stage (RIFLE) classification format (Table  16.1)  [6]. The classification system includes separate criteria for creatinine (Cr) and urine output (UO); a patient can fulfill the diagnosis through changes in either serum Cr, UO, or both. AKI includes a wide range of abrupt changes to kidney function ranging from mild elevations in serum Cr to acute need of renal replacement therapy (RRT). The most clinically useful definition of AKI is a rise in serum Cr of ≥0.3 mg/dL in a 48-h period and/or a UO less than 0.5 cc/kg/h for 6 h.

Critical Care Obstetrics, Seventh Edition. Edited by Luis D. Pacheco, Jeffrey P. Phelan, Torre L. Halscott, Leslie A. Moroz, Arthur J. Vaught, Antonio F. Saad, and Amir A. Shamshirsaz. © 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.

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Table 16.1 Criteria for acute renal failure according to the Risk–Injury–Failure–Loss–End stage (RIFLE) classification. Category

GFR criteria

UO criteria

Risk

Increase in serum Cr × 1.5 or GFR decrease >25%

UO 50%

UO 75%

UO 4 weeks

ESKD

End-stage kidney disease: >3 months

CR, creatinine; ESKD, end-stage kidney disease; GFR, glomerular filtration rate; UO, urine output. Source: Adapted from Bellomo et al. [6].

Although the definition of AKI has been standardized for non-pregnant patients, no specific criteria exist for parturients  [7]. The American College of Obstetricians and Gynecologists (ACOG) classifies renal insufficiency as a serum Cr level of >1.1 mg/dL or a doubling of the serum Cr concentration in the absence of other renal disease [8]. This working classification is also advocated by other authors [9,10]. However, RIFLE criteria have been utilized more often in pregnancy in recent years [11,12], and have been shown to have a discriminative power in predicting the risk of mortality in obstetric intensive care unit (ICU) patients [13]. Recent studies have suggested the use of biomarkers that signal cell cycle arrest such as tissue inhibitor of metalloproteinase 2 and insulin-like growth-factorbinding protein 7 are effective in predicting AKI before it occurs; the utility of these markers in pregnancy is unknown [14]. In summary, we recommend a diagnosis of AKI is made during pregnancy in patients with an acute rise in serum Cr of 0.3 mg/dL or more in a 48-h period and/or UO less than 0.5 cc/kg/h for 6 h or more. The latter should be based on ideal body weight.

­Changes of renal function in pregnancy The length of the kidney increases by 1–1.5  cm in pregnancy, while its volume increases up to 30% because of changes in the vascular and interstitial spaces. The urinary collecting system is dilated with hydronephrosis seen in up to 80% of pregnant women. Within weeks of conception, glomerular filtration rate (GFR) increases by 40–60%, and kidney blood flow by 80%. The average serum Cr level is 0.5–0.6  mg/dL, while blood urea nitrogen (BUN) level drops to approximately 8–10  mg/dL. Therefore, even a modest increase in serum Cr level to 1.0 mg/dL, although within the normal range for non-pregnant individuals, is reflective of kidney impairment. Total body water increases by 6–8 L, 4–6 L of which is extracellular and accounts for the edema of pregnancy. This volume expansion is due to the activation of the rennin–aldosterone–angiotensin system that is also responsible for a cumulative average sodium (Na) retention of up to 950 mmol [15,16]. Normal protein excretion in pregnancy is less than 300  mg in 24 h  [8]. An increase in protein excretion to 180–250 mg/day is seen in the third trimester because of an increase in filtered load combined with less efficient tubular reabsorption. Women with preexisting proteinuria may exhibit worsening of protein excretion in the second and third trimesters due to the physiologic increase in GFR [17,18]. Urine protein-to-creatinine ratio (P/Cr) estimation has recently been advocated to supplant or replace the more cumbersome 24 h protein collection method, with ratios >0.3 defined as abnormal [19]. The diagnosis of renal dysfunction is even more challenging in pregnancy as the true estimation of GFR is not reliable until a timed urine Cr excretion (24 h urine Cr clearance) is used; in fact, estimates used even for nonpregnant individuals are not reliable [20].

Etiologies of acute kidney injury The initial approach to the pregnant patient with AKI is similar to that of the non-pregnant patient; however, diseases unique to pregnancy (Table  16.2) should be

Table 16.2 Common causes of acute kidney injury during pregnancy. Prerenal

Renal (intrinsic)

Postrenal (obstructive)

Includes any condition associated with renal hypoperfusion such as hypovolemia, dehydration from gastrointestinal losses, hepatorenal syndrome, diuretic abuse

Established damage to renal tissue including acute tubular necrosis from sustained hypoperfusion, acute interstitial nephritis secondary to medications, and glomerulonephritis

May be secondary to anatomical obstruction of the urinary tract (tumors, surgical ligation of ureters) or induced by therapeutic agents (crystalluria from acyclovir therapy)

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considered in the differential diagnosis [15]. For academic purposes, causes of AKI may be classified into three categories: prerenal, intrarenal, and postrenal [7]. Disorders causing AKI in pregnancy include prerenal azotemia, intrinsic renal disease, urinary obstruction, preeclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), acute fatty liver of pregnancy (AFLP), and thrombotic microangiopathies, to name a few. The sole differentiation of prerenal vs intrinsic disease (acute tubular injury) in obstetrical emergencies is of little clinical significance since both should be treated similarly with hemodynamic optimization and avoidance of nephrotoxins. In developing nations, septic abortion plays a significant role as a culprit of AKI in pregnancy  [20]. As expected, baseline kidney disease secondary to chronic hypertension, diabetes, and lupus increases the risk of AKI during pregnancy [20]. Renal biopsy is infrequently performed during pregnancy as the clinical presentation and timing of renal failure are usually enough to establish a diagnosis. A renal biopsy may be indicated in cases of pregnancy-related AKI associated with proteinuria, hematuria, and/or when serologic studies indicative of glomerulonephritis (GN) of unknown cause to guide treatment decisions (e.g., unlike lupus nephritis, IgA nephropathy responds poorly to immunosuppressive therapy). If a diagnosis of preeclampsia is in question around the time of viability, occasionally a renal biopsy may help avoid premature delivery if an alternative diagnosis is found after performing a biopsy. A systematic review of renal biopsies performed during pregnancy and within 2 months following delivery was performed in 2013 [21]. There were four cases of major bleeding complications requiring blood transfusions in biopsies performed between 23 and 26  weeks of gestation. Minor but relevant complications, including small perirenal hematomas not requiring transfusion and gross hematuria, occurred in 5% of biopsies. Biopsies that were performed to differentiate between GN and preeclampsia led to therapeutic changes (mainly steroidal treatment) in 66% of cases [9]. This study concluded that the risk of adverse outcomes because of renal biopsies was higher during pregnancy than the postpartum period, 7 versus 1%, respectively. In summary, a renal biopsy is rarely indicated during pregnancy, but if considered necessary in the specific clinical setting, it should not be delayed just because of pregnancy. Prerenal azotemia

Prerenal AKI is the result of decreased renal perfusion commonly secondary to intravascular volume depletion and/or decreased cardiac output. Common etiologies include heart failure, hemorrhage, severe vasodilation and

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third spacing as seeing in sepsis or pancreatitis, and dehydration from gastrointestinal losses. Timely resuscitation with fluids, blood products, vasopressors, inotropes, and surgical interventions as indicated will limit further injury limiting kidney damage [22]. Classically, sepsis-induced AKI has been thought to be secondary to decreased renal perfusion leading to acute tubular necrosis (ATN). This is a very simplistic approach. Sepsis leads to AKI through multiple other mechanisms including efferent arteriole dilation mediated by nitric oxide, microvascular thrombosis due to disseminated intravascular coagulation, and abnormal oxygen diffusion secondary to third spacing edema within the kidney tissue. In fact, many cases of sepsis-induced AKI are accompanied by normal renal perfusion. Some suggest that infections originating from the kidney, as pyelonephritis, could have an added effect in the degree of kidney damage. In many cases, the polymicrobial nature of infections during pregnancy should be appreciated [23]. As previously discussed, restoration of hemodynamic stability (optimized blood volume and cardiac output) is the cornerstone of management in all cases of AKI (prerenal or intrinsic). Patients with preeclampsia may be particularly susceptible to AKI associated with hemorrhage due to preexisting alterations in maternal physiology such as decreased intravascular volume, heightened vascular responsiveness to catecholamines and angiotensin II, and altered prostaglandin synthesis [24,25]. Hyperemesis gravidarum is a common cause of AKI in pregnancy. Not uncommonly, significant elevations in creatinine occur due to severe hypovolemia. Aggressive fluid administration together with use of antiemetics restores kidney function in most patients [26]. Laboratory studies that may be of benefit in establishing the diagnosis of prerenal azotemia include urinary electrolytes and osmolality (Table  16.3). The urine sodium is Table 16.3 Urine and laboratory values in acute kidney injury. Prerenal AKI

Intrinsic AKI

Urine Na+ (mmol/L) 20

Fractional excretion of Na+ (FENa+)

1%

Urine osmolality (mOsm/kg)

>500

300–500

Urine-specific gravity >1.020

1.010–1.020

Urine sediment

Granular or red cell casts

Benign*

AKI, acute renal injury. * Hyaline casts and/or absence of other tubular or glomerular elements. Source: Adapted from Van Hook [15].

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typically low, as is the fractional excretion of sodium [urine Na/serum Na/(urine creatinine/serum creatinine) 100%], reflecting a sodium avid state; and urine osmolality is high, indicating intact urinary concentrating ability [15]. A low urine chloride may also provide a clue to surreptitious vomiting. While these markers are commonly obtained and cited in the literature, they have a minimal role in dictating management strategies during episodes of AKI; that is, irrespective of prerenal or intrinsic status, management will still include fluid resuscitation, optimization of cardiac output, and avoidance of nephrotoxins. Postpartum hemorrhage (PPH), defined as an estimated blood loss of >1000 mL with delivery, is an important cause of hypovolemia and AKI. Primary postpartum hemorrhage, defined as within 24 h of delivery, occurs in 4–6% of deliveries and is a result of uterine atony in >80% of cases [27]. Additional causes of PPH include retained placenta, coagulopathy, infection, and retained products of conception. Intrinsic renal disease

AKI may result from a variety of intrinsic renal diseases similar to those in the non-pregnant patient. Different components of the kidney may be involved depending on the disease process: involvement of the glomeruli predominates in GN, renal tubules are mainly affected in ATN, and the interstitium is the primary area of injury in acute interstitial nephritis. Both clinical presentation and examination of the urinary sediment can provide valuable clues to the diagnosis, although renal biopsy may be required (rarely during pregnancy) to distinguish among the different etiologies (Table 16.4). When renal ischemia is prolonged and persistent, ATN develops. The combination of parenchymal edema and the sloughing of necrotic tubular epithelium into the tubule obstructing the tubular lumen results in decreased GFR and granular casts present in the urinary Table 16.4

sediment  [29]. While ATN is mostly caused by acute episodes of renal hypoperfusion, other infrequent causes include the use of nonsteroidal anti-inflammatory agents, aminoglycosides, radiographic contrast, heavy metals, and several chemotherapeutic agents. Moreover, pigment-induced ATN may occur in cases of rhabdomyolysis or massive hemolysis [30]. Urinalysis typically reveals muddy brown granular casts and renal tubular epithelial cells. In light of impaired renal tubular function, laboratory evaluation reveals a high urinary sodium excretion as well as urine that is neither concentrated nor dilute. The recovery phase is characterized by polyuria with eventual return of renal function. Maintenance of urine output throughout the course of AKI is a general indicator of a milder presentation [31,32]. Renal injury in ATN involves both the tubules and the glomeruli and while injury to the nephron may not result in cell death, it may cause kidney malfunction. Injury may be transient or permanent [33]. In the obstetrical population, the injury is reversible in the vast majority of cases. Renal cortical necrosis is a rare severe injury secondary to renal ischemia. Currently, up to 50–70% of cases are associated with obstetrical etiologies such as placental abruption, septic abortion, and placental insertion anomalies. Patients usually present with severe and prolonged oliguria or anuria, flank pain, gross hematuria, and urinalysis demonstrating red blood cell and granular casts  [26]. Diagnosis is established by renal arteriogram demonstrating a virtual absence of cortical blood flow (interlobular arteries), despite patency of the renal arteries. More recently, ultrasonography, contrast-enhanced computed tomography (CT) (demonstrating areas of cortical lucency), and magnetic resonance imaging (MRI) have also been described as diagnostic tools [34]. The prognosis for patients with bilateral renal cortical necrosis is extremely poor, likely related to the severity of illness, with one study reporting a mortality rate of 93%  [26,34,35].

Acute renal failure: evaluation of intrinsic renal disease.

Acute tubular necrosis

Acute glomerulonephritis

Acute interstitial nephritis

Consequence of severe renal hypoperfusion resulting in intrinsic kidney damage or exposure to nephrotoxic agents. Urine sediment reveals muddy brown granular epithelial cell casts. Management centers on hemodynamic optimization.

Common causes include lupus, IgA nephropathy, vasculitis, post-streptococcal infection, cryoglobulinemia, anti-glomerular base membrane disease infective endocarditis, and medications. Present with AKI, hematuria, red cell casts and dysmorphic red cells on urinary sediment; with or without proteinuria Treatment includes blood pressure management and usually immunosuppressive therapy.

Most commonly secondary to use of beta-lactam, nonsteroidal antiinflammatory agents, antiacids, diuretics, and antiepileptics. May develop fever, rash, and eosinophilia. Urine sediment with pyuria, hematuria, and sometimes eosinophiluria. Treatment includes discontinuation of offending agent and steroids.

Source: Adapted from McConnell et al. [28].

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Most patients require dialysis, and up to 90% of survivors are dialysis-dependent upon hospital discharge. Those who recover typically exhibit some degree of renal insufficiency [26]. GN may be responsible for AKI occurring during pregnancy. As displayed in Table 16.5, the numerous causes of acute GN include primary glomerular disease such as poststreptococcal GN, membranoproliferative GN, idiopathic rapidly progressive (or crescentic) GN, as well as secondary glomerular disorders such as lupus nephritis, systemic vasculitis, and bacterial endocarditis [36]. Acute GN is a rare complication of pregnancy with an incidence of 1 in 40,000 pregnancies [37]. The classic presentation of acute GN includes hypertension, edema, hematuria, volume overload, electrolyte abnormalities, and active urinary sediment with red blood cell casts with or without proteinuria (Table 16.4). The overlap or misdiagnosis of preeclampsia in the patient with glomerular disease is a challenge that obstetricians often have to face. Hypertension and proteinuria are hallmarks of preeclampsia; however, they are often seen in patients with glomerular disease. When these signs present at a preterm or pre-viable gestational age, a diagnostic and therapeutic dilemma arises as preeclampsia with severe features may ultimately require delivery, while glomerular disease is not treated with delivery. Moreover, underlying renal disease may increase the chance of developing preeclampsia [26]. Table 16.5

Causes of glomerulonephritis.

Primary Minimal change disease Focal segmental glomerulosclerosis IgA nephropathy (most common cause) Membranoproliferative glomerulonephritis Membranous nephropathy Focal or segmental proliferative disease Secondary Post-streptococcal disease SLE Henoch–Schönlein purpura Cryoglobulinemia (associated with chronic hepatitis C infection) Polyarteritis nodosa ANCA vasculitis Hypersensitivity vasculitis

Table 16.6

Causes of acute interstitial nephritis.

Drug-induced (antibiotics, antiacids, diuretics, nonsteroidal anti-inflammatory agents, antiepileptics) Infections (CMV, malaria, leptospirosis, Streptococcus sp.) Autoimmune disorders (SLE, Sjogren’s syndrome) Transplant rejection Leukemic or lymphomatous infiltration CMV, cytomegalovirus; SLE, systemic lupus erythematosus.

Clinical presentation, presence or absence of other disease-related signs or symptoms, and examination of urinary sediment may provide clinical guidance. Unlike preeclampsia, patients with GN usually exhibit an active urinary sediment with epithelial cell and red blood cell casts. Inflammatory infiltration within the renal interstitial parenchyma and peritubular space defines acute interstitial nephritis (AIN). The incidence of AIN in pregnancy is not known, although it accounts for up to 15% of hospitalized AKI patients in the United States [38]. AIN has been associated with exposure to medications (nonsteroidal anti-inflammatory agents, diuretics, β-lactam antibiotics, antiepileptics, and antacids), infections, and autoimmune disorders. The most common cause of AIN is drug exposure including β-lactam antibiotics, sulfa-based drugs, histamine H2 blockers, proton pump inhibitors, and nonsteroidal antiinflammatory drugs (NSAIDs) [39,40]. While NSAID use is usually avoided in pregnancy, it may be encountered in the case of an intentional overdose. AIN may also occur in association with infections (cytomegalovirus, infectious mononucleosis, direct bacterial invasion, malaria, and leptospirosis) and autoimmune disorders such as systemic lupus erythematosus (SLE) and sarcoidosis (Table 16.6). AIN typically presents with modest proteinuria, pyuria, eosinophiluria (rare), hematuria, and white blood cell casts on urinalysis. Systemic manifestations may include fever, rash, eosinophilia, and arthralgias. Hypertension and edema are infrequent. Withdrawal of the offending agent or treatment of the underlying infection or disease usually results in improvement of renal function. In some cases of drug-induced or idiopathic AIN, steroids have been used with varying degrees of success. When history, physical examination, and laboratory evaluation are inadequate to establish a diagnosis, renal biopsy may be necessary.

Goodpasture’s syndrome (anti-basal membrane antibodies)

Urinary obstruction as a cause of AKI

Infective endocarditis

While urinary obstruction is an uncommon cause of AKI, it is readily reversible and, therefore, must be considered in the differential. Obstruction may occur at any level of the

IgA, immunoglobulin A; SLE, systemic lupus erythematosus; ANCA, antineutrophil cytoplasmic antibodies

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Table 16.7 Causes of urinary obstruction. Potential obstructive causes of AKI

Renal calculi Clots Tumors Polyhydramnios, uterine fibroids, uterine incarceration, multiple pregnancies Retroperitoneal fibrosis secondary to radiation Ureteral surgical ligation Neurogenic bladder

urinary tract due to a wide variety of causes, many of which are not unique to pregnancy (Table  16.7). Additionally, gravidas with an abnormally configured or overdistended uterus, such as those with uterine leiomyomata, polyhydramnios, or multiple gestations, may be particularly susceptible. Another cause unique to pregnancy is an incarcerated uterus, which may cause acute urinary retention as the gravid uterus enlarges but becomes trapped in the pelvis secondary to significant retroversion, compressing the bladder neck [26,41,42]. Other risk factors for urinary obstruction in pregnancy include pyelonephritis and nephrolithiasis [15]. Renal ultrasound is the first step in the evaluation of possible urinary tract obstruction, although results may be inconclusive due to the physiologic dilation of the collecting system often seen in pregnancy due to both the effects of progesterone and the mechanical pressure of the gravid uterus. Relief of the obstruction may be accomplished by ureteral stent placement, percutaneous nephrostomy, manual reduction of an incarcerated uterus, or amnioreduction in the case of polyhydramnios. If the fetus is significantly premature, correcting the obstruction should allow for a substantial delay in delivery as well as recovery of renal function. If the patient is near term, however, delivery may be indicated to remove both the mechanical and hormonal causes of the obstruction [43]. Pyelonephritis

Pyelonephritis is a potentially serious complication of pregnancy and can lead to AKI. As a result of the normal physiologic changes that accompany pregnancy, the urinary collecting system is prone to dilation and urinary stasis. These normal changes result in an increased incidence in both upper and lower tract infections. The incidence of pyelonephritis in pregnancy is approximately 1–2%, and it is one of the most common causes of hospitalization [37]. Presenting symptoms generally include fever, flank pain, and dysuria [44]. The most common causative organism is E. coli, which accounts for nearly 70–80% of cases, and it

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is important to remember that during pregnancy, women are more susceptible to acute respiratory distress syndrome due to an endotoxin-invoked lung injury [43]. Other potential pathogens include Proteus mirabilis, Klebsiella pneumoniae, group B streptococci, Enterobacter, and S. aureus. Prompt and appropriate antibiotic treatment is generally very effective in treating pyelonephritis during pregnancy, with improvement usually seen in the first 24–72 h. After resolution of the initial infection, suppressive antibiotic treatment throughout pregnancy should be considered as the recurrence rate is as high as 30–40% [43]. Preeclampsia

Among causes of AKI unique to pregnancy, preeclampsia and HELLP syndrome account for 40% of cases  [44]. In women with preeclampsia with severe features, about 1% will develop AKI, while 3–15% of women with HELLP syndrome will develop the complication. Pathologically, preeclampsia is characterized by incomplete trophoblastic invasion of the uterine arteries, causing narrow spiral artery lumens and impairment of placental blood flow. In addition, there is widespread endothelial dysfunction that leads to vasoconstriction, third spacing, and distal organ ischemia. Different mechanisms contribute to AKI in preeclampsia including hypovolemia, increased systemic vascular resistances, decreased cardiac output, and microvascular thrombosis affecting renal perfusion [45,46]. Histopathologic lesions of preeclampsia include glomeruloendotheliosis and significant podocyte injury. The lesion is characterized by decreased glomerular size and increased cytoplasmic volume, which account for reduced capillary lumen diameter leading to prerenal AKI and ATN  [11]. As decreased renal perfusion from reduced intravascular volume is often the cause of oliguria in preeclamptic patients, empiric volume resuscitation is the first recommended treatment for oliguria. Although invasive hemodynamic monitoring is now generally not recommended for treatment of oliguria, the use of continuous oxygen saturation monitoring and careful volume resuscitation is often effective for restoration of intravascular volume. We strongly recommend that, when available, fluid replacement should be guided with the use of dynamic measures of preload (such as pulse pressure variation or passive leg raising) as opposed to static measures of preload like central venous pressure. Treatment of severe preeclampsia and associated renal failure ultimately depends on delivery of the infant, blood pressure management, and seizure prophylaxis with magnesium sulfate during the delivery and for at least 24 h postpartum. It is important to monitor fluid administration closely while magnesium sulfate is given, as patients with impaired renal function will not clear the medication as

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well and dose reductions may be necessary to avoid magnesium toxicity. Recovery of renal function is usually seen within days to weeks after delivery  [44]. Although uncommon, a study performed in Norway found women with a history of preeclampsia to have a 2.7-fold increased risk for end-stage renal disease [47]. HELLP syndrome is an acronym used to describe a constellation of findings, including hemolysis, elevated liver enzymes, and low platelets. HELLP syndrome is diagnosed in a patient with preeclampsia when certain arbitrary laboratory cutoffs are met. The pathophysiology and management mirrors that of preeclampsia [48,49]. Acute fatty liver of pregnancy

Acute fatty liver of pregnancy (AFLP) is another uncommon cause of AKI in pregnancy, with a reported incidence ranging between 1 in 5000 and 1 in 10,000 deliveries [15]. Acute liver failure is caused by an underlying defect in the long-chain mitochondrial fatty acid β-oxidation metabolism. A fetal autosomal recessive defect in the production of long-chain 3-hydroxya-cyl-CoA dehydrogenase accounts for excessive fetal long-chain fatty acids to be transported across the placenta into the maternal circulation. Fetal long-chain fatty acids are then deposited into the maternal liver, resulting in hepatic dysfunction and, if not recognized and treated by delivery of the fetus, fulminant maternal liver failure [50,51]. This disease usually presents in the third trimester of pregnancy with nausea, vomiting, fever, malaise, and may progress to full-blown liver failure with encephalopathy and coagulopathy  [7,44]. Laboratory evaluation reveals elevation of serum transaminase levels, thrombocytopenia, leukocytosis, coagulation abnormalities, and occasionally hypoglycemia [44,52]. Hypertension and proteinuria may also be present. While liver imaging and even liver biopsy have been described to diagnose AFLP, the diagnosis is almost always made based on clinical and laboratory findings. Management of AFLP is mainly supportive and includes continuous fetal monitoring, maternal stabilization, and delivery. Although cesarean delivery may be necessary, AFLP is not an indication for cesarean delivery due to the increased risk of bleeding as a result of coagulopathy [52]. AKI develops in approximately 60% of cases, and, if left untreated, patients may progress to fulminant hepatic failure with jaundice, encephalopathy, DIC, gastrointestinal hemorrhage, and death [15]. Maternal and fetal mortality rates as high as 85% were seen in the past, although with earlier diagnosis and treatment, maternal mortality now ranges between 0 and 12.5%, and perinatal mortality occurs in 6.6–15% of cases [7].

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Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are thrombotic microangiopathies (TMAs) characterized by diffuse microthrombi resulting in microangiopathic hemolytic anemia and thrombocytopenia. While any organ may be affected, most affected are the kidneys and the brain  [53,54]. Histopathologic findings in the kidney include endothelial cell swelling, subendothelial protein deposits, and double contouring of the basement membrane, which are indicative of intrinsic renal damage [53]. TMAs are more common in women (70% of cases) and up to one in seven cases are diagnosed during pregnancy. The median gestational age at diagnosis is 23 weeks, which is earlier than preeclampsia, although they can occur at any time during pregnancy or the postpartum. Due to breakthroughs in our understanding of TMAs, this disorder has been reclassified into complement dysregulation TMAs (mainly atypical HUS), ADAMTS13 (a  disintegrin and metalloprotease with thrombospondin type 1 motif 13 repeats) deficient TMAs, and TMAs linked to other mechanisms (verotoxin and vascular endothelial growth factor deficiency). Despite different pathogenesis, there is a clear overlap among all these forms. This classification is more helpful for choosing the appropriate treatment, with systemic disorders requiring therapy directed at the underlying disorder [55]. TTP is characterized by fever, severe thrombocytopenia, hemolysis, neurological symptoms, and usually relatively mild renal insufficiency. The latter pentad of symptoms is present in a minority of patients and TMA should be suspected when there is evidence of microangiopathic hemolytic anemia and thrombocytopenia with no other alternate diagnosis. TTP is characterized by a decrease in activity of the metalloproteinase ADAMTS 13 (less than 10% activity). The decrease in activity may be secondary to congenital deficiency or more commonly from acquired autoantibodies. The lack of ADAMTS 13 results in failure to cleave the  large von Willebrand factor multimers (which are extremely procoagulant) resulting in platelet adhesion to the multimers and subsequent systemic microthrombi formation [9]. Microthrombi result in distal organ ischemia/ dysfunction and hemolysis from mechanical injury to red cells as they collide with thrombi. Typical HUS is more common in pediatrics and is associated with diarrhea from E. coli 0157:H7 shiga toxin disease. Atypical HUS, the most common variant seen in pregnancy, is secondary to mutations in different complement inhibitors (e.g., Factor H, Factor I) resulting in complement mediated diffuse endothelial injury leading to microthrombi formation. Pregnancy may be a trigger for HUS. HUS is frequently

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Table 16.8 Key differences between preeclampsia and imitators. Preeclampsia/HELLP

AFLP

TTP

HUS

Usually diagnosed after 20 weeks Hypertension with or without proteinuria Hemolysis Thrombocytopenia Elevated transaminases Jaundice is rare AKI is rare Coagulopathy is rare Hypoglycemia is rare

More common in third trimester and postpartum May have hypertension and proteinuria and thrombocytopenia Elevated transaminases Elevated conjugated bilirubin with jaundice May do hypoglycemia and encephalopathy Coagulopathy with prolonged INR Urine is bright yellow due to elevated conjugated bilirubin

May happen any time in pregnancy or postpartum May develop hypertension Severe thrombocytopenia Nonimmune microangiopathic hemolytic anemia with schistocytes Normal coagulation studies Minimal liver involvement ADAMTS 13 activity less than 10% Purpura, neurologic symptoms, AKI Urine is tea colored due to hemoglobinuria

May happen any time in pregnancy or postpartum May develop hypertension Severe thrombocytopenia Nonimmune microangiopathic hemolytic anemia with schistocytes Normal coagulation studies Minimal liver involvement ADAMTS 13 activity is normal Purpura, severe AKI Urine is tea colored due to hemoglobinuria Genetic complement system mutations in atypical form

ADAMTS13, a disintegrin and metalloprotease with thrombospondin type 1 motif 13 repeats; AFLP, acute fatty liver of pregnancy; AKI, acute kidney injury; HELLP, hemolysis, elevated fiver enzymes, low platelets; HUS, hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura.

seen in conjunction with severe AKI and the need for RRT is common  [56]. Table  16.8 summarizes the differences between imitators of preeclampsia. The differential diagnosis between preeclampsia and TMA is extremely difficult. In fact, TMA is commonly diagnosed after failure of improvement following delivery of a presumed case of preeclampsia  [11]. TMA should be strongly suspected in any patient in whom delivery for preeclampsia fails to improve hemolysis and thrombocytopenia 2–3 days postpartum. TTP is treated with plasmapheresis and steroids. Plasmapheresis with fresh frozen plasma substitution works by removing autoantibodies against ADAMTS 13 and it restores the metalloproteinase as it is present in fresh frozen plasma  [7,57,58]. Unlike preeclampsia and AFLP, delivery does not improve TTP or UHS and therefore is not indicated. First line therapy for atypical HUS is eculizumab, a monoclonal antibody against C5 [59]. Eculizumab is the most potent treatment available and appears safe for use in pregnancy; however, due to the high cost (approximately $500,000 annually per patient), its use varies  [20,53]. Patients receiving eculizumab should receive meningococcal vaccination (B and ACWY). In most cases, since treatment is started emergently, nonimmunized patients should be vaccinated upon treatment initiation and start prophylactic antibiotics for at least 2  weeks (rifampin or ciprofloxacin). When TMA is suspected, results of ADAMTS 13 activity will not be available for days in most cases. Consequently,

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plasmapheresis is commonly started together with steroids until results are available. If ADAMTS 13 activity is >10%, then TTP is less likely; plasmapheresis may be discontinued and eculizumab started for a presumed diagnosis of atypical HUS. Bilateral renal cortical necrosis (BRCN)

Acute BRCN is a pathologic entity consisting of partial or complete ischemic destruction of the renal cortex due to a prolonged decrease in renal perfusion [60]. Obstetric renal cortical necrosis rarely occurs following a massive obstetric hemorrhage, which accounts for approximately 50–70% of all BRCN cases [26]. One small retrospective study identified 18 cases of renal cortical necrosis caused by postpartum hemorrhage between 2009 and 2013 [60]. All of these women had deliveries complicated by an estimated blood loss of >1000 mL with mean blood loss of 2.6 ± 1.1  L. Uterine atony was identified as the cause of PPH in 83% of the cases, with the remaining cases attributed to DIC, placental abruption, or amniotic fluid embolism. All 18 cases required dialysis. Eight of the 18 women remained dependent on dialysis at 6  months postpartum, and none of the women regained normal kidney function. Patients with BRCN experience abrupt onset of severe oliguria or anuria, flank pain, gross hematuria, and hypotension. Diagnosis may be established by ultrasonography, contrast-enhanced CT demonstrating areas of cortical lucency, and MRI; however, histology remains the gold standard  [26,44]. Long-term renal function for patients

Management: general principles

with BRCN is extremely poor, with many patients requiring dialysis and only 20–40% having partial recovery of renal function [26].

­Management: general principles Treatment of AKI involves management of the underlying condition, containment of renal damage, and restoration of renal function. In the past, specific treatments of AKI have focused on restoration of urine output; however, we now know that this is not synonymous with kidney function recovery. “Conversion” of oliguric to non-oliguric renal failure was hypothesized to result in improved prognosis and survival, but “conversion” does not actually occur [15]. Continued urine production in a patient with AKI may reflect a lower degree of renal injury, less additional hypoperfusion from prerenal AKI, or gradual recovery. The Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for AKI emphasize that goal-directed pharmacological treatment of perfusion or urinary output is not associated with improvement in outcomes [61]. Low-dose (1–3 μg/kg/min) dopamine infusion was formerly thought to improve prognosis promoting urine output, but the benefits of such agents have been refuted [62]. Loop diuresis theoretically reduces tubular oxygen consumption and increases urinary output. However, the use of furosemide for prevention or treatment of AKI does not reduce in-hospital mortality or the need for RRT, and it is indicated only if signs of pulmonary congestion are present. Atrial natriuretic peptide augments GFR by afferent arteriolar vasodilation, but no clear benefits have derived from its use. The KDIGO Guidelines also underline the lack of benefit from using fenoldopam (a pure dopamine type-1 receptor agonist and a β-adrenergic agonist) or insulin-like growth factor-1 in the setting of AKI. They also rule against the use of oral N-acetylcysteine (NAC) for the prevention of postsurgical AKI [61]. Although serum albumin levels are often found to be low and infusions have been shown to increase both serum albumin and colloid osmotic pressures, it does not stabilize renal function and was associated with higher fetal mortality  [63]. Finally, mannitol should theoretically be beneficial in preventing AKI in high-risk patients, but no trials have been performed in pregnant women to assess its efficacy [29]. In summary, no pharmacological agent has been shown to improve outcomes in women with AKI. Although not specifically tailored to the obstetric population, several other important recommendations have been issued on AKI management [61]. The use of isotonic crystalloids rather than colloids is encouraged for volume

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expansion, as randomized clinical trials have found no differences in outcomes [64]. Furthermore, certain colloids such as hyperoncotic starch are associated with AKI [65]. Hydroxyethyl starch should not be used in patients with AKI. It has also been suggested that the use of lactated Ringer’s solution and Plasma-Lyte is associated with less renal injury than normal saline because higher concentrations of chloride can lead to vasoconstriction and ischemia [15]. Protein restriction to prevent or delay initiation of RRT is not recommended; instead, administering 0.8–1 g/kg/day of protein is recommended in non-catabolic AKI patients without the need for dialysis, 1–1.5 g/kg/day in AKI patients on intermittent hemodialysis, and 2–2.5 g/kg/day in patients on continuous renal replacement therapy. Avoidance of nephrotoxic agents (such as aminoglycosides or NSAIDs) is encouraged. Protocol-based management of hemodynamic parameters and oxygenation is recommended to prevent development or worsening of AKI, especially in postoperative and septic patients. Close monitoring for signs and symptoms of electrolyte abnormalities is essential in AKI management; moreover, electrolyte abnormalities as well as the presence of underlying kidney or cardiac disease may influence the choice and rate of fluid administration. When preeclampsia is the underlying etiology leading to AKI, treatment is primarily supportive. Hypertension is commonly treated with labetalol or dihydropyridine calcium channel blockers  [8]. Hyperkalemia can be treated with insulin, glucose, calcium, bicarbonate, β-agonists, hyperventilation, and ion exchange resins. The management of potassium and phosphate imbalances is like that of the non-pregnant patient. Hypermagnesemia may develop in patients with preeclampsia and eclampsia who have AKI when magnesium sulfate is administered. This is especially a concern in those with oliguria or anuria. Frequent assessment of serum magnesium level is therefore recommended  [8]. Significant blood loss should be replaced early, especially in the event of obstetric hemorrhage. In the case of AKI secondary to sepsis, early broadspectrum antibiotic administration is fundamental to achieve source control, until cultures allow a more specific antibiotic therapy  [66]. When treating septic abortion or chorioamnionitis, evacuation of the uterine contents is necessary, because antibiotic penetration of the uterine cavity is suboptimal [11]. Finally, cause-specific treatments should be initiated according to the different AKI etiologies, such as in the event of TMAs or GN. Contrast-induced (CI) AKI is rarely of clinical significance when using the minimal amount necessary of iso-osmolar or low-osmolar contrast media. The only intervention of proven benefit to prevent CI is intravenous hydration (isotonic crystalloids, 1–1.5 mL/kg/h for 2–12 h

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before and 6–12 h after contrast administration). The use of sodium bicarbonate or n-acetyl cysteine is not beneficial to prevent CI AKI [61].

­Renal replacement therapy As previously stated, management of AKI consists of hemodynamic optimization, avoidance of nephrotoxic medications, dose adjustment of those medications that are required for patient care, and treatment of the underlying cause (e.g., plasmapheresis in TTP, eculizumab in HUS, delivery in preeclampsia, antibiotics and source control in sepsis). While the latter is instituted, patients may require RRT. Patients requiring RRT during pregnancy should be managed by a multidisciplinary team involving maternal– fetal medicine specialists, neonatology, nephrology, pharmacists, social workers, and dieticians [67]. Common indications for RRT in the setting of AKI include volume overload with pulmonary edema, hyperkalemia >6–6.5 meq/L, and metabolic acidosis with PH < 7.15–7.2. Other indications for RRT such as uremic encephalopathy, hemorrhagic diathesis, and pericarditis are less common in AKI and more common in chronic end-stage renal disease.  [68,69]. Table  16.9 summarizes common indications for RRT. In patients with acute respiratory distress syndrome (ARDS), early initiation of RRT to achieve a fluid negative balance is associated with improved oxygenation and commonly improves acidemia by allowing better CO2 clearance [68]. Importantly, there is no creatinine level at which RRT should be initiated. If none of the previously mentioned indications are present, RRT is not indicated based on serum creatinine levels alone. The same applies to BUN values outside of pregnancy (no clear cutoff exists at which RRT is indicated in the absence of uremic symptoms); however, during pregnancy, RRT should be considered if BUN is greater than 60 mg/dL [69]. Pregnant patients with elevated BUN tend to develop polyhydramnios due to an

Table 16.9 Common indication for initiation of renal replacement therapy. Severe hyperkalemia (>6–6.5 meq/L) Metabolic acidosis (pH < 7.1–7.2 with serum bicarbonate level < 12–15 mmol/L) Volume overload with pulmonary edema Uremia (causing encephalopathy or pericarditis) Hemorrhagic diathesis Intoxications with dialyzable toxins

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increase in fetal BUN with osmotic diuresis  [70]. Polyhydramnios can have adverse consequences in pregnancy such as preterm labor and delivery. In the critical care setting, controversy has existed for many years regarding the potential benefits of early RRT implementation. Recent studies have found no benefit of early start (defined usually as stage 3 AKI) compared to delaying RRT until one of the following develops: metabolic acidosis with PH 112  mg/dL, or oliguria/anuria persistent for 72 h [71,72]. In fact, delaying RRT reduces the total number of patients receiving dialysis without affecting clinical outcomes. At present, early initiation of RRT in critically ill patients is not indicated. Once the decision to start RRT is made, central intravascular access is required. The latter is ideally obtained through the right internal jugular vein, followed by the femoral vein, and then the left internal jugular vein. Access through the subclavian vein should be the last option as potential subclavian vein stenosis secondary to line placement may jeopardize the use of the ipsilateral upper extremity for a future arteriovenous fistula, if needed. Dialysis catheters are 12 French in width, and the two most used are known as a “trauma catheter” (3  lumens) or a “Quinton catheter” (2 lumens). While a detailed description of all RRT techniques is outside the scope of this chapter, we will briefly describe the key factors of each form of RRT. The two most used RRT modalities are continuous renal replacement therapy (CRRT) and intermittent hemodialysis (IHD)  [73]. The current data do not support the superiority of either in terms of renal recovery or mortality [73,74]. Hemodialysis may be intermittent (IHD) or continuous (CRRT in the form of CVVHD: continuous venous–venous hemodialysis). It operates based on the principle of diffusion; blood is exposed through a semipermeable membrane to a dialysate that has low concentrations of creatinine, BUN, potassium, acids, and a high concentration of other solutes such as bicarbonate. Solutes will move from areas of high concentration to those of lower concentration allowing clearance of unwanted metabolites [69]. In IHD, each session lasts close to 4 h and is performed three times a week. High flows of blood and dialysate allow rapid removal of solutes. Fluid removal in hemodialysis is achieved through an alternate process known as “ultrafiltration” (UF). One may think of UF as negative pressure applied as blood flows through the extracorporeal circuit allowing fluid removal [14,68,73]. The rapid fluid removal during IHD may result in hypotension in patients who are hemodynamically unstable. Similarly, the rapid clearance of solutes leads to a decrease in serum osmolarity that

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may  worsen cerebral edema in patients with brain injuries  [75,76]. The latter makes CVVHD a safer option for these patients as CVVHD runs 24/7, with lower blood and dialysate flows permitting more gradual solute and fluid clearance. An alternate technique of CRRT is CVVH (continuous venous–venous hemofiltration). Hemofiltration operates through convection, not diffusion. As such, extremely elevated negative pressure is utilized to pull large amounts of fluid (ultrafiltration) as blood flows through the circuit resulting in dragging of solutes through a semipermeable membrane. A replacement fluid with physiologic electrolyte concentrations is used to restore the large amounts of volume ultrafiltered. Diffusion and convection may be used together in CRRT in a modality known as “continuous venous–venous hemodiafiltration” (CVVHDF). There is no evidence that any mode of CRRT (CVVHD, CVVH, or CVVHDF) is superior to another. As previously discussed, there is also no evidence that CRRT improves outcomes compared to IHD [77]. Anticoagulation is rarely needed during IHD as high blood flows rarely result in circuit clotting. In CRRT, since blood flow is significantly slower, anticoagulation is commonly instituted. In pregnancy, we recommend the use of intravenous unfractionated heparin (UFH) as the anticoagulant of choice for CRRT. Because of the physiologic increase in blood volume during pregnancy, the frequency of IHD is increased to 5–6 sessions per week. Episodes of hypotension during IHD are not uncommon and may compromise uterine perfusion; at our center we perform continuous fetal monitoring in viable pregnancies during each session of dialysis. Patients requiring antihypertensive therapy should receive their medication after (not before) dialysis to decrease the risk of intradialytic hypotension. Table  16.10 summarizes the different forms of RRT.

Table 16.10

Different modalities of renal replacement therapy.

Intermittent hemodialysis

High blood and dialysate flow rates Rapid fluid removal, poorly tolerated in hemodynamically unstable patients Avoid in patients with cerebral edema Rarely requires systemic anticoagulation

Continuous renal replacement therapy

Lower blood and dialysate flows allow for a more gradual removal of solutes and fluid Better tolerated in hemodynamically unstable patients May use in patients with cerebral edema Commonly requires systemic anticoagulation May use diffusion (CVVHD), convection, (CVVH), or a combination of both (CVVHDF)

CVVHD: continuous venous–venous hemodialysis; CVVH: continuous venous–venous hemofiltration; CVVHDF: continuous venous–venous hemodiafiltration

­Summary Evaluation of the pregnant patient with AKI encompasses a broad range of disorders, some of which are unique to pregnancy. Prerenal azotemia, intrinsic renal disease, and urinary obstruction should be considered based on clinical presentation. Evaluation of AKI during pregnancy is like that in the non-pregnant patients, including urinalysis, urinary diagnostic indices, imaging, and, in some cases, renal biopsy. In addition, diseases unique to pregnancy and those more common during pregnancy must be considered, such as preeclampsia, HELLP syndrome, AFLP, HUS, and TTP. Treatment of AKI focuses on hemodynamic optimization, avoidance of nephrotoxic agents, disease-specific therapy (when available), and watchful surveillance for the development of indications for RRT.

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JAMA. 2016 Feb 23;315(8):775–787. doi:10.1001/ jama.2016.0289 Tangren J, Nadel M, Hladunewich MA. Pregnancy and end-stage renal disease. Blood Purif. 2018;45(1–3): 194–200. doi:10.1159/000485157 Tandukar S, Palevsky PM. Continuous renal replacement therapy: Who, when, why, and how. Chest. 2019 Mar;155(3):626–638. doi:10.1016/j.chest.2018.09.004 Pacheco LD, Saade GR, Hankins GDV. Maternal medicine. New York: McGraw-Hill Education; 2015. Reddy SS, Holley JL. Management of the pregnant chronic dialysis patient. Adv Chronic Kidney Dis. 2007 Apr;14(2):146–155. doi:10.1053/j.ackd.2007.01.005 Palevsky PM, Liu KD, Brophy PD, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury. Am J Kidney Dis. 2013 May;61(5):649–672. doi:10.1053/j.ajkd.2013.02.349 Bagshaw SM, Wald R, Adhikari NKJ, et al. Timing of initiation of renal-replacement therapy in acute kidney injury. N Engl J Med. 2020 Jul 16;383(3):240–251. doi:10.1056/NEJMoa2000741

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73 Nash DM, Przech S, Wald R, O’Reilly D. Systematic review and meta-analysis of renal replacement therapy modalities for acute kidney injury in the intensive care unit. J Crit Care. 2017 Oct;41:138–144. doi:10.1016/ j.jcrc.2017.05.002 74 Vinsonneau C, Benyamina M. Intermittent hemodialysis. In: Jörres A, Ronco C, Kellum J, eds. Management of acute kidney problems. New York: Springer; 2010. 75 Davenport A, Honore PM. Continuous renal replacement therapy under special conditions like sepsis, burn, cardiac failure, neurotrauma, and liver failure. Semin Dial. 2021 Nov;34(6):457–471. doi:10.1111/sdi.13002 76 KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9(Suppl. 3):S1–S155. doi:10.1111/j.1600-6143.2009.02834.x 77 Vinsonneau C, Camus C, Combes A, et al. Continuous venovenous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: A multicentre randomised trial. Lancet. 2006 Jul 29;368(9533):379–385. doi:10.1016/s0140-6736(06)69111-3

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17 Cardiopulmonary Bypass Erin G. Sreshta1, Tris M. Miller2, and Alexis L. McQuitty1,3 1

Cardiac Anesthesiology, The University of Texas Medical Branch, Galveston, TX, USA Anesthesiology Critical Care Medicine, The University of Texas Medical Branch, Galveston, TX, USA 3 Shriners Children’s Texas, Galveston, TX, USA 2

Introduction Women with structural cardiac or coronary artery disease may have an attenuated ability to adapt to the cardiovascular changes associated with pregnancy. There is an increasing incidence of advanced maternal age, obesity, hypertension, diabetes mellitus, and improved congenital heart disease treatments; due to these conditions, cardiac disease is becoming more common and may complicate up to 4% of pregnancies [1,2]. Maternal heart disease is now the most common cause of maternal deaths in the United Kingdom per 2016  MBRRACE-UK report  [3]. Many of these patients have a World Health Organization (WHO) III or IV classification of disease, in which pregnancy is contraindicated or has a high risk of maternal and fetal mortality [4]. Cardiac surgery may be required for this subset of parturients and should be performed only with maternal cardiac decompensation and failure of medical therapy or interventional procedures. Cardiopulmonary bypass (CPB) involves the use of an extracorporeal circuit in series with the maternal circulation and provides artificial oxygenation, ventilation, and perfusion. The use of CPB may be necessary and unavoidable for many urgent or emergent cardiac surgical repairs. The types of surgical pathology requiring CPB in parturients include the following [5,6]: ●

●

●

Native or prosthetic valvular pathology (including severe mitral/aortic stenosis and endocarditis) Massive pulmonary embolism (saddle) or amniotic fluid embolism (with cardiovascular collapse) Acute aortic pathology (Type A dissection, ascending aneurysm)

●

●

● ●

Acute coronary syndrome (coronary artery disease [CAD] or dissection requiring bypass grafting) Complications/congestive heart failure due to congenital heart disease Cardiac tumors Hypertrophic cardiomyopathy (with left ventricular outflow tract obstruction).

Whereas gestational age and surgical timing cannot always be controlled, there are many clinical interventions that may provide optimization before, during, and after CPB procedures and improve maternal and fetal outcomes. In most patients, it is not possible to delay open heart surgery until the recommended 6  weeks postpartum  [7]. If there is adequate time for medical therapy and the mother’s life is not threatened, cardiac surgery should occur (1) at the conclusion of first trimester organogenesis, (2) prior to maximal maternal hemodynamic load, and (3) before cardiac decompensation  [8]. With modified CPB protocols for parturients and a multidisciplinary team approach, the maternal mortality rate is like that in non-pregnant adults. Maternal risk is higher with emergent, unplanned surgeries and in those with a poor functional class [9,10]. Poor fetal outcomes (prematurity and death) remain high and are associated with the effects and duration of CPB, high-risk surgeries, use of vasopressors and inotropic agents, maternal comorbidity, an early gestational age, intraoperative and postoperative use of anticoagulants, anesthetic agents, and prolonged mechanical ventilation  [10,11]. Despite extraordinary research, there are still many unknown effects of CPB on fetal well-being and adequate circulatory needs [12].

Critical Care Obstetrics, Seventh Edition. Edited by Luis D. Pacheco, Jeffrey P. Phelan, Torre L. Halscott, Leslie A. Moroz, Arthur J. Vaught, Antonio F. Saad, and Amir A. Shamshirsaz. © 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.

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Open heart surgery may have negative effects on the biological balance of the fetoplacental unit because of hemodilution, hypothermia, inhibition of normal coagulation, removal of pulsatile blood flow, and changes in acid–base balance  [13]. Due to the significant risk of fetal loss with CPB, available alternatives must be considered in these cases. Medical therapy should be optimized, and percutaneous interventions should be considered. If the patient’s status allows waiting until the third trimester, then cardiac surgery can be performed after the delivery, either soon after or with a concurrent cesarean section. This strategy improves the chances of the neonate surviving, but it adds risk for the mother, who must withstand the hemodynamic stresses of late pregnancy. Another alternative is to proceed with maternal surgery using standard techniques, regardless of gestational age, with the understanding that saving the life of both the mother and fetus may not be possible. A multidisciplinary team needs to discuss the risks, benefits, and alternatives with the mother and help her navigate the difficult decisions regarding the goals of surgery and its timing [14].

­ aternal and fetal risks M of cardiopulmonary bypass The first reported case by Duborg et  al.  [15] of CPB in a pregnant patient occurred in 1958; this patient had a repair of tetralogy of Fallot, which resulted in a stillbirth at 6 months of gestational age. Although fetal mortality is still high, safer and more contemporary medical management of CPB has improved both maternal and fetal outcomes. Comparing the early 1990s to 2002–2004, Immer et al. [16] noted a significant decline in fetal mortality for aortic dissection repairs utilizing CPB. Accurate maternal and fetal risk assessment prior to surgery is fundamental for preoperative care. An analysis of high-risk parturients in a tertiary center showed that the CARPREG (Cardiac Disease in Pregnancy) risk index may be used to predict complications in pregnant women with heart disease  [17]. The CARPREG study analyzed 562  pregnant women with heart disease and identified four predictors for maternal complications. There was a 75% risk of a cardiac event if patients had >1 of these factors [9,18]: 1) A prior cardiac event, such as heart failure, transient ischemic attack, stroke before pregnancy, or an arrhythmia 2) A prepregnancy NYHA (New York Heart Association) class greater than II or the presence of cyanosis

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3) Left heart obstruction with a mitral valve area less than 2 cm2, or an aortic valve area less than 1.5 cm2, or an aortic outflow gradient greater than 30 mmHg 4) A left ventricular ejection fraction less than 40%. A cardiac event is defined as pulmonary edema, arrhythmia, cerebrovascular event, cardiac arrest, or death. More recently, the CARPREG II study analyzed 1938 pregnancies and derived a risk stratification index with an expansion to 10 weighted predictors for maternal complications [19]. Similarly, an increased risk of neonatal complications in women with heart disease has been associated with an NYHA > II or cyanosis, maternal left heart obstruction, smoking during pregnancy, multiple gestation, oral anticoagulation in pregnancy, and presence of a mechanical valve prosthesis [4]. Elassy et al. showed a higher maternal morbidity and fetal loss in those with mechanical valves presenting for cardiac surgery, especially if the need for CPB was emergent, patients had a prior sternotomy, or CPB times were prolonged [20–23]. Identification of these higher-risk patients may allow time for medical optimization before cardiac surgery; as in the non-pregnant cardiac patients, this should improve maternal outcome. Stangl et al. [24] reviewed 93 patients with heart disease. Patients with an NYHA class III–IV left heart obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), or an ejection fraction 35, functional class, reoperation, emergency surgery, myocardial protection type, and CPB crossclamp times. With such significant fetal death rates, it is likely that fetal morbidity is similarly high in the fetal survivors of CPB. At present, there are few studies assessing the longterm effects of CPB on those with fetal exposure to CPB. The confounding effects of maternal cardiac disease, pharmacologic management, and possibly other cardiac interventions would make such assessments difficult. In a review of 21 pregnant patients requiring CPB by John et al. [21], there were 52% with premature deliveries and three fetal deaths (14%). Neonatal morbidity included small for gestational age, respiratory distress syndrome, prolonged postnatal hospitalization, and developmental delays. Despite the significant number of series that have been published describing mortality rates associated with CPB in pregnancy, few correlations can be made with CPB techniques and reduction in maternal and fetal morbidity and mortality. An optimal gestational age at the time of surgery, fetal heart rate (FHR) monitoring, high-flow CPB, normothermic CPB, and possibly pulsatile CPB have all been proposed to improve outcomes.

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­Alternatives to CPB The adaptive hemodynamic changes of pregnancy may unmask previously compensated cardiac disease. Women with left-sided obstructive lesions (mitral or aortic stenosis) or CAD may be unable to adapt to these cardiovascular demands; symptoms of dyspnea, angina, and congestive heart failure may develop. Patients may have signs of decreased cardiac output or pulmonary hypertension. With the significant risks of CPB, pregnant women may be candidates for percutaneous procedures or bypass grafting without CPB. These cases may include percutaneous balloon mitral valvuloplasty (commissuroplasty), aortic balloon valvuloplasty, or off-pump coronary artery bypass grafting (CABG). The best time to intervene is after the fourth month in the second trimester. By this time, organogenesis is complete, and the volume of the uterus is still small, so there is a greater distance between the fetus and the chest than in later gestation. Fluoroscopy times should be as brief as possible and the gravid uterus should be shielded from direct radiation, although the required radiation doses are not likely to be harmful to the fetus [4,36]. Although ideally performed before conception, percutaneous balloon mitral valvuloplasty (PBMV) is indicated for pregnant women with symptomatic severe mitral stenosis (MS) unresponsive to medical therapy  [37,38]. Contraindications to PBMV are left atrial thrombi, moderate mitral regurgitation, and subvalvular stenosis  [38]. PBMV can be performed in the second or early third trimester under echocardiographic guidance or limited fluoroscopy with pelvic and abdominal shielding to minimize radiation exposure [4,37]. Although some studies have reported improved fetal outcomes after PBMV during pregnancy, others have shown a high incidence of prematurity, low birth weight, and fetal loss [39]. As mitral valve surgery with CPB has been associated with a 16–33% rate of fetal loss [21,40], PBMV should be considered after the 20th week as a bridge to surgery or a temporizing measure [40]. Aortic balloon valvuloplasty has been described in pregnancy with good outcomes  [41]; if symptoms recur, then an elective valve replacement can be performed after delivery. Fetal monitoring should occur, as short periods of hemodynamic deterioration may occur during the balloon inflation, or the rapid ventricular pacing often required in these cases. Due to the systemic inflammatory response and lack of pulsatility with most CPB procedures, off-pump CABG may be an alternative during pregnancy. Compared to on-pump CABG, a recent literature review showed similar mortality indices and comparable organ protection, but offpump cases usually had less distal coronary anastomoses completed [42]. There is ongoing controversy on whether

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using off-pump versus traditional on-pump CPB for CABG; it depends on the underlying coronary lesions, maternal status, and surgical expertise. Studies performed during off-pump procedures have shown that cardiac manipulation on a beating heart brings significant fluctuation in the patient’s hemodynamics [43]. Due to intermittent periods of hypotension and the requirement for vasopressors (due to cardiac positioning and manipulation), off-pump CABG procedures may also have harmful fetal effects. Repair to coronary lesions on the anterior part of the heart usually requires less perturbations in blood pressure. Silberman et al. [44] described a case of off-pump CABG in a patient at 22 weeks of gestation who presented with spontaneous dissection of the left anterior descending artery. She then delivered a healthy baby at term.

­ urgical timing and concurrent S cesarean section In parturients with cardiac disease, the strategy for surgical timing involves an assessment of three risks: (1) fetal loss with CPB and continuation of a high-risk pregnancy, (2) fetal age and concern of neonatal prematurity with a preoperative delivery, and (3) maternal mortality with or without surgery  [45]. The time for surgical intervention is a challenging and critical clinical decision that needs to be made on a case-by-case basis by a multidisciplinary team. Early intervention will decrease maternal risk but may result in fetal demise. Alternatively, delaying cardiac surgery until after a term delivery may result in maternal death  [21,46]. Typically, in obstetric medicine, what is in the best interest of maternal health is in the best interest of the fetus. This, however, is not always true in patients with cardiac disease. The adaptive changes of a normal pregnancy may be poorly tolerated, and surgery may be deemed emergent. Pregnant women, particularly those with CAD, aortic aneurysms, or left-sided obstructive lesions, may become symptomatic after the first trimester due to an inability to compensate for the physiologic anemia of pregnancy, decrease in systemic vascular resistance, increase in cardiac output (due to an increase in stroke volume and heart rate), and aortocaval compression after week 20 (limiting preload and cardiac output) [10,47]. Optimal timing can be controversial and depends on the maternal condition; to balance maternal and fetal risks, current European guidelines recommend surgery between the 13th and 28th weeks [4,10]. High-risk cardiac lesions (e.g., aortic root dilation or severe valvular stenosis) may warrant surgery before the third trimester. Surgery may be required in the second trimester, after completion of organogenesis and before maternal cardiac compromise.

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Heart failure or aortic rupture may occur with the higher hemodynamic loads of late pregnancy  [13,29]. The need for complex cardiac surgical repairs in early pregnancy requires the options and risks to be discussed with the mother. Maternal survival should be the priority. Because of the high risk of fetal death at an early gestational age with deep hypothermia and longer CPB times, pregnancy termination may be an option [35,45]. Even if the fetus is viable, concurrent cesarean delivery may not be an option if the surgery is emergent and the mother is hemodynamically unstable  [21,48]. Post-CPB cesarean deliveries can occur; this may be advised in patients who will need prolonged anticoagulation (e.g., valve replacement surgery) or in those with expected difficult postoperative intensive care unit (ICU) recovery [48]. When maternal surgery is anticipated to be complicated and prolonged, or when anticoagulation will be needed postoperatively, delivery prior to CPB should be considered if the fetus has reached a viable gestational age  [4,21,35,48,49]. Delivery before CPB may be considered after 24–26 weeks depending on fetal weight, prior administration of corticosteroids, and capabilities of the neonatal unit. When gestational age is more than 28  weeks, delivery before CPB is advised  [4,5,30,49]. When a concurrent cesarean delivery is planned, steroids should be given. The American College of Obstetricians and Gynecologists (ACOG) guidelines recommend a single course of antenatal corticosteroids, defined as either betamethasone (12 mg intramuscularly q24h × two doses) or dexamethasone (6  mg intramuscularly q12h × four doses), be given after 23–24  weeks of gestation to any pregnant woman in whom delivery before 34  weeks of gestation is threatening [4,50–52]. Cesarean delivery during CPB should be avoided because of significant bleeding risk to the mother during heparinization. To lessen maternal bleeding risks, the cesarean incision may be left open and packed; after heparin reversal, the incision may be closed. This will allow post-CPB exploration and removal of any hematoma formation  [30,49]. Slower infusions of oxytocin can be implemented and continued during CPB. For example, 10 IU/h over 24 h will have less cardiac effects (less hypotension)  [53]. In addition, placement of an intrauterine balloon (such as a Bakri balloon) will provide tamponade and facilitate monitoring of bleeding from the uterine cavity [49,54]. Bilateral uterine artery ascending branch ligation can minimize the risk of postpartum hemorrhage, and concurrent hysterectomy may be required  [55]. The sternotomy together with isolation of the femoral vessels prior to delivery may be the safest course of action. In the event of maternal decompensation, urgent cannulation and CPB can commence while the fetus is delivered [56,57].

­tecnrtees tooenerttopAltrnery ryoneses

Cesarean delivery followed by valve replacement may be an appropriate choice for patients who are not candidates for percutaneous interventions and have failed medical management. While mortality rates for pregnant and nonpregnant women undergoing valve replacements are similar, fetal mortality rates are high; necessitating delivery prior to CPB when possible [58].

­Mechanics of cardiopulmonary bypass CPB is a technique required during most cardiac surgeries and creates a motionless, semi-bloodless operative field. Venous blood is diverted away from the heart, carbon dioxide is removed, oxygen is added, and then the blood is returned to the maternal arterial system with a specific flow rate and perfusion pressure. Nonphysiologic conditions are artificially created upon the initiation of CPB including normovolemic hemodilution to improve viscosity, intermittent periods of low systemic vascular resistance, nonpulsatile flow, and varying degrees of hypothermia for organ protection  [25,59]. Myocardial preservation occurs with the use of local hypothermia (ice slush placed in the chest cavity) and with different types of cardioplegia (potassium solutions used to arrest

myocardial electrical activity). In general, normothermic CPB is only utilized for short periods of time. Without hypothermia, higher flow rates are required to meet the metabolic oxygen demands [60]. A typical CPB machine has seven basic components: a venous reservoir, an oxygenator, a heat exchanger, a  main pump, an arterial filter, tubing that conducts venous blood to the venous reservoir, and tubing that  conducts oxygenated blood back to the patient (Figure 17.1). Anticoagulation must be established before CPB to prevent acute disseminated intravascular coagulation and formation of clots in the CPB pump [62]. Between 300 and 400 units/kg of heparin are given prior to arterial cannulation; this anticoagulation is reversed with protamine after CPB. The ACT (activated clotting time) is used to measure the appropriate degree of anticoagulation. An ACT of 400–480 s is considered adequate at most institutions. The CPB circuit is primed with a balanced salt solution, such as Plasma-Lyte A. Other components are frequently added, including albumin, heparin, mannitol, and sodium bicarbonate. Smaller adults, children, and severely anemic patients may need blood added to the circuit or a smaller prime volume, which is usually 1200–1800  mL for adults [62].

Figure 17.1 A typical cardiopulmonary bypass circuit interfaced with a patient. ALF, arterial line filter; K, potassium; LV, left ventricular. Source: Nussmeier tlonA. [61]/ with permission of Elsevier.

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K Suction Heat exchanger

ALF

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Arterial pump Oxygenator

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­Physiology of CPB Maternal effects CPB causes significant alterations in patient physiology, with virtually every organ system affected. Some of the prominent adverse effects include: (1) profound alterations in coagulation (dilution of all clotting factors, intense heparinization, and platelet dysfunction), (2) disturbances in cardiovascular function (hypotension, nonpulsatile blood flow, myocardial ischemia, cardiac stunning, and arrhythmias), and (3) a significant generalized systemic inflammatory response with an increase in stress hormones and activation of the fibrinolytic system [59,62]. The systemic inflammatory response syndrome (SIRS) related to CPB  may vary from mild (with minimal effects) to a life-threatening condition with multi-organ failure and profound vasoplegia. Patients with poor compensatory mechanisms prior to surgery or long CPB times may develop this syndrome, characterized by vasodilation, hypotension, and increased vascular permeability [63]. Systemic embolization of particulate material and air embolization are risks of open cardiac procedures. Embolic phenomena are thought to be major contributors to the significant risks of cerebrovascular accident (2–6%) and neurocognitive dysfunction (20–60%)  [64–66]. Neurologic complications increase the postoperative morbidity and mortality, particularly in older patients. Many therapeutic options for neuroprotection during CPB have been proposed: heparin-coated circuits, assessment of aortic atheromatous disease with echocardiography, pulsatile perfusion, alpha-stat pH management, pharmacologic interventions (e.g., lidocaine and thiopental), and hypothermia (to decrease cerebral metabolic rate during CPB) [67]. Direct surgical trauma, surface contact activation, and ischemia–reperfusion injury are some of the factors contributing to post-CPB complications. Severe anemia may also contribute to perioperative complications and cause inadequate oxygen delivery (to maternal organs and to the fetus). The degree of anemia due to hemodilution depends on the preoperative red blood cell (RBC) mass and the extracorporeal circuit prime volume  [68]. One should be aware that maternal hypotension is relatively common upon initiation of CPB; it is likely due to hemodilution with non-blood priming fluids. It is recommended to maintain a hematocrit of at least 28% to optimize maternal oxygen delivery during CPB  [4]. While prevention of severe anemia is important, overtransfusion should be avoided to maintain the physiologic anemia of pregnancy (hemoglobin about 11 g/dL or hematocrit 35%). Teleologically, the decreased viscosity likely occurs to maintain

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uteroplacental perfusion. This is illustrated by the fact that elevations of maternal hematocrit are associated with placental infarction [69]. Prevention strategies to reduce the inflammatory effects of CPB include the following: limited hemodilution (miniaturized CPB circuits, retrograde autologous prime, and ultrafiltration), more biocompatible circuits, adequate cardioplegia use (for cardioprotection), leukocyte filtration of blood products, shorter duration of CPB, intraoperative steroids, avoidance of cardiotomy suction, and limited transfusion of blood products  [25,70–73]. Acute kidney injury is relatively common with longer CPB cases. It is associated with ischemia–reperfusion injury, altered blood flow patterns (hypotension and nonpulsatile flows), hemolysis and hemoglobinuria (seen after long CPB times), and blood transfusions [73]. Adequate heparinization and ACTs must be monitored carefully in the parturient on CPB. The coagulation system is in a state of accelerated, compensated intravascular coagulation. This hypercoagulable state is suggested by an increase in most coagulation factors, a decrease in prothrombin and partial thromboplastin times, and a decrease in antithrombin III. Increased fibrinolysis is  suggested by an increase in fibrin degradation products [74]. Higher amounts of heparin may be needed, and ACTs should be checked more frequently; monitoring and prevention of deep vein thrombosis should occur postoperatively. Antifibrinolytic agents to reduce blood loss in cardiac surgery are routinely used; however, this therapy may not be needed in pregnancy (exception: high-risk cases with potential for significant blood loss). If needed, antifibrinolytics may be used safely in pregnancy. To balance the maternal oxygen supply and demand, invasive monitoring with measurement of the mixed venous oxygen saturation (SVO2) is routine in many CPB cases. SVO2 reflects the average oxygen saturation of the blood returning from the body to the right heart, weighted by the respective regional blood flows. It is a measure of the balance between global oxygen delivery and global oxygen uptake (or demand)  [75]. Normal values range from 65 to 80% and are affected by several factors including arterial oxygen saturation, global oxygen consumption, hemoglobin, and cardiac output. Maintaining optimal maternal hemodynamics, including an adequate SVO2, may be one key factor for fetal well-being. Occasionally, even with a normal SVO2, hypoperfusion of some vascular beds can still occur. Therefore, it is important to monitor other parameters such as lactic acid and base deficit. SVO2 values in pregnancy are similar to non-pregnant women.

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decreased uteroplacental perfusion, if significant, results in fetal hypoperfusion. In the acute setting, UBF is related to perfusion pressure (the difference between uterine arterial pressure and uterine venous pressure) and vascular resistance, as represented in the following equation:

Fetal effects The main pathophysiological changes that can affect the fetus under CPB are uterine contractions, placental hypoperfusion, and fetal hypoxia  [5]. Interventions to prevent fetal hypoxemia require a balance between both maternal and fetoplacental oxygen supply and demand. These measures include increases in CPB flow, mean arterial pressure (MAP), and the prime’s hematocrit, as well as the use of uterine relaxants [12]. Hypoperfusion with reduced oxygen delivery is further minimized by avoiding excessive vasopressors, hemodilution, and prolonged periods of CPB and cardioplegic arrest [14]. Uteroplacental blood flow (UPBF) is the major determinant of oxygen and nutrient transport to the fetus. A direct correlation between uterine blood flow (UBF) and fetal oxygenation has been demonstrated in both animal models and humans [76,77]. UPBF is derived primarily from uterine arteries, with a smaller contribution coming from the ovarian arteries. Uterine artery blood flow increases twofold to threefold during pregnancy and can represent up to 12% of the maternal cardiac output. Increases in UBF during pregnancy are due to both physical (increased diameter of the uterine artery) and physiologic (decreased responsiveness of the uterine artery to endogenous circulating vasoconstrictors) mechanisms. Selective uterine artery relaxation during pregnancy may be the result of vasodilators released from its endothelium, such as PGI2 or nitric oxide, or local hormonal actions, which diminish the activity of certain intracellular enzymes that mediate vasoconstriction. Under normal circumstances during pregnancy, uteroplacental circulation is a widely dilated, low-resistance system with perfusion that is largely pressure dependent. Systemic hypotension results in vascular dilation to maintain blood flow for autoregulated organs such as the brain and kidneys. In contrast, the placental vasculature cannot further vasodilate in response to hypotension, and

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Uterine perfusion pressure/Uterine vascularre sistance.

Perfusion pressure is the difference between uterine MAP and uterine venous pressure (UVP). Decreasing the maternal MAP (and hence perfusion pressure) may be a result of aortic compression or hypotension (due to hypovolemia, decreased systemic vascular resistance, or decreased cardiac output). An increase in UVP may be caused by the supine position (caval compression), uterine contractions, and high maternal intrathoracic pressure (high tidal volumes or peak inspiratory pressures). Exogenous vasopressors and local mediators may increase the uterine vascular resistance [78]. An example of typical fetal hemodynamics during CPB is shown in Figure 17.2. Maternal MAP is compared to FHR and the uterine artery pulsatility index (PI). At induction of anesthesia (point A), despite maintenance of maternal MAP and FHR, the PI fell. Once CPB was established (point B), the hemodynamics was maintained. The mother was weaned from bypass at point C. The onset of CPB is typically characterized by fetal bradycardia, while the conclusion of CPB demonstrates fetal tachycardia with minimal beat-to-beat variability  [79,80]. The cause of initial fetal bradycardia is thought to be secondary to placental hypoperfusion because it has been found to be reversible in most cases by increasing the perfusion rate. Other theories for this initial fetal bradycardia have included maternal hypothermia resulting in fetal bradycardia, fetal hypoxia from hemodilution acutely decreasing the maternal oxygen content, and uterine contractility at the onset of CPB increasing the uterine vascular resistance and decreasing placental perfusion  [81].

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Figure 17.2 Typical fetal hemodynamics throughout the perioperative period, comparing maternal mean arterial pressure (square shape) with fetal heart rate (diamond shape) and uterine artery pulsatility index (triangle shape). bpm, beats per minute. Source: Adapted from Yates tlonA. [29].

UBF

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Many reports indicate that FHR directly correlates with perfusion throughout CPB such that, when flow rate is increased, the FHR is restored  [33,82,83]. Although not seen in Figure 17.2, fetal tachycardia with minimal beat-tobeat variability often occurs at the conclusion of CPB, and this is presumed to be secondary to fetal acidosis developing from continuous uteroplacental insufficiency throughout CPB. Long periods of nonpulsatile flow may have also caused an increase in placental resistance, resulting in decreased blood flow.

­Management of cardiopulmonary bypass Anesthesia and maternal hemodynamics There are three primary aims in the anesthetic management of patients undergoing CPB: providing safe maternal hemodynamic management, avoiding teratogenic agents, and minimizing effects of CPB that may induce premature labor  [84]. The anesthesiologist needs to understand the hemodynamic goals for each specific cardiac lesion before proceeding with surgery. Stabilization and optimization of the maternal condition must occur to maintain fetal well-being. Maternal hypotension can result in lower UBF and fetal oxygenation [85]. As CPB in pregnancy is an unusual circumstance, it is important not to forget the basics of anesthetic care in pregnancy. Left uterine displacement, aspiration prophylaxis, and rapidsequence induction with cricoid pressure are indicated for any anesthesia in a pregnant woman after approximately 18 weeks of gestation [86]. Careful attention should be paid to the obstetric airway. Oxygen consumption increases and functional residual capacity decreases during pregnancy, increasing the risk for sudden hypoxemia  [74]. Anesthesiologists should be aware that pregnant women have increased rates of failed intubation compared to non-pregnant patients  [87,88]. Increasing edema of the airway structures as pregnancy progresses may impede direct laryngoscopic view. If maternal hemodynamic parameters are maintained, a total intravenous anesthetic or a volatile-based anesthetic may be used. The specific type of anesthetic does not affect outcome [23]. To minimize the anesthetic time, it may be prudent to place the invasive monitoring lines with local anesthetics prior to the induction of general anesthesia. Short-acting narcotics with minimal fetal effects, such as remifentanil, may be used for the stimulating sternotomy and concurrent cesarean section. In high-risk cases (such as a Type A aortic dissection), an opioid-based anesthetic may be used to provide better maternal hemodynamic control (less hypertension and tachycardia). For better control

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of hemodynamic parameters, high-dose sufentanil has been used for general anesthesia in a case of pre-CPB cesarean delivery. The opioid effects in the neonate need to be reversed pharmacologically after delivery  [89,90]. Inhalation (or volatile) agents, such as isoflurane, can help achieve uterine relaxation but should be avoided if the delivery precedes CPB [91]. The volatile anesthetics, which in high doses can decrease SVR, have been shown in isolated pregnant human uterine muscle to inhibit spontaneous contractility in a dose-dependent manner  [92]. Maternal cardiac output must be adequate for fetal oxygen delivery. Although inotropic medications, used to improve contractility, may be harmful to the fetus, the priority of saving the mother’s life will dictate their use. The pregnancy outcomes were worse when the women needed inotropic medications  [93]. If needed, inotropic agents (dobutamine or milrinone) should be used as indicated. Intraoperative transesophageal echocardiography (TEE) can be useful in managing obstetrical patients with refractory hypotension during cardiac surgery. In this high-risk population, the ability of the anesthesiologist to assess cardiac performance quickly and continuously, determine the need for cardiac surgical intervention, and monitor the efficacy of resuscitative efforts is critical in directing definitive maternal and fetal interventions. The immediate availability of TEE equipment and physicians with experience in performing and interpreting echocardiography examinations in a critical setting is an asset to the multidisciplinary team responsible for the care of these obstetric patients. Perioperative hemodynamic instability is a class I indication for TEE; it may assist with the etiology of hypotension and guide appropriate therapy [94,95]. The effects of general anesthesia need to be considered separately from the effects of CPB. The most thorough evaluation of the risks of all types of anesthesia and surgery during pregnancy retrospectively evaluated a population of 720,000 pregnant women who underwent 5405 surgical procedures [96]. The incidence of congenital malformations or stillbirths was not increased in the offspring in the women who underwent surgery, regardless of gestational age at the time of surgery. The incidences of prematurity and low-birth-weight infants, and the rate of infant death, within 168 h of birth were slightly increased. This increase, however, was not linked to the gestational age at the time of surgery. Furthermore, patients who require surgery may have underlying illnesses that affect the health of their pregnancy. This confounds the results, making it difficult to determine the singular risk of surgery during pregnancy. Very few cases in this series involved CPB. Therefore, although we can state that anesthesia at any time during pregnancy is safe, the risks of fetal exposure to CPB at various times during gestation are less clear.

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Fetal heart rate monitoring Continuous fetal monitoring should be used in the perioperative period  [4,10,97]. Fetal bradycardia and loss of beat-to-beat variability, suggesting poor fetoplacental perfusion, can be corrected by increasing the flow rate (≥5 L/min), maternal pressure, and maternal temperature; by lateral tilt; and by preventing (or halting) uterine contractions  [98]. Because fetal cardiac output is heart-rate dependent, bradycardia is a sign of distress, usually a result of poor oxygen delivery at the maternal or placental level  [45,99]. Maternal cardiac output and oxygenation (pO2) should be optimized to ensure adequate uterine and placental oxygen delivery. Multimodal FHR monitoring, combined with intermittent uterine and umbilical artery Doppler interrogation, can reflect placental perfusion, and may be used to guide bypass management  [29,100,101]. The velocity of the umbilical artery systolic and diastolic flow can be analyzed, and the resistive index can be calculated; this information can be used to diagnose fetal perfusion. Low-dose nitroglycerin improved a case of fetal bradycardia that occurred despite normal MAP, pump flows, and temperature. The absence of the diastolic velocity flow profile occurred with fetal bradycardia and improved with higher maternal MAP [101]. Importantly, decreased FHR variability and fetal decelerations may occur because of central anesthetics and even mild hypothermia (despite normal pump flows, temperature, maternal blood pressure, and pH); normal FHR patterns usually return after anesthetic recovery and rewarming  [100,102,103]. FHR monitoring should continue in the ICU, as an early respiratory acidosis followed by a metabolic acidosis can develop in the fetus. This may be due to continued uteroplacental malperfusion and part of the fetal stress response (decreased fetal cardiac output due to increased catecholamines and systemic vascular resistance) [99,104]. While fetal monitoring may be used to guide hemodynamic management during CPB, the decision to intervene with an emergent cesarean section (if delivery is not accomplished prior to cardiac surgery) should be carefully discussed prior to the case.

Myometrial activity and tocolysis CPB, especially with cooling and rewarming, is a strong stimulus for uterine contractions, and their frequency increases with increasing gestational age. Uterine contractions are associated with significant fetal loss during CPB  [30,105,106]. Cardiotocographic monitoring can be beneficial during CPB and has been reported to reduce fetal mortality rate to 9.5% [33]; early detection of fetal distress will allow for appropriate and timely interventions  [107].

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The dilutional effect of CPB (related to the prime volume) has been postulated to reduce the stabilizing levels of progesterone resulting in increased uterine excitability [30,45,108]. Very limited data suggest that progesterone supplementation, started prior to surgery, may be beneficial in preventing uterine contractions during CPB [101]. Although used in many institutions, the prophylactic use of tocolytic medication before CPB is controversial. Betamimetics (e.g., terbutaline), dihydropyridine calcium channel blockers (e.g., nifedipine and nicardipine), progesterone, nitrates (e.g., nitroglycerin), volatile anesthetics, magnesium sulfate, and prostaglandin inhibitors (e.g.,  indomethacin) have all been described with varying effects in decreasing uterine contractions associated with CPB [30,48,101,109]. Indomethacin suppositories have been used to prevent contractions  [106], and steroids may mitigate placental dysfunction during CPB. The effectiveness of prostaglandin inhibitors was implicated in a study by Sabik et al. [104]. Thromboxane production increases in patients during CPB and may be responsible for the increased placental vascular resistance and decreased blood flow. Magnesium sulfate (although usually only 2 g) is a part of many CPB protocols. This dose should not be considered a first line for tocolysis. In addition to fetal neuroprotection provided before 32 weeks of gestation, magnesium may also be used as a tocolytic for the prolongation of pregnancy to allow for the administration of antenatal corticosteroids [109,110]. Calcium channel blockers have been reported to be a preferred first line tocolytic with regard to fetal outcomes and prevention of neonatal complications [109]; however, they should be avoided if hypotension is evident. Prostaglandin inhibitors tend to have the best probability of delaying delivery by at least 48 h; however, these drugs are contraindicated during CABG and may increase bleeding complications from platelet dysfunction [109,111]. Many cardiac medications to treat tachycardia or hypertension may interfere with uterine tone. To avoid interference with β2-mediated uterine relaxation and peripheral vasodilation, beta 1 selective blockers are preferred (metoprolol, esmolol)  [112]. In general, uterine contractions should be first treated with increased perfusion pressure and CPB flows; then, depending on the current maternal hemodynamics, the volatile anesthetic can be increased or a tocolytic can be administered. Severe coronary disease, aortic or mitral stenosis, or aortic dissections/large aneurysms may preclude the use of β2-adrenergic agonists. These medications can cause significant tachycardia and may increase myocardial work and oxygen demand in a system that is physiologically compromised by pregnancy and the initiation of CPB [43,113].

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Temperature during CPB Mild to moderate hypothermia is used in most nonpregnant CPB cases to provide organ protection during nonpulsatile blood flow. Temperature manipulation during hypothermic CPB may cause many of the FHR changes seen during CPB  [81]. It has been known for some time that maternal temperature change results in FHR changes, with hyperthermia causing fetal tachycardia and hypothermia causing fetal bradycardia (Figure 17.3) [114]. However, multiple cases of normothermic CPB demonstrate the characteristic initial bradycardia and post-CPB tachycardia, sustaining the theory that although temperature influences FHR, the typical changes observed during CPB are likely a result of uteroplacental hypoperfusion. Sustained uterine contractions, which occur most often during the cooling and rewarming phases, reduce uterine and placental blood flow. The result is fetal acidosis, hypoxia, and higher intraoperative fetal death rates [113]. Experimental studies have shown that normothermia plays an important role in improving fetal outcome. With hypothermia, gas exchange is decreased at the placental level  [115] and placental vascular resistance increases. Although the pCO2 was lower in a study of hypothermic ewes, fetal oxygenation was worse, indicating that the placenta acts as a poor oxygenator with hypothermic CPB. Both hypothermia at normal flows and normothermia with low flows were associated with hypoxia, compared to normal CPB flows with normothermia [60,106]. Moderate to deep hypothermia is needed for many aortic repair surgeries (for cerebral protection) and may result

in worse fetal outcomes. Pardi et  al.  [116] demonstrated that lamb fetuses can tolerate maternal temperatures above 20 °C. Significant bradycardia ensues; however, oxygen demand is reduced at these low temperatures. The reduction of fetal pO2 is compensated by the left shift on the oxygen–hemoglobin dissociation curve. The most influential study demonstrating the potential fetal benefit of normothermic CPB retrospectively evaluated 69 reports of CPB during pregnancy from 1958 to 1992 [33]. In evaluating the 40 most recent cases, hypothermic CPB was associated with a fetal mortality of 24%, while normothermic CPB was associated with no fetal losses. Because of this demonstrated improvement in fetal survival as well as reports of fetal asystole, uterine contractions, and decreased placental blood flow during hypothermic CPB, normothermic CPB is preferred when possible.

Pump prime Priming of the CPB circuit produces hemodilution, which is an important element of CPB. It decreases blood product utilization and its attendant costs and risks. Hemodilution also improves the rheology of blood by decreasing its viscosity, resulting in a lower arterial resistance and improved peripheral perfusion  [117]. Other purported benefits of hemodilution during CPB include decreases in major organ complications, such as cerebral vascular accidents, and renal and pulmonary dysfunction. Excessive hemodilution will decrease progesterone levels and result in severe anemia, which may compromise oxygen delivery at the

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Figure 17.3 Maternal temperature and fetal heart rate (FHR). The FHR plot directly parallels the maternal temperature. The arrow at 0800, 1/1/86, represents the nadir of maternal BP: 87/46 mmHg (mean arterial pressure, 69). Within 20 min, the BP was 94/57 mmHg (mean arterial pressure, 69). The mean arterial pressure during the rest of the illustrated time ranged from 64 to 76. Previous and subsequent pressures during this pregnancy ranged from 90/50 to 110/65 mmHg (mean arterial pressure, 63–80). BP, blood pressure; bpm, beats per minute. Source: Reproduced by permission from Jadhon and Main [114].

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tissue level and contribute to hypotension during CPB [68]. Progesterone has been added to the pump prime, but this is not a common practice [54]. Whole blood or RBCs can be added to the prime of the CPB circuit so that the resultant hematocrit is no less than 28% [4,118]. Hypertonic glucose is usually added to the extracorporeal perfusate to avoid fetal hypoglycemia [32]. Mannitol is often added to the CPB prime to promote osmotic diuresis and to scavenge oxygen free radicals from the circulation. During pregnancy, some recommend omitting mannitol from the CPB prime to decrease the risk of fetal blood hemoconcentration  [119]. Mannitol slowly accumulates in the fetus, and fetal hyperosmolality leads to physiological changes such as reduced fetal lung fluid production, reduced renal blood flow, and increased plasma sodium concentration [45]. Albumin or other colloids can favor tissue perfusion and contribute to avoid interstitial edema. An oncotically adjusted prime makes addition of mannitol or furosemide unnecessary and can avoid effects of diuretics on the fetus. The CPB perfusate pH and temperature should be adjusted to preserve fetal maternal exchanges at the placental level [99].

Cardioplegia Myocardial protection during CPB is essential to reduce perioperative cardiac morbidity. Both cold and warm blood cardioplegia have been shown to reduce cardiac morbidity [120], by reducing myocardial oxygen demand and creating a diastolic arrest of myocardial tissue. The application of cardioplegia may need to be more frequent with the maintenance of high flows during CPB, especially if normothermia or only mild hypothermia is employed. Normothermic perfusion often results in early rewarming of the left ventricle, leading to difficulties with myocardial protection [30]. Cardiac activity may return as frequently as every 10 min under these circumstances. In one study, 3.5 L of cardioplegia was required to adequately suppress cardiac activity [121]. The use of cold cardioplegia has been associated with fetal bradycardia  [122], and continuous cold pericardial irrigation or warm blood cardioplegia have been suggested as effective alternatives [123]. Bicaval cannulation has been recommended to open the right atrium and scavenge the high-potassium cardioplegia [32,99,106]. This may protect the fetal heart from the effects of the temporary maternal hyperkalemia and cardiac arrest [118].

CPB flows and perfusion pressure Because normal cardiac output in pregnant women is often greater than 6  L/min  [124], usual flows (approximately 2.2–2.5  L/m2) employed during CPB may not be

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enough. Changes in baseline FHR have been identified after initial flow rates as high as 80 mL/kg/min, even in the absence of maternal hypotension  [82]. Increases in CPB flows to 3.0–4.0 L/m2 have been successfully (if only temporarily) employed during surgery in pregnant patients, especially in response to fetal bradycardia [82,108,125]. Koh and associates [79] were the first to describe improvement in fetal bradycardia by increasing flow rate by 16%. Other investigators have since confirmed the value of increasing pump flow rate to improve fetal bradycardia  [83,121,126,127]. Furthermore, fetal bypass animal models have shown that moderately high flow rates improve placental function  [128]. In a swine model, reductions in pump flow significantly reduced perfusion of all visceral organs. Increasing the pump flow restored perfusion to the pancreas, colon, and kidneys, whereas restoration of systemic pressures with phenylephrine did not [129]. The ideal MAP during CPB is not firmly established for cardiac surgical patients in general. Advantages of higher mean pressures during CPB include enhanced tissue perfusion, improved collateral flow to tissues at risk for ischemia, and the ability to use higher pump flow rates. Potential disadvantages include more red cell trauma due to shear injury, more cardiotomy suction, and higher embolic load [68]. The best evidence of an adequate arterial pressure is the fetal response to CPB; in general pump flow should be sufficient to maintain a MAP above 70  mmHg. During CPB on pregnant patients, MAP and CPB flow correlate with fetal cardiotocography patterns [99]. As previously discussed, it is common that shortly following CPB initiation fetal bradycardia develops  [79,80,125,127]. This is generally treated with increases in both MAP and pump flow. It is preferable to increase MAP with fluid and high flow rates as opposed to excessive vasopressor administration as the latter may  increase uteroplacental vascular resistances. Perioperative inflammation, reduced viscosity, and anesthetic depth may all decrease maternal blood pressures. A recent small study showed no differences in uterine perfusion between phenylephrine and ephedrine [130]. A prior study showed, however, that ephedrine increased fetal oxygen consumption more than phenylephrine resulting in fetal academia [131]. If adequate fluid resuscitation has been accomplished, the use of vasopressors in pregnancy is safe, including norepinephrine. Phenylephrine could have an adverse placental effect if bradycardia and subsequent decreased cardiac output occur. Phenylephrine may be more beneficial in tachycardic patients, whereas ephedrine can be used in bradycardic patients [48].

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Pulsatility Pulsatile pump function during CPB may offer significant physiologic advantages compared to continuous flow by providing diastolic runoff and stimulation of the endothelium. Pulsatile perfusion patterns may improve major organ blood flow and augment oxygen delivery at the tissue level [68]. Achieving this physiologic flow from a noncompliant high-resistance CPB circuit is difficult. The required higher flows and resultant shear stresses can result in more damage to blood elements, and the CPB circuit will be more complex [68,132]. These higher flows and increased MAP, however, may be necessary to perfuse the placenta when nonpulsatile perfusion is utilized, as this may be a cause of placental vasoconstriction. Pulsatility may reduce uterine contractions by releasing endothelium-derived growth factor from the vascular endothelium  [133]. Similarly, pulsatility with CPB, compared to nonpulsatile flows, may decrease the systemic inflammatory response and maintain placental perfusion by decreasing placental vascular resistance [21,133]. Although maintenance of pulsatility appears to have multiple benefits, most CPB cases are performed with nonpulsatile flow. John et  al.  [21] showed that short CPB times, normothermia, higher flow rates, and maintenance of perfusion pressure play a greater role in fetal perfusion. An alternative to providing CPB pulsatile flows, which may be difficult at some institutions, is the use of an intra-aortic balloon pump (IABP). Usually placed to increase myocardial perfusion pressure and to decrease afterload, IABPs have also been used during CPB and may help reverse the signs of fetal distress. IABPinduced pulsatile perfusion allows for lower endothelial activation and higher anti-inflammatory cytokines secretion [134]. O’Neill et  al. reported that pulsatile perfusion, with a pulse pressure of 25 mmHg, attenuates SIRS by preserving microcirculatory flow, decreasing leukocyte activation [135]. A split of opinion still exists, as this study only reported preservation of flow in the sublingual mucosa. It is unknown if pulsatile CPB is beneficial during pregnancy. Pregnancy while on sustained nonpulsatile continuous blood flow has been previously described in a woman with a Heartmate IITM left ventricular assist device (LVAD); the patient delivered vaginally at 34 weeks [136]. Similarly, venoarterial extracorporeal life support (VA ECMO) has been described in cardiovascular collapse during pregnancy, especially with massive pulmonary emboli cases [137,138]. VA ECMO can temporarily maintain perfusion pressure and oxygenation and may be utilized for days to weeks  [139]. The latter suggests that human development can occur with predominant continuous flow [136].

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Blood gases: acid–base, oxygenation, and ventilation Acid–base status may vary significantly during CPB, and evidence of metabolic acidosis (e.g., lactate elevation) may be a sign of poor tissue oxygenation. The most common approaches to the management of acid–base status during CPB are alpha-stat and pH-stat. Briefly, alphastat management attempts to maintain a normal enzymatic milieu. This is accomplished by targeting normocarbia, as determined by blood gas analysis of a blood sample at a temperature of 37 °C. pH-stat management attempts to maintain a pH of 7.4, no matter what the patient’s temperature. This usually involves the addition of carbon dioxide to the CPB oxygenator to maintain a calculated patient blood pCO2 of 40  mmHg at  the patient’s temperature during hypothermic CPB. Alpha-stat management is used in almost all adult cases; this approach attempts to achieve electrochemical neutrality and couples cerebral blood flow with cerebral metabolic rate. pH-stat is rarely used, apart from the initial cooling phase in deep hypothermic circulatory arrest cases [140]. During pregnancy, PaCO2 decreases to 30  mmHg by week 12, bicarbonate concentration decreases to about 30 mEq/L, the base excess decreases to 2–3 mEq/L, and the blood pH increases by 0.02–0.06 units  [141]. Normally, the fetal pH is 0.1 units lower than that of the mother. Maintenance of a normal acid–base balance is paramount for the parturient and her fetus. Maternal acidosis can result in fetal acidosis. Therefore, maternal pH should be kept as close to 7.44 as possible. Likewise, hyperventilation and alkalosis should be avoided because this shifts the oxyhemoglobin dissociation curve to the left with subsequent decreased unloading of oxygen from mother to fetus. In sheep, it has been demonstrated that maternal hyperventilation with hypocapnia and alkalemia decreases UBF and fetal oxygenation [18,142,143]. Therefore, maternal PaCO2 should be maintained within the physiologic range of pregnancy (28–32 mmHg) [144]. Prolonged or serious maternal hypoxemia causes uteroplacental vasoconstriction and decreased perfusion that can result in fetal hypoxemia, acidosis, and death [145]. Attempts should be made to increase maternal oxygenation when fetal bradycardia occurs in response to CPB. Maneuvers may include correction of severe anemia, increasing the fraction of inspired oxygen (FiO2), and ensuring adequate ventilation and normal maternal pCO2. The effect of a FiO2 of 1.0 on fetal blood and tissue has been examined in ewes [146,147]. High-inspired oxygen concentrations did increase the

References

fetal tissue pO2 in healthy subjects; however, a high maternal FiO2 did not improve fetal pO2 in the presence of uterine contractions.

Table 17.1 Management guidelines for cardiopulmonary bypass during pregnancy.

Summary

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The following principles of cardiopulmonary bypass performed during pregnancy, published in 2015, maintain validity today: (1) avoid cardiac surgery in the first trimester during the period of fetal organogenesis; (2) optimize uteroplacental perfusion by using a high-flow, highpressure, normothermic perfusion strategy during CPB; and (3) employ continuous fetal and uteroplacental monitoring and make adjustments to the CPB strategy in the presence of hypoperfusion and/or fetal bradycardia  [14]. Based on multiple studies and case reports, recommendations for the management of CPB in a parturient are listed in Table 17.1. Although CPB during pregnancy is safe for the mother, it poses a significant fetal risk. Adherence to the management guidelines and safety principles, strict evaluation of the surgical indication [7], and utilization of a multidisciplinary team can result in successful outcomes.

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Avoid CPB if possible, during pregnancy; optimize medical management first High-risk cases: may consider pre-CPB cesarean if GA >24–26 weeks; should consider delivery if >28 weeks Anesthetic management: left lateral tilt, aspiration prophylaxis, and rapid-sequence intubation Continuous fetal and uterine monitoring Tocolytic therapy should be available (including possible progesterone supplementation) State-of-the-art arterial blood gas management: alpha-stat pH, and avoid hypocarbia and hypoxemia Consider scavenging of cardioplegia from right atrium: maintain maternal serum potassium 70 mmHg CPB flows: >2.5 L/min/m2 Hematocrit >28% (minimize pump prime volume) Pulsatile perfusion if possible (consider IABP) Multidisciplinary team during surgery: cardiac surgeon and anesthesiologist, cardiologist, maternal–fetal medicine specialist/obstetrician, and neonatologist

CPB, cardiopulmonary bypass; GA, gestational age; IABP, intra-aortic balloon pump; MAP, mean arterial pressure. Source: Refs. [4,5,18,20,21,31–33,49,72,83,106,133,144,147].

­References 1 Sahni G, Elkayam U. Cardiovascular disease in pregnancy. Cardiol clin. 2012;30(3):xi–xii. DOI: 10.1016/j.ccl.2012.05.005. 2 Sommerkamp SK, Gibson A. Cardiovascular disasters in pregnancy. Emerg med clin N Am. 2012;30(4):949–959. DOI: 10.1016/j.emc.2012.08.007. 3 Freedman R, Lucas D. MBRRACE-UK: Saving lives, improving mothers’ care—implications for anesthetists. Obstet Anesth Dig. 2016;36(1). DOI: 10.1097/01.aoa. 0000479477.03978.83. 4 Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, et al. 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J. 2018;39(34):3165–3241. DOI: 10.1093/eurheartj/ehy340. 5 Yuan SM. Indications for cardiopulmonary bypass during pregnancy and impact on fetal outcomes. Geburtshilfe Frauenheilkd. 2014;74(1):55–62. DOI: 10.1055/s-0033-1350997. 6 Harrington PB PC, Bardawil E, Binongo J, Lattouf O. Emergency-Cardiac-Surgery-in-Pregnancy-and-Postpartum-Women. 4th International Congress on cardiac problems in pregnancy. Las Vegas: Emory University; Feb 28 2016. 7 Liu Y, Han F, Zhuang J, et al. Cardiac operation under cardiopulmonary bypass during pregnancy. J Cardiothorac Surg. 2020;15(1):92. DOI: 10.1186/s13019-020-01136-9.

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8 Aprile F. Pregnancy & CPB. Circuitperfusioncom. 2012: Cardiovascular perfusion forum (online). 9 Siu SC, Sermer M, Colman JM, et al. Prospective multicenter study of pregnancy outcomes in women with heart disease. Circulation. 2001;104(5):515–521. DOI: 10.1161/hc3001.093437. 10 Warnes CA. Pregnancy and heart disease. In: Mann D, ed. Braunwald’s heart disease: A textbook of cardiovascular medicine. 10th ed. New York: Saunders; 2015:1755–1770. 11 Jha N, Jha AK, Chand Chauhan R, et al. Maternal and fetal outcome after cardiac operations during pregnancy: A meta-analysis. Ann Thorac Surg. 2018;106(2):618–626. DOI: 10.1016/j.athoracsur.2018.03.020. 12 Neema PK. Cardiopulmonary bypass during pregnancy-fetal demise: An enigma. Ann Card Anaesth. 2014;17(1):1–3. DOI: 10.4103/0971-9784.124111. 13 Birincioglu CL, Unal EU, Çelik İH, et al. Surgery for rheumatic valve disease in pregnancy: What about the newborn? Heart Lung Circ. 2014;23(1): 63–67. DOI: http://dx.doi.org/10.1016/j.hlc. 2013.05.639. 14 Balsam LB, DeAnda A, Jr. Double the jeopardy: Balancing maternal and fetal risk during cardiac surgery.

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28 Piegas L, Bittar O, Haddad N. Myocardial revascularization surgery: Results from national health system. Arq Bras Cardiol. 2009;93(5):555–560. 29 Yates MT, Soppa G, Smelt J, et al. Perioperative management and outcomes of aortic surgery during pregnancy. J Thorac Cardiovasc Surg. 2015;149(2): 607–610. DOI: 10.1016/j.jtcvs.2014.10.038. 30 Parry A, Westaby S. Cardiopulmonary bypass during pregnancy. Ann Thorac Surg. 1996;61:1865–1869. 31 Weiss B, von Segesser LK, Alon E, et al. Outcome of cardiovascular surgery and pregnancy: A systematic review of the period 1984–1996. Am J Obstet Gynecol. 1998;179(6, Part 1):1643–1653. 32 Arnoni RT, Arnoni AS, Bonini RCA, et al. Risk factors associated with cardiac surgery during pregnancy. Ann Thorac Surg. 2003;76(5):1605–1608. DOI: 10.1016/ s0003-4975(03)01188-3. 33 Pomini F, Mercogliano D, Cavalletti C, et al. Cardiopulmonary bypass in pregnancy. Ann Thorac Surg. 1996;61(1):259–268. 34 Carpenter AJ. Invited commentary. Ann Thorac Surg. 2011;91(4):1197. DOI: 10.1016/j.athoracsur.2010.12.023. 35 Zhu J-M, Ma W-G, Peterss S, et al. Aortic dissection in pregnancy: Management strategy and outcomes. Ann Thorac Surg. 2016;103(4):1199–1206. DOI: 10.1016/ j.athoracsur.2016.08.089. 36 Pieper PG, Hoendermis ES, Drijver YN. Cardiac surgery and percutaneous intervention in pregnant women with heart disease. Neth Heart J. 2012;20(3):125–128. DOI: 10.1007/s12471-012-0244-3. 37 Hameed A, Mehra A, Rahimtoola S. The role of catheter balloon commissurotomy for severe mitral stenosis in pregnancy. Obstet Gynecol. 2009;114:1336–1340. 38 Tsiaras S, Poppas A. Mitral valve disease in pregnancy: Outcomes and management. Obstet Med. 2009;2(1):6–10. DOI: 10.1258/om.2008.080002. 39 Elkayam U, Bitar F. Valvular heart disease and pregnancy, Part I: Native valves. J Am Coll Cardiol. 2005;46(2):223–230. 40 Joint Task Force on the Management of Valvular Heart Disease of the European Society of C, European Association for Cardio-Thoracic S, Vahanian A, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J. 2012;33(19):2451–2496. DOI: 10.1093/eurheartj/ehs109. 41 Dawson J, Rodriguez Y, De Marchena E, et al. Aortic balloon valvuloplasty in pregnancy for symptomatic severe aortic stenosis. Int J Cardiol. 2012;162(1):e12–e13. DOI: 10.1016/j.ijcard.2012.04.143. 42 Raja S. Off-pump versus on-pump coronary artery bypass grafting: Comparative effectiveness. Comp Eff Res. 2015:73. DOI: 10.2147/cer.s62637. 43 Do Q, Goyer C, Chavanon O, et al. Hemodynamic changes during off-pump CABG surgery. Eur J Cardiothorac Surg. 2002;21(3):385–390.

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18 ECMO in Obstetrics Emily E. Naoum1, Amir A. Shamshirsaz2,3, and Luis D. Pacheco4 1

Harvard Medical School/Massachusetts General Hospital, Boston, MA, USA Department of Obstetrics and Gynecology, Division of Maternal–Fetal Medicine, Texas Children’s Hospital/Baylor St. Lukes Medical Center, Houston, TX, USA 3 Department of Medicine, Division of Pulmonary Critical Care, Baylor College of Medicine/Texas Children’s Hospital, Houston, TX, USA 4 Departments of Obstetrics, Gynecology, and Anesthesiology, Divisions of Maternal–Fetal Medicine and Surgical Critical Care, The University of Texas Medical Branch, Galveston, TX, USA 2

Introduction The prevalence of medical diseases during pregnancy has increased dramatically, resulting in more pregnant women suffering from severe cardiopulmonary complications that may require advanced medical support, including extracorporeal life support (ECLS) and extracorporeal membrane oxygenation (ECMO) [1–3]. Historically, ECMO was rarely utilized during pregnancy and postpartum; however, in the last two decades, the use of ECMO has dramatically increased [4–6]. The first case series of ECMO utilization in pregnancy or postpartum was reported during the H1N1  influenza pandemic in 2009  [7–9]. In a systematic review and metanalysis of pregnant or postpartum patients who received ECMO for acute respiratory distress syndrome (ARDS) secondary to H1N1, Saad et  al. found the pooled estimate of maternal survival was approximately 75% with a rate of live birth of 70% [9]. Following the latter, ECMO utilization in obstetrical patients increased dramatically and reaffirmed the previously described favorable outcomes [4–6,10]. During the recent COVID-19 pandemic, infection in pregnant and peripartum women resulted in higher risk for preterm birth, preeclampsia, cesarean delivery, perinatal death, intensive care admission, and need for invasive treatments such as mechanical ventilation or ECMO  [11–13]. Importantly, data on pregnant and postpartum ECMO use during the pandemic highlighted the feasibility and efficacy with higher survival rates compared to the general population  [14–16]. The two main modalities of ECMO that are currently used in clinical practice are venous–venous ECMO (VV-ECMO), which provides respiratory support,

and venous–arterial ECMO (VA-ECMO), which provides both respiratory and circulatory support. The purpose of this chapter is to understand the basic components of each and their potential application in the obstetrical population and to evaluate the existing evidence regarding the use of these modalities.

VV-ECMO Indications VV-ECMO provides respiratory support by extracting deoxygenated blood from the venous system, oxygenating and removing carbon dioxide (CO2) by way of a pump and oxygenator, and returning oxygenated blood to the venous system [17]. The most common indication for VV-ECMO in the general population is ARDS [18]. ARDS accounts for up to 80% of the indications for VV-ECMO during pregnancy and the postpartum period [10]. Conventional treatment for ARDS includes lung-protective mechanical ventilation, conservative fluid management, paralysis via neuromuscular agents, prone positioning, and inhaled pulmonary vasodilators [19]. In severe ARDS, ECMO may be considered as a rescue therapy to provide maximal respiratory support. Beyond its ability to rescue patients with very severe gas exchange abnormalities that do not respond to standard treatment, the ECMO to Rescue Lung Injury in Severe ARDS (EOLIA) trial strongly suggested that the main benefit of ECMO is through ameliorating ventilatorinduced lung injury (VILI) [20]. ECMO provides a period of “lung rest” by enabling so-called “ultraprotective ventilation strategies,” which use low tidal volume and low

Critical Care Obstetrics, Seventh Edition. Edited by Luis D. Pacheco, Jeffrey P. Phelan, Torre L. Halscott, Leslie A. Moroz, Arthur J. Vaught, Antonio F. Saad, and Amir A. Shamshirsaz. © 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.

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ECMO in Obstetrics

Table 18.1

Proposed indications and contraindications to ECMO for ARDS.

Indications

Relative contraindications

Absolute contraindications

EOLIA criteria† PaO2/FiO2 3 h PaO2/FiO2 6 h PH 6 ha

Invasive mechanical ventilation for more than 7–10 days Contraindication to anticoagulation Severe coagulopathy

Moribund state with established multiple organ failure Prolonged cardiac arrest Severe anoxic brain injury Massive intracranial hemorrhage Severe chronic respiratory failure with no possibility of lung transplantation Metastatic malignancy or hematological disease with poor short-term prognosis

a

 With respiratory rate increased to 35 breaths per minute and mechanical ventilation settings adjusted to keep a plateau airway pressure of 30 cm of water. †  These criteria should be taken into account in addition to patient trajectory and fetal considerations such as gestational age.

airway pressures to facilitate lung tissue repair  [21]. Table 18.1 provides the indications and contraindications for ECMO during pregnancy. Although ARDS accounts for the vast majority of cases, other indications for respiratory ECMO in the peripartum population include hypertensive disorders of pregnancy, asthma, cardiac disease, and sepsis [5,10].

Principles of VV-ECMO and pregnancy considerations Cannulation Membrane oxygenators are artificial “organs” designed to replace gas exchange function in the lungs by supplying oxygen and removing carbon dioxide (CO2) from the blood. Dual-site cannulation and single-site dual-lumen VVECMO are the modalities of ECLS for severe ARDS [18]. Typically, during dual-site cannulation VV-ECMO, venous blood is drawn from the inferior vena cava through the femoral vein, and after oxygenation, it is infused into the jugular vein  [17]. In single-site cannulation, a bicaval double-lumen cannula may be placed in the right internal jugular vein. A distal and a proximal lumen will drain blood from the inferior and the superior vena cava, respectively, into the extracorporeal circuit. Oxygenated blood is then returned through a second lumen (within the same cannula, located in the midportion of the catheter) with its opening close to the right atrium facing the tricuspid valve, from which blood flows into the right atrium and then into the right ventricle. This mode was initially promising given the single jugular cannulation and, in pregnant patients, evades the issues with uterine compression; however, circuit blood flow rates are limited by the diameter of the

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shared lumen for drainage, and its effectiveness is very dependent on optimal placement of the reinfusion port (the port with opening close to the right atrium), limiting its use in some patients during the acute phase of ARDS  [18]. Proper positioning of the reinfusion port requires image guidance with ultrasound or fluoroscopy and can be challenging and carries the risks of ionizing radiation. In a recent large international report, it was used only in 7% of patients as the primary ECLS approach [22]. Cannulation for pregnant patients is similar to nonpregnant adults. Again, one issue to emphasize is that of aortocaval compression by the gravid uterus which may impede femoral guidewire advancement at the time of cannulation. Left uterine displacement by placing a cushion or wedge under the right hip may be helpful during this process [23]. Inability to achieve adequate blood flow despite optimized patient positioning and judicious intravascular volume administration may require insertion of a second venous drainage cannula.

Mechanical ventilation and gas exchange targets Within the circuit, blood passes through an oxygenator and a heat exchanger that warms the blood before it returns to the body. Fresh air and oxygen are mixed in a blender (sweep gas) prior to exposure of the gas to the blood through a semipermeable membrane [20]. Oxygenation is determined by the flow rate in the circuit. The oxygen content of blood is dependent on hemoglobin level, the partial pressure of oxygen (PaO2), the oxyhemoglobin dissociation curve, and, to a lesser extent, the dissolved oxygen. This has implications for the minimal blood

Lung rest strategies

flow required to provide full oxygenation, which is on the order of 3–4 L/m2/min [24]. During pregnancy, oxygen consumption increases by 20%  [25], and cardiac output increases by 30–50% by the third trimester due to an increase in both stroke volume and heart rate [26]. For these two reasons, an initial ECMO flow of 5–6 L/m2/min is often necessary to compensate for the increased cardiac output and need for oxygenation. Any further increases in the blood flow rate may lead to recirculation phenomena, where reinfused oxygenated blood is withdrawn through the drainage cannula without passing through the systemic circulation, and other complications including circuit chatter, hemolysis, or thrombocytopenia [27,28]. Oxygen saturation (SaO2) >80% represents adequate oxygenation during ECMO support in the general adult population. However, this degree of hypoxemia is unacceptable in pregnant patients, as it may significantly affect the fetal well-being  [25]. Assuming normal uteroplacental blood flow a minimal PaO2 of 60 mmHg correlates with a maternal SaO2 >90% [25]. Historically, the blood flow rate is titrated to achieve a maternal PaO2 of ≥70 mmHg and SaO2 >95% [27,29]. At any given blood flow, CO2 removal is more efficient than oxygenation. In the general population, at physiologic levels, the CO2 content of a given volume of blood is substantially higher than the oxygen content, and thus for a given ECMO flow rate a greater percentage of CO2 production can be removed compared with the percentage of the oxygen consumption that can be provided  [30]. In addition, CO2 is more soluble than O2, allowing it to diffuse across the membrane with greater efficiency  [31]. CO2 removal is largely dependent on the amount of sweep gas flow by the operator. For a given membrane lung size and blood flow rate, CO2 removal will be increased with increasing sweep gas flow rates up to 10–15 L/min [24] (sweep gas flow can go as high as 30  L/min but requires a second oxygenator). During pregnancy, the increase in minute ventilation creates a state of chronic, partially compensated respiratory alkalosis. The serum PaCO2 is reduced to a range of 28–32 mmHg, which creates a partial pressure gradient for fetal carbon dioxide removal [25,32]. The fetus has a limited capability to buffer for major acid–base disturbances. It is ideal to maintain PaCO2 in the normal range to allow for diffusion of fetal CO2 to the maternal circulation [33,34]. Therefore, hypercapnia (PaCO2 >40–45 mmHg) should be avoided, and a target in the range of 28–32 mmHg should be gradually achieved by increasing the sweep gas flow rates, which initially might be challenging  [27,35,36]. Importantly, upon starting VV-ECMO, the sweep gas should be increased gradually as rapid corrections of a

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previously elevated PaCO2 may result in extreme cerebral vasoconstriction and ischemic stroke. Maternal acidosis with arterial pH MIC)  – time-­dependent antibiotics are most effective if their concentration is maintained for as long as possible above the MIC (the lowest concentration should be at least four times the MIC)  [42]; (2) the peak serum ­concentration in relation to the MIC (Cmax/MIC) – concentration-­dependent antibiotics require high concentration peaks, as bacterial clearance depends on concentration rather than the duration of exposure  [43]; and (3) the area under the concentration curve (AUC) over time to the MIC (AUC/MIC). Dose optimization of these drugs aims to maximize overall exposure  [44]. Some ­antibiotics, such as the β-­lactams, are considered ­“time-­dependent,” with effectiveness contingent upon the duration of antibiotic concentration above the MIC for at least 50% of the dosing interval [42]. In contrast, aminoglycosides exhibit concentration-­dependent bacterial killing, with the best responses occurring at concentrations 8–10 times the MIC. Increasing the antibiotic level above this threshold may not improve bacterial killing [43]. When a concentration-­dependent antibiotic cannot be used at a  level close to 10 times the MIC because of toxicity, ­effectiveness becomes a function of the AUC/MIC. The AUC/MIC is for treatment with antibiotics, including fluoroquinolones, vancomycin, and linezolid [44]. A bacteriostatic agent is one that prevents bacterial growth, as compared to bactericidal agents, which kills off pathogens [45]. As with MIC, the determinations are based on in vitro analyses. A bactericidal antibiotic kills 99.9% or

The burden of infections due to extended-­spectrum beta-­ lactamase-­producing Enterobacteriaceae (ESBL-­E) and MDR Pseudomonas aeruginosa is rising steadily, and carbapenem-­ resistant Acinetobacter baumannii and carbapenemase-­ producing Enterobacteriaceae (CRE) are spreading globally, while methicillin-­resistant Staphylococcus aureus (MRSA) and vancomycin-­resistant enterococci (VRE) generate major issues in several geographical areas [46–49]. At the patient level, antimicrobial exposure allows the overgrowth of pathogens with intrinsic or acquired resistance to the administered drug within commensal ecosystems or, to a lesser extent, at the site of infection. Between 30% and 74% of pregnant women are exposed to at least one antibiotic  [50]. Up to 70% of ICU patients receive empirical or definite antibiotic therapy on a given day [51]. This is almost three times higher than in ward patients, with marked disparities for broad-­spectrum agents such as third-­generation cephalosporins [52]. Antibiotic resistance can result from the intrinsic properties of the organism, adaptation of environmental pressures through chromosomal mutation, and/or genetic alteration through transferable plasmids [53]. The most common method of resistance in Gram-­ negative bacteria is enzymatic degradation of β-­lactam antibiotics. These enzymes are classified based on their amino acid sequences and the characteristics of their substrate and inhibitors [54]. Group 1 is composed of cephalosporinases, which use serine for β-­lactam hydrolysis and are coded on Enterobacteriaceae chromosomes. The resistance of ESBLs is mediated by plasmids that spread microbials across ­bacterial species and is responsible for resistance to fourth-­ generation cephalosporins  [53]. Group  2  has the largest numbers of enzymes, ESBLs, and serine carbapenemases,

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­Antibiotics resistanc  339

Table 19.4

Mechanism of action and activity spectrum of antibiotics.

Antibiotic (example)

Mechanism of action

Spectrum of activity

Cephalosporins First generation (cefazolin) Second generation (cefoxitin) Third generation (ceftriaxone) Fourth generation (cefepime) Fifth generation (ceftolozane)

Inhibition of cell wall synthesis Inhibition of cell wall synthesis Inhibition of cell wall synthesis Inhibition of cell wall synthesis Inhibition of cell wall synthesis

MSSA, G− Extended G− Streptococcus pneumoniae, G− G−, including Pseudomonas aeruginosa MDRB, Pseudomonas aeruginosa

Penicillin (ampicillin)

Inhibition of cell wall synthesis

Streptococcus, susceptible Enterococcus

Anti-­staphylococcal penicillin (nafcillin)

Inhibition of cell wall synthesis

MSSA

Carbapenems (meropenem)

Inhibition of cell wall synthesis

MSSA, G−, anaerobes, ESBL, MDRB

β-­lactam/β-­lactam inhibitor (piperacillin/tazobactam)

Inhibition of cell wall synthesis

MSSA, G− including Pseudomonas aeruginosa, anaerobes

Glycopeptides (vancomycin)

Inhibits cell wall synthesis of the polymers N-­acetylmuramic and N-­acetylneuraminic acid

MRSA, Streptococcal species, susceptible Enterococcus

Oxazolidinones (linezolid)

Inhibits protein synthesis by binding to 50S ribosome subunit

MRSA, VRE

Lincosamides (clindamycin)

Inhibits protein synthesis by binding to 50S ribosome subunit

Susceptible Staphylococcus, Streptococcus, anaerobes

Fluoroquinolones (ciprofloxacin)

Inhibit topoisomerase to prevent unwinding of bacterial DNA

G−, susceptible Pseudomonas aeruginosa, Salmonella

Metronidazole

Inhibits nucleic acid synthesis by disrupting the DNA of anaerobic cells

Anaerobes

Aminoglycosides (gentamicin)

Inhibits protein synthesis by binding to 30S ribosome subunit, preventing translational accuracy

G−, combined with β-­lactam for Staphylococcus aureus, Enterococcus, Streptococcus

Macrolides (azithromycin)

Inhibits protein synthesis by binding to 50S ribosome subunit, preventing RNA transfer

Mycoplasma pneumoniae, Legionella, GAS

Daptomycin

Inserts in membrane, causing loss of membrane potential, which inhibits DNA and RNA synthesis

MRSA

Rifamycin (rifampin)

Inhibits bacterial RNA synthesis by inhibiting DNA-­dependent RNA polymerase

Synergy with other antimicrobials for biofilm penetration; never used alone

Colistin

Displaces ions in outer membrane lipopolysaccharides and solubilizes membranes

G−, MDRB

Aztreonam

Inhibition of cell wall synthesis

G−, Pseudomonas aeruginosa

Tetracyclines (doxycycline)

Binds 30S ribosomal subunit and blocks protein synthesis

Staphylococcus, Stenotrophomonas, Rickettsia infections

Sulfonamides (trimethoprim/ sulfamethoxazole)

Disrupts folate synthesis

MRSA, G−

ESBL = extended-­spectrum β-­lactamase; GAS = group A Streptococcus; G− = Gram-­negative; MDRB = multidrug-­resistant bacteria; MRSA = methicillin-­resistant Staphylococcus aureus; MSSA = methicillin-­sensitive Staphylococcus aureus; VRE = vancomycin-­resistant Enterococcus spp.

which are characterized by their inhibitor resistance. This group includes Klebsiella-­producing carbapenemases (KPCs), which can hydrolyze β-­lactams of all classes [53]. Sulbactam and tazobactam are modified penicillins that act as β-­lactam inhibitors and are used in combination with ampicillin and piperacillin, respectively. When the

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β-­lactamases covalently bind to these molecules, enzyme activity is inactivated  – a concept called “suicide inhibition” [53]. Porins are trimers of proteins that create transmembrane channels, which are the entry portals for some antibiotics [53]. The porin structure in the outer cell membrane of

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Gram-­negative bacteria impedes access to porin-­binding protein (PBP). The chromosome-­mediated reduced affinity of PBPs for β-­lactams is responsible for MRSA and the resistance of Streptococcus pneumoniae to penicillin  [50]. Vancomycin inhibits cell wall peptidoglycan cross-­linking by binding to terminal d-­alanine, but the operon-­mediated substitution of d-­lactate or d-­serine for d-­alanine is responsible for vancomycin resistance by Enterococcus faecium (VRE) [55]. Gram-­negative pathogens have intrinsic resistance to vancomycin because their porins are too small to allow its passage into the cell. Efflux transporters located in cell membranes actively expel antibiotics, such as fluoroquinolones, that have penetrated microbial cells. Moreover, these transporters play a significant role in conferring Pseudomonas aeruginosa with resistance to multiple ­antibiotics, contributing to the bacterium’s acquired resistance [53]. Multidrug-­resistant bacteria (MDRB) have several ­mechanisms to avoid killing, including producing ESBLs, reducing the permeability to porins, and enhancing efflux pumps [56,57]. The acronym “ESKAPE” is a useful mnemonic for the MDRBs – E. faecium, Staphylococcus aureus (MRSA), Klebsiella pneumonia, Acinetobacter baumannii, P. aeruginosa, and Enterobacter species [56]. MDRBs also include Stenotrophomonas maltophilia, an opportunistic nosocomial pathogen.

Antibiotic treatment in critically ill pregnant patients Time to antibiotics The available evidence supports a beneficial effect of prompt antibiotic administration on survival rate in sepsis and septic shock, irrespective of the numbers of organ dysfunction [55,59]. However, the clinical diagnosis of maternal sepsis is challenging, mostly due to physiologic changes of pregnancy that can mimic symptoms and signs of ­sepsis  [60], with up to 50% of febrile episodes being of ­noninfectious origin  [61]. Furthermore, cultures remain negative in 30–80% of patients clinically considered infected  [62] (diagnosis and recognition of sepsis are beyond the scope of this chapter). It is imperative to provide antibiotics to the patient’s bedside as early as possible; however, this must be balanced against the potential harms associated with administrating unnecessary antimicrobials to patients without infection  [63,64]. The range of adverse events includes hypersensitivity and allergic reaction, antimicrobial resistance, kidney injury, thrombocytopenia, and Clostridium difficile infection [65–67].

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Several studies have documented a connection between the time of administration of antibiotics and mortality. This correlation appears notably pronounced among patients experiencing septic shock, while it presents a comparatively milder correlation among patients with sepsis (excluding septic shock) [10,58,68]. It should be noted that all studies in septic shock were observational analyses and hence at risk for biases [69]. Two randomized clinical trials in patients with sepsis without septic shock did not demonstrate survival benefit with initiation of antibiotics within the first hour  [70,71]. Observational studies in sepsis ­(without septic shock), however, suggest that mortality may increase after intervals exceeding 3–5 h from hospital arrival and/or sepsis recognition [58,70–72]. Overall, given the high risk of death with septic shock and the strong association of antimicrobial timing and mortality, SSC in 2021 issued a strong recommendation to administer antimicrobial immediately – within 1 h – in all patients with potential septic shock  [73]. For patients with possible ­sepsis without septic shock, the panel recommended that a rapid assessment of infectious and noninfectious etiologies of illness be undertaken to determine, within 3 h, whether antibiotics should be administered or whether antibiotics should be deferred while continuing to monitor the patient closely [73]. Limited data from resource-­limited settings suggest that timely administration of antimicrobials in patients with sepsis and septic shock is beneficial and potentially feasible  [74–76]. The availability and turnaround time for ­laboratory testing, rapid infectious diagnostic, imaging, etc., vary widely by regions and settings. Recent recommendations pertaining to the use of antimicrobials in patients with sepsis (without septic shock) and septic shock in resource-­limited settings are in line with the current recommendation [74].

Biomarkers to initiate antibiotics Biomarkers may help to identify or perhaps rule out bacterial infections, thus limiting unnecessary antibiotic use and encouraging clinicians to search for alternative diagnoses. Several cytokines, soluble receptors, cell membrane surface markers, complement factors, and acute phase reactants have been evaluated for sepsis diagnosis, yet most offer poor discrimination  [77,78]. Procalcitonin levels are undetectable in healthy states and low in viral infections and in most cases of noninfectious systematic inflammation response syndrome (SIRS), but are high in bacterial sepsis  [79]. However, a procalcitonin-­based algorithm for initiation or escalation of antibiotic therapy in ICU patients neither decreases overall antibiotic consumption nor improves

­Methicillin-­resistant Staphylococcus aureus (MRSA)  341

patient outcomes  [80]. Therefore, procalcitonin alone is currently not recommended as part of the decision-­making process for antibiotic initiation in ICU patients. Published guidelines for the management of community-­acquired pneumonia recommend initiation of antimicrobials for patients with community-­acquired pneumonia regardless of procalcitonin level [81]. SSC suggests against using procalcitonin plus clinical evaluations to decide when to start antimicrobials, as compared to clinical evaluations alone, in patients with suspected sepsis or septic shock [73].

Table 19.5 Causes of maternal sepsis and septic shock. ●● ●●

Antimicrobial choice Causes of maternal sepsis differ from non-­obstetric population, i.e., women who are not pregnant. In 2019, the National Readmission Database showed that the most ­frequent sources of sepsis during and after hospitalization for delivery were genitourinary (44%), unknown (21%), respiratory (16%), and gastrointestinal (10%) [4]. In comparison, the most frequent sources in non-­obstetric population admitted to ICU were respiratory, abdominal, and blood stream infections [82]. Causes of maternal sepsis vary based on the timing of infection in antepartum, intrapartum, or postpartum periods. During the antepartum period, genitourinary infections are most common  [12,83] as compared to sepsis associated with chorioamnionitis, which is most likely to present during the intrapartum period  [4]. The causes of maternal sepsis and septic shock are summarized in Table 19.5. Knowledge of potential pathogens associated with maternal sepsis can guide the choice of antibiotics as well as ­antibiotic stewardship. The most common pathogens in puerperium are Escherichia coli, Group B Streptococcus, Staphylococcus aureus, Listeria monocytogenes, and anaerobic bacteria [12,84]. Group A Streptococcus (Streptococcus pyogenes) is not part of the normal urogenital tract microbiome (so routine screening is not recommended), which can lead to invasive infection [85]. Group A Streptococcus can cause a diverse range of infections including endomyometritis, necrotizing fasciitis, pneumonia, cellulitis, and pharyngitis [86]. Patients with this infection have rapid clinical deterioration. About 75% of patients develop septic shock in less than 9 h from the first signs of infection, and this progression occurs in less than 2 h in 50% of patients [87]; 20% of women die within 7 days of diagnosis [88]. Once a diagnosis of sepsis is suspected, antibiotics should be initiated. Table  19.6 summarizes some of the ­recommended initial empiric antibiotic regimens for the most common infectious processes in critically ill pregnant women.

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●●

●●

●●

●●

Acute pyelonephritis Pneumonia –– Bacterial ○○ Pneumococcus ○○ Staphylococcus ○○ Mycoplasma ○○ Legionella –– Viral ○○ Influenza ○○ SARS-­2 ○○ Varicella ○○ Herpes Neglected chorioamnionitis or endometritis –– Pelvic abscess –– Uterine micro abscess or necrotizing myometritis Retained products of conception –– Septic abortion Necrotizing fasciitis –– Abdominal incision –– Episiotomy –– Perineal laceration Intraperitoneal infection (non-­obstetric) –– Bowel perforation –– Ruptured appendix or acute appendicitis –– Necrotizing pancreatitis –– Acute cholecystitis –– Acute cholangitis

Source: Adapted from Barton and Sibai [86].

Methicillin- resistant Staphylococcus aureus (MRSA) The decision for initiation of antibiotics against MRSA depends upon three main issues: (a) the likelihood that patient’s infection is caused by MRSA; (b) the harm associated with withholding treatment for MRSA in a patient with MRSA; and (c) the risk of harm associated with MRSA treatment in a patient without MRSA. Patient’s risk factors for MRSA include recent IV antibiotics, prior history of MRSA infection or colonization, presence of invasive devices, recent hospital admission, history of chronic wounds, or recurrent skin infections and hemodialysis  [96–98]. MRSA accounts for approximately 5% of culture-­positive infections among critically ill patients [99]. Observational studies focusing on documented MRSA infections have shown that delays of more than 24–48 h until antibiotic administration are associated with increased mortality in some studies  [100–102], but not in  others  [103–105]. The observational data included ­undifferentiated patients with pneumonia or sepsis, which demonstrated that adding broad-­spectrum regiments

Table 19.6 Recommended initial antibiotic regimen in critically ill pregnant patients by suspected etiology. Suspected sourceInitial antibiotic selectionAlternative antibiotic selectionPenicillin- allergic antibiotic selection

Endometritis

Ampicillin plus gentamicin plus metronidazole

Ceftriaxone plus metronidazole

Gentamicin plus clindamycin (if MRSA is suspected, start vancomycin) or metronidazole (if cesarean delivery is performed)

Chorioamnionitis

Ampicillin plus gentamicin plus metronidazole (if cesarean delivery is anticipated)

Vancomycin plus piperacillin/ tazobactam

Vancomycin plus meropenem

Pyelonephritis or renal abscess

Ampicillin plus gentamicin

Ceftriaxone or piperacillin/ tazobactam

Mild allergy: carbapenem Severe allergy: consult with ID specialist

Intra-­abdominal or pelvic abscess community acquired (low risk) including acute cholecystitis and ascending cholangitis

Single agent: piperacillin/tazobactam Combination: ceftriaxone plus metronidazole

Carbapenem

Carbapenem

Intra-­abdominal or pelvic abscess community acquired (high risk)§ including acute cholecystitis and ascending cholangitis

Single agent: piperacillin/tazobactam Combination: cefepime or ceftazidime plus metronidazole

Carbapenem

Consult with ID specialist

Acute appendicitis

Cefoxitin plus metronidazole

Cefoxitin plus clindamycin

Carbapenem

Necrotizing Pancreatitis (with infected necrotic tissue)

Single agent: carbapenem Combination: ceftazidime, cefepime plus metronidazole

Combination: levofloxacin or ciprofloxacin (if postpartum) plus metronidazole

Carbapenem Consult with ID specialist

Pneumonia community acquired requiring hospital admission

Ceftriaxone daily plus azithromycin

Cefotaxime, ceftriaxone, ertapenem, or ampicillin plus clarithromycin or erythromycin

Mild allergy: ceftriaxone single daily dose plus azithromycin Severe allergy: consult with ID specialist

Pneumonia hospital acquired (low risk)

Ceftriaxone or ampicillin/sulbactam

Ertapenem Meropenem If postpartum first-­line monotherapy is quinolone alternative to meropenem

Meropenem Consult with ID specialist

Pneumonia hospital acquired (high risk)*

Two of the following: piperacillin/tazobactam, cefepime, levofloxacin or ciprofloxacin (if postpartum), imipenem, meropenem, aztreonam plus vancomycin or linezolid

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Consult with ID specialist

Pneumonia ventilator associated (double coverage for Pseudomonas)

Vancomycin or linezolid plus antipseudomonal (beta-­lactam) activity piperacillin/tazobactam, cefepime, ceftazidime, imipenem, meropenem, aztreonam plus antipseudomonal (non-­beta-­ lactam) activity amikacin, gentamicin, levofloxacin, or ciprofloxacin (if postpartum), colistin†, polymyxin†

Toxic shock syndrome or soft tissue necrotizing infections

Vancomycin plus piperacillin/tazobactam plus clindamycin‡

Endocarditis

Native valve: vancomycin (MRSA), nafcillin (MSSA) plus ceftriaxone Mechanical valve: vancomycin plus gentamicin plus cefepime or carbapenem for pseudomonas (imipenem or meropenem)

Mild allergy: cefotaxime or ceftriaxone Severe allergy: vancomycin

Meningitis community acquired

Ceftriaxone plus vancomycin plus ampicillin¥

Vancomycin plus moxifloxacin

Cefotaxime plus metronidazole

Gentamicin plus metronidazole

Source: Data from Shields et al. [89], Pacheco et al. [90], Plante et al. [91], Metlay et al. [81], Kalil et al. [92], Chen et al. [93], Kazy et al. [94], Chambers and Bayer [95]. §  High risk: medical comorbidities (renal or liver disease, chronic malnutrition, malignancy), immunocompromising condition (poorly controlled diabetes mellitus, chronic high-­dose steroids use, other immunosuppressive agents use, neutropenia), high severity of illness (i.e., sepsis), and diffuse peritonitis. * High risk: inpatient for more than 5 days, received antibiotic in the previous 90 days, prevalence of multidrug-­resistance bacteremia greater than 10% locally, septic shock, and structural lung disease (cystic fibrosis). †  Colistin or polymyxin reserved for high prevalence of multidrug-­resistant bacteria. ‡  Add clindamycin to inhibit exotoxin production from Gram-­positive bacteria. ¥  Add ampicillin for Listeria monocytogenes.

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including agents against MRSA was associated with higher  mortality, particularly among patients without MRSA  [104,106]. The undesirable effects associated with unnecessary MRSA coverage were also supported by studies showing an association between early discontinuation of MRSA antibiotics and better outcomes in patients with negative nares or bronchoalveolar lavage (BAL) MRSA using polymerase chain reaction (PCR) [107,108]. Unnecessary coverage for MRSA can be harmful in a patient without MRSA; however, failure of coverage for MRSA in patients with MRSA may also be harmful. Studies on rapid diagnostic tools and clinical prediction rules for MRSA are needed.

Multidrug- resistant bacteria The purpose of identifying risk factors for MDRB infection in a clinical setting is to provide guidance for empirical therapy prior to obtaining culture results  [109]. In the empiric phase before causative agent(s) and susceptibilities are known, the optimal choice of antibiotic therapy depends on the local prevalence of resistant organisms, patients’ risk factors for resistant organisms, and the severity of illness. In the directed/targeted phase, once the causative organism(s) and susceptibilities are known, sustained double Gram-­negative coverage is rarely necessary except for patients infected with highly resistant organisms. The risk factors for MDRB are depicted in Figure 19.1 [110–112].

SSC suggests using two Gram-­negative agents for empiric treatment in patients with risk factors for MDRB, while in patients with a low-­risk MDRB, it suggests using a single agent against Gram-­negative organisms to decrease risk for antimicrobial-­associated undesirable effects, including drug toxicity, Clostridium difficile infection, and antibiotic resistance [73,113].

Antibiotics dosing The key factors for deciding the optimal dosing of a given antibiotic include the MIC of the pathogen and the site of infection. Yet, clear guidance of how to adapt the right dosage based on these characteristics is lacking and needs further investigation. Determining the right dosage in patients with negative culture results is another challenge, although targeting potential pathogens with the highest MIC may appear to be reasonable [114]. As mentioned earlier in this chapter, antibiotics are subject to changes in PK/PD parameters in patients with sepsis and septic shock [14,115,116]. Underdosing of antibiotics is frequent in critically ill non-­pregnant patients. One out of six patients receiving beta-­lactam does not reach the MIC target, and many more do not reach the target associated with maximal bacterial killing (i.e., concentrations above four times MIC during 100% of the dosing interval) [117]. Augmented renal clearance [118], AKI [119], renal replacement therapy [120,121], and ECMO [122] are examples of

Risk factors for MDRB

Hospital admission Current: > 5 days Past: 2 days within past 90 days Nursing home/Long-term care.

Exposure Prior antibiotics*/antifungal within the preceding 90 days Home wound care Family member with MDRB High frequency of MDRB in hospital Previous colonization with MDRB

Medical condition Immunosuppression Dialysis within 30 days

Figure 19.1 Risk factors for multidrug-­resistant bacteria and empirical broad-­spectrum treatment [110–112]. MDRB: multidrug-­ resistant bacteria. * Especially in agents with broad-­spectrum and/or potent activity against intestinal anaerobes

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common scenarios that affect the ­concentrations of some antibiotics. Furthermore, the physiologic changes that occur during pregnancy can affect PK/PD. Administration of antibiotics that adhere to PK/PD principles and using dosing regiments developed in patients with sepsis and septic shock are more likely to result in effective and safe drug concentrations (compared to one provided by the manufacturer’s product information) [123]. The volume distribution – an important determinant of adequate antibiotic concentrations – is not measurable in critically ill patients. Those with evidence of increased ­volume of distribution such as positive fluid balance ­(specifically in the setting of pregnancy) require a higher loading dose to rapidly ensure adequate tissue ­concentrations, particularly for hydrophilic antibiotics (Table 19.1) [124], and for both intermittent and continuous infusion schemes  [125]. The first dose must not be adapted to the renal function for antibiotics with predominant or exclusive renal clearance [114]. Applying a PK/PD approach to antibiotic dosing requires support from knowledgeable clinician team members  [126], use of a patient-­population-­specific  [127] ­guideline document, and use of therapeutic drug monitoring [128]. Guidance on how to apply a PK/PD approach for specific drug classes has been described by Roberts et al. [115]. Table 19.7 provides the commonly used dosage in critically ill patients.

Continuous prolonged or intermittent administration of  time- dependent antibiotics Beta-­lactam antimicrobials and other time-­dependent antibiotics may be subject to changes in pharmacokinetics parameters in the setting of sepsis and septic shock resulting in subtherapeutic concentrations  [134,135]. This parameter may be increased by reducing interdose interval and/or by using extended infusion over 3–4 h or continuous infusion. Extended infusion or continuous infusion results in sustained beta-­lactam concentration and increases the probability of target attainment against isolates with borderline MIC, especially in patients with increased volume of distribution [136]. Most randomized control trials comparing intermittent versus prolonged beta-­lactam infusions could not find significant difference in outcome; however, two meta-­analyses showed reduced  short-­term mortality with prolonged infusion of beta-­lactam [39,137]. Prolonged infusion might only be needed in those patients with beta-­lactam underdosing using intermittent administration schemes, or infections caused by isolates

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with elevated MICs. Because these features cannot be anticipated, it is reasonable to consider using prolonged infusion of sufficiently stable antipseudomonal beta-­ lactams in all patients with sepsis [114]. Administration of a loading dose of antibiotic before prolonged infusion is essential to avoid delays in achieving effective beta-­lactam concentrations [125]. Both extended and continuous infusions will occupy a venous catheter or lumen more than an intermittent infusion, and drug–drug compatibility considerations are important to ensure effectiveness of antibiotics and other IV drug therapies [138]. For other drugs such as vancomycin, which ratio of AUC/MIC is considered the PK/PD parameter for ­efficacy [44]? Continuous infusion of vancomycin is associated with lower nephrotoxicity, but not lower mortality, than intermittent infusion  [139]. SSC suggests using ­prolonged infusion of beta-­lactams for maintenance (after an initial bolus) over conventional bolus infusion in patients with sepsis or septic shock [73].

Duration of antibiotic therapy Prolonged duration of antibiotic therapy has been associated with the emergence of antimicrobial resistance [140]. Studies conducted on community-­acquired pneumonia (CAP) [141], ventilation-­associated pneumonia (VAP) [142], urinary tract infections (UTI)  [143,144], intra-­abdominal infection  [145,146], and bacteremia  [147,148] compared “short” courses versus traditional “long” courses, and have shown “shorter” courses to be effective and safe with fewer adverse consequences. Shorter duration of antimicrobial therapy is in general recommended; however, 40–50% of inpatient bacterial infections receive antibiotics for more days than necessary  [149]. The shortening of antibiotic duration on the basis of procalcitonin (PCT) has also been shown to be safer, including in patients with sepsis  [62,150]. The ProACT trial failed to confirm the ability of PCT to reduce the duration of antibiotic exposure compared to usual care in suspected lower respiratory tract infections  [151]. A meta-­analysis suggested improved mortality in patients who were managed using PCT versus control, while there was no effect on length of stay in ICU or hospital [152]. SSC suggests using PCT along with clinical evaluation to decide when to discontinue antibiotics in patients with sepsis or septic shock and adequate source control, if the optimal duration of therapy is unclear and if PCT is available [73]. Many national and international guidelines now recommend shorter duration of antibiotic therapy for a number of infections including pneumonia, UTI, and intra-­ abdominal infection with source control  [73,153–157].

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Table 19.7 Common antibiotics dosage in critically ill patients. AntibioticsDosageComments

Ampicillin

1–2 g IV every 6 h

Good coverage against Enterococcus faecalis

Ampicillin/sulbactam

3 g IV every 6 h

Increased resistance from Gram-­negative bacteria; not first line for complicated abdominal or pelvic infections

Azithromycin

500 mg IV daily

Potential for QT prolongation

Aztreonam

1 g IV daily

May be used in beta-­lactam anaphylaxis

Cefepime

2 g IV every 8–12 h

Good coverage against Pseudomonas species

Cefoxitin

2 g IV every 6 h

Anaerobic coverage

Ceftazidime

2 g IV every 8 h

Adequate Gram-­negative coverage including Pseudomonas species

Ceftriaxone

2 g IV every 8 h

No Pseudomonas species coverage

Ciprofloxacin

400 mg IV every 8–12 h*

Potential for QT prolongation

Clindamycin

900 mg IV every 8 h

Risk of Clostridium difficile infection

Colistin (polymyxin E)

2.5 mg/kg IV every 12 h

More renal toxicity in comparison to polymyxin B

Daptomycin

4 mg/kg IV daily (soft tissue infection) and 6–8 mg/kg IV daily (bacteremia and endocarditis)

Risk of rhabdomyolysis

Doxycycline

100 mg IV every 12 h

First line for soft tissue infections associated with Vibrio vulnificus

Ertapenem

1 g IV daily

No coverage against Pseudomonas species

Gentamicin

5 mg/kg/day† IV

Once daily dosing is less toxic and more effective

Imipenem/Cilastatin

500 mg IV every 6 h

Consider administration as a prolonged infusion

Linezolid

600 mg IV every 12 h

Bone marrow suppression if used > 14 days

Levofloxacin

500 mg IV daily (750 mg daily for pneumonia)

Potential for QT prolongation

Metronidazole

500 mg IV every 8 h

First-­line anaerobic coverage

Meropenem

1 g IV every 8 h

Consider administration as a prolonged infusion

Nafcillin/oxacillin

2 g IV every 4 h

First line for MSSA infections

Penicillin

4–6 million units IV every 4–6 h

First line against group A Streptococci and Clostridium perfringens

Piperacillin/tazobactam

3.375 g IV every 6 h (4.5 g if pneumonia)

Consider administration as a prolonged infusion

Polymyxin B

Load 2.5 mg/kg IV, followed by 1.5 mg/ kg every 12 h

Less renal toxicity as compared to colistin

Trimethoprim/ sulfamethoxazole

15–20 mg/kg (trimethoprim component) IV daily Divided every 8 h

Vancomycin

20–30 mg IV load followed by 10–15 mg/kg every 12 h; for Clostridium difficile 125 mg PO every 6 h

Administer to faster than 1 g/h to avoid red man syndrome, which is histamine release, follow-­through levels to avoid kidney injury

Source: Data from Pacheco et al. [90], Shields et al. [89], Kalil et al. [92], Chambers and Bayer [95], Solomkin et al. [129], Horita et al. [130], Metlay et al. [81], Álvarez et al. [131], Klibanov et al. [132], Chen et al. [93], and Vardakas et al. [133]. * Every 8 h in case of Pseudomonas species. †  If actual body weight is more than 30% of ideal body weight, use adjusted body weight according to following formula: adjusted body weight (kg) = ideal body weight + 0.4 (actual body weight − ideal body weight).

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­Pharmacokinetics, drug absorption, drug

Clinicians should be aware that there are circumstances when short-­duration antibiotic treatment might be detrimental, such as in patients with neutropenia, lack of source control, Gram-­negative multidrug resistance, and bacteremia due to foreign body infection [142,158].

Pharmacokinetics and pharmacodynamics of antivirals Within the context of sepsis, antimicrobial therapy continues to have robust recommendations where there remains a paucity of data within the context of viral sepsis. Further, viral illness is generally within the context of pulmonary disease and special population (i.e., immunocompromised)  [159]. In general, the pregnant woman is at increased risk of viral sepsis and/or needing antiviral treatment secondary to the innate immunological changes that occur during pregnancy. Further, pregnant women have been shown to have higher mortality in viral illness, especially influenza and COVID-­19 [160,161]. This section will explore the nuances of medication administration and utilization in the setting of viral sepsis. Because this discussion is based on high-­acuity critical care settings, antiviral medications discussed will be limited to intravenous formulations.

Pharmacokinetics, drug absorption, drug metabolism, and clearance Acyclovir Acyclovir is one of the most widely used antiviral medications in the US owing to its wide range of available ­administration modalities – that is, topical, oral, and intravenous. It is active in the treatment of disseminated ­herpes simplex virus (HSV-­1 and HSV-­2), varicella zoster virus (VZV), and Epstein–Barr virus (EBV). Acyclovir has a modest oral ­bioavailability of about 20–30%  [162]; thus, for serious infections requiring hospital admission or ICU admission, intravenous dosage should always be used [163]. Despite the bioavailability, acyclovir itself is not tightly bound to any proteins and achieves excellent tissue ­penetration, including the cerebrospinal fluid, which is important for diseases such as meningitis and encephalitis  [163]. Renal excretion is paramount, and dose adjustments should be made with reduced estimated glomerular filtration rates [164]. Another factor that affects acyclovir is obesity. In patients with BMI ≥ 30, weight-­based dosing should be scaled to the patient’s body weight.

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Ganciclovir Ganciclovir is the first antiviral agent approved for the treatment of cytomegalovirus (CMV). This is incredibly important, as the CMV is resistant to acyclovir. CMV infections affect a host of patients, especially immunocompromised hosts and transplant recipients. Valganciclovir is the oral formulation and will not be discussed, as it should not be used in acute critical illness [165]. Ganciclovir is a competitive inhibitor of the ­deoxyguanosine triphosphate incorporation into DNA and  ­preferentially inhibits viral DNA polymerases of CMV  [165]. Although originally intended for CMV infections, ganciclovir also has coverage for HSV-­1, HSV-­2, EBV, and VZV. Neurologic penetration is optimal and is used to treat many CNS viral infections. Resistance can occur with long-­term ganciclovir usage or long-­term valganciclovir (oral) use. This is usually used in the setting of AIDS infection in the context of CMV retinitis [166]. Like acyclovir, ganciclovir is renally cleared and should be modified based on ­estimated creatinine clearance [165].

Foscarnet Foscarnet is a pyrophosphate ring analog that binds at the pyrophosphate binding site of DNA polymerases. After binding, foscarnet blocks the cleavage deoxynucleotide triphosphates, thus halting DNA chain synthesis and elongation  [167]. Foscarnet mainly inhibits HSV, hepatitis B virus, and other viruses  [167]; however, clinically it is employed exclusively to treat CMV infection when ganciclovir cannot be used. Foscarnet is excreted by the kidney, and it can be directly toxic to them  [167]. Further, it can cause electrolyte abnormalities, including hypocalcemia, hypokalemia, and hypophosphatemia  [168]. Thus, basic electrolyte panels should be performed serially in use of this medication.

Oseltamivir Oseltamivir is one of the most widely used antivirals in the US and the world over, as its use was bolstered during the 2009  influenza pandemic  [169]. Oseltamivir, through hydrolysis, becomes oseltamivir carboxylate (OC) and cleaves the budding viral progeny from its cellular envelope prior to viral release. Unlike other viral medications, oseltamivir is metabolized by the liver on the cytochrome P450 system. Oseltamivir is only given in oral formulation, so the bioavailability of 75% is crucial for drug effect. Generally, oseltamivir is administered before a person becomes critically ill, as it is a protective measure for newly diagnosed individuals  [170]. However, a number of

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observational studies have shown clinical benefits of ­neuraminidase inhibitors such as oseltamivir in hospitalized and critically ill patients [171–174]. In fact, Muthuri et al. showed a 38% reduction in mortality risk in critically ill adults when comparing early antiviral use to later treatment [172]. However, it is overall clear that the use of oseltamivir or neuraminidase inhibitors decreases mortality, ICU length of stay, and morbidity. The medication is most effective with early diagnosis and use even when the patient becomes critically ill.

Ribavirin Ribavirin is the first synthetic nucleoside analog ever reported to be active against HCV, respiratory syncytial virus (RSV), and influenza  [175]. It can even be used in some hemorrhagic fever viruses such as Lassa fever. Its antiviral spectrum is incredibly broad; however, it is rarely used in the critical care setting. Like many antivirals, the medication is administered orally and has a 64% bioavailability. Drug metabolism is both hepatic and intracellular, but excretion is urinary. Thus, renal impairment should be considered before initiation.

Antiviral use and treatment in critically ill pregnant patients Although viral infections are common, they are rarely the cause of primary sepsis or critical illness. When they are implicated in critical illness, they are usually in the forms of pulmonary (i.e., influenza, COVID-­19) and neurologic (HSV meningitis) disease. In fact, viruses encompass less than 4% of sepsis that requires ICU admission [176]. Immunocompromised hosts are by far the highest-­risk patient population. This category includes individuals who are on long-­term steroid and immunomodulator treatments, those with HIV/AIDS, and transplant recipients. Pregnancy and the extremes of age also serve as risk factors for viral sepsis. When these patients become critically ill, superimposed and primary viral infections should be considered. If highly suspected, these diseases should be appropriately treated. However, empiric antiviral treatment in low-­risk individuals has yet to reveal benefits, and its use is controversial  [177]. This can be disconcerting when caring for patients at high risk of viral illness, especially when diagnostics for confirmed infection are underdeveloped when compared to bacterial disease. Therefore, it is much more important to understand the potential for a viral cause of severe infection and disease. Although many antiviral drugs are more targeted, “broad-­spectrum” antivirals such

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as ribavirin and favipiravir can be used [159]. In this ­setting, it is prudent to measure blood viral levels of suspected viruses when applicable (HSV, CMV, HCV, etc.). Although there are a small host of antivirals, the pathway to critical illness in viral infection is not necessarily the virus, but also the host’s response to the virus. By understanding the host’s response to the virus and modifying it, practitioners may be able to abate sepsis-­like ­illness and shock from viral infections [159]. An example of this strategy is the use of immunomodulator therapy to prevent harmful and excessive inflammation. This alters and counteracts the host’s inflammatory mediators such as tumor necrosis factor-­alpha  [178]. This was a common strategy in the COVID-­19 pandemic with the use of monoclonal antibodies and other medications such as tocilizumab [179,180].

Fungal therapy Fungemia and fungal infection are incredibly serious in the critically ill patient. Fungal infections, including invasive fungal infections, can give a broad spectrum of host responses on different sides of the spectrum of sepsis. For example, patients can be incredibly febrile or hypothermic, have leukocytosis or leukopenia, and are more likely to have altered mental status [181]. Fungal infections can be classified as opportunistic (candidiasis, cryptococcosis, and aspergillosis) and endemic mycoses (histoplasmosis, blastomycosis, coccidiodomycosis, and penicilliosis), which are fungal diseases endemic to demographic areas of immunocompetent hosts [181]. Understanding the pathogenesis of fungal infections is important, as they affect 15% of all healthcare-­associated infections. Where Candida species accounts for 70% of all fungal infections, Aspergillus accounts for 10–20%  [181]. Risk factors include the ­prolonged length of stay of invasive fungal infections, prolonged antibiotics use issues (disruption of normal human flora  – gut, skin), invasive catheters, diabetes, receiving parenteral nutrition, and pancreatitis [181]. In all, fungal infections construe a large proportion of critical illness, and antifungal mechanisms of action, pharmacokinetics, and dynamics should be understood.

Pharmacokinetics and pharmacodynamics of antifungals: azoles and echinocandins When it comes to antifungal therapy, the most common antifungals utilized in critical illness are azoles and ­echinocandins. Azoles work primarily by inhibiting lanosterol 14-­alpha-­methylase, a cytochrome P450-­dependent

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Table 19.8

Common antifungal therapies: type, pharmacokinetics, and coverage.

Azole

Pharmacokinetics

Coverage

Fluconazole

Hydrophilic with 90% bioavailability in oral form. Only 10% protein bound; thus, high concentrations in the urine, cerebrospinal fluid 80% excreted in the urine, thus dose adjustment is warranted

Excellent activity against Candida (except C. glabrata and C. krusei). Has activity against endemic fungi (Histoplasma, Blastomyces, Coccidioides, Paracoccidiodes)

Voriconazole

Oral bioavailability 90% but is also given IV Large volume of distribution with excellent CSF penetrability IV preparations are limited to patients with CrCL > 50 secondary to the use sulfobutyl ether-­beta-­cyclodextrin Also, patients with hepatic insufficiency should have dosage adjustment secondary to metabolism via CYP2C19 and CYP450 3A4

Excellent activity against Aspergillus, Scedosporium, and Fusarium Excellent activity to C. glabrata and C. krusei

Posaconzole/isavuconazole

15% undergo hepatic metabolism and are excreted by the urine and feces

Broad spectrum of activity, inclusive of Mucorales, with maintained activity against yeast and molds

enzyme [182]. This causes disruption of the cell membrane, which in turn causes cell lysis and death [182]. Although the mechanism of action for all azoles is similar, the pharmacokinetics and penetrance are unique and should be fully understood during administration (Table 19.8). The development of echinocandins was essential to expanding antifungal therapy. and they are the first ­antifungals to target the fungal cell wall. The three echinocandins developed for use in the US are caspofungin, micafungin, and anidulafungin. These three antifungals are structurally similar, and they all target fungal cell wall synthesis as beta-­D-­glucan (BDG) inhibitors [183]. As a whole, echinocandins have the major advantage of having excellent activity against Candida spp. including C. glabrata and C. krusei, along with relatively low potential for renal and hepatic activity. They are all approved for the treatment of esophageal candidiasis and invasive candidiasis in adults. Although coverage of echinocandins can be viewed as similar, the pharmacokinetics differ. Caspofungin has triphasic nonlinear kinetics, and tissue distribution has rapid falls after intravenous infusion with gradual re-­ release of drug from extravascular tissue. When coupled with slow hepatic metabolism, it leads to a prolonged half-­ life of 27–50 h  [184]. Because metabolism is exclusively through the liver, renal adjustment is not necessary. Micafungin demonstrates linear elimination with a half-­ life of 15 h. It is also metabolized hepatically, and less than 1% of the drug is excreted via the urine. Anidulafungin also exhibits linear elimination pharmacokinetics that are predictable and relatively stable. Anidulafungin is not metabolized, but eliminated by slow degradation, which results in a half-­life of 40–50 h  [185]. Thus, there does not need to be adjustment for renal or hepatic impairment.

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Antifungal treatment in critically ill pregnant patients Empiric coverage of the critically ill patient is a split of opinion. Some believe empiric coverage should be considered in patients with risk factors, and these risk factors can vary (Table  19.9). Septic shock with fungal origins is observed in the ICU setting and has very poor outcomes compared to bacterial infections. This includes increased mortality owing to delayed initiation of antifungals

Table 19.9 Risk factors for fungemia and invasive fungal infections. Demographic risk factors Immunocompromised Environmental exposures (camping, spelunking) Cancer diagnosis Invasive catheter Central parenteral nutrition Clinical risk factors Neutropenic fever Hypothermia Very high white blood cell count (WBC > 40K) Fungal mass “ball” seen on chest imaging Surgical risk factors Perforated stomach Perforated duodenum (D1, D2) Burns

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secondary to lapse in blood culture results and inadequate source control of fungal infections  [176,186]. However, routine antifungal coverage in septic shock is not routinely done. In the largest randomized control trial undertaken (EMPIRICUS), there were no differences in outcome between patients receiving empiric antifungal coverage (micafungin) and those receiving no coverage  [187]. However, the EMPIRICUS study did show a decrease in rates of new invasive fungal infections from 12% to 3%. Diagnostic modalities in fungemia and invasive fungal disease can cause delays in care; thus, practitioners should start empiric coverage if the patient is at high risk from demographic, clinical, and surgical risk factors [177].

Diagnosis of antifungal infections Although blood cultures should be obtained in all patients with sepsis and septic shock, culture data regarding fungal cultures are often delayed. When risk of fungal infection is high, other modalities of diagnosis should be utilized, including direct culture of mass (if available) with histopathology, galactomannan antigen, and BDG assay. Direct examination and culture of respiratory specimens can be evaluated for fungal elements (i.e., hyphae). However, these mechanisms may tell you that a fungus is present but not the specific organism (i.e., Fusarium versus Aspergillus). Although culture is possible, organisms can be difficult to identify secondary to slow sporulation in organisms such as Aspergillus, Neosartorya, and others  [188]. There are other mechanisms for the diagnosis of fungal infections. Galactomannan antigen detection is often utilized in the hospital and outpatient setting for the diagnosis of fungal infections. Galacto­ mannan is a polysaccharide and a major constituent of the Aspergillus cell wall [189]. It has also shown overall adequate testing in the clinical setting with a specificity of 90%. However, clinical sensitivity has a range from 30% to 100%  [190]. Either way, practitioners can use galactomannan to help start and guide therapy. However, it should not be used as a singular test secondary to its variable sensitivity rate. Another highly utilized test is the BDG assay. BDG is a cell wall component with several commercial assays available. The results are interpreted as negative (80 pg/ mL) [191]. Further, sensitivity was 93.3%, specificity was 77.2%, positive predictive value was 51.9%, and negative predictive value was 97.8%  [191]. Also, these results

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remained comparable to a 2011  meta-­analysis with ­sensitivity of 77% and specificity of 85% [192]. Although BDG can be helpful in the diagnosis of invasive fungal candidiasis, this measure should be used in the context of critical illness and risk factors. Further, the following caveats should be considered when using BDG, as this can produce false results: hemodialysis with cellulose membranes, use of intravenous immunoglobulin, use of ­albumin as a resuscitant, cellular filters in intravenous administration, Pseudomonal infections, and the use of amoxicillin/­clavulanic acid [193].

Treatment and duration It is clear that patients with known fungal infections should be treated with antifungals, and critically ill patients at high risk should receive empiric fungal coverage. However, the duration of antifungal treatment is more nuanced. Patients with fungal infections are more likely to have delays in the initiation of broad coverage, even in septic shock [176,177,186]. Further, these patients have difficulty in obtaining source control secondary to a multitude of reasons (i.e., fungal pulmonary masses, peritoneal candidiasis, or emphysematous organs). Because of these reasons, critically ill patients with fungemia are more likely to begin their clinical course with more ­morbidity. This makes duration and cessation of antifungals less clear. Stewardship in antifungal therapy is important because adverse effects such as drug–drug interactions, organ toxicity, and resistance are prevalent in its use. For this reason, review of antifungal coverage should be multidisciplinary and individualized. In one study, review by a member of an infection/microbial team occurred in 80% of all ICU patients receiving antifungal coverage  [194]. The most common recommendation was to test for invasive fungal infection (60%), recommend a duration of therapy (40%), and to stop antifungal treatment (38%). Further, practitioners were more likely to discontinue antifungal coverage if the BDG was 3)-­beta-­D-­glucan assay for diagnosis of invasive fungal infections. J Clin Microbiol. 2005;43(12):5957–5962. 192 Karageorgopoulos DE, Vouloumanou EK, Ntziora F, et al. β-­D -­glucan assay for the diagnosis of invasive fungal infections: A meta-­analysis. Clin Infect Dis. 2011;52(6):750–770. 193 Marty FM, Koo S. Role of (1-­-­>3)-­beta-­D-­glucan in the diagnosis of invasive aspergillosis. Med Mycol. 2009;47(Suppl. 1):S233–S240.

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194 Logan C, Hemsley C, Fife A, et al. A multisite evaluation of antifungal use in critical care: Implications for antifungal stewardship. JAC Antimicrob Resist. 2022;4(3):dlac055. 195 De Pascale G, Posteraro B, D’Arrigo S, et al. (1,3)-­β-­D-­ Glucan-­based empirical antifungal interruption in suspected invasive candidiasis: A randomized trial. Crit Care. 2020;24(1):550.

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20 Noninvasive Monitoring in Critical Care Sarah Rae Easter Division of Maternal–Fetal Medicine, Division of Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

Introduction If critical illness is characterized by life-threatening conditions that compromise the function of vital organs, then critical care centers on the identification and management of this end-organ dysfunction [1]. The juxtaposition of monitoring and critical care in the same phrase brings to mind invasive techniques such as pulmonary artery catheters (PACs), central venous catheters (CVCs), and intraarterial catheters (a-lines). These so-called “invasive devices” do serve a role in contemporary critical care and can be helpful monitoring adjuncts when they are in place for other indications [2,3]. That said, the vast majority of contemporary monitoring occurs through less invasive approaches with the fetal heart rate monitoring ubiquitous on labor and delivery (L&D) as a prime example. While technology is often involved in monitoring – particularly in the setting of critical illness – in some circumstances, the most valuable monitoring can occur through a simple subjective assessment of clinical status as well-appearing or sick. The aim of this chapter is to integrate physiology with available evidence to propose a clinically relevant and intuitive approach to monitoring for the obstetrician tasked with caring for the critically ill patient.

­Approach to monitoring In some ways, the term “monitoring” can be used to describe every diagnostic interaction in clinical medicine. In the setting of critical illness, monitoring typically applies to hemodynamic monitoring focused on the identification and improvement of end-organ dysfunction. One theoretical framework for the description of monitoring as it relates to

the cardiopulmonary system is to characterize a technique as an upstream or downstream indicator of organ perfusion. Upstream monitoring attempts to quantify markers of circulatory function and often centers on flow or pressure in the cardiopulmonary tree such as the superior vena cava (SVC), inferior vena cava (IVC), pulmonary artery (PA), and aorta. Downstream monitoring addresses the interaction between the cardiopulmonary circulation and tissue perfusion in the organ of interest and includes routine clinical parameters as well as labs. The choice of an upstream or downstream technique will vary based on the disease of interest, patient comorbidities, and available resources, but in most settings will involve a hybrid of the two approaches.

­Role in diagnosis and therapy Many monitoring techniques can also be characterized as diagnostic studies. For example, the data provided by a PAC  – often considered the gold standard of continuous monitoring in critical illness – yields the same information as the data provided by the diagnostic study of a right-heart catheterization. The feature that differentiates a given technology into a diagnostic study or a monitor is that of time. Many hemodynamic monitors may actually complicate or worsen our understanding of a clinical scenario when used once or in isolation, but can be enlightening if not diagnostic when observed for trends over time. Routine obstetric care capitalizes on this principle of monitoring with the use of serial beta-human chorionic gonadotropin levels to evaluate a pregnancy of unknown location, or the reliance on the trend of estimated fetal weight percentiles to diagnose and determine level of concern in the setting of fetal growth restriction.

Critical Care Obstetrics, Seventh Edition. Edited by Luis D. Pacheco, Jeffrey P. Phelan, Torre L. Halscott, Leslie A. Moroz, Arthur J. Vaught, Antonio F. Saad, and Amir A. Shamshirsaz. © 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.

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Though monitoring is pervasive in clinical medicine, the frequency of data acquisition is a differentiating feature of monitoring in the setting of critical illness when compared to routine clinical monitoring. The ability to evaluate and reconsider a patient’s clinical status and response to a given intervention on a time frame of minutes to hours underscores the possible clinical utility of monitoring in a critical care setting. Just like the provider caring for a patient on L&D assesses a category 2 fetal heart rate tracing in response to a fluid bolus or position change, the intensivist uses monitoring to understand and improve pathophysiology by observing the response to a given intervention. Determining and optimizing intravascular volume is the hallmark example of this principle and one of the greatest challenges of caring for patients in the intensive care unit (ICU) setting. Imagine a patient admitted to the ICU with hypotension and oliguria in the setting of undifferentiated shock. Early and rapid restoration of circulating volume through administration of intravenous (IV) crystalloids could be life-saving in the setting of septic shock, but could hasten clinical decline in the setting of cardiogenic shock where diuretics are the indicated therapy. Applying the hemodynamic and tissue perfusion data outlined in subsequent sections can help ensure the appropriate therapy is prioritized, provide insights into the underlying diagnosis, and offer guidance about the prognosis and anticipated course.

­Evidence and implementation Monitoring is fundamental to critical care, but it is important to acknowledge that many techniques ubiquitous in contemporary ICUs and encouraged by contemporary guidelines may not be evidence-based. A review of available literature may be considered by some to be only of historic interest, but the insights gleaned from trials examining the utility of invasive hemodynamic monitors inform contemporary monitoring practices in critical care. The PAC has been considered the “gold standard” of hemodynamic monitoring for decades with severe preeclampsia listed as an indication for their use in many contemporary references [4]. The use of PACs was called into question in the early 2000s when a number of small randomized controlled trials (RCTs) performed in the setting of specific diseases demonstrated similar or even worse outcomes associated with PAC use. Meta-analyses of these studies as well as a multicenter RCT evaluating the use of PACs in the setting of critical illness failed to show a benefit in terms of reduction or mortality or hospital length of stay with their use  [5]. These studies coupled with the

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landmark paper on the benefits of early goal-directed therapy in the setting of septic shock pushed intensivists away from routine PAC use in favor of the less invasive more versatile central venous therapy [6]. The publication of a single-center RCT by Rivers and colleagues demonstrating improved outcomes in septic shock with the use of an algorithm guided by data obtained from the central venous catheter generated enthusiasm for the routine use of CVCs in critical illness in the early 2000s [6]. Enthusiasm for the CVC as the “new” PAC was so tremendous that the multidisciplinary internationally recognized experts of the Surviving Sepsis Campaign highlighted the importance of basing resuscitation on parameters obtained from a CVC as the leading recommendation in the 2004  iteration of the Surviving Sepsis Campaign Guidelines  [7]. Follow-up multicentered RCTs failed to replicate the initial results of the Rivers’ trial with a patientlevel meta-analysis of these subsequent studies demonstrating increased costs without an improvement in outcomes associated with the use of invasive hemodynamic monitors to guide resuscitation [8–12]. Although pregnant subjects were excluded from these randomized trials (as is frequently the case, to our continued knowledge deficit in this and other fields) and the aforementioned review addresses invasive, as opposed to noninvasive, hemodynamic monitoring, the principles demonstrated by these trials are informative for the clinician tasked with caring for the critically ill obstetric patient. From an academic standpoint, they demonstrate the challenges of applying a single universally accepted recommendation to a heterogeneous patient population. Perhaps one explanation for the failure of PAC to show improved outcomes is that those patients who may benefit the most from this monitoring technology were excluded from randomization because the ICU team felt the data obtained were essential to their care. A commonly accepted explanation for the 15% mortality reduction seen in the Rivers’ trial that cannot be replicated in other settings is that it was the presence of a senior intensivist at the patient’s bedside  – not the CVC that was placed – that improved outcomes for the intervention group [6]. Taken together, these essentially negative monitoring studies of nearly two decades emphasize two key points for monitoring of the critically ill patient. The first is that data obtained from hemodynamic monitoring must be integrated with complementary historic and real-time data to formulate an assessment and should not be considered an assessment of clinical status in isolation. The second lesson is that any assessment – regardless of monitoring technology used to formulate it – can inform but not dictate the next steps in management. The subsequent section will review principles of physiology that form the basis of

­Oxgen conssumtionn, oOxgen eliverxn, an  car iac ostmst

monitoring technology commonly encountered in the ICU before translating this into disease-specific strategies for integrating monitoring into clinical management.

­Physiology of monitoring The term “monitoring” can encompass the majority of clinical care from a simple “looks-good-from-the-door” assessment to one based on invasive procedures and complex calculations. Intensivists often focus clinically the failure of an organ or organ system such as altered mental status, shock, or acute kidney injury. Each type of endorgan failure can be associated with countless combinations of clinical diagnoses that may interact in complex or even unpredictable ways. At the cellular level, the majority of end-organ dysfunctions can be described as a mismatch between oxygen delivery (DO2) and oxygen consumption (VO2). The key clinical components of oxygen delivery and consumption are outlined in Figure 20.1 and form the basis for monitoring of these end organs. In an ICU setting, monitoring is often used to signify the upstream cardiopulmonary monitoring obtained through invasive and noninvasive devices  – the most salient of which is cardiac output. Though the PAC is seldom encountered in contemporary ICUs, the foundational knowledge

of physiology used to obtain or calculate physiologic parameters of interest is of relevance when considering other noninvasive approaches to monitoring ubiquitous in clinical care.

­ xygen consumption, oxygen delivery, O and cardiac output If the PAC is the “gold standard” of hemodynamics in the ICU, then the Fick principle could be considered the golden rule. This principle states that the amount of a substance taken up by the body per unit time equals the difference between the arterial and venous levels multiplied by the blood flow [13]. In other words, oxygen consumption by the body divided by the arteriovenous oxygen difference equals the cardiac output, which is expressed mathematically as: Cardiac output Q

Oxygen consumption VO2 Arteriovenous oxygen difference

Basic algebra would suggest that if you know two of these variables, you can solve for the third. In the case of the Fick equation, VO2 is assumed based on a person’s age, sex, and body surface area. The arteriovenous oxygen difference is calculated from measured values of arterial

Equations for oxygen consumption and delivery DO2 = Cardiac output (Q) × arterial oxygen content (CaO2) Where CaO2 = (1.34 × hemoglobin × SpO2) + (0.003 × PaO2) VO2 = Cardiac output (Q) × (arteriovenous oxygen difference) Where AV O2 difference = 1.34 × Hgb × (SaO2 – SvO2)

Increased Oxygen consumption (VO2)

Exercise Breastfeeding Pregnancy Sepsis

Calculating perfusion Pulse pressure = Systolic blood pressure (BP) – diastolic BP Mean arterial pressure (MAP) = diastolic BP + 1/3 (pulse pressure) Cerebral perfusion pressure = MAP – intracranial pressure Coronary perfusion pressure = Left ventricular end diastolic volume – diastolic BP

Low hemoglobin (Hgb) Low cardiac output (Q)

Inaccuracies in

Low oxygen saturation (SpO2)

Oxygen saturation Anemia Polycythemia Carboxyhemoglobin Methemoglobin Hypothermia Hypoperfusion latrogenic dyes

Low arterial oxygen (PaO2) Decreased Oxygen delivery (DO2)

Figure 20.1 Factors impacting oxygen delivery and consumption.

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.

Measuring oxygenation Oxygenation terms Arterial oxygen (PaO2) is partial pressure of O2 in arterial blood (in mmHg on arterial blood gas) Arterial oxygen saturation (SaO2) is % of Hgb binding sites carrying O2 in arterial blood Oxygen saturation (SpO2) is % of Hgb binding sites carrying O2 as measured by pulse oximetry Failures in oxygenation Hypoxemia = low O2 in blood Hypoxia = low O2 in tissue

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oxygen saturation (SaO2), venous oxygen saturation (SvO2), and hemoglobin (Hgb) according to the following formula: Arteriovenous oxygen difference 1.34 hemoglobin SaO2 SvO2 . Theoretically, the SaO2 should be measured from the pulmonary veins – the point of maximum oxygenation in the circulatory system. In clinical practice, this value is most often obtained from an a-line most commonly placed in a radial artery. The proximal branching of the subclavian and brachiocephalic arteries from the ascending aorta suggests that a value from a left or a right radial a-line accurately assesses the SaO2 of blood returning from the pulmonary circulation to the left side of the heart. The location measurement of SvO2 requires more precision, as the deoxygenated blood coming from the cerebral circulation via the SVC mixes with blood from the remainder of the systemic circulation via the IVC in the right atrium (RA). That deoxygenated blood passes through the right ventricle (RV) into the main PA before its branching to perfuse the left and right lungs. Measurement of SvO2 occurs at this point in the main PA and is referred to as “mixed venous oxygen saturation” in clinical practice – a term specific to the measurement of the percentage of hemoglobin saturated with oxygen in the main PA obtained from an appropriately positioned PAC. Contemporary PACs rely on a method known as “thermodilution” to calculate cardiac output – a technology that was outlined in 1970 by Dr. Swan and Dr. Ganz [14]. The true Swan–Ganz catheter has long been replaced by modern PACs consisting of four separate lumens inside one single line. One line is dedicated to injecting air into the balloon that facilitates placement of the line as the balloon is captured in the flow of blood through the RA and RV before reaching the PA. The distal port is used to obtain pressure measurements during placement or as a part of monitoring while the remaining two ports  – a proximal port and a port containing a thermistor wire capable of measuring temperature  – facilitate the approximation of cardiac output via thermodilution. Thermodilution relies on injection of an indicator (typically normal saline) at a known temperature in the proximal port, and then measurement of the temperature of the blood containing the indicator by the time it reaches the thermistor. The change in temperature coupled with calculus allows the approximation of flow over time which is translated into cardiac output in liters per minute [15]. The physics and calculus underscoring this methodology are too complex and of low yield to review in detail, but the general principle of thermodilution has some limited academic and clinical relevance. From a historic standpoint, the interchangeable use of the terms

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“pulmonary artery” and “Swan–Ganz catheter” in clinical practice underscores the significance of this breakthrough because true Swan–Ganz catheters have not existed in the lifetime of many of those using the term. This achievement is even more remarkable when one considers that their technology was effectively replaced with the more modern device invented by a middle author on their 1970 publication and first reported by their former colleague in  1972  – less than 2  years after the publication of the  aforementioned landmark paper by Swan and colleagues  [16,17]. This 1972 technology reigned supreme until refinement of the line alongside modern computer technology facilitated continuous cardiac output monitoring in the 1990s [14]. The uplifting tale of medical achievement and academic curiosity is balanced by the clinically relevant indication for reviewing thermodilution – its significant limitations. Though PACs are taught and treated as the gold standard of hemodynamic monitoring, both Fick principle and thermodilution have significant flaws. The direct relationship between true cardiac output and the accuracy of thermodilution for measurement of cardiac output is frustratingly ironic when encountered in clinical care. In these low flow states, Fick calculation of cardiac output has improved accuracy compared to thermodilution, but it still assumes a standardized value for oxygen consumption. While oxygen consumption at rest may vary less across a population, VO2 at physiologic extremes can vary drastically [18,19]. Simple intuition would suggest that maximum VO2 would differ between a professional athlete and an average person of similar age, height, and weight. When viewed through the lens of obstetric critical care – a state where the two physiologic extremes of pregnancy and critical illness overlap – one might argue that a standardized value is a euphemism for our best guess. This detailed review of the underpinnings and failures of invasive hemodynamic monitoring in a chapter dedicated to noninvasive hemodynamic monitoring could seem like an attempt to put down one approach to bolster another. Outlining these limitations is less of an attempt to argue that one is superior as much as it is a statement that they are equally limited. Highlighting the theoretical pitfalls of invasive hemodynamic monitoring serves three important roles when considering noninvasive hemodynamic monitoring in obstetric critical care. First, emphasizing the potential for inaccuracy underscores the aforementioned concept that all monitoring simply provides a data point. While these data can be observed over time to develop trends, even serial assessments must be interpreted within the overall clinical context. The second key point relates to interpretation and the need for mental discipline establishing a priori plans for

Meassreuent oo oOxgenation

the use of the results obtained from an assessment – an idea previously discussed alongside evidence and implementation. An academic description of this concept would include an integrated assessment of test characteristics, pretest probability, cost-effectiveness, and quantification of utility. A more clinically relevant summary of this idea would be to ensure that you know why you are ordering a study and what you are going to do with the result. The potential to anchor or fixate on inaccurate results is arguably a bigger threat to patient safety than watchful observation and judicious use of targeted monitoring. The third key principle emphasized with this detailed review redirects the conversation away from philosophy and back to physiology. Fick and the numerous equations presented in this review all focus on oxygen delivery to peripheral tissues and the upstream force required to do this in the form of cardiac output. While cardiac output is the focus of these monitors and equations, their presence allows for direct measurement or indirect ascertainment of a range of additional hemodynamic parameters that can provide insights into diagnosis, approach to management, and monitoring of response to a given therapy.

­ he Frank–Starling mechanism T in clinical practice If Swan and Ganz are celebrities of hemodynamic monitoring, Frank and Starling are legends. These physiologists described the fundamental relationship between preload and contractility that still informs the majority of hemodynamic monitoring and management over a century later [20]. Otto Frank first observed the linear relationship between the volume of blood in the left ventricle (LV) and systolic blood pressure (SBP) in 1895. Earnest Starling affirmed that observation 20 years later at the cellular level when he observed that increasing levels of tension on cardiac myocytes result in more forceful contraction  [21]. Rephrased in clinical terms, the Frank–Starling law notes that increased left ventricular end-diastolic pressure (LVEDP) increases stroke volume through increased tension on cardiac myocytes  [22]. The Fick principle is the favored approach to describe cardiac output because it accounts for oxygen delivery in peripheral tissues. That said, a more intuitive and clinically helpful description of cardiac output is that: Cardiac output

stroke volume heart rate,

where Stroke volume = end-diastolic volume (EDV) – endsystolic volume (ESV).

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Integrating the aforementioned formula with the Frank– Starling law, we arrive at the recognition that stroke volume is a function of EDV, ESV, and contractility (which has a relationship with EDV mediated through enddiastolic pressure (EDP)). Stated another way, stroke volume is a function of preload, contractility, and afterload. Physiologists may object to this definition of cardiac output, which admittedly fails to account for oxygen delivery in the periphery. But from a clinical standpoint, the aforementioned definition captures an essential concept in critical care and hemodynamic monitoring  – cardiac output is controlled by venous return. Table  20.1 outlines the measurements of oxygenation, volume, and pressure available to the clinician tasked with assessing the balance between oxygen delivery and consumption and classifies these according to anatomic location within the systemic, pulmonary, and coronary circulations [23–25].

­Routine noninvasive monitoring These physiologic principles offer some insight into the information that can be gleaned from the most ubiquitous hemodynamic monitoring in the form of routine vital signs. Integration of information obtained through noninvasive blood pressure (NIBP) measurement, heart rate (HR) or cardiac telemetry, oxygen saturation, and respiratory rate with knowledge of physiology and clinical history can provide a tremendous amount of information about underlying diagnosis and response to therapy. In obstetrics, assessment of the second patient through fetal HR monitoring offers insight into end-organ perfusion. Though this information is acquired for assessment of fetal wellbeing, it can provide supplemental insights into maternal hemodynamics.

­Measurement of oxygenation Ensuring oxygen delivery is greater than oxygen consumption is the fundamental purpose of hemodynamic monitoring. Figure  20.1 defines the key measurements for oxygenation, but the one most familiar to clinicians is oxygen saturation as measured by pulse oximetry (SpO2). SpO2 is defined as the percentage of hemoglobin-binding sites carrying oxygen with the target goal in pregnancy of 95% or greater. In most cases, this is the same as the arterial oxygen saturation (SaO2) – a calculated measurement obtained from direct measurement of arterial oxygen obtained via arterial blood gas (ABG) sampling. These percentage-based values differ from the arterial oxygen (PaO2), which is a measure of the partial pressure of oxygen in arterial blood reported in

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Table 20.1

Measures of oxygenation, volume, and pressure in the pulmonary, systemic, and coronary circulation.

Location

Oxygenation

Volume

Pressure

Vena cava and right atrium

ScvO2 PCO2 pH Lactate

CVP IVC diameter IVC collapsibility

CVP RA pressure IVC diameter

Right ventricle

ScvO2

RV end-diastolic volumea PA systolic pressurea

RV pressure PA pulsatility index (PAPI)b TAPSEc

Pulmonary artery and capillaries

SvO2 A–a gradient

PA systolic pressurea

PA pressure PVR

Left atrium and left ventricle

SpO2 SaO2 PaO2

LV end-diastolic volume Stroke volume Stroke volume index

PA occlusion pressure (synonymous with pulmonary capillary wedge pressure)

Aorta and peripheral tissues

SpO2, SaO2, PaO2 PCO2 pH Lactate

Systolic blood pressure Stroke volume variation

Diastolic blood pressure Systemic vascular resistance

Electrocardiogram biomarkers

Heart rate

Coronary perfusion pressured

Pulmonary circulation

Systemic circulation

Coronary circulation Coronary arteries

Abbreviations: central venous O2 (ScvO2), partial pressure of carbon dioxide (PCO2), central venous pressure (CVP), inferior vena cava (IVC), right atrium (RA), right ventricle (RV), pulmonary artery (PA), tricuspid annular plane systolic excursion (TAPSE), mixed venous oxygen saturation (SvO2), alveolar–arteriolar O2 gradient (A–a gradient), pulmonary vascular resistance (PVR), oxygen saturation (SpO2), arterial O2 saturation (SaO2), arterial O2 content (PaO2). a  Measures of RV and PA volume are unreliable and not as clinically relevant as measures of left ventricular volume. RA pressure as measured by CVP is likely the most useful estimate of RV volume assuming a competent tricuspid valve. b  PA pulsatility index = PA pulse pressure/RA pressure. CVP considered RA pressure in clinical practice. PAPI greater than or equal to 2 is associated with RV failure and adverse outcomes. c  Tricuspid annular plane systolic excursion (TAPSE) is a measurement obtained using echocardiography with M-mode. TAPSE less than 17 mm is associated with RV failure. d  Coronary perfusion pressure = diastolic blood pressure – left ventricular end-diastolic pressure.

mmHg and obtained from an ABG. While some rare conditions can lead to falsely low or elevated SpO2 compared to true PaO2 (see Figure 20.1), pulse oximetry is typically adequate to monitor for hypoxemia with assessment of PaO2 as a backup should concerns about its accuracy arise [26]. It is worth noting that the aforementioned measurement techniques are for the evaluation of hypoxemia which is typically adequate to monitor for hypoxia. Hypoxemia is defined as inadequate levels of oxygen in the arterial blood, while hypoxia is defined as inadequate oxygen levels in the tissues. In most settings, adequate PaO2 ensures adequate tissue oxygenation. Key exceptions to this assumption include failure of oxygen delivery to peripheral tissues or inability of cells to adequately use oxygen despite adequate arterial oxygen supply. Anemia and shock are the two most

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common examples of the former, while poor diffusion of oxygen into cells in the setting of edema or toxins (for example, in cases of cyanide poisoning) is an example of hypoxia at the cellular level. Monitoring for hypoxia often requires the integration of clinical data including physical exam, labs, and other hemodynamic parameters with the approach dictated by the clinical scenario.

I­ nvasive assessment of arterial oxygenation While SpO2 accurately assesses SaO2 with rare exception, there are some scenarios beyond concerns for errors in SpO2 that may warrant obtaining an ABG as a component

­ssessing ventilation an  evalsating oor aci euia

of monitoring – even without a need for an invasive arterial line. One example comes in the form of quantifying the degree of hypoxemia or arterial oxygen tension. The arterial oxygen tension is most often communicated in clinical practice as the ratio of PaO2 to fraction of inspired oxygen (FiO2). The ratio of PaO2 to FiO2, or P:F ratio, is used to diagnose and quantify acute respiratory distress syndrome (ARDS) and serves as a means of monitoring degree of hypoxemia over time [27]. The FiO2 can be calculated for all oxygen delivery devices, but intubation with mechanical ventilation is the most straightforward for an illustrative example. A PaO2 of 90  with 30% FiO2 yields a P:F ratio of 300, whereas the same PaO2 with 90% FiO2 results in 100. The former scenario represents essentially normal oxygenation, while the latter reflects a severity of oxygenation consistent with severe ARDS. The two scenarios demonstrate the same PaO2 from ABG (and likely SpO2 on pulse oximetry), but the degree supplemental oxygen required to reach that PaO2 differs drastically. This normalization for supplemental oxygen makes P:F ratio a useful standard for monitoring and communicating oxygenation over time. While this value is routinely followed in the setting of respiratory failure with mechanical ventilation via an a-line, a one-time assessment of this value can be helpful to characterize the patient’s respiratory failure and anticipate the clinical course and appropriate intervention. The second scenario where sampling of PaO2 can be useful comes in the form of the alveolar–arterial oxygen gradient (A–a gradient). The A–a gradient is calculated from the difference of alveolar oxygen and arterial oxygen (PAO2 − PaO2). The arterial oxygen content is obtained from ABG, whereas the alveolar oxygen content is calculated from the alveolar gas equation (PAO2 = (Patm − PH2O) FiO2 − PACO2/RQ) which is most easily done from one of the host of available calculators. An elevated A–a gradient can help ascertain the underlying mechanism of hypoxemia. Causes of hypoxemia with an elevated A–a gradient include mismatch of ventilation and perfusion (V/Q mismatch), a right-to-left shunt, and a diffusion defect. A less commonly considered but physiologically valid cause of an elevated A–a gradient is one of increased oxygen extraction as seen in states of decreased cardiac output, anemia, or hypermetabolism. Hypoxemic respiratory failure in the setting of a normal A–a gradient typically reflects hypoventilation or reduction in inspired oxygen tension as seen in changes in altitude. While the distinction of these causes and evaluation of hypoxemic respiratory failure is beyond the scope of this chapter, discussion of the A–a gradient is warranted to highlight another scenario where an invasive assessment of arterial oxygenation may be warranted for a patient with otherwise noninvasive monitoring.

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­ ssessing ventilation and evaluating A for acidemia A conversation about oxygenation would be incomplete without mentioning ventilation  – the removal of carbon dioxide (CO2). The need to discuss ventilation alongside hemodynamic monitoring reflects not just the presence of respiratory rate (RR) as a part of routine vital signs. Consideration of ventilation is necessary because of its impact on pressure – particularly in the pulmonary circulation. RR is the routine vital sign that best approximates minute ventilation which is calculated by multiplying the RR and the tidal volume (TV). TV is challenging to assess objectively in the absence of mechanical ventilation, which is why RR becomes our clinical surrogate. A decreased RR raises concern for hypoventilation due to central causes, whereas an increased RR can be the body’s attempt to compensate for another process by enhancing the removal of CO2. Objective assessment of ventilation by measuring PCO2 via ABG sampling can confirm differentiate hypercarbic respiratory failure from appropriate compensation. Capnography can be used to measure end-tidal CO2 (EtCO2) during exhalation and serves key roles in clinical medicine including procedural monitoring, confirmation of intubation, and assessing for adequate chest compressions during cardiopulmonary resuscitation  [28]. If endtidal CO2 is to be the approach for assessing ventilation over time in the absence of more invasive interventions like an a-line, best practice would suggest the value is first correlated with PCO2 on an ABG. Many disease states can result in V/Q mismatch at the level of the pulmonary capillaries. This so-called “dead space ventilation” can mean that the CO2 measured from gas leaving the alveoli is underestimating the PCO2 in the pulmonary arterioles that is unable to diffuse into the diseased alveoli to leave the body [29,30]. Even in the absence of significant differences between PCO2 measured with ABG and EtCO2 assessed via capnography, checking an ABG in the evaluation of a disorder of ventilation holds the added benefit of ascertaining the pH which can help elucidate the underlying mechanism of hypercarbia. The diagnosis of hypercarbic respiratory failure is of significant clinical importance, as there are fewer ways to supplement ventilation than oxygenation, which means that acute episodes often require intubation and mechanical ventilation to correct the physiologic state. A discussion of acid–base analysis is beyond the scope of this chapter, but it is worth remembering that elevations in pH and PCO2 have a unique impact on oxygen delivery in the peripheral tissues and pressures in the central circulation. CO2 is a potent vasoconstrictor throughout the body, but most

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clinically relevant in the pulmonary circulations. Acidemia causes similar vasoconstriction, whereas alkalemia has the opposite effect. Respiratory acidosis can therefore impact hemodynamics throughout the body, but can precipitate decompensation within the pulmonary circulation through the pH and PCO2-mediated increase in pulmonary vascular resistance (PVR). From the perspective of the RV, this acute increase in afterload can lead to a decrease in cardiac output, which in turn impacts LV filling and systemic cardiac output further exacerbating the pathophysiology.

­Assessment of blood pressure A multitude of noninvasive, invasive, and emerging techniques for hemodynamic monitoring exist, but a host of information can be gathered through critical assessment of NIBP measurement. In routine practice, this is reported as a SBP over a diastolic blood pressure (DBP) with normal and abnormal values engrained into the minds of clinicians from an early stage in training. While the absolute values of these numbers may drive diagnosis and management, the relationship between the two numbers can offer insights into physiology. SBP is the pressure the blood exerts on the vessels during LV contraction (systole), while DBP is the pressure the arteries exert on the blood while the LV is filling and at rest (diastole). In critical care settings, these values are most often reported as mean arterial pressure (MAP). MAP has the advantage of summarizing the interaction between volume and pressure in a succinct number with a standard of 65 mmHg as the clinical target. MAP is calculated as: Mean arterial pressure diastolic BP 1 / 3 pulse pressure , where Pulse pressure = systolic BP – diastolic BP. The definitions of SBP and DBP underscore the tremendous information captured by the pulse pressure in extremes of BP such as hypertensive urgency or shock. Consider a nonclinical scenario of liquid in a container. If the container is at risk of overflowing, one can either lessen the amount of liquid or use a bigger container to avoid a spill. Conversely, if the task is to raise the level of liquid in the container, the available options are adding more liquid or using a smaller container. The examples of the overflowing container and the need to raise the level of liquid parallel the options for management of hypertension and shock, respectively, and illustrate the use of pulse pressure to inform management. In this example, hypertension can be managed by removing plasma volume through diuresis or reducing systemic vascular resistance (SVR) through afterload

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reduction. In  cases of hypertension with a wide pulse pressure (i.e., elevated SBP), diuresis or use of an agent to promote venous pooling may be the preferred approach, whereas a more narrow pulse pressure (i.e., elevated DBP) calls for afterload reduction. In the other extreme of shock, volume resuscitation or use of vasopressors could both be viable management options. In hypotension with a narrow pulse pressure, simple volume resuscitation may be all that is required to raise SBP to achieve a perfusing MAP. Hypotension with a wide pulse pressure (implying that the SBP is closer to normal with a low DBP) may be ideally addressed with vasopressors to increase the SVR directly while indirectly impacting venous return, preload, and cardiac output. While this is an oversimplification of the complexities of clinical medicine, it demonstrates the utility of routine NIBP measurement in the care of critically ill patients.

­Ascertaining cardiac output An upstream approach to monitoring of cardiac output almost invariably requires invasive hemodynamic monitoring, but adequate information about cardiac output can be obtained through a combination of routine vital signs and downstream markers of end-organ perfusion. The regulation of HR by the sympathetic and parasympathetic nervous systems means that abnormalities in HR or rhythm can often be the first clues to a state of inadequate cardiac output. An increase in HR is one of the earliest physiologic adaptations of pregnancy made to increase cardiac output to support a growing pregnancy until the gradual increase in plasma volume is adequate to meet needs. Sinus tachycardia is therefore the most common arrhythmia seen in both obstetric and nonobstetric patients and can be a normal physiologic adaptation to pregnancy. The frequency of sinus tachycardia in clinical practice underscores the importance of avoiding two key mistakes in the assessment of a patient with this arrhythmia. The first clinical pitfall is to assume sinus tachycardia is normal or physiologic in nature without fully investigating possible causes. Accepting the least concerning explanation as the correct one, even when it is the most likely one, can lead to delays in diagnosis that worsen clinical outcomes  [31,32]. An electrocardiogram is essential to not only confirm that the tachycardia is sinus in origin but to assess for the presence of other morphologic changes that may portend more significant pathology within the coronary circulation such as changes in ST segments, T-waves, or R-wave progression. Cardiac telemetry is therefore an essential component of noninvasive hemodynamic assessment in the setting of known critical illness or during the

­n d-organ uonitoring in critical illness

Table 20.2 Anticipated hemodynamic parameters according to type of shock. Parameter

Hypovolemic

Distributive

Cardiogenic

Obstructive

Systolic blood pressure (BP)

Low

Varies

Low

Low

Diastolic BP

High

Low

High

Low

Pulse pressure

Narrow

Wide

Narrow

Narrow

Straight leg raise

BP increases

BP increases

BP decreases

BP decreases

Inferior vena cava diameter

Collapsible (2 cm)

Left ventricular fillinga

Low volume

Low volume

Normal volume

Low volume

Left ventricular contractility

Normal

Hyperdynamic

Reduced

Reduced

Stroke volume variationb

High

Varies

Low

Low

Central venous pressure

Low

Varies

High

High

Pulmonary artery wedge pressureb

High

Low

High

High

Systemic vascular resistanceb

Normal

Normal/high

Low

High

Mixed venous oxygen

Normal

Normal/high

Low

Low

Cardiac outputb

Normal

High

Low

Low

a

a

b

b

a

 Parameters obtained through point-of-care ultrasound.  Parameters obtained through invasive hemodynamic monitoring including arterial line (stroke volume variation), central venous catheter (central venous pressure), or pulmonary artery catheter (wedge pressure, systemic vascular resistance, mixed venous oxygen, cardiac output).

b

initial stages of evaluation while the underlying diagnosis is unknown. The second cognitive error occurs in the evaluation and management of nonphysiologic sinus tachycardia seen in conjunction with other abnormalities of vital signs such as hypoxemia or hypotension. From an epidemiology standpoint, the combination of hypotension and tachycardia in an obstetric patient most often represents hypovolemia due to hemorrhage or infection. From a physiologic standpoint, however, tachycardia and hypotension can be the presenting signs of cardiogenic shock. Cardiac output is a combination of stroke volume and HR, and patients who cannot augment stroke volume (SV) via the Frank–Starling mechanism have no other choice than to increase their HR to meet hemodynamic demands. Obstructive shock in the setting of tamponade or tension pneumothorax can lead to this phenomenon, but more commonly encountered clinical conditions leading to this finding would be settings of heart failure with either reduced or preserved ejection fraction. While heart failure would most often be accompanied by some abnormalities in oxygenation, this is neither sensitive nor specific to distinguish hypovolemic from cardiogenic shock. In cases of hypovolemic shock due to hemorrhage or sepsis, fluid resuscitation is a mainstay of therapy, but in the setting of cardiogenic shock, administration of IV fluids can trigger decompensation and lead to avoidable iatrogenic morbidity.

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The comparison of these shock states reveals the importance of using more than just routine vital signs for the diagnosis and management of the patient with concern for critical illness. Additional noninvasive monitoring techniques coupled with downstream markers of end-organ perfusion are essential data points in this setting. Table 20.2 outlines potential findings from both invasive and noninvasive hemodynamic monitoring according to shock state.

­End-­organ monitoring in critical illness The discussion of hemodynamic monitoring until this point has been focused on an upstream approach, as this type of monitoring outlines the physiologic principles that inform clinical care. Despite this attention to upstream monitoring, the vast majority of noninvasive hemodynamic monitoring is of the downstream variety focusing on clinical manifestations of end-organ injury. Table 20.3 outlines these downstream markers with associated high-yield clinical insights when applied through the lens of commonly encountered diseases in obstetric critical care  [33–46]. A comprehensive review of each marker is likely low-yield when divorced from components of clinical management reviewed elsewhere, but two specific approaches to downstream monitoring warrant additional discussion.

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Table 20.3 Markers for downstream monitoring of end-organ function by organ system. Organ system

Marker

Clinical considerations

Neurologic

Mental status

Objective assessment using validated tools (such as the confusion assessment method) can increase sensitivity and document longitudinal changes.

Neurologic exam

Asymmetric changes raise concern for failure of cerebral perfusion. Exam assessed in settings of critical illness through daily spontaneous awakening trial.

Transcranial Dopplers (TCD)a

Ultrasound study to evaluate blood flow in middle cerebral artery with elevations in cerebral blood flow velocities raising concern for vasospasm. Most often used as adjunctive neurologic examination after cerebrovascular accident (CVA), but abnormalities in TCDs seen in patients with preeclampsia without CVA.

Troponin (TnT)

Elevations in either biomarker associated with ischemic injury. Higher values of TnT seen in the setting of preeclampsia, even in the absence of overt ischemia. The placental excretion of CK–MB limits specificity and utility in pregnancy.

Cardiovascularb

Creatine kinase–myoglobin binding (CK–MB)

Respiratoryc

Gastrointestinal

Brain natriuretic peptide (BNP)

Slightly elevated in pregnancy compared to nonpregnant values without established reference range. A person’s BNP values tend to be but stable across pregnancy and the postpartum period in the absence of pathologic elevations as seen in cardiac dysfunction or preeclampsia.

A–a gradient

Elevations in A–a gradient reflect mismatch of ventilation and perfusion as seen in cases such as alveolar consolidation (limiting O2 flow into alveoli), pulmonary edema (limiting diffuse of O2 across capillaries), or pulmonary embolism limiting blood flow as classic examples also encountered in obstetrics.

Minute ventilation (MV)

Increased or decreased MV suggesting hyperventilation or hypoventilation as a result of primary abnormalities in respiratory rate or tidal volume or failure to compensate for competing metabolic process leading to excess CO2 generation. Interpretation of pH and PCO2 must account for compensated respiratory alkalosis of pregnancy.

Lactate

Clinical signs of inadequate visceral perfusion such as nausea or ileus may be confounded by pregnancy and critical illness. Elevated lactate or dropping hemoglobin can be signs of intestinal ischemia due to malperfusion.

Hemoglobin (Hgb) Transaminases Direct bilirubin INR Renal

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Transaminases are elevated prior to bilirubin in the setting of liver hypoperfusion and downtrend prior to bilirubin with liver recovery. Elevated international normalized ratio (INR) suggests failure of synthetic function beyond injury. Liver injury can decrease lactate clearance.

Urine output (UOP)

Oliguria defined by UOP 0.5 cc/kg/h. Urinary response to fluid bolus can be indicator of fluid responsiveness (similar to passive leg raise).

Creatinine (Cr)

Cr decreased in pregnancy due to increased filtration. Small changes in low values of Cr reflect more nephron loss than larger changes at a higher Cr. Prerenal acute kidney injury (AKI) is not specific to hypovolemia as exemplified by the prerenal AKI seen in cardiorenal syndrome due to poor perfusion and venous congestion.

Blood urea nitrogen (BUN)

Electrolytes

Changes in sodium and potassium may reflect regulation of vascular tone to meet end-organ needs mediated by renin–angiotensin– aldosterone system.

pH or HCO3

Pregnancy can be considered a state of HCO3 deficiency due to renal compensation for physiologic respiratory alkalosis of pregnancy leaving the kidneys with less reserve to compensate for acidemia.

Anion gap

Abnormalities in anion gap suggest source of anions (such as lactate or beta-hydroxybutyrate) warranting further exploration with arterial blood sampling

Noninvasive uonitoring an  tte oetss

Table 20.3

(Continued)

Organ system

Marker

Clinical considerations

Hematologic

Hematocrit (Hct)

While DO2 is based on Hgb, changes in Hct relative to Hgb can give insights into volume status (particularly when congruent with other hematologic parameters).

Fibrinogen

Dropping fibrinogen below the typically elevated value seen in pregnancy can be a marker of placental abruption associated with uterine hypoperfusion.

Distal pulses and skin

Abnormal pulses or cool clammy skin more likely to reflect malperfusion due to hypovolemia or vasoconstriction (as opposed to peripheral vascular disease).

Capillary refill

Capillary refill at or beyond 2 s suggests failure of perfusion

Lactate

Elevation in lactate reflects failure to meet oxygen demands of peripheral tissues resulting in anaerobic metabolism and is not specific to poor perfusion of extremities. Abnormal lactate should be repeated at 3-h intervals until clinical interventions lead to a trend toward normal values.

Cardiotocography

See Table 20.4.

Extremities

Placental a

 Transcranial Dopplers are a more targeted assessment of cerebral blood flow (CBF). Cerebral perfusion pressure (CPP) is the difference between the mean arterial pressure and the intracranial pressure. Extremely low MAPs or high intracranial pressures (ICPs) can alter CBF through inadequate CPP. However, CBF is maintained by precise autoregulation at the intracranial arterial level. TCDs can detect subclinical abnormalities in this end-organ before traditional imaging without the need to travel with an unstable patient. Most abnormalities in CBF will warrant more dedicated neuroimaging with computed tomography (CT) or magnetic resonance imaging (MRI). The three most common measures for TCD are: 1) Mean cerebral blood flow velocity using peak systolic velocity (PSV) and EDV where mean cerebral blood flow velocity = [PSV + (EDV × 2)/3]. 2) Resistive index (RI), where RI = (PSV − EDV)/PSV. 3) Lindegaard ratio (LR) normalizing middle cerebral artery (MCA) blood flow to internal carotid artery (ICA) blood flow, where LR = mean MCA velocity/mean ICA velocity. The LR has the advantage of limiting false positives by distinguishing elevations in MCA velocity due to vasoconstriction (abnormal) from those due to hyperemia from increased ICA flow (normal). An LR 95% or PaO2 > 70 mmHg

Worsening ventilation

pCO2 < 45 and pH > 7.35

Increasing vasopressor requirement

MAP > 65

Worsening acidemia

pH < 7.30

New or worsening fever

Temperature < 100.4° Fahrenheit

New onset hypertension with systolic blood pressure ≥160 or diastolic blood pressure ≥100 Significant change in laboratory values including new or worsening transaminitis, elevation in creatinine, decrease in platelets New onset tachycardia (possible sign of labor) or arrhythmia Unexplained increase in sedation requirement based on RASS or BIS (possible sign of labor) Obstetric issues such as vaginal bleeding or leakage of amniotic fluid Cardiac arrestc or pathologic arrhythmia with concern for need for resuscitative delivery and presence of neonatology team Abbreviations: oxygen saturation (SpO2), arterial O2 content (PaO2), mean arterial pressure (MAP), partial pressure of carbon dioxide (PCO2), Richmond agitation and sedation scale (RASS), bispectral index (BIS). a  This list is not exhaustive but includes scenarios that may benefit from multidisciplinary management or could warrant increased fetal monitoring. b  These targets are based on best practices in general obstetrics, but may not be achievable based on disease state. Targets are intended to be a reference and envisioned as a starting point from which to individualize care. c  Cardiac arrest should be managed in accordance with contemporary guidelines with key modifications including need for manual left uterine displacement to relieve aortocaval compression, use of intravenous access above diaphragm, and preparation for resuscitative delivery with hopes of achieving return of spontaneous circulation (ROSC) if no ROSC by 4 min of arrest.

guidelines [59]. Corresponding disease-specific algorithms such as the “bedside lung ultrasound in emergency” (BLUE) protocol for acute respiratory failure or the “cardiac limited ultrasound examination” (CLUE) for assessment of cardiac function are emerging as key approaches for the evaluation of these complaints  [60,61]. The “rapid ultrasound for shock and hypotension” (RUSH) protocol outlines a formal approach for the evaluation of hypotension using the parasternal long-axis and subcostal views with additional adjuncts to differentiate hypovolemic, distributive, cardiogenic, and obstructive shocks (Table 20.2) [62].

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These protocols or their components can be integrated with the use of ultrasound for hemodynamic monitoring to provide a rapid and comprehensive clinical assessment with ease. While an adequate review of the potential Table 20.6

indications for POCUS in obstetrics is beyond the scope of this chapter, Table  20.6 summarizes the standard views, pathologic findings, and associated clinical diagnoses relevant to obstetrics [63–65]. When considering POCUS as

Standard cardiopulmonary point-of-care ultrasound views relevant to obstetrics.

View

Details of view

Clinical utility

Pathologic findings

Example obstetric diagnoses

Apical lung

Imaging pleural interface and lung parenchyma

Identification of pulmonary edema or pneumothorax (absence of lung sliding)

Pneumothorax

Trauma

Pulmonary edemaa

Preeclampsia

Imaging of the costophrenic angles bilaterally

Identification of B-lines suggesting pulmonary edema, accumulation of fluid suggesting pleural effusion, or consolidation of lung parenchyma

Pulmonary edemaa Pleural effusiona

Pulmonary consolidation

Bacterial pneumonia

Identification of LV dysfunction and underfilling or overfilling and atrial enlargement. Assessment of left atrial enlargement, grossly abnormal valvular function or presence of pericardial effusion

Pericardial effusion

Pericarditis

LV dysfunction

Peripartum cardiomyopathy

Basal lung

Parasternal long-axis

Visualization of the LV size and contractility, left atrium, left ventricular inflow (mitral valve) and outflow tracts (aortic valve), and pericardium

TACO or TRALI ARDS Cardiomyopathy Viral pneumonia Aspiration pneumonitis Atelectasis

Septic shock Valvular pathology

Aortic or mitral stenosis Aortic or mitral insufficiency

Dynamic LVOT obstruction

Hypertrophic cardiomyopathy Stress cardiomyopathy

Parasternal short-axis

Apical four chamber

Subcostal

Subcostal-IVC

Cross-sectional imaging of left and right ventricles (and interventricular septum) sweeping from apex to base

Evaluation of uniformity in LV contractility or regional wall motion abnormalities. Assessment of RV dysfunction and presence of septal bowing suggesting RV volume or pressure overload

RV failure

Amniotic fluid embolism

Regional wall motion abnormalities

Spontaneous coronary artery dissection

Septal bowing

Pulmonary embolism

Visualization of four chambers to compare RV and LV when subcostal view is not feasible

Evaluation of biventricular function and comparison of LV and RV chamber sizes

Pericardial effusion

Pericarditis

LV dysfunction

Peripartum cardiomyopathy

Visualization of four chambers and comparison of LV and RV size

Evaluation of biventricular function and comparison of LV and RV chamber sizes

RV failure

Amniotic fluid embolism

Septal bowing

Pulmonary embolism

Diameter and collapsibility of inferior vena cava

Noninvasive marker of right-sided filing pressures and volume responsiveness

Collapsible IVC

Postpartum hemorrhage Sepsis Hyperemesis

Plethoric IVC

TACO Cardiogenic shock Preeclampsia

Abbreviations: transfusion-associated circulatory overload (TACO), transfusion-related acute lung injury (TRALI), acute respiratory distress syndrome (ARDS), left ventricle (LV), right ventricle (RV), left ventricular outflow tract (LVOT), inferior vena cava (IVC). a  Pulmonary edema can be detected on apical or basal lung views by the presence of B-lines with preeclampsia, TACO, TRALI, cardiomyopathy, viral pneumonia, or aspiration pneumonitis as possible explanations for B-lines in either view.

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­ssessuent oo olsi resmonsiveness

a tool for noninvasive hemodynamic monitoring, the parasternal long-axis view and the subcostal inferior vena cava view are two clinically valuable and easily attainable views warranting discussion [66].

­Assessment of cardiac function The parasternal long-axis view is ideally obtained by placing a phased-array probe to the left of the sternum in the third or fourth intercostal space. This view is best obtained with the patient positioned in the left lateral tilt familiar to obstetricians. This positioning optimizes cardiac output by avoiding aortocaval compression while taking advantage of gravity to bring the heart closer to the anterior chest wall. Slight rotation, angling, and sliding of the probe can optimize a view that includes both ventricles, the left atrium, and the mitral and aortic valves (Table 20.6). The parasternal long-axis view was designed for a global assessment of LV function, which is assessed as qualitatively normal or abnormal by focusing on the degree of excursion of the anterior leaflet of the mitral valve toward the interventricular septum. The aforementioned CLUE protocol proposes use of M-mode to capture and then measure this distance  [59]. Failure of the mitral valve to approach the ventricular septum within 7 mm during diastole – the socalled “E-point septal separation”  – is associated with a modest sensitivity (65%) but high specificity (92%) for the detection of severe LV dysfunction with an ejection fraction less than 40% [67]. The parasternal long-axis view is useful beyond assessment of LV function and can provide insights into LV filling and the need for additional resuscitation or diuresis to optimize hemodynamics in critical illness. Ventricular walls that come into close proximity during systole suggest underfilling, whereas an LV that appears full throughout the cardiac cycle with a suggestion of impaired function raises concern for a cardiogenic component to changes in hemodynamics. The parasternal long-axis view allows for visualization of the pericardium in settings of shock with the possibility of cardiac tamponade and includes visualization of the RV. A simple modification in probe position can aid in the assessment of both LV and RV functions. Focusing on the mitral valve and rotating the probe clockwise 90° achieve the parasternal short-axis view which allows for the user to assess for symmetric concentric contraction of the LV and to evaluate the relationship between RV and LV in cases with concern for elevation of RV pressure reflecting RV failure or acute increase in PVR [65,68]. Progressive changes in the angle of the probe scanning from the apex of the heart to the base can aid in the detection of regional wall motion abnormalities in cases of suspected myocardial ischemia or

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may offer specificity to the underlying etiology of cardiogenic shock as seen in cases of stress cardiomyopathy with apical ballooning.

­Assessment of fluid responsiveness The aforementioned assessment of LV filling alongside sonographic examination of the IVC can offer insights into right-sided filling pressures to narrow the diagnosis and to assess for fluid responsiveness. The subcostal-IVC view is obtained with a phased-array or curvilinear probe placed inferior and slightly lateral to the xiphoid process of the sternum to visualize the insertion of the IVC into the RA. Rotation of the probe and angling caudally can then elongate the IVC to obtain a view as it courses through the liver [66]. Visualization of the IVC at this junction is important to ensure that the vena cava (and not the aorta) is the vessel being imaged and provides enough distance from the thoracic cavity to generate reliable data. The absolute diameter of the IVC in conjunction with assessment for variations in IVC diameter with respiration may suggest insights into fluid responsiveness and the optimization of hemodynamics. Fluid responsiveness is typically defined as a 10–20% improvement in cardiac output and downstream tissue perfusion after the administration of IV fluids. This concept differs slightly from volume tolerance which refers to the notion that IV fluids will not harm the patient. Values obtained from invasive hemodynamic monitors such as CVP or pulmonary capillary wedge pressure have limited predictive value for assessing fluid responsiveness. Simple maneuvers such as the passive leg raise (PLR) maneuver or an empiric fluid bolus are the most practical ways to assess fluid responsiveness  [69]. In cases of decreased cardiac output, the administration of 250 ccs of crystalloid over 5–10 min and monitoring of BP in response are the easiest ways to assess fluid responsiveness. In more tenuous clinical scenarios where this small volume of fluid could worsen cardiopulmonary function, the PLR can provide the same information without compromising hemodynamics. The PLR is performed by elevating the legs to 30° or 45° and monitoring for changes in BP in response to the autotransfusion from the blood in the lower extremities. The PLR may be more cumbersome than a fluid bolus, but it offers the advantage of being reversible in settings where the increase in preload worsens cardiac output. The principles underscoring the use of PLR or assessment of variation in IVC diameter rely on the concept of stroke volume variation (SVV) – an assessment of fluid responsiveness typically derived from invasive hemodynamic monitoring with an arterial line. SVV is a naturally occurring physiologic phenomenon in which arterial pulse pressure falls and rises

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Noninvasive Monitoring in Critical Care

Mechanical ventilation

Spontaneous respiration

Inspiration

SVC and IVC Collapse

+ Pressure

Inspiration Decreased Cardiac output Less preload

– Pressure

Positive intrathoracis pressure during inspiration decreases preload and caridac ouptput in the setting of fluid responsiveness leading to decreased systolic blood pressure. This is reflected in the respiratory variation of the arterial waveform.

More preload

Increased Cardiac output

Increased Cardiac output More preload

Assessment of IVC for respiratory variation gathers information about fluid responsiveness without need for mechanical ventilation or arterial line.

Exhalation + Pressure

SVC and IVC collapse

Less pressure

Increased venous return via SVC and IVC

Exhalation

Increased venous return via SVC and IVC

Inspiration

Exhalation

376

Less preload

Decreased Cardiac output

Figure 20.2 Respiratory variation and fluid responsiveness.

in conjunction with respiration as a result of the impact of changes in intrathoracic pressure on venous return, preload, and cardiac output. Figure  20.2 outlines the physiologic underpinnings of SVV in the setting of mechanical ventilation. SVV is validated as a measure of fluid responsiveness in the setting of sinus rhythm and a controlled mode of mechanical ventilation with tidal volumes at or above 8 cc/kg and in the absence of spontaneous respiration  [70]. These conditions are necessary to remove other variables that may impact stroke volume from the clinical picture. Assuming these conditions are met, SVV greater than 10% has a 94% sensitivity and specificity for fluid responsiveness. The evidence supporting SVV for hemodynamic assessment along with the multitude of proprietary technologies derived from this concept provides accurate assessments of cardiac output in the aforementioned controlled settings. Measurements relying on SVV typically involve invasive BP monitoring with an a-line in conjunction with another invasive hemodynamic parameter monitor (such as CVP). In the absence of invasive hemodynamic monitoring and mechanical ventilation, these physiologic principles can still be useful when applied to POCUS. Figure 20.2 demonstrates the physiologic underpinnings of IVC assessment in the setting of spontaneous respiration with negative intrathoracic pressure for inspiration and positive intrathoracic pressure for expiration [25].

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In the setting of spontaneous breathing, the increased intrathoracic pressure with expiration decreases the volume of blood passively returning to the RA from the venous circulation. This results in an increase in IVC diameter when assessed outside of the thoracic cavity. At the other extreme, the inspiration-associated decrease in intrathoracic pressure facilitates rapid return of blood to the heart, narrowing the IVC. This is seen sonographically as variation in the diameter of the IVC with respiration as shown on a still image in the inset in Figure  20.2. The objective measurements associated with these findings are reviewed in Table 20.2, but it is the subjective assessment of IVC diameter and dynamic change in conjunction with other clinical variables that provides the most insight into preload from the systemic circulation and RV filling and function.

­ dynamic approach to noninvasive A hemodynamic monitoring Hemodynamic monitoring is ubiquitous in clinical medicine, but often conjures up images of invasive catheters and sophisticated monitors when mentioned in the context of critical care. The ability to interpret and recall values from these catheters has the same limited relevance in the

References

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expedite diagnosis while working toward goal-directed treatment. Contemporary guidelines outlining best practices for high-risk diseases like sepsis support this serial assessment of downstream markers of end-organ perfusion such as lactate as the standard of care [7]. These guidelines also encourage the use of dynamic over static variables with point-of-care ultrasound for maternal indications holding particular promise for obstetricians who have experience with POCUS for fetal indications [71]. The intersection of critical illness and obstetrics is a comparatively rare event in clinical medicine that challenges even the most astute and experienced clinician. A strong understanding of the physiologic underpinnings of contemporary approaches to noninvasive monitoring modified through the lens of pregnancy can expedite diagnosis and targeted treatment to optimize outcomes for pregnant persons and their neonates.

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32 Edwards SE, Grobman WA, Lappen JR, et al. Modified obstetric early warning scoring systems (MOEWS): Validating the diagnostic performance for severe sepsis in women with chorioamnionitis. Am J Obstet Gynecol. 2015 Apr;212(4):536.e1–e8. 33 Inouye SK, van Dyck CH, Alessi CA, et al. Clarifying confusion: The confusion assessment method. A new method for detection of delirium. Ann Intern Med. 1990;113(12):941–948. 34 Halpern SD, Becker D, Curtis JR, Fowler R, Hyzy R, Kaplan LJ, Rawat N, Sessler CN, Wunsch H, Kahn JM; Choosing Wisely Taskforce; American Thoracic Society; American Association of Critical-Care Nurses; Society of Critical Care Medicine. An official American Thoracic Society/American Association of Critical-Care Nurses/ American College of Chest Physicians/Society of Critical Care Medicine policy statement: The Choosing Wisely® Top 5 list in Critical Care Medicine. Am J Respir Crit Care Med. 2014 Oct 1;190(7):818–826. 35 Zimmerman JJ, Harmon LA, Smithburger PL, et al. Choosing wisely for critical care: The next five. Crit Care Med. 2021 Mar 1;49(3):472–481. 36 Polito A, Ricci Z, Di Chiara L, et al. Cerebral blood flow during cardiopulmonary bypass in pediatric cardiac surgery: The role of transcranial Doppler: A systematic review of the literature. Cardiovasc Ultrasound. 2006;4(1):47. 37 Belfort MA, Tooke–Miller C, Allen JC, et al. Changes in flow velocity, resistance indices, and cerebral perfusion pressure in the maternal middle cerebral artery distribution during normal pregnancy. Acta Obstet Gynecol Scand. 2001;80(2):104–112. 38 Carlson BE, Arciero JC, Secomb TW. Theoretical model of blood flow autoregulation: Roles of myogenic, shear-dependent, and metabolic responses. Am J Physiol Heart Circ Physiol. 2008;295(4):H1572–H1579. 39 Hameed AB, Chan K, Ghamsary M, Elkayam U. Longitudinal changes in the B-type natriuretic peptide levels in normal pregnancy and postpartum. Clin Cardiol. 2009 Aug;32(8):E60–E62. 40 Tanous D, Siu SC, Mason J, et al. B-type natriuretic peptide in pregnant women with heart disease. J Am Coll Cardiol. 2010 Oct 5;56(15):1247–1253. 41 Dockree S, Brook J, Shine B, et al. Cardiac-specific troponins in uncomplicated pregnancy and pre-eclampsia: A systematic review. PLoS ONE. 2021 Feb 26;16(2):e0247946. 42 Ravichandran J, Woon SY, Quek YS, et al. High-sensitivity cardiac troponin I levels in normal and hypertensive pregnancy. Am J Med. 2019 Mar;132(3):362–366. 43 Ronco C, Bellomo R, Kellum JA. Acute kidney injury. Lancet. 2019 Nov 23;394(10212):1949–1964. doi: 10.1016/ S0140-6736(19)32563-2. PMID: 31777389.

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44 Bitker L, Burrell LM. Classic and nonclassic renin–angiotensin systems in the critically ill. Crit Care Clin. 2019;35(2):213–227. 45 Erez O, Novack L, Beer-Weisel R, et al. DIC score in pregnant women—a population based modification of the International Society on Thrombosis and Hemostasis score. PLoS ONE. 2014 Apr 11;9(4):e93240. 46 Houwink AP, Rijkenberg S, Bosman RJ, van der Voort PH. The association between lactate, mean arterial pressure, central venous oxygen saturation and peripheral temperature and mortality in severe sepsis: A retrospective cohort analysis. Crit Care. 2016 Mar 12;20:56. 47 ACOG. ACOG Practice Bulletin No. 106: Intrapartum fetal heart rate monitoring: Nomenclature, interpretation, and general management principles. Obstet Gynecol. 2009 Jul;114(1):192–202. 48 Lappen JR, Chien EK, Mercer BM. Contractionassociated maternal heart rate decelerations: A pragmatic marker of intrapartum volume status. Obstet Gynecol. 2018 Oct;132(4):1011–1017. 49 Hendricks CH, Quilligan EJ. Cardiac output during labor. Am J Obstet Gynecol. 1956 May;71(5):953–972. 50 Robson SC, Dunlop W, Boys RJ, Hunter S. Cardiac output during labour. Br Med J (Clin Res Ed). 1987 Nov 7;295(6607):1169–1172. 51 ACOG. ACOG Obstetric Care Consensus No. 3: Periviable Birth. Obstet Gynecol. 2015 Nov;126(5):e82–e94. 52 Melchiorre K, Sutherland GR, Liberati M, Thilaganathan B. Maternal cardiovascular impairment in pregnancies complicated by severe fetal growth restriction. Hypertension. 2012 Aug;60(2):437–443. 53 Melchiorre k, Sutherland GR, Baltabaeva A, et al. Maternal cardiac dysfunction and remodeling in women with preeclampsia at term. Hypertension. 2011;57(1):85–93. 54 Jeejeebhoy FM, Zelop CM, Lipman S, et al.; American Heart Association Emergency Cardiovascular Care Committee, Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation, Council on Cardiovascular Diseases in the Young, and Council on Clinical Cardiology. Cardiac arrest in pregnancy: A scientific statement from the American Heart Association. Circulation. 2015 Nov 3;132(18):1747–1773. 55 Leovic MP, Robbins HN, Foley MR, Starikov RS. The “virtual” obstetrical intensive care unit: Providing critical care for contemporary obstetrics patients in nontraditional locations. Am J Obstet Gynecol. 2016 Dec;215(6):736. e1–736.e4. 56 Moore CL, Copel JA. Point-of-care ultrasonography. N Engl J Med. 2011 Feb 24;364(8):749–757. 57 Ultrasound Guidelines: Emergency, point-of-care and clinical ultrasound guidelines in medicine. Ann Emerg Med. 2017 May;69(5):e227–e254.

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58 Frankel HL, Kirkpatrick AW, Elbarbary M, et al. Guidelines for the appropriate use of bedside general and cardiac ultrasonography in the evaluation of critically ill patients—Part I: General ultrasonography. Crit Care Med. 2015 Nov;43(11):2479–2502. 59 American Institute of Ultrasound in Medicine, American College of Emergency Physicians. AIUM practice guideline for the performance of the focused assessment with sonography for trauma (FAST) examination. J Ultrasound Med. 2014 Nov; 33(11):2047–2056. 60 Lichtenstein DA, Meziere GA. Relevance of lung ultrasound in the diagnosis of acute respiratory failure: The BLUE protocol. Chest. 2008 Jul;134(1):117–125. 61 Kimura BJ, Yogo N, O’Connell CW, et al. Cardiopulmonary limited ultrasound examination for “quick-look” bedside application. Am J Cardiol. 2011;108(4):586–590. 62 Perera P, Mailhot T, Riley D, Mandavia D. The RUSH exam: Rapid Ultrasound in Shock in the evaluation of the critically ill. Emerg Med Clin North Am. 2010 Feb;28(1):29–56. 63 Pachtman S, Koenig S, Meirowitz N. Detecting pulmonary edema in obstetric patients through point-of-care lung ultrasonography. Obstet Gynecol. 2017 Mar;129(3):525–529. 64 Lictenstein D, Goldstein I, Mourgeon E, et al. Comparative diagnostic performances of auscultation, chest radiography, and lung ultrasound in acute respiratory distress syndrome. Crit Care Med. 2017 Mar;45(3):e290–e297. 65 Pacheco LD, Clark SL, Klassen M, Hankins GD. Amniotic fluid embolism: Principles of early clinical management. Am J Obstet Gynecol. 2020 Jan;222(1):48–52. 66 Levitov A, Frankel HL, Blaivas M, et al. Guidelines for the appropriate use of bedside general and cardiac ultrasonography in the evaluation of critically ill patients—Part II: Cardiac ultrasonography. Crit Care Med. 2016 Jun;44(6):1206–1227. 67 Silverstein JR, Laffely NH, Ritkin RD. Quantitative estimation of left ventricular ejection fraction from mitral valve E-point septal separation and comparison to magnetic resonance imaging. Am J Cardiol. 2006;97:137–140. 68 Simard C, Yang S, Koolian M, et al. The role of echocardiography in amniotic fluid embolism: A case series and review of the literature. Am J Emerg Med. 2021 Mar;42:28–34. 69 Marik PE, Monnet X, Teboul JL. Hemodynamic parameters to guide fluid therapy. Ann Intensive Care. 2011 Mar 21;1(1):1. 70 AU Biais M, Nouette-Gaulain K, Cottenceau V, et al. Uncalibrated pulse contour-derived stroke volume variation predicts fluid responsiveness in mechanically ventilated patients undergoing liver transplantation. Br J Anaesth. 2008;101(6):761. 71 Easter SR, Hameed AB, Shamshirsaz A, et al. Point of care maternal ultrasound in obstetrics. Am J Obstet Gynecol. 2022 Sep 29. Epub ahead of print.

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21 Critical Care Drills in Obstetrics Monica A. Lutgendorf 1 and Shad H. Deering2 1 2

Department of Gynecologic Surgery & Obstetrics, Uniformed Services University of the Health Services, Bethesda, MD, USA Department of Obstetrics and Gynecology, Baylor College of Medicine, Children’s Hospital of San Antonio, San Antonio, TX, USA

Obstetric care is a high-stake endeavor with a delicate balance of maternal and neonatal interests. Maternal morbidity and mortality are increasing in the United States, and obstetric emergencies can occur suddenly and unexpectedly in otherwise low-risk women  [1]. Simulation and teamwork training are important components of improving both individual and team performance and afford the opportunity to practice and learn in a safe environment [2]. Additionally, obstetric simulation allows both novice and experienced providers the opportunity to practice highacuity, low-frequency emergencies and procedures. Simulation results in improved participant knowledge and confidence and superior clinical management of obstetric emergencies compared to didactic learning  [3]. Increasingly, obstetric simulation training is being shown to improve clinical outcomes; however, the literature is limited, and many of the clinical improvements demonstrated relate to improved neonatal outcomes [4]. The Joint Commission identified that 72% of the root causes in events related to infant death and injury during delivery were related to organizational culture and communication failures [4]. This directly relates to their recommendation to conduct team training in perinatal areas using clinical drills and debriefing to assess team performance and identify opportunities for improvement. Obstetrical emergency simulations have been shown to improve obstetric outcomes and improve patient safety when used as part of a comprehensive perinatal safety initiative [5]. Obstetric simulation is currently recommended as part of a comprehensive patient safety program, and development of obstetric scenarios is recommended by multiple national organizations (see Table  21.1)  [2,6,7]. A recent Cochrane Review on simulation-based team training for obstetric

emergencies included eight randomized controlled trials with more than 1,000 participants and more than 200,000 births.  [8] This review concluded that simulation-based obstetric team training of multiprofessional teams may help improve team performance and contribute to improved maternal and perinatal outcomes. However, they note that high-certainty evidence is lacking [8]. When it comes to actually introducing simulation drills into training, simulation design is a critical step, as poorly designed and executed simulations may serve only to reinforce bad habits. The most important first step is to assess the learners, determine their needs, and develop specific goals and objectives. Strong simulation designs include components of didactic education, a simulation event, and a debrief. Simulation can also be a proactive component of a highly reliable organization where latent threats are identified before harm occurs. Additionally, simulations conducted in situ (in the actual clinical spaces) offer the opportunity to change the culture and empower individuals to be involved in process changes that can improve systems as a whole. When it comes to obstetrics, every location where the emergency may occur should be considered as an opportunity to train. Patients may have issues in the clinic, present to the emergency room or in the antepartum and postpartum units. Simulation design should account for these factors, and simulation scenarios can be created to test a system and team’s ability to handle obstetric emergencies. Successful simulation programs include a dedicated team to develop and implement simulations. Ideally, personnel will have an interest in education, technical expertise, as well as creativity, perseverance, and the time, energy, and leadership support to conduct the scenarios [9].

Critical Care Obstetrics, Seventh Edition. Edited by Luis D. Pacheco, Jeffrey P. Phelan, Torre L. Halscott, Leslie A. Moroz, Arthur J. Vaught, Antonio F. Saad, and Amir A. Shamshirsaz. © 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.

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Table 21.1

Recommended obstetric scenarios.

American College of Obstetricians and Gynecologists

Shoulder dystocia Eclampsia Postpartum hemorrhage Vaginal breech delivery Fourth-degree laceration repair Operative vaginal delivery

Society for Maternal-Fetal Medicine

Invasive fetal needle diagnostics Invasive fetal therapy Cardiopulmonary arrest Thyroid storm Diabetic ketoacidosis Critical care obstetrics

The Joint Commission

Shoulder dystocia Emergency cesarean delivery Maternal hemorrhage Neonatal resuscitation

Source: Argani et al. [2], Wagner et al. [5], The Joint Commission Elements of Performance [7].

Obstetric emergencies Simulation allows for practice and skills acquisition for uncommon emergencies that require timely and appropriate responses. Simulation-based intervention programs improve the ability of teams to perform in these emergency scenarios. In a study of drills involving residents and midwives managing eclampsia, postpartum hemorrhage (PPH), shoulder dystocia, and breech vaginal delivery, common and recurrent mistakes were identified among teams. Common errors included insufficient maternal ventilation and failure to detect magnesium toxicity in the eclampsia case. In the PPH case, participants commonly underestimated blood loss, incorrectly administered uterotonic medications, and had an unacceptable delay in transport to the operating room. For the shoulder dystocia case, inadequate documentation and delays in episiotomy were seen, and there was a general lack of familiarity with the maneuvers used for breech vaginal delivery [10].

Shoulder dystocia Shoulder dystocia is an unpredictable and unpreventable obstetric emergency that occurs in approximately 0.5–1.5% of vaginal deliveries. It results from impaction of the fetal shoulder behind the maternal symphysis pubis. Prompt recognition and appropriate management are important to  minimize fetal injury and neonatal death. Shoulder dystocia simulations have been shown to improve

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performance for residents, and both resident and attending communication improved following shoulder dystocia simulations [11,12]. When assessing the frequency of training, Crofts et al. demonstrated retention of shoulder dystocia skills at 3 weeks (82% achieved delivery), 6 months (84% achieved delivery), and 12  months (85% achieved delivery) after shoulder dystocia simulation training [13]. Additionally, these same investigators found that training with a highfidelity simulator with force feedback devices had greater improvement in ability to achieve vaginal delivery (94%), compared to those trained with a low-fidelity simulator where 72% achieved delivery  [14]. Other studies have demonstrated an improvement in maneuvers for delivery, decreased use of excessive force, and decreased neonatal injury at birth with a trend toward decreased rates of persistent brachial plexus injuries  [15]. Significant and sustained reductions in rates of brachial plexus injuries have also been shown with shoulder dystocia simulation training  [16–19]. Recent studies have also shown that multidisciplinary simulations on shoulder dystocia have led to sustained improvements in documentation and appropriate maneuvers over a 2-year period  [18]. Given the evidence for improved outcomes, the relative simplicity of training for this emergency, and the low cost of the simulators needed, training for shoulder dystocia is often an excellent place to start simulation training at an institution.

Postpartum hemorrhage PPH affects approximately 4–6% of deliveries and remains an important cause of maternal morbidity and mortality worldwide. Simulation has been used to test and train providers on management of PPH in both high- and lowresource settings [9,20–22]. These studies have shown the ability to detect important deficiencies in trainee knowledge, improve skills, and even decrease response times in actual hemorrhages [23]. Hemorrhage training drills have also been implemented as part of hemorrhage education projects, including didactic education, hands-on skills stations, and standardized simulation drills, with resultant improvements in knowledge and skills. Information about the impact on clinical outcomes is more limited. Recent studies have shown that implementation of a multidisciplinary simulation program improves clinical response, with faster times to administration of uterotonic medications, quicker transfusion of blood products, and lower estimated blood loss [24]. Positive impacts of interprofessional simulation team training on PPH management include improved teamwork, communication, and protocol adherence [25].

Obstetric emergencies

Emergent cesarean delivery Emergent cesarean delivery can result from several clinical scenarios, including cord prolapse and uterine rupture. In these cases, rapid delivery can be lifesaving for both the mother and the neonate. Multidisciplinary simulation training has been used to assess the performance of emergency cesarean delivery with umbilical cord prolapse and was shown to decrease the diagnosis-to-delivery intervals in actual cases from 25 min before the training to 14.5 min after training  [26]. Other studies have reported similar findings of shorter decision-to-delivery intervals with improvements in the umbilical artery pH  [27]. However, other investigators did not find a difference in decision-todelivery interval or perinatal mortality rates with the use of a multidisciplinary obstetric emergency team training program for cord prolapse [28]. In another study, a large academic center found that response times for emergent cesarean delivery in simulated uterine rupture scenarios required a median of 9 min 27 s (range: 8 min 55 s to 10 min 27 s)  [29]. As this occurred in an academic setting with immediate staff availability and an anticipated scenario, the authors postulated that times could be longer in settings where staff were not available in-house [30]. Due to the in situ nature of these drills, the teams were able to identify real-life barriers to efficient transport within their system and then address them.

Eclampsia Eclampsia is an obstetric emergency associated with seizure activity in the setting of preeclampsia (hypertension and proteinuria in pregnancy). Studies have shown that simulation is more effective for training residents on the management of eclampsia and magnesium toxicity when compared to more traditional lectures [30]. In situ eclampsia simulation scenarios have been used to identify areas for improvement [31] and also have been shown to decrease time to complete expected tasks and improve completion of critical tasks  [32]. When evaluating skills obtained in different training locations, there was no difference between those trained in situ versus those trained at a simulation center [32].

Breech vaginal delivery Although breech vaginal deliveries are relatively uncommon in modern practice, knowledge of breech vaginal delivery maneuvers is important in emergency situations and because the maneuvers are essentially the same during cesarean section. Simulation training has been used to improve resident performance of critical maneuvers in

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simulated breech vaginal deliveries [33]. Given the rarity of breech vaginal deliveries at the present time, simulation offers an excellent opportunity to practice this high-stake procedure in a safe environment.

Operative vaginal delivery Rates of operative vaginal deliveries have declined over time, and simulation offers an opportunity to train and maintain skills in this area. Simulation has been used to train and evaluate skills for both vacuum and forceps operative deliveries [34–37] and to assess traction during forceps deliveries  [38]. While much of what has been published about operative delivery simulation addresses technique and documentation, a recent study examined the effect of simulation training of residents on perineal lacerations during actual deliveries  [39]. This study by Gossett looked at over 6,000 operative vaginal deliveries and found a 26% reduction (p = 0.002) in the risk of severe perineal lacerations for residents who were trained with simulation, after adjusting for other maternal and delivery risk factors.

Maternal cardiac arrest Maternal cardiac arrest is another rare obstetric emergency where effective performance and response are critical. Simulation has been used to both identify deficits in maternal cardiac arrest codes [29] and also improve skills, knowledge, and performance in simulated maternal cardiac arrest scenarios [40]. A resuscitative cesarean delivery simulation course has been shown to increase the use of this intervention in cases of maternal cardiac arrest  [41]. Importantly, current advanced cardiac life support (ACLS) courses do not emphasize maternal resuscitation techniques, such as left uterine displacement and resuscitative cesarean section and 2-year cycles of training may not allow sufficient practice and maintenance of skills for this rare emergency [42].

Endocrine emergencies Endocrine emergencies such as diabetic ketoacidosis and thyroid storm may also occur in pregnancy, and they are another area where simulation scenarios can provide practice opportunities in a safe environment. Simulation has been used to assess clinical management of diabetes in nonpregnant patients [43] and is likely to provide benefit in assessing team response and provider skills for managing thyroid storm as well. This type of training has been included at national critical care simulation meetings run by the Society for Maternal-Fetal Medicine over the past several years.

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Location

Communication

In situ training allows teams to identify and address latent safety threats with local solutions and improvements in patient care  [3]. Mobile obstetric simulators have been used successfully to develop and maintain skills in a clinical setting and have the ability to identify and address latent safety threats across large healthcare systems [44]. These benefits of in situ simulation must be balanced by the practicality of dedicated training time and space in a busy clinical setting, and the possibility of postponing or canceling drills or having team members pulled for actual clinical activities. Training in a simulation center may mitigate some of these realworld challenges, but it is often difficult to get the entire care team together away from the unit, and it may not allow the same robust evaluation of barriers and latent safety threats in the actual clinical area.

Communication errors can have direct negative effects on patient outcomes, and lapses in communication can also upset patients and families and affect patient satisfaction, leading to loss of confidence in care provided and leading to concerns about safety [50]. Simulation has been shown to improve patient-actor perception of communication and safety. Patient-actor perception of care was improved by training in PPH, eclampsia, and shoulder dystocia; however, training with mannequins did not improve patientactor perception of communication and safety as much as training with patient-actors  [51]. This is likely because training with patient-actors is more patient-centered and allows for more realistic interactions, thus requiring teams to complete technical tasks while interacting and attending to the needs of the patient. Simulation has also been used effectively to improve communication and teamwork between obstetricians and anesthesiologists [52].

Teamwork and behaviors Teamwork is another important component in managing obstetric emergencies, but teamwork training independent of the actual environment may be of limited benefit  [45]. To be most effective, teamwork training must be conducted in situ and in a multidisciplinary fashion to demonstrate an improvement in outcomes. In a prospective study, teamwork training combined with a 4-h high-fidelity medical simulation and debriefing session resulted in improved dimensions of the safety culture in labor and delivery (L&D) and improved outcomes as measured by a significant decrease in the Adverse Outcome Index (AOI)  [46]. The basic concept is that teamwork is best learned by interaction rather than through lectures. It is also possible that the act of working in teams during simulations without additional teamwork training results in improved outcomes. In situ simulation training for shoulder dystocia resulted in reductions in Erb’s palsy, hypoxic ischemic encephalopathy, low pH at delivery, and malpractice claims  [3]. Additionally, in situ training can result in organizational climate change with positive attitudes toward safety climate and culture, improved teamwork, and reduced hierarchical barriers. Full participation of units is an important component that results in improved perinatal outcomes  [47–49]. These clinical improvements can be achieved with regular simulation training in a threat-free learning environment.

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Simulators Simulators and different modalities, including actors and hybrid task trainers, have unique benefits and limitations. The use of patient-actors in simulations results in more realistic scenarios and has been shown to improve communication among healthcare providers and patients  [3,51]. The use of a MamaNatalie™ trainer (a low-cost, low-tech simulator that is worn by a simulation actor/ model) has been shown to be as effective as a high-fidelity mannequin for training medical students on how to perform a vaginal delivery; however, the effect of the actor on this scenario has not been assessed [53]. High-fidelity mannequins may provide benefit for technical skills, such as by demonstrating force feedback with a simulated shoulder dystocia, and allow for more invasive scenarios such as maternal cardiac arrest. Such mannequins have been shown to result in a higher chance of successful shoulder dystocia management when compared to low-fidelity models [14].

Education Simulation has been shown to be an effective educational and training modality in many areas, including twin vaginal birth [54] and PPH, with sustained improvement in the clinical management of PPH [55]. Simulation is also effective for training in the management of shoulder dystocia

Debriefing

and eclampsia, with simulation-trained teams demonstrating superior performance in L&D drills [56]. When considering the different areas where simulation can be useful, it is helpful to break down distinct situations. Simulation training is useful for initial learning of skills, for allowing trainees to learn without placing patients at risk, for maintenance of skills for infrequent occurrences, for testing and demonstration of proficiency for reentry into profession, and potentially as part of credentialing, certification, and insurance coverage [6].

scheduled to participate in full-scale simulation scenarios involving obstetrics, neonatology, and anesthesiology team members with the goal of testing key processes and identifying latent safety threats. The group was able to identify several important deficiencies and correct them prior to opening the new unit. Such planning and testing can facilitate smooth transitions and ensure full functional capabilities with new hospitals or critical moves.

Frequency and skill retention

Increasingly, simulation has been shown to improve patient outcomes. Common features of units with improved outcomes include institutional-level support and incentives for training, coupled with high participation rates and regular in situ training  [3]. These successful training programs also incorporate integrated clinical and teamwork training using patient-actors and high-fidelity simulation models. Obstetric emergency simulations as part of comprehensive perinatal safety initiatives have resulted in decreased AOI scores, lowered rates of return to the operating room and birth trauma, and improved both staff perceptions of safety/ collaboration  [59] and patient perceptions of staff teamwork as well as documentation [5,46].

Simulation scenarios should be planned in advance, with the development of specific goals and objectives to train learners and assess critical processes. Input from multiple disciplines, including physicians and nurses for multidisciplinary training, will ensure robust realistic scenarios with relevant learning points. Scenarios can be task-oriented with specific task trainers and the goal of teaching critical actions, maneuvers, and skills for a variety of emergencies including but not limited to shoulder dystocia, breech vaginal delivery, and operative vaginal delivery. Scenarios can also be specifically developed to assess knowledge and skills as well as interpersonal and team communication. Care should be taken to develop interesting, challenging, and relevant scenarios, as much of the learning in simulation depends on the impact of the simulation experience. While creating scenarios can be interesting and rewarding, a basic scenario is included in the Appendix and the Resources section of this chapter. This can be used as a basic template upon which to build additional clinical cases. Advance planning should include assessment of simulation location – in situ versus a simulation lab – and consideration of logistics such as scheduling of personnel and space to conduct the debriefing as well as equipment needed to conduct the simulation. Evaluation forms should be created (general forms are also included in the Appendix) and facilitators and simulation technicians to run the scenario identified. Additionally, it is helpful to identify debriefer(s) who can evaluate the simulation and facilitate the presimulation brief and postsimulation debrief.

In situ testing of new facilities

Debriefing

In situ simulation scenarios have also been used successfully to identify real-life operational deficiencies to assess facility and system readiness to open a new children’s hospital obstetric unit  [61]. In this study, participants were

Debriefing is a critical element in the conduct of critical care drills. Although the debrief can seem stressful and intimidating, this is where the “magic” happens! Adult learners will gain the most from connecting ideas and

The frequency with which training should be repeated for optimum skill retention has been studied to some degree, with Crofts et  al. demonstrating excellent retention of shoulder dystocia training at 6 and 12 months [13]. Other studies have shown initial improvement of PPH management skills with training and a retention of skills at 3 months [57,58] and at 9–12 months [59]. Vaginal breech delivery skills taught in simulation were retained at 10–26  weeks  [60]. These studies suggest that a training interval of 6–12 months may be appropriate.

Outcomes

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Scenarios

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knowledge with the simulation experience and their decisions and interactions. The debrief actually starts with the presimulation review/introduction. This is where learners are oriented to the simulation with a description of the purpose, learning objectives, and basic rules and expectations of the simulation. It is important to reinforce the concept of psychological safety for the planned simulation by reminding participants that they are well-trained, competent personnel that are here to practice and improve patient care in a safe environment. Explaining that the simulation is not a test is a good place to start. Participants should be prepared to get involved, treat the scenario as realistically as possible, and perform to the best of their abilities. While individual skills training can and should involve direct instruction and feedback, debriefing after team exercises must take team and interpersonal dynamics into account. Following the simulation, debriefing should ideally be conducted in a quiet, comfortable, private space with minimal interruptions. In reality, when the simulation is performed in situ, it is often difficult to get the entire team to a separate location and running the debrief on the unit or in the actual room is a reasonable option. The goal of debriefing is to foster learning and discussion in a nonconfrontational fashion while encouraging participants to realize and learn from their performance and the scenario. The goal should be to include all participants and encourage thoughtful and insightful reflections. Open-ended questions and a spirit of genuine inquiry can be helpful in these situations. Debriefers should identify key decisions and explore participants’ thoughts and decisions (particularly if these differ from expectations). In general, you will find that even when incorrect actions were taken, there was a rational reason behind them that can be addressed. You will not be able to correct behavior until you understand why the error was made. Although it is important to discuss all aspects of the simulation and to correct medical errors, this should be done in a nonjudgmental fashion; in

essence, debriefing with good judgment [62]. In multidisciplinary team settings, it is important to also assess and discuss teamwork and communication elements.

Conclusions Sustainable improvements in learning and outcomes will follow from quality improvement projects that include effective communication among patients, families, and healthcare teams; high-functioning multidisciplinary teams; consistent protocols; and adequate infrastructure in the healthcare system. Robust simulation drills, including multidisciplinary teams and in situ environments, can benefit providers, nurses, and patients and result in durable improvements in healthcare and patient safety in obstetrics.

Resources https://www.cmqcc.org/resource/role-medical-simulation https://www.cmqcc.org/resources-tool-kits http://www.obsafety.org/content/blogcategory/43/97/ h tt p : / / m a i l . ny. a c o g . o r g / w e b s i t e / O p t i m i z i n g _ Hemorrhage/ Simulation_Drills.pdf http://www.sim-central.com/documents/scenarios.pdf

Disclaimer The views expressed in this chapter are those of the authors and do not necessarily reflect the official policy or position of the Uniformed Services University of the Health Sciences, Department of the Navy, Department of the Army, Department of the Air Force, Department of Defense, or the US Government. Mention of trade names, commercial products, or organizations does not imply endorsement by the US Government.

References 1 Arora KS, Shields LE, Grobman WA, et al. Triggers, bundles, protocols and checklists – what every maternal care provider needs to know. Am J Obstet Gynecol. 2016;214(4):444–451. 2 Argani CH, Eichelberger M, Deering S, et al. The case for simulation as part of a comprehensive patient safety program. Am J Obstet Gynecol. 2012;206(6):451–455. 3 Siassakos D, Crofts JF, Winter C, et al. The active components of effective training in obstetric emergencies. BJOG. 2009;116:1028–1032.

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4 Crofts JF, Winter C, Sowter MC. Practical simulation training for maternity care – where we are and where next. BJOG. 2011; 118(Suppl. 3):11–16. 5 Wagner B, Meirowitz N, Shah J, et al. Comprehensive perinatal safety initiative to reduce adverse obstetric events. J Health Qual. 2011;34(1):6–15. 6 Joint Commission for Accreditation of Healthcare Organizations. Sentinel event no. 30. Sentinel Event Alert. 2004;(30):1–2.

References

7 The Joint Commission Elements of Performance https:// www.jointcommission.org/standards/r3-report/r3-reportissue-24-pc-standards-for-maternal-safety/#. YjdbAerMJzo Accessed 3/20/22 8 Fransen AF, van de Ven J, Mol BW, Oei SG. Multiprofessional simulation-based team training in obstetric emergencies for improving patient outcomes and trainees’ performance. Cochrane Database Syst Rev. 2020;12:CD011545. 9 Ennen CS, Satin AJ. Training and assessment in obstetrics: The role of simulation. Best Pract Res Clin Obstet Gynaecol. 2010;24:747–758. 10 Maslovitz S, Barkai G, Lessing JB, et al. Recurrent obstetric management mistakes identified by simulation. Obstet Gynecol. 2007;109(6):1295–1300. 11 Deering S, Poggi S, Macedonia C, et al. Improving resident competency in the management of shoulder dystocia with simulation training. Obstet Gynecol. 2004 Jun 103(6):1224–1228. 12 Goffman D. Heo H, Pardanani S, et al. Improving shoulder dystocia management among resident and attending physicians using simulations. Am J Obstet Gynecol. 2008;199(3)294.e1–294.e5. 13 Crofts JF, Bartlett C, Ellis D, et al. Management of shoulder dystocia skill retention at 6 and 12 months after training. Obstet Gynecol. 2007;110(5): 1069–1074. 14 Crofts JF, Bartlett C, Ellis D, et al. Training for shoulder dystocia: A trial of simulation using low-fidelity and high-fidelity mannequins. Obstet Gynecol. 2006;108(6):1477–1485. 15 Draycott TJ, Crofts JF, Ash JP, et al. Improving neonatal outcome through practical shoulder dystocia training. Obstet Gynecol. 2008;112(1):14–20. 16 Inglis S, Feier N, Chetiyaar J, et al. Effects of shoulder dystocia training on the incidence of brachial plexus injury. Am J Obstet Gynecol. 2011;204:322.e1–322.e6. 17 Crofts JF, Lenguerrand E, Bentham GL, et al. Prevention of brachial plexus injury – 12 years of shoulder dystocia training: An uninterrupted time-series study. BJOG. 2016;123:111–118. 18 Olson DN, Logan L, Gibson KS. Evaluation of multidisciplinary shoulder dystocia simulation training on knowledge, performance and documentation. Am J Obstet Gynecol MFM. 2021;3:100401. 19 Dahlberg J, Nelson M, Dahlgren MA, Blomberg M. Ten years of simulation-based shoulder dystocia training – impact on obstetric outcome, clinical management, staff confidence, and the pedagogical practice – a time series study. BMC Pregnancy Childbirth. 2018;18:361. 20 Deering SH, Chinn M, Hodor J, et al. Use of a postpartum hemorrhage simulator for instruction and evaluation of residents. J Graduate Med Ed. 2009;1(2):260–263.

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21 Nathan LM, Patauli D, Nsabimana D, et al. Retention of skills 2 years after completion of a postpartum hemorrhage simulation training program in rural Rwanda. Int J Gynaecol Obstet. 2016;134:350–353. 22 Nelissen E, Ersdal H, Mduma E, et al. Helping mothers survive bleeding after birth: Retention of knowledge, skills and confidence nine months after obstetric simulation-based training. BMC Pregnancy Childbirth. 2015;15:190. doi:10.1186/s12884–015–0612–2 23 Marshall NE, Vanderhoeven J, Eden KB, et al. Impact of simulation and team training on postpartum hemorrhage management in non-academic centers. J Matern Fetal Neonatal Med. 2015;28(5):495–499. 24 Dillon SJ, Kleinman W, Fomina Y, et al. Does simulation improve clinical performance in management of postpartum hemorrhage? Am J Obstet Gynecol. 2021;225:435.e1–8. 25 Greer JA, Lutgendorf MA, Ennen CS, et al. Obstetric simulation training and teamwork: Immediate impact on knowledge, teamwork, and adherence to hemorrhage protocols. Simul Healthc. 2022 Feb 8; 18(1):32–41. doi: 10.1097/SIH.0000000000000641 26 Sissakos D, Hasafa Z, Sibanda T, et al. Retrospective cohort study of diagnosis-delivery interval with umbilical cord prolapse: The effect of team training. Br J Obstet Gynaecol. 2009;116(8):1089–1096. 27 Iitani Y, Tsuda H, Ito Y, et al. Simulation training is useful for shortening the decision-to-delivery interval in cases of emergent cesarean section. J Matern Fetal Neonatal Med. 2018;31:3128–3123. 28 Copson S, Calvert K, Raman P, et al. The effect of a multidisciplinary obstetric emergency team training program, the In Time course, on diagnosis to delivery interval following umbilical cord prolapse: A retrospective cohort study. Aust NZ J Obstet Gynaecol. 2016 Sep 7. doi:10.1111/ajo.12530 29 Lipman SS, Carvalho B, Cohen SE, et al. Response times for emergency cesarean delivery: Use of simulation drills to assess and improve obstetric team performance. J Perinatol. 2013;33:259–263. 30 Fisher N, Bernstein PS, Satin A, et al. Resident training for eclampsia and magnesium toxicity management: Simulation or traditional lecture. Am J Obstet Gynecol. 2010;203:379.e1–e5. 31 Thompson S, Neal S, Clark V. Clinical risk management in obstetrics: Eclampsia drills. BMJ. 2004;328:269–271. 32 Ellis D, Crofts JF, Hunt LP, et al. Hospital, simulation center and teamwork training for eclampsia management. Obstet Gynecol. 2008;111(3):723–731. 33 Deering S, Brown J, Hodor J, et al. Simulation training and resident performance of singleton vaginal breech delivery. Obstet Gynecol. 2006;107(1):86–89.

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34 Cheong YC, Abdullah H, Lashen H, et al. Can formal education and training improve the outcome of instrumental delivery? Eur J Obstet Gynecol Reprod Biol. 2004;113(2):139–144. 35 Bahl R, Murphy DJ, Strachan B. Qualitative analysis by interview and video recording to establish the components of a skilled low-cavity non-rotational vacuum delivery. Br J Obstet Gynecol. 2009;116(2):319–326. 36 Dupuis O, Moreau R, Silveira R, et al. A new obstetric forceps for the training of junior doctors: A comparison of the spatial dispersion of forceps blade trajectories between junior and senior obstetricians. Am J Obstet Gynecol. 2006;194(6):1524–1531. 37 Dupuis O, Moreau R, Silveira R, et al. Assessment of forceps blade orientations during their placement using an instrumented childbirth simulator. Br J Obstet Gynecol. 2009;116(2):327–332. 38 Leslie KK, Dipasquale-Lehnerz P, Smith M. Obstetric forceps training using visual feedback and isometric strength testing unit. Obstet Gynecol. 2005;105(2):377–382. 39 Gossett D, Gilchrist-Scott D, Wayne D, et al. Simulation training for forceps-assisted vaginal delivery and rates of maternal perineal trauma. Obstet Gynecol. 2016 Sep;128(3):429–435. 40 Fisher N, Eisen LA, Bayya JV, et al. Improved performance of maternal-fetal medicine staff after maternal cardiac arrest simulation-based training. Am J Obstet Gynecol. 2011;205:239.e.1–239.e.5. 41 Dijkman A, Huisman CM, Smit M, et al. Cardiac arrest in pregnancy: Increasing use of perimortem cesarean section due to emergency skills training? BJOG. 2010;117(3):282–287. 42 Lipman SS, Daniels KI, Arafeh J, et al. The case for OBLS: A simulation-based obstetric life support program. Semin Perinatol. 2011;35(2):74–79. 43 Yu CH, Straus S, Brydges R. The ABCs of DKA: Development and validation of a computer-based simulator and scoring system. J Gen Intern Med. 2015;30(9):1319–1332. 44 Guise JM, Lowe NK, Deering S, et al. Mobile in situ obstetric emergency simulation and teamwork training to improve maternal-fetal safety in hospitals. Jt Comm J Qual Patient Saf. 2010;36(10):443–453. 45 Nielsen PE, Goldman MB, Mann S, et al. Effects of teamwork training on adverse outcomes and process of care in labor and delivery. Obstet Gynecol. 2007;109(1):48–55. 46 Phipps MG, Lindquist DG, McConaughey E, et al. Outcomes from a labor and delivery team training program with simulation component. Am J Obstet Gynecol. 2012;206(1):3–9. 47 Pratt S, Mann S, Salisbury M, et al. Impact of CRM-based team training on obstetric outcomes and clinician’s

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patient safety attitudes. Jt Comm J Qual Patient Saf. 2007;33:720–725. Scholefield H. Embedding quality improvement and patient safety at Liverpool Women’s NHS Foundation Trust. Best Pract Res Clin Obstet Gynaecol. 2007;21:593–607. Draycott T, Sibanda T, Owen L, et al. Does training in obstetric emergencies improve neonatal outcome? BJOG. 2006;113:177–182. White AA, Pichert JW, Bledsoe SH, et al. Cause and effect analysis of closed claims in obstetrics and gynecology. Obstet Gynecol. 2005;105:1031–1038. Crofts JF, Bartlett C, Ellis D, et al. Patient-actor perception of care: a comparison of obstetric emergency training using manikins and patient-actors. Qual Saf Health Care. 2008;17:20–24. Kirschbaum KA, Rask JP, Brennan M, et al. Improved climate, culture and communication through multidisciplinary training and instruction. Am J Obstet Gynecol. 2012;207(3):200.e1–200.e7. DeStephano CC, Chou B, Patel S, et al. A randomized controlled trial of birth simulation for medical students. Am J Obstet Gynecol. 2015;213:91.e1–91.e7. Easter SR, Gardner R, Barrett J, et al. Simulation to improve trainee knowledge and comfort about twin vaginal birth. Obstet Gynecol. 2016;128(4 Suppl.):34S–39S. Birch I, Jones N, Doyle PM, et al. Obstetric skills drills: Evaluation of teaching methods. Nurse Educ Today. 2007;27(8):915–922. Daniels K, Arafeh J, Clark A, et al. Prospective randomized trial of simulation versus didactic teaching for obstetrical emergencies. Simul Healthcare. 2010;5(1):40–45. Birch I, Jones N, Doyle PM, et al. Obstetric skills drills: Evaluation of teaching methods. Nurse Educ Today. 2007;27(8):915–922. Van de Ven J, Fransen AF, Schuit E, et al. Does the effect of one-day simulation team training in obstetric emergencies decline within one year? A post-hoc analysis of a multicenter cluster randomized controlled trial. Eur J Obstet Gynecol and Reprod Biol. 2017;216:79–84. Marshall NE, Vanderhoeven J, Eden KB, et al. Impact of simulation and team training on postpartum hemorrhage management in non-academic centers. J Matern Fetal Neonatal Med. 2015;28(5):495–499. Stone H, Crane J, Johnston K, Craig C. Retention of vaginal breech delivery skills taught in simulation. J Obstet Gynaecol Can. 2018;40:205–210. Ventre KM, Barry JS, Davis D, et al. Using in situ simulation to evaluate operational readiness of a children’s hospitalbased obstetrics unit. Sim Healthcare. 2014;9:102–111. Rudolph JW, Simon R, Rivard P, et al. Debriefing with good judgement: Combining rigorous feedback with genuine inquiry. Anesthesiology Clin. 2007;25:361–376.

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Appendix: In Situ Critical Care Simulation Example Preterm Premature Rupture of Membranes and Postpartum Hemorrhage

Introduction Please use this outline/instructions to familiarize yourself with the simulation process and the planned simulation. It can be used to evaluate teams on medical knowledge as well as communication and teamwork skills. (Note: Although the sample simulation was written for a highfidelity birthing mannequin, important training can be realized at many institutions using readily available equipment and lower-fidelity models.) Evaluation forms are included for your use and review.

Roles and responsibilities Please begin each simulation by reviewing these basic assumptions with all participants: Everyone participating today is well-trained, intelligent, wants to do their best, and is here to improve patient care. Simulation is and should be a safe environment for practicing in a complicated healthcare system. At the beginning of the scenario, participants will make nametags to identify their roles in the scenario. During the scenario, you may have to relay or discuss specific findings; however, for the most part, facilitators and debriefers are not part of the scenario and should refrain from having participants direct questions to them during the scenario. During the simulation, the facilitator will monitor the flow of the simulation, while the debriefer will primarily monitor performance and complete the evaluation form. Debriefing is one of the most important parts of the exercise. During this time, the debriefer will lead the discussion, with additional input from the facilitator. Key debriefing and teaching points are outlined, and you can use the evaluation checklist to help review as well. It is often helpful to ask the team at the beginning how they thought the scenario went, and to proceed with openended questions. If not brought up initially, the debriefer and facilitator should cover appropriate and inappropriate

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actions, as well as communication and teamwork observations (e.g., closed-loop communications, identification of team leader, etc.). At the conclusion of the simulation, please encourage participants to complete an evaluation form to help make the exercise and scenarios better for the future.

Simulation Case: Preterm premature rupture of membranes (PPROM) complicated by placental abruption → Postpartum hemorrhage requiring activation of massive transfusion protocol Case overview: The case will start with a patient admitted for PPROM. The patient will quickly progress in labor, have vaginal bleeding from a placental abruption, and have a rapid vaginal delivery. Following this, the patient will demonstrate uterine atony and experience a significant PPH. Despite administration of uterotonic medications and other interventions, the patient will continue to bleed and require activation of the massive transfusion protocol with administration of large volumes of blood products. Participants may complete any indicated medical interventions to control bleeding (uterine packing, Bakri balloon placement) and should eventually decide to move to the operating room for operative interventions.

Learning objectives and key debriefing points Medical knowledge PPROM ●

●

●

Understand the complications associated with PPROM (including cord prolapse, placental abruption, and infection), and be able to monitor for and treat these. Understand and be able to interpret and manage fetal heart rate (FHR) tracings. Understand how to treat and when to deliver patients with PPROM.

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Postpartum hemorrhage ● ● ●

●

Understand risk factors for PPH. Be able to make the diagnosis of PPH. Be able to resuscitate and treat patients with a significant PPH and utilize the institution’s massive transfusion protocol. Understand indications to proceed to operative management of hemorrhage when medical management is not effective.

Patient care PPROM ●

●

●

Be familiar with management of PPROM to include antibiotic therapy and indications for delivery. Order appropriate consultations (e.g., anesthesia and neonatal intensive care unit consultation). Monitor and evaluate for complications such as intrauterine infection and cord prolapse.

Postpartum hemorrhage ●

●

●

Know how to use and be able to activate the institution’s massive transfusion protocol. Be able to provide appropriate care during PPH – such as maternal resuscitation and massive transfusion  – and understand when operative management is indicated. Demonstrate an understanding of medical and operative management of PPH.

Teamwork and communication PPROM ●

● ●

Be able to clearly communicate your rationale regarding treatment. Be able to assign critical tasks to team members. Practice closed-loop communication.

Postpartum hemorrhage ●

● ●

● ●

●

Be able to effectively communicate in an emergency situation. Be able to assign critical tasks to team members. Practice closed-loop communication during treatment of hemorrhage. Accurately record events and blood products given. Efficiently obtain blood products using your institution’s massive transfusion protocol. Communicate effectively with blood bank and ancillary personnel.

Case flow overview State 1: Management of PPROM and management of rapid labor and delivery with placental abruption State 2: Diagnosis and management of PPH with massive transfusion protocol

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Simulators A high-fidelity birthing mannequin or hybrid simulator with a simulated patient that has the ability to simulate: ● ● ●

Vaginal delivery Maternal and fetal vital signs Postpartum hemorrhage.

Personnel required Simulation technician (if high-fidelity mannequin used) Simulated patient (if hybrid simulator used) Simulated family member: Responsible for providing updates on how the patient is feeling and asking questions during the simulation Simulation facilitator(s): Responsible for guiding the team through the simulation Simulation debriefer(s): Responsible for evaluating and debriefing the teams (facilitators will also contribute to evaluation and debriefing)

Roles to be assigned* 1) 2) 3) 4) 5)

Staff physicians (1 or 2) Residents or fellows/certified nurse–midwives (CNMs)* Staff anesthesiologist Nurses #1, #2, and #3 OR techs #1 and #2

Medical equipment, medication, and supplies Simulation will be conducted on the ward and operating room using available equipment and supplies. This will increase the “reality” of the simulation and will also identify any systems or processes that may need additional attention or revision. It is important to explain to the team that they should go and obtain all medications and supplies as they would in a real case, but that they should not open medications during the simulation.

Moulage instructions State 1: Fetus in vertex position ready to deliver with fake blood on the perineum State 2: Continued vaginal bleeding with uterine atony after the vaginal delivery

* The number of providers participating will determine how many of these are assigned. If you have students or residents, they can participate in their normal roles.

Appendix

Case notes and instructions

After the team reaches the final objective of the simulation (team has moved to the operating room for additional interventions), the facilitator will clearly state that the simulation is over. Patient history and background

The nurse calls you to see Mrs. Beth Thomas, who was just admitted with a diagnosis of PPROM from triage. She is a 22-year-old G1P0 at 32  weeks and reports regular, painful uterine contractions every 2 min. Her most recent ultrasound last week reported an estimated fetal weight of 3200 g. The fetus is in vertex position at this time. The FHR has a baseline in the 160s with moderate variability and no decelerations at this time. The patient has just called out for the nurse because she is in pain and says she is now having vaginal bleeding. She has a history of asthma but has not needed to use her inhaler much during this pregnancy. She had no other significant past medical history or pregnancy complications. Patient age: 22

Simulation case states State 1: Diagnosis and management of PPROM with placental abruption State 2: Diagnosis of PPH with activation of massive transfusion protocol State 1: PPROM

Background information to read to OB nurse #1, CNM, and/or resident physician: The nurse calls you to see Mrs. Beth Thomas, who was just admitted with a diagnosis of PPROM from triage. She is a 22-year-old G1P0 at 32 weeks and reports regular, painful uterine contractions every 2 min. Her most recent ultrasound last week reported an estimated fetal weight of 3200 g. The fetus is in vertex position at this time. The FHR has a baseline in the 160s, with moderate variability and no decelerations at this time. The patient has just called out for the nurse because she is in pain and says she is now having vaginal bleeding. She has a history of asthma but has not needed to use her inhaler much during this pregnancy. She had no other significant past medical history or pregnancy complications. Provide the first provider to see the patient with the following information (may print this out and use as the patient’s chart): Physical exam

General: Alert and oriented HEENT: Mucous membranes moist

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Neck: Normal, no masses or thyromegaly Lungs: Clear to auscultation bilaterally Heart: Tachycardic with regular rhythm Abdomen: Gravid, exquisitely tender to palpation over the uterus Extremities: Trace LE edema, normal DTRs Back: Nontender Neuro: Intact, no focal findings Cervical examination: completely dilated, 2 cm at time of admission (30 min ago) Toco: Regular uterine contractions every 2 min FHR tracing: Baseline of 165  with moderate variability and no decelerations Vital signs

Temp: 99.3 °F Respiratory rate: 20/min Heart rate: 120 bpm BP: 113/63 SpO2: 98% on RA Weight: 135 pounds Height: 62 inches BMI: 24.7 Pain score: 8/10, in her abdomen Labs

WBC: 16 Hb: 12 Hct: 34 Platelets: 206 Na: 137 K: 3.8 Cl: 99 CO2: 24 BUN: 15 Cr: 0.8 Glucose: 110 AST: 32 ALT: 27 Tbili: 1.8 INR: 1.1 PT: 16 PTT: 25.1 Fibrinogen: 458 Blood Type: A– Ab Screen: Negative Type and screen current

GBS: Negative UA: Neg LE, trace blood, neg nitrites, 25 epithelial cells Urine drug screen: Negative

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Standardized patient script (if used)

You were admitted to the hospital with premature rupture of the membranes about an hour ago. You have started to have a small amount of vaginal bleeding with very painful contractions that are coming every 2 min. If the team palpates your abdomen, complain of pain. You experience more abdominal pain as the scenario continues. If the team does not clearly communicate their plans and medical recommendations, ask questions and make them explain them to you. The goal is to allow the team time to begin medical treatment of your PPROM (antibiotics, steroids for fetal lung maturity, and IV access). You will then begin to have worsening bleeding, then progress very quickly to have a vaginal delivery, and then continue to have bleeding that the team will have to address.

After delivery, as you are continuing to bleed, you should complain of feeling dizzy and lightheaded, and your simulated vital signs will worsen until they decide to move you to the operating room.

Family member script (if used)

You are concerned about the patient’s pain and frequently ask about how the baby is doing before the delivery and how the patient is doing after the delivery as she continues to bleed. If the providers do not explain what they are doing, you should become more excited/agitated and ask questions. When the team moves to the operating room, you may be escorted away. Do not argue, but ask that they take good care of her.

Case flow for State #1

Set up simulator as stated here: Brief the initial provider (Nurse #1) on the clinical scenario. ↓ The rest of the care team will enter the room as called and be briefed by the current team. ↓ Review of vital signs and exam/history demonstrates a patient with PPROM and mild vaginal bleeding. Electronic fetal monitoring (EFM) shows FHR baseline of 165 with moderate variability and no decelerations. ↓ Initial resuscitative measures (reposition on side, O2, and IV fluids) Team should discuss interventions (antibiotics, steroids for fetal lung maturity). If the team checks her cervix, she is 6/90/-3/vertex. Appropriate consultation of other team members such as anesthesia, and notification of staff physician. ↓ Once team has started interventions (antibiotics, IV access, etc.), there should be additional bleeding and worsening contractions with rapid progression to vaginal delivery. After delivery, continue bleeding and worsening vital signs consistent with hypovolemia. ↓ Team should begin interventions to treat uterine atony that include medications and activation of a massive transfusion protocol, but patient will not improve. **The team may order labs, but no results will be available during the scenario, and they will have to treat the patient based on clinical symptoms.** ↓ Patient continues to hemorrhage and provide updates to the team on EBL (which should get up to 1500 in the delivery room); uterus is atonic, and vital signs progressively worsen (BP, 80–90/40–50; pulse, 120–130 s/min). ↓ PATIENT MOVES FROM STAGE 0 to STAGE 3 HEMORRHAGE OVER APPROXIMATELY 4–5 MIN The team should recognize the need for and activate the massive transfusion protocol. Additional personnel should be called, and a runner sent to blood bank to obtain blood/products. Team should recognize need to move to operating room for additional interventions. ↓ The scenario is over after the team successfully moves the patient to the operating room. End scenario: Clearly state scenario is over, and inform the team that after a laparotomy and B-lynch suture, the bleeding decreased and the patient is in stable condition. Take 3–5 min to fill out the evaluation form, and then begin debriefing.

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Appendix

Multidisciplinary simulation clinical event plan Date:

Title: PPROM/Abruption/Uterine Atony/PPH/Massive Transfusion

Time: 1 h total Learning objectives

See Simulation Manual.

Initial scenario

Beth Thomas DOB: June 6, 2000 Age: 22 Weight: 135#, Height 62 in MR#: 76554321 Presenting complaint: Admitted for PPROM Meds: None All: NKDA State 1: Patient is a 22-year-old G1P0 at 32 weeks. Her pregnancy is complicated by a preterm premature rupture of the membranes. She has a history of asthma. She was just admitted for PPROM. Recent normal growth US with baby in the VTX presentation. The patient develops worsening vaginal bleeding and then has a PPH from uterine atony. The fetus has fetal tachycardia but no decelerations on the monitor.

Moulage/supplies/props

*If using simulated monitors, use the setting below. If no monitors, then write sets of vital signs on cards or print them out, and use for cues during the scenario. Monitor alarms ON: Maternal: Heart rate 110, SBP 160, RR 25, temp >38.5, O2 sat. 4–5 mg/d has been questioned [16]. Earlier studies suggested that pregnant women taking enzyme-inducing antiseizure medications had relative increases in vitamin K metabolism. Their newborns were at increased risk for hemorrhagic disease of the newborn because of decreased levels of vitamin-Kdependent clotting factors. It was, thus, recommended that these women receive vitamin K (10 mg orally daily) beginning 4 weeks before expected delivery to minimize the risk of neonatal hemorrhage [18]. However, a recent review by the American Academy of Neurology and the American Epilepsy Society concluded that there is insufficient evidence to support or refute the benefit of prenatal vitamin K supplementation for reducing the risk of hemorrhagic complications in the newborns of women who were taking antiseizure medications during pregnancy  [19]. This same review also emphasized the importance of all newborns exposed to enzyme-inducing antiseizure drugs in utero routinely receiving vitamin K at delivery, consistent with an American Academy of Pediatrics Policy Statement [20].

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Seizure and Status Epilepticus

Because of the rapid postpartum changes in maternal blood volume, women receiving antiseizure medications during pregnancy should have drug levels assessed at 2  weeks postpartum. Serum levels commonly rise in the first few weeks after delivery with the resolution of the hormonally mediated effects of pregnancy. If medication doses were increased during the pregnancy, the patient might develop symptoms of medication toxicity if doses are not appropriately lowered again in the postpartum period.

Evaluation of new-onset seizures in pregnancy While most seizure disorders manifest before pregnancy, the initial onset of seizures and epilepsy can occur during pregnancy (see Table 23.2). Acute etiologies of seizures (hemorrhage, thrombosis, etc.) must be ruled out, and any underlying predisposing factors treated appropriately. A careful history, ideally provided and substantiated by eyewitnesses, is critically important for establishing a diagnosis. Witnesses, family members, and the patient should be specifically questioned about the seizure episode’s onset, duration, and characteristics. The setting in which the episode occurred should be

defined. The possibility of precipitating factors must be pursued, including: 1) Infection (recent history of febrile illness with or without change in mental status, history of parenteral drug use, recent dental work, heart murmur, or valvular heart disease) 2) Alcohol or drugs (consider cocaine, or amphetamine withdrawal), or toxin exposure 3) Mass lesions (history of malignancy, or focal findings on examination) 4) Intracranial hemorrhage (sudden onset of “the worst headache of my life”) 5) Intracranial thrombosis (fluctuating neurologic deficits) 6) Trauma. For much of the history, witnesses are better sources than patients, but patients are the best source for the presence and type of aura. Determine whether the patient completely lost consciousness and whether bowel or bladder incontinence occurred. Determine whether there was an aura and whether there was antegrade amnesia or postictal confusion. Vital signs should be promptly assessed, and patients evaluated for orthostatic hypotension. Fetal heart rate monitoring should be undertaken if the woman is within the realm

Table 23.2 Differential diagnosis of the initial seizure(s) during pregnancy. Condition

Clinical presentation

Diagnostic considerations

Brain tumor

Most likely to become symptomatic in the first trimester. Rare.

Papilledema should be prominent with supratentorial tumors.

Intracranial hemorrhage

Sudden severe headache or loss of consciousness. May have been preceded by a “sentinel” bleed.

Arteriovenous malformations are more likely in younger, nonhypertensive women. Aneurysms are more likely in older, parous, hypertensive women.

Syncope

Usually limp, motionless events with prompt reorientation.

Most syncopal episodes are benign vasovagal episodes, but cardiac-related etiologies must always be excluded.

Cerebral venous thrombosis

Usually with focal seizures. Fluctuating deficits and/or consciousness. Headache is often prominent.

Most common in late pregnancy and the first few weeks after delivery.

Meningitis and encephalitis

Usually associated with fever and systemic inflammation.

Onset of illness is usually gradual (hours or days).

Gestational epilepsy

Variable. Very rare.

A diagnosis of exclusion.

Eclampsia

Usually preceded by generalized headache, visual disturbances, and/or abdominal pain.

Associated with hypertension, proteinuria, and other symptoms and laboratory abnormalities (elevated liver function studies, decreased platelet counts).

Pseudoseizures

Often with atypical physical findings, such as unresponsiveness without movement, asynchronous extremity movement, forward pelvic thrusting, and geotropic eye movements (i.e., the eyes deviate toward the ground in a nonphysiologic manner whether the head is turned left or right).

Past history of psychiatric disorders.

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Status epilepticus

of potential viability. A complete physical examination should be performed, with particular attention to the neurologic (fundoscopy, cranial nerves, speech, mental status, neck, and motor, sensory, and deep tendon reflexes) and cardiovascular (heart murmur and arrhythmia) systems. Initial laboratory evaluation should focus on a complete blood count (CBC), chemistry profile, liver function testing, toxicology screen, and urinalysis. In women of Asian ancestry, including South Asian Indians, consideration should also be given to assessing their HLA-B*1502 allele status. The US Food and Drug Administration (FDA) recommends screening these women for this allele before starting carbamazepine, oxcarbazepine, or phenytoin because of the increased risk of Stevens–Johnson syndrome or toxic epidermal necrolysis in such women [21]. Consultation with a neurologist is particularly important in the setting of an initial seizure (unless the diagnosis of eclampsia is reasonably certain), particularly if the neurologic examination is abnormal, the seizure is focal, or the electroencephalogram (EEG) is abnormal. An EEG and brain-imaging study are still indicated if the patient has a normal neurologic examination. A computed tomography (CT) scan should be considered if intracranial hemorrhage is suspected, as the CT scan is the procedure of choice for detecting acute intracranial hemorrhage. If the clinical situation is less urgent, a magnetic resonance imaging (MRI) study would be preferable, as MRI technology is more sensitive to intracranial anatomy than the CT scan. If cerebral venous sinus thrombosis is suspected, then magnetic resonance venogram (MRV) would be indicated. If an intracranial infection is suspected, a lumbar puncture should be performed. The radiation exposure at the uterus level from a cranial CT scan is minimal and should not preclude the performance of an otherwise indicated imaging study. However, contrast media should be avoided during pregnancy whenever possible. The most common differential diagnosis of a seizure is syncope. In contradistinction to seizures, syncope is not associated with incontinence, tongue biting, or confusion (before or after the episode). Eclampsia must also be considered in the latter half of pregnancy and up to 6  weeks postpartum, particularly if the woman has had any signs or symptoms suggestive of preeclampsia [22].

the differential considerations outlined in Tables  23.1 and 23.2 must be considered, particularly in the seizing or postictal patient for whom no history is available. Pregnant women known to have epilepsy requiring medical treatment who have recurrent seizures should be questioned about adherence to their treatment regimen. It is estimated that 30–50% of adults with epilepsy are noncompliant with their recommended medications because of side effects, cost, or impaired cognition  [23]. Antiseizure medication levels should be obtained to confirm adherence. These results should ideally be compared to known preconceptional “therapeutic” drug levels. Providers should possess knowledge of and utilize the most efficient antiseizure medications corresponding to each specific seizure classification (see Table 23.1). When initial seizure prophylaxis is indicated, therapy should be initiated with a single drug, as the likelihood of side effects and resultant noncompliance increases substantially. Evidence strongly suggests that pregnant women take the medication that best controls their epilepsy. Switching medications during pregnancy is not generally recommended because of the risk of losing seizure control unless the patient is on valproate; in such a case, the patient should be switched to safe antiseizure medication. The peripartum period is associated with disrupted medication, sleep, and eating schedules; administration of concurrent medications; pain; and physical stress. All of these factors are known to increase the potential for recurrent seizures. This potential should always be considered in the labor and delivery setting for women known to have a seizure disorder. It is, thus, essential that antiseizure medication doses are not missed during labor and the immediate puerperium. Although most women with epilepsy should anticipate a vaginal delivery, intravenous (IV) access should be routinely established, and expertise in airway management should be immediately available, as should appropriate emergency medications. Generalized seizures in labor and delivery should be promptly treated with a benzodiazepine (see Table 23.1). IV levetiracetam or lacosamide is a viable alternative. Although magnesium sulfate is not a recommended treatment for symptomatic epilepsy in labor and delivery, it should be administered if there is any suggestion that the woman has ongoing preeclampsia that may have progressed to eclampsia.

Treatment of seizures

Status epilepticus

This chapter emphasizes that optimum treatment should be based on the known or presumed diagnosis. Although this information is often historical and available either from the patient, her friends, family, or her medical records,

Status epilepticus, defined as 5  min or more of either (1) continuous clinical and/or electrographic seizure activity or (2) recurrent seizure activity without recovery between seizures  [24], is a true obstetric emergency that requires

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prompt maternal treatment and resuscitation (see Table 23.3) to prevent permanent brain damage or death to both mother and fetus. Pregnancy is not thought to increase the risk of status epilepticus, and it can occur at any gestational period [19]. Although treatment will be administered to both mother and fetus, immediate attention should be directed to the mother since maternal resuscitation and stabilization will optimally resuscitate her fetus. Initial attention must be paid to the maternal airway. As soon as the airway is secured, maternal oxygen saturation should be assessed and sufficient oxygen administered to return these values to normal, with intubation if necessary. Concurrent assessments should evaluate maternal blood pressure and forebrain and brain stem status. Concurrent with this, the patient must be admitted to an intensive care area, and appropriate specialty consultations obtained. In addition to securing the maternal airway, IV access must be established to administer normal saline, glucose, thiamine, and antiseizure medication. Additional critical initial evaluations should include a history (if available from accompanying persons) and baseline laboratory studies (CBC, glucose, calcium, electrolytes, phosphorus, arterial blood gases, urinalysis, and antiseizure medication levels). Injury precautions and lateral recumbent maternal positioning will protect and optimally perfuse the fetus. Fetal well-being in the form of fetal heart rate monitoring (if there is a potentially viable fetus) should then be undertaken. The differential diagnosis of status epilepticus includes two conditions that can respond dramatically to therapeutic and, therefore, diagnostic IV infusions. These conditions are hypoglycemia and Wernicke’s encephalopathy. A glucose bolus should be initially administered  – usually 50 mL of D50. If the woman is seizing because of hypoglycemia, this administration can be life-saving. If the woman is hyperglycemic, the additional amount of glucose will not make her problem significantly worse. Although Wernicke’s encephalopathy (thiamine, or vitamin B1 deficiency) is rare in women of reproductive age, the dramatic improvement that can be seen with thiamine administration warrants administration of thiamine, 100 mg IV, followed by 50–100 mg IM/IV daily if a significant response is seen. Eclampsia must also be considered in the diagnosis, mainly if the pregnancy is beyond 20  weeks of gestation and if hypertension and proteinuria are present. It should be emphasized that magnesium sulfate is not an appropriate alternative therapy for epileptic seizures. However, when seizures first present during either the third trimester or the puerperium and up to 6  weeks postpartum, it

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may be difficult to distinguish eclampsia from epilepsy of other etiologies. For women in whom imaging is considered, an initial CT without contrast is the procedure of choice because of the availability and utility of the test in detecting acute hemorrhage. Additional neuroimaging could be considered if questions exist about the etiology of the status or if the episode is difficult to control. Although MRI offers better anatomic detail than CT scan, the longer test time, difficulties with patient management, and uneven availability all weigh against the use of MRI in the acute setting. However, in the case of venous sinus thrombosis, MRI and MRV are recommended. Specific medical therapy should be promptly undertaken if the woman is not responsive to these initial therapeutic measures. This should consist of an IV benzodiazepine (10  mg diazepam or 4  mg lorazepam), which can be repeated in 10–15  min if seizure activity continues. If IV access is not available, midazolam (0.2 mg/kg up to a maximum of 10  mg) can be administered IM. If convulsions continue after initial benzodiazepine treatment, an appropriate anticonvulsant should be administered, usually levetiracetam, lacosamide, or fosphenytoin (see Table  23.3). These medications are all short-acting, which allows the woman to regain consciousness more rapidly and, therefore, be more quickly and thoroughly assessed from a neurologic perspective. If seizures persist at this point ( 60  min), the patient should be intubated and sedated, usually with midazolam or Propofol (see Table 23.3). If seizures persist, the patient should be anesthetized using a general anesthetic, while continuous EEG monitoring is performed under the supervision of a neurologist. Significant physiologic changes also accompany status epilepticus. Many of these systemic responses result from the catecholamine surge that accompanies the seizures. Hypertension, tachycardia, and cardiac arrhythmias are examples of these systemic effects. Body temperature may increase in patients following the vigorous muscle activity that accompanies status epilepticus, but infection etiologies must first be excluded in such situations. Lactic acidosis can also occur. While seizure disorders could initially present as status epilepticus during pregnancy, the possibility of other underlying conditions must also be considered. One series of psychogenic nonepileptic spells (PNES) reported that being unresponsive without movement was their most common presentation [25]; other features can be fluctuating course, head shaking, and hip thrusting [26]. If there is any question of recent exposure, serum or urine screens for abused substances should also be performed (within the informed consent guidelines of the individual

Status epilepticus

Table 23.3

Treatment of status epilepticus in pregnancy.

1. Initial stabilization ● Secure the airway. ● Establish IV access. ● Call for appropriate consultations (e.g., obstetrics/maternal-fetal medicine, neurology, anesthesia, and neonatology). ● Admit to intensive care unit. ● Protect and perfuse the fetus (injury precautions, lateral recumbent position). ● Initial history (if available). ● Baseline laboratory studies (CBC, glucose, calcium, electrolytes, phosphorus, arterial blood gases, urinalysis, and antiseizure medication levels when appropriate). 2. Therapeutic trials (to be administered sequentially) Medication Dosage

Intent

Glucose 50 mL of D50 IV

Correct hypoglycemia.

Thiamine (vitamin B1) 100 mg IV, followed by 50–100 mg IM/IV QD

Correct Wernicke’s encephalopathy.

Magnesium sulfate Standard obstetric regimen

Treatment of eclamptic convulsions, if MgSO4 is NOT a treatment clinically suspected. For status epilepticus.

3. Initiate first-line anticonvulsants

i – ONE from EACH drug class.

Drug class Specific drug

Dosage

Therapeutic levels

Precautions

Precautions

Benzodiazepine Diazepam

5–10 mg IV q 10–15 min

Maximum dosage 30 mg

Lorazepam

4 mg IV; may repeat once in 10–15 min

Maximum dosage 8 mg/12 h

Midazolam

0.2 mg/kg up to maximum of 10 mg IM

Maximum dosage 8 mg/12 h

Anticonvulsant Levetiracetam Lacosamide Fosphenytoin

20–30 mg/kg IV over 5 min 400 mg IV bolus over 5 min 15–20 mg/kg IV x 1; begin maintenance dose 12 h after loading dose

12.0–46.0 mcg/mL 1.0–10.0 μg/mL Total = 10–20 μg/ mL Free = 1–2 μg/mL

Continuous EEG and blood pressure monitoring recommended during IV infusions. Use non-glucose-containing IV fluids.

Phenytoin

15–20 mg/kg IV q 30 min prn; begin maintenance dose 12 h after loading dose.

Total = 10–20 μg/ mL Free = 1–2 μg/mL

Continuous EEG and blood pressure monitoring recommended during IV infusions. Use non-glucose-containing IV fluids.

4. Intubation and sedation a) Intubation b) IV sedation: i) Midazolam (0.02–0.10 mg/kg/h) ii) Propofol (5–50 μg/kg/min, start at 5 μg/kg/min IV x 5 min, then increase 5–10 μg/kg/min q 5–10 min until desired effect). iii) Phenobarbital (20–25 mg/kg, administration not to exceed 100 mg/min) 5. General anesthesia

a) If seizures still persist, institute general anesthesia with halothane and NMJ blockade.

6. Further consideration of differential diagnoses a) Toxicology b) Lumbar puncture c) Imaging d) Hepatic encephalopathy CBC: Complete blood count; EEG: electroencephalogram; IM: intramuscularly; IV: intravenously; NMJ: neuromuscular junction; prn: as needed; q: every; QD: daily.

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jurisdiction). Other considerations should include infection (e.g., meningitis, brain abscess, and encephalitis), electrolyte abnormalities (hyponatremia, hypernatremia, and hypercalcemia), and hepatic encephalopathy, tumor, hypoxic injury, and subarachnoid hemorrhage.

Subsequent management and prognosis With control of the seizures, attention must be directed to treating any underlying or predisposing conditions and the prevention of recurrence. The most common cause of status epilepticus in the epileptic population is noncompliance with antiseizure medications. It is, therefore, critical to ascertain if the patient was taking her medication. If she simply forgets to take her medications, a pillbox or other memory aid should be suggested. Medication dosing must be optimized. Ideally, preconception antiseizure medication levels would be available so that medication dosage can be readjusted accordingly. The establishment or resumption of a supportive lifestyle must also be emphasized. Women should be encouraged to eat regular meals; get adequate rest, nutrition, and sleep; and avoid stress. They should be counseled to avoid hazardous situations as well as alcohol and other sedatives. Given the high frequency of unplanned pregnancy in the United States, all women of reproductive age with a seizure disorder should be particularly encouraged to maintain their daily intake of folic acid (at least 1 mg daily) throughout their reproductive lifespan. During pregnancy, the physiologic changes that may alter antiseizure medication dosages rapidly resolve within the first 2 weeks postpartum. A return to preconceptional dosage schedules should be considered. However, the impact of the chronic fatigue that accompanies caring for a new baby has led some to recommend that slightly higher dosages be considered [22]. Epilepsy is not a contraindication to breastfeeding. While most antiseizure medications cross into breast milk, they achieve much lower levels than in maternal serum, ranging between 0.1 and 0.4 mcg/mL for phenytoin and carbamazepine, respectively  [23]. The proportion of women with epilepsy reported to be breastfeeding is lower than in the general population despite studies indicating breastfeeding safety in women with epilepsy  [27]. In a prospective Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, antiseizure medication concentrations in blood samples of infants who were breastfed were substantially lower than maternal blood concentrations. Given the well-known benefits of breastfeeding and the prior studies demonstrating no ill effects when the mother was receiving antiseizure

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medications, these findings support the breastfeeding of infants by mothers with epilepsy who are taking antiseizure medication therapy [28]. Contraindications to breastfeeding would be increased seizure activity due to sleep deprivation or medication-related infant sedation or irritability (most commonly a concern with phenobarbital). Enzyme-inducing antiseizure medications including carbamazepine, phenytoin, phenobarbital, primidone, felbamate, and topiramate (at a dose higher than 200  mg daily), and oxcarbazepine (at an amount higher than 600  mg daily), eslicarbazepine, or cenobamate, decrease the efficacy of birth control pills. Some antiseizure medications cause this drug interaction in a dose-dependent manner, with a negligible effect at low doses, for example, topiramate and oxcarbazepine. To mitigate this effect, providers should consider a higher-dose estrogen pill (at least 50 mcg Ethinyl estradiol) or use depot medroxyprogesterone acetate injections or use intrauterine devices as they are not affected by antiseizure medications. An alternative and possibly preferred approach is to use a second method of contraception [11]. Providers should also be aware of sudden unexpected death in individuals with epilepsy (SUDEP). The incidence of sudden death in individuals with seizure disorders is two to three times higher than the incidence of sudden death in the general population and occurs most commonly in individuals with the recently diagnosed disease and individuals with congenital epilepsy or developmental conditions [29]. However, it is also seen in individuals with uncontrolled seizures and people with poor compliance. The mechanism of death in these cases is not uniform, but suggestions include cardiac arrhythmias, pulmonary edema, autonomic failure, and suffocation during a convulsion. Primary preventive measure to counter SUDEP is to control the seizures in general and convulsive seizures in particular with medications or surgical options.

Key points ●

●

With few exceptions continuing with optimal treatment of preexisting neurologic disorders will result in optimal outcomes for the pregnant woman and her baby(ies). Free (i.e., non-protein-bound) antiepileptic drug levels offer the best measure of therapeutic efficacy. These levels should be determined preconceptionally whenever possible, as they are not affected by the multiple physiologic changes associated with pregnancy. Antiseizure medication levels should be checked periodically during pregnancy as these levels drop with progressing pregnancy.

References ●

●

●

Valproate has significant teratogenic potential and should be avoided, if possible, during pregnancy. Whenever possible, women taking valproate should  be  switched to alternative medications preconceptionally. Women on antiseizure medications should receive folic acid supplementation. The initial onset of seizures can occur during pregnancy, most commonly in the first trimester. A careful history, ideally provided and substantiated by eyewitnesses, is

●

particularly important for establishing a diagnosis, but a thorough evaluation is required. Status epilepticus is a medical emergency. The airway must be secured, IV access established, and appropriate consultations initiated in an intensive care setting. Glucose, thiamine, and magnesium sulfate should be administered, followed by first-line antiseizure medications. If necessary, intubation, sedation, and general anesthesia may be required. Further evaluation of differential diagnoses should also be pursued.

References 1 Zack MM, Kobau R. National and state estimates of the numbers of adults and children with active epilepsy— United States, 2015. MMWR Morb Mortal Wkly Rep. 2017;66(31):821–825. 2 Harden CL, Hopp J, Ting TY, et al. Practice Parameter update: Management issues for women with epilepsy— Focus on pregnancy (an evidence-based review): Obstetrical complications and change in seizure frequency: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009;73(2):126–132. 3 Scheffer IE, French J, Hirsch E, et al. Classification of the epilepsies: New concepts for discussion and debate-Special report of the ILAE Classification Task Force of the Commission for Classification and Terminology. Epilepsia Open. 2016;1(1–2):37–44. 4 Edey S, Moran N, Nashef L. SUDEP and epilepsy-related mortality in pregnancy. Epilepsia. 2014;55(7):e72–74. 5 Battino D, Tomson T, Bonizzoni E, Craig J, Lindhout D, Sabers A, et al. Seizure control and treatment changes in pregnancy: Observations from the EURAP epilepsy pregnancy registry. Epilepsia. 2013;54(9):1621–1627. 6 Pennell PB, French JA, May RC, et al. Changes in seizure frequency and antiepileptic therapy during pregnancy. N Engl J Med. 2020; 383(26):2547–2556. 7 Tomson T, Landmark CJ, Battino D. Antiepileptic drug treatment in pregnancy: changes in drug disposition and their clinical implications. Epilepsia. 2013;54(3):405–414. 8 Appendix B: AAN summary of evidence-based guideline for clinicians: Management Issues for women with epilepsy – focus on pregnancy: obstetrical complications and change in seizure frequency. Continuum (Minneap Minn). 2016;22(1 Epilepsy):283–284. 9 Arfman IJ, Wammes-van der Heijden EA, Ter Horst PGJ, et al. Therapeutic drug monitoring of antiepileptic drugs in women with epilepsy before, during, and after pregnancy. Clin Pharmacokinet. 2020;59(4):427–445.

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10 Polepally AR, Pennell PB, Brundage RC, et al. Modelbased lamotrigine clearance changes during pregnancy: Clinical implication. Ann Clin Transl Neurol. 2014;1(2):99–106. 11 Li Y, Meador KJ. Epilepsy and pregnancy. Continuum (Minneap Minn). 2022;28(1):34–54. 12 Weston J, Bromley R, Jackson CF, et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Epilepsy Group, editor. Cochrane Database of Systematic Reviews [Internet]. 2016 [cited 2022]. Available from: https://doi. wiley.com/10.1002/14651858.CD010224.pub2 13 Błaszczyk B, Miziak B, Pluta R, Czuczwar SJ. Epilepsy in pregnancy-management principles and focus on valproate. Int J Mol Sci. 2022;23(3):1369. 14 Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): A prospective observational study. Lancet Neurol. 2013;12(3):244–252. 15 Baker GA, Bromley RL, Briggs M, et al. IQ at 6 years after in utero exposure to antiepileptic drugs: A controlled cohort study. Neurology. 2015;84(4):382–390. 16 Murray LK, Smith MJ, Jadavji NM. Maternal oversupplementation with folic acid and its impact on neurodevelopment of offspring. Nutr Rev. 2018;76(9):708–721. 17 ACOG Committee on Practice Bulletins. ACOG practice bulletin. Clinical management guidelines for obstetriciangynecologists. Number 44, July 2003. (Replaces Committee Opinion Number 252, March 2001). Obstet Gynecol. 2003;102(1):203–213. 18 Deblay MF, Vert P, Andre M, Marchal F. Transplacental vitamin K prevents haemorrhagic disease of infant of epileptic mother. Lancet. 1982;1(8283):1247. 19 Harden CL, Pennell PB, Koppel BS, et al. Practice Parameter update: Management issues for women with epilepsy – Focus on pregnancy (an evidence-based review): Vitamin K, folic acid, blood levels, and

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breastfeeding: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009;73(2):142–149. American Academy of Pediatrics Committee on Fetus and Newborn. Controversies concerning vitamin K and the newborn. American Academy of Pediatrics Committee on Fetus and Newborn. Pediatrics. 2003;112(1 Pt 1):191–192. Shukla S, Rastogi S, Abdi SAH, et al. Severe cutaneous adverse reactions in Asians: Trends observed in culprit anti-seizure medicines using VigiBase®. Seizure. 2021;91:332–338. Magley M, Hinson MR. Eclampsia. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 [cited 2022]. Available from: http://www.ncbi.nlm. nih.gov/books/NBK554392/ Leppik IE. How to get patients with epilepsy to take their medication. The problem of noncompliance. Postgrad Med. 1990;88(1):253–256.

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24 Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17(1):3–23. 25 Leis AA, Ross MA, Summers AK. Psychogenic seizures: Ictal characteristics and diagnostic pitfalls. Neurology. 1992;42(1):95–99. 26 Duncan AJ, Peric I, Boston R, Seneviratne U. Predictive semiology of psychogenic non-epileptic seizures in an epilepsy monitoring unit. J Neurol. 2022;269(4): 2172–2178. 27 Johnson EL, Burke AE, Wang A, Pennell PB. Unintended pregnancy, prenatal care, newborn outcomes, and breastfeeding in women with epilepsy. Neurology. 2018;91(11):e1031–e1039. 28 Birnbaum AK, Meador KJ, Karanam A, et al. Antiepileptic drug exposure in infants of breastfeeding mothers with epilepsy. JAMA Neurol. 2020;77(4):441–450. 29 Devinsky O, Spruill T, Thurman D, Friedman D. Recognizing and preventing epilepsy-related mortality: A call for action. Neurology. 2016;86(8):779–786.

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24 Acute Spinal Cord Injury Lisa R. Wenzel1,2, Angela Vrooman3, and Hunter Hammill2 1

Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, TX, USA Department of Physical Medicine, Spinal Cord Injury Attending at TIRR Memorial Herman Hospital, Houston, TX, USA 3 Department of Physical Medicine, University of Texas Health Science Center, San Antonia, TX, USA 2

Introduction Spinal cord injury (SCI) affects approximately 17,810 Americans each year and is associated with significant loss of physical and personal independence [1]. Since 20–30% of these individuals are women and the peak incidence of SCI is in the late teens and early twenties, consideration must be given to their reproductive potential  [2]. While 30–70% of chronically injured women will choose to use either temporary or permanent contraceptive methods secondary to the concern of possible pregnancy complications, many look forward to a rewarding life as a mother following their acute injury, and around 14% will go on to achieve pregnancy after their injury [3]. It is recommended that all females of childbearing age involved in a traumatic accident should be screened with a quantitative β-human chorionic gonadotropin (β-hCG) level [4]. Many of the physiologic adaptations to pregnancy addressed in this chapter occur before the fetus is viable and possibly before the mother is aware of her pregnancy. Management of the pregnancy will understandably vary significantly based on the gestational age of the fetus. An obstetrician or subspecialist in maternal-fetal medicine may become involved as part of the team working to stabilize the pregnant patient in the critical first hours after an acute SCI, and in managing the subsequent pregnancy, labor, and delivery of injured patients while pregnant. Many of these recommendations may also apply to patients with chronic SCI, but this chapter will focus on recently injured patients.

­ aternal primary survey and specific M considerations due to SCI The primary goal of emergent care of a pregnant patient with an acute SCI is to diagnose and treat life-threatening injuries while preventing any unnecessary traction or motion of the spinal column. As with any trauma patient, ensuring the pregnant patient’s and her fetus’s survival begins with a primary survey and prompt attention to the ABCs: airway management, breathing, and circulation. The physiologic adaptations of the mother to her pregnancy, superimposed with a myriad of physiologic complications related directly to SCI, necessitate a multidisciplinary team of emergency, trauma, neurosurgery or orthopedic spine surgery, obstetric, and rehabilitation physicians to optimize outcomes for mother and baby. While there are a number of articles published on the management of pregnant trauma patients and additional articles looking at trauma patients who sustain SCI, there is scant literature on acute SCI in the pregnant trauma patient.

Airway Cervical spine stabilization

For more than 50 years, spinal immobilization has been considered a mainstay of trauma care. However, the evidence basis for this recommendation has been reexamined in recent years and may change in the coming years  [5]. The presumed need for immobilization in patients with possible cervical spine instability has resulted in increased

Critical Care Obstetrics, Seventh Edition. Edited by Luis D. Pacheco, Jeffrey P. Phelan, Torre L. Halscott, Leslie A. Moroz, Arthur J. Vaught, Antonio F. Saad, and Amir A. Shamshirsaz. © 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.

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difficulty with airway management, irrespective of pregnancy [6]. This is complicated in the pregnant patient by significant capillary engorgement of the mucosa throughout the respiratory tract, leading to swelling of the nasal and oral pharynx, larynx, and trachea. This can increase the challenge of intubating a patient suspected of having an acute SCI [7]. It has previously been documented that pregnancy at baseline increases a woman’s Malampati score and neck circumference, which are independent predictors of increased difficulty with intubation [8]. Pregnant women without SCI have been reported to be eight times more likely to have a failed intubation attempt than non-pregnant women [9]. The initiation of tracheal protective procedures such as jaw-thrust, bag-valve-mask ventilation, and cricoid pressure, while necessary, can inadvertently cause cervical spine movement and possibly subsequent damage if meticulous stabilization is not practiced [5,10,11]. Many trauma departments routinely remove the cervical collar and provide manual inline stabilization (MILS) during intubation in order to open the mouth wide enough for visualization. This is provided by a second provider utilizing both hands to keep the head and neck neutral  [12]. The jaw-thrust maneuver was superior to the head-tilt–chin-thrust in cervical spine instability in cadavers with surgically simulated, unstable, dissociative C1–C2 fractures, but still results in increased movement in the cervical spine [5,12]. This same study showed a minimal difference between using MILS during intubation versus keeping the cervical collar in place [12]. Recommendations for method of intubation

In recent years, rigid video fluoroscopes, lighted stylets, and flexible fiberoptic bronchoscopes have become increasingly available options in addition to direct laryngoscopes for providing definitive airway protection. Video laryngoscopy, in particular, has become increasingly common in the trauma and emergency setting, and multiple devices have shown improved likelihood of first-pass intubation with decreased risk of complications compared to more conventional methods such as direct laryngoscopy  [13]. The use of external laryngeal manipulation, a maneuver to facilitate laryngeal visualization, during intubation attempts by video laryngoscopes can decrease motion at the occiput-C1 segment by as much as 35% and is recommended  [14]. Ultimately, the method associated with the best chance of success and lowest degree of cervical motion is recommended and may vary based on provider training and patient-specific factors  [6]. A smaller endotracheal tube may also be considered to maximize the chances of success on the first attempt [15].

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Prevention of aspiration

While all trauma patients should be considered to have a full stomach, the pregnant patient in late gestation has the additional risk of aspiration due to her reduced gastric sphincter tone attributable to both pregnancy and SCI. This is compounded by the mechanical effects of increased gastric pressure from her gravid uterus. Consequently, appropriately applied cricoid pressure may be considered to prevent reflux of gastric contents into the trachea [15]. It is also recommended that unconscious or semiconscious pregnant patients should have a nasogastric tube inserted in order to avoid aspiration  [15]. The subsequent risk of aspiration is compounded by the use of cervical collars and increased postoperative edema. As such, providers must remain vigilant in taking measures to prevent aspiration pneumonia, and all cervical SCI patients should be evaluated for dysphagia before resuming an oral diet.

Breathing Compensatory physiology

Normal physiologic changes in the woman with advanced pregnancy include displacement of the diaphragm and enlargement of the chest wall by up to 2  cm in both the anterior–posterior and transverse diameters, with a resulting decrease in chest wall compliance  [8,16]. It is important to note that this occurs early in pregnancy, likely due to increased relaxin, and should not be attributed to late pregnancy and an enlarging uterus alone [8]. Thoracic circumference increases 6 cm, while diaphragmatic excursion increases by 2  cm in the pregnant patient, allowing larger tidal volumes and a 15–25% decrease in residual volume and expiratory reserve volume resulting in lower function residual capacity [8]. Most of these compensatory mechanisms are lost through neurologic weakness in patients with cervical SCI. Assessment of ventilatory status

In non-pregnant patients, a mainstay of the trauma assessment is to “Look, listen, and feel” for pulmonary ventilation. This is still vital in the pregnant SCI patient, but a lack of chest rise and decreased breathing must quickly be evaluated to determine if the causative factor is paralysis of the muscles of inspiration attributable to a cervical SCI versus a primary injury to the lung itself, such as a tension pneumothorax. Due to the cephalad position of the diaphragm in pregnant patients, it is recommended that any thoracostomy tube needs to be placed two intercostal spaces higher than recommended in the non-pregnant patient [15].

­MaterMal eriMery sertry Mrnd terire ecr rnteMarcr nstdac SC  425

Mechanical ventilator management and prevention of atelectasis

Patients with an injury at the level of C3–C5  may have phrenic nerve impairment that directly affects the ability of the diaphragm to contract and may result in variable amounts of weakness or complete paralysis. Since the diaphragm is responsible for completing 65% of the muscular work of inspiration, these patients, and those with more cephalad lesions, require mechanical ventilation in the acute setting and possibly beyond. The most significant complication seen from this muscular weakness is atelectasis with a resultant risk for pneumonia and respiratory failure. It is estimated that one-third of patients with high cervical injury will go on to develop atelectasis, but with low tidal volumes, this number rises to 60% [17]. Current clinical practice guidelines for patients with SCI have recommended utilizing starting tidal volumes of 10–15 mL/kg of ideal body weight based on height and then increasing in daily 100-mL increments as tolerated up to an ideal tidal volume of 15–20 mL/kg in patients without intrinsic lung disease who have peak pressures below 30–40  cm of water  [18,19]. However, at least one study has recently called this into question showing a higher rate of ventilatorassociated pneumonia at these higher tidal volumes compared to more traditional volumes 90% and PO2 >70 mmHg to maximize fetal oxygenation  [15,23,24]. Animal studies suggest that a drop in maternal saturation into the mid-1980s may result in a 20% decrease in fetal oxygenation [24]. Limited human reports indicate a high fetal or neonatal death rate when maternal oxygen saturations persist between 50% and 88% [25].

Table 24.1 Respiratory medications. Drug name

Starting dose

Use

Side effects

Pregnancy risk

Lactation risk

Albuterol

2.5 mg neb q4–6 h

Bronchoconstriction

Nervousness, tremor, tachycardia, bronchospasm

Adverse events in animal studies. Crosses placenta. Possible association with cleft palate and limb defects. May decrease uterine contractility

Unknown if secreted into breast milk. Caution advised

Guaifenesin

600 mg q12h max: 2400 mg/ day

Thick secretions

Dizziness, drowsiness, headache, nausea

Limited studies do not show fetal harm. Alcohol may be present in liquid forms

Unknown if secreted into breast milk. Caution advised

Glycopyrrolate

15.6 mcg capsule inhaled BID

Copious secretions

Drowsiness, bronchospasms, arrhythmia

Adverse events in animal studies. IM formulations cross placenta; inhaled unknown

Unknown if secreted into breast milk. May decrease milk production

Ipratropium

500 mcg neb q4–6 h

Bronchoconstriction

Bronchitis, bronchospasms, sinusitis

No adverse events in animal studies

Unknown if secreted into breast milk. Caution advised

N–acetylcysteine

3–5 mL 20% solution neb QID

Thick secretions

Autoimmune disease, anaphylaxis, rash, pruritus, nausea, fluid overload

No adverse events in animal studies. Crosses the placenta

Unknown if secreted into breast milk. Caution advised

Scopolamine

1.5 mg patch q72h

Copious secretions

Drowsiness, acute psychosis, bradycardia, visual disturbance

Adverse events in animal studies. Crosses placenta. Maternal use may cause fetal respiratory depression and neonatal hemorrhage

Excreted into breast milk. Caution advised

BID: twice daily; neb: nebulized; QID: four times daily. Source: Drug information obtained from Lexicomp, Inc.

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Circulation

­Circulation The evaluation of the circulatory system in a pregnant trauma patient with acute SCI can be very difficult. The typical assessment parameters may be obscured by the altered hemodynamics of pregnancy, the autonomic derangements of neurogenic shock, and cardiovascular instability from acute hemorrhage. The presence of hypotension, a common component of both hemorrhagic and neurogenic shock, can be confused with the normal reduction in blood pressure (BP) associated with pregnancy. Supine hypotension can further complicate the assessment of trauma patients as aortocaval compression stimulates sympathetic output, increasing both BP and heart rate. Even the normal dilutional anemia of pregnancy can be misinterpreted as a sign of acute blood loss.

Autonomic nervous system impact on circulatory system following SCI To better understand circulatory changes following SCI in the pregnant trauma patient, it is important to briefly review the relevant pregnancy-related changes and innervation levels related to the spinal cord. The most important change in the vascular system is the loss of sympathetically mediated vasoconstriction below the level of injury. This concept is central to understanding spinal neurogenic shock, autonomic dysreflexia (AD), and the development of a lower baseline BP following SCI. The most relevant vascular bed is the splanchnic bed, innervated by the greater and lesser splanchnic nerves and usually innervated from the T5 through T12  levels of the sympathetic chain. The inability to control the vasoconstriction in this area leads to many of the life-threatening complications encountered after SCI. Over time, vascular sympathetic receptors are believed to develop hyper-responsiveness due to decreased baseline sympathetic output that further exacerbates acute changes [3].

Initial management of hypotension The emergency team must be alert to the contradictory influences of pregnancy, hypovolemia, and neurogenic autonomic disruption while evaluating and stabilizing the pregnant trauma patient. Because of time constraints in deciphering these various factors, pregnant patients with SCI may be treated with fluid resuscitation even before hypovolemia is clinically evident [26]. The primary survey should be accompanied by simultaneous intravenous (IV) fluid resuscitation through two large-bore IV cannulae, serial vital sign measurements, and the placement of a Foley catheter [26]. Conventional wedging of the patient’s

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back to avoid caval compression can exacerbate spinal trauma. However, these same benefits may be achieved by a 15° tilt of the backboard if the patient is immobilized or by simple manual displacement of the gravid uterus to the left. Failure to relieve vena cava compression may result in  up to a 30% decrease in cardiac output  [15]. Multiple studies have suggested improved neurologic outcomes when mean arterial pressure (MAP) is maintained above 85 mmHg for the first 7 days following SCI [27,28].

Risk of pulmonary edema While fluid resuscitation is imperative in the acute setting, providers must remain cognizant of the increased risk of pulmonary edema during pregnancy secondary to a low colloid oncotic pressure and hypoalbuminemia  [9]. This risk is further heightened because a subset of patients with acute SCI can experience a catecholamine surge at the time of injury that triggers a significant increase in preload and afterload, leading to worsening pulmonary edema  [3]. Given a lack of evidence-based guidelines to recommend how much and what type of fluids to use in resuscitation, it is essential for the emergency team to be aware of potential complications of treatment.

Spinal neurogenic shock Hypovolemic shock is extremely common after trauma, but it must be quickly differentiated from neurogenic  shock when evaluating patients with acute SCI. Neurogenic shock occurs in many, but not all, patients after traumatic SCI and occurs more frequently in complete injuries arising above the level of T6 [29]. It occurs when sympathetic innervation is initially lost to the splanchnic bed and lower limbs, resulting in diffuse vasodilatation that is manifested as a drop in BP (systolic BP 90 on two separate occasions >4 h apart in a previously normosystolic patient OR one reading of SBP >160 or DBP >110

SBP >20 OR DBP >10 acutely elevated above recent baseline measures

Time course

Sustained

Episodic

Other diagnostic criteria and symptoms

New proteinuria or thrombocytopenia Impaired liver or renal function Pulmonary edema OR visual/cerebral changes Sometimes asymptomatic

Heart rate may fall >10 points from baseline Severe pounding headache Nasal congestion Flushing and sweating above the level of injury Feelings of apprehension or impending doom Sometimes asymptomatic

Level of SCI

Any

Typically T6 or above, although has been noted to occur as distally as T8

Gestational age

Typically after 20 weeks

Any, independent of pregnancy

Initial management strategies

Further workup: CBC w/differential, CMP, 24 h urine protein Fetal ultrasound for weight, AFI, NST, possible BPP Manage blood pressure as needed with antihypertensives Magnesium sulfate prophylaxis for severe preeclampsia Consider delivery versus expectant management

1) Sit the patient up, loosen tight clothing, and check skin 2) Empty bladder: perform in/out catheterization with lidocaine, or flush/change indwelling catheter 3) Using dibucaine and a gloved finger, check rectum for retained stool 4) Look for other noxious stimuli below the level of SCI, and seek expert consultation

When to use antihypertensives

Sustained SBP >160 mmHg or DBP >110 mmHg

May consider if SBP >150 mmHg despite steps 1 and 2 above. Administer prior to moving on to step 3

Choice of antihypertensive

IV labetolol or hydralazine; oral nifedipine

Bite and swallow nifedipine; 2% nitroglycerin paste – wipe off once BP drops

Delivery considerations

Deliver at 34 weeks for severe preeclampsia or 37 weeks for preeclampsia without severe symptoms

AD related to labor and delivery should be treated with placement of an epidural. Cesarean may be necessary if blood pressure does not improve with epidural placement

AFI: amniotic fluid index; BP: blood pressure; BPP: biophysical profile; CBC: complete blood count; CMP: complete metabolic panel; DBP: diastolic blood pressure; IV: intravenous; NST: nonstress test; SBP: systolic blood pressure.

Prevention of a “silent,” unattended, unnoticed delivery Another unique complication to obstetric management of the pregnant trauma patient is the patient’s inability to reliably feel and report expected bodily changes that accompany many pregnancy complications. Uterine sensory afferents synapse with the spinal cord at the T11–L1 levels. As such, patients with injuries at T10 or higher may have lost complete sensory innervation to the uterus and be unable to report the normal pain of uterine contractions or placental abruption  [55]. Even women with injuries lower than T12 may have such a reduction in pain perceived from the uterus that they could potentially miss the onset of uterine contractions, especially while asleep or under the effect of sedating medications  [52,54,56]. Patients with injuries that involve the S2–S4 levels may be unable to feel the discomfort of cervical dilatation or pressure from the

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passing infant on the surrounding perineal tissues [52]. As such, cardiotocography is essential to monitoring for these complications during the acute period  [56] to prevent a silent, unattended delivery that could place the infant at risk of suffocation. It is recommended that internal cervical exams be performed with anesthetic jelly at all prenatal visits after 28 weeks for patients who may be coming to outpatient clinic and at least weekly while hospitalized [52,56].

Presentation of labor in the patient with spinal cord injury Thankfully, available literature does suggest that women with SCI are at no higher risk of preterm delivery than pregnant patient with no SCI  [56]. In a recent Swedish study, results showed predominantly favorable outcomes of pregnancy and delivery in women with SCI as well as

Additional medical SCI complications

their infants in compared to general population (among 109 pregnant patients with SCI) [58]. While many of these women will not experience typical labor pains, most of them will present with some baseline change in condition. Signs of impending labor in this population may include the onset of AD, “gas” pains, shortness of breath, increased focal spasms of the legs or abdomen, increased general spasticity, backache, shoulder pain, or pelvic pressure [4,54,55,56]. Interestingly, pregnant women with SCI are also not at increased risk of postterm delivery because uterine myometrium is actually denervated during pregnancy and spared from the many changes in the autonomic nervous system that the rest of the body endures [56].

Technical considerations of vaginal delivery While delivery of patients who have sustained an SCI may occur relatively infrequently, it has an intriguing historical reference. Sir James Young Simpson (1811–1870), the father of obstetric anesthesia, conducted early animal studies with spinal cord transection to demonstrate that uterine contractions were not dependent on spinal cord innervation. Human case reports were published as long ago as 1897  – a time when most individuals with SCI had very limited life expectancies due to infections and renal failure [47]. Duration of labor is typically not found to be statistically different than in patients without SCI  [52]. Available patient case series show that about one-third of patients can deliver spontaneously, one-third require assisted vaginal deliveries due to failure to push, and the final one-third go on to require cesarean delivery  [56]. While there are currently no available publications comparing methods of assisted deliveries, this author has a slightly higher than published vaginal success rate utilizing a midforceps technique with Salinas Cucharas, a nonlocking spoon type of forceps held in by the maternal pelvis and fetal head, in indicated operative vaginal deliveries (see Figure 24.1) [59].

­Additional medical SCI complications Due to the interruption of nerve supply to the organs below the injury, individuals with spinal cord injuries are at risk of many secondary complications. As noted above, the imbalance in the autonomic nervous system between the parasympathetic and sympathetic nervous systems leads to autonomic dysfunction often due to impaired sympathetic response. This can result in BP irregularities, cardiac dysrhythmias, stress ulcers, and hypothermia postinjury. A study by Bertschy et al. found that 10 of 17 pregnant women with SCI were hospitalized during their pregnancies.

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Figure 24.1

Salinas Cucharas’ nonlocking forceps is pictured.

Reasons for hospitalization included urinary tract infection (UTI)/pyelonephritis, falls, hypertension, pneumonia, preeclampsia, preterm labor or tachycardia  [60]. A study by Ghindi of 23 women found complications of pregnancy during SCI of thrombosis (8%), urinary complications (59%), AD (27%), and worsened spasticity (22%) [61]. Since SCI affects multiple organ systems, attention to detail early on is important to prevent long-lasting complications such as pressure injuries (PIs), contractures, and fecal impaction.

Neurogenic bowel Bowel dysfunction is prevalent in individuals with an SCI. Frequently, there is loss of cortical input into the gastrointestinal system leading to bowel incontinence with loss of voluntary control. The enteric nervous system is usually intact in patients with SCI. Byrne et al. found that inadequate bowel control can cause social isolation, affect ability to work, and can lead to constipation with fecal impaction or bowel obstruction causing visits to emergency rooms or hospitalization  [62]. Craig reported that most women found that they experienced worse constipation during pregnancy than baseline [63].

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The Consortium for Spinal Cord Medicine recommends the development of a conservative bowel program after comprehensive evaluation [64]. Depending upon the location of lesion and timing of injury, the patient may have tight (reflexic) or loose (areflexic) rectal tone. A scheduled daily multifaceted bowel program is used to promote evacuation and prevent incontinence. Stool softener and motility agents, such as senokot or polyethylene glycol, are often used for patients out of spinal shock that have a reflexic bowel, usually cervical or thoracic injuries. Digital stimulation combined with suppository promotes the rectocolic reflex to promote peristalsis. A commonly used initial bowel program includes stool softener twice daily, two senokot (an herbal laxative) given together 8 h prior to rectal suppository with digital stimulation daily or every other day. Adjustments can be made based off results with a goal of medium to large bowel movements daily or large to extra-large one every other day. With areflexic bowels, manual evacuation and fiber with or without a motility agent are often used if decreased rectal tone is present as no spinal cord mediated reflex peristalsis occurs. Minienemas have been successfully used for both reflexic and areflexic bowel programs. Adequate hydration and a consistent schedule are important to prevent incontinence. Unplanned bowel movements, or accidents, should be rare. The most common cause is constipation with loose stool passing around hard stool in the colon. Enemas can be used for a bowel cleanout due to constipation but should be avoided for daily bowel programs due to the possibility of colonic microtrauma and potential trigger for labor. Probiotics are not routinely recommended but may assist with reduction in antibiotic associated diarrhea Clostridium difficile-associated diarrhea [64].

Stress ulcer prophylaxis There is unopposed vagal stimulation due to the interruption of sympathetic vasoconstrictors after SCI. This places individuals at risk for stress ulcers with potential for gastrointestinal bleeding. Appropriate prophylaxis with H2 receptor blockers or proton pump inhibitors should be used for one month. Early diagnosis with prompt management of ulcers is important to prevent further complication [65].

Neurogenic bladder Neurogenic bladder dysfunction is commonly a result of either failure to store (incontinence) or failure to empty (retention) the bladder. Urinary incontinence is common with SCI and pregnancy, and one study reported its increase in half of the women with pregnancy [66]. Anticholinergic medications, such as oxybutynin, are often used to relax

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bladder smooth muscle and inhibit involuntary detrusor muscle contractions (see Table 24.4). Management of neurogenic bladder is usually by indwelling Foley catheter or an intermittent catheter program (ICP) every 4–6 h, with target bladder volumes upper thoracic > lower thoracic SCI. PPD is likely underdiagnosed as selfreported PPD was more commonly reported than clinically diagnosed PPD. Women with SCI, particularly high level, should be screen for anxiety and depression due to possible increased risk [74,75]. Family support, especially the father of the baby, if supportive, is important and can help deter depression  [76]. Staff education is also important. Westgren found that some nurses and staff had nonsupportive attitudes toward pregnant women with SCI about needing to terminate the  pregnancy or the inability of the woman with SCI to mother  [77]. Postpartum depression (35%) was a common complication in the puerperium  [61]. Screening for depression and adequate resources, that is, caregiver, financial, and so on, are needed both during and after pregnancy.

Pain Pain is a frequent complication of SCI and per SCIRE multiple studies report an incidence ranging anywhere from 11% to 94% [78]. Intensity, type, and duration of pain can vary. Neuropathic pain originating from nerve injury can  be described as tingling, burning, pins and needles, pressure, tightness, or heaviness. It is commonly treated with antiseizure or antidepressant medications, as well as

Medications useful in the management of hypotension.

Drug name

Starting dose

Fludrocortisone

Use

Side effects

Pregnancy risk

Lactation risk

0.1 mg/day

Symptomatic hypotension CI: systemic fungal infection

Hypertension, emotional lability, dermatologic changes, hypokalemia, Cushing’s syndrome, easy bruising, impaired healing

May be associated with oral clefts in first trimester. May reduce fetal growth or cause hypoadrenalism. No human or animal studies

Corticosteroids are secreted in breast milk. Caution advised

Midodrine

5 mg BID (7 am, 12 noon)

Symptomatic hypotension CI: severe heart or renal disease

Supine hypertension, paresthesias, piloerection, pruritus, dysuria, polyuria

Adverse events in animal studies

Unknown if secreted into breast milk. Caution advised

Pseudoephedrine

60 mg TID prn

Symptomatic hypotension CI: w/in 14 days of MAOI use

Hypertension, tachycardia, CNS stimulation, thickening of respiratory secretions, urinary retention

Avoid during first trimester: increased risk of gastroschisis, intestinal atresia, facial deformities. Risk is likely less during second and third trimester, still not preferred

May decrease milk production. Excretion roughly 4% maternal dose, maximum concentration 1–2 h following dose. May lead to infant irritability

BID: twice daily; CI: contraindicated; CNS: central nervous system; MAOI: monoamine oxidase inhibitor; TID: three times daily. Source: Drug information obtained from Lexicomp, Inc.

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Rehabilitation

desensitization or lidocaine patches. A sudden increase in neuropathic pain can be a sign of an underlying medical issue such as an ingrown toenail, constipation, or a UTI. Nociceptive pain often has a musculoskeletal etiology and can be described as dull, achy, or throbbing in nature. This is often treated with modalities, including heat, cold, manual therapy, and so on, or narcotics. A patient with either chronic or acute SCI may have pain requiring large dosages not usually given to pregnant patients. Pain relief may require a combination of medications that should be titrated often based off patient condition. It is essential that the anesthesiologist and the obstetrician coordinate. In the antepartum period, the patient may need to be hospitalized for pain management and frequent fetal monitoring. The infant will need to be monitored for withdrawal in the nursery for adverse effects although this rarely occurs even with long-term high-dose medications for pain (see Table 24.6).

Spasticity Spasticity as defined by Lance is: “a motor disorder characterized by a velocity dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks, resulting from hyper-excitability of the stretch reflexes, as one component of the upper motoneuron syndrome [79].” This may develop once the patient is out from spinal shock. Spasticity can be a natural evolution of the SCI as the body tries to regain function. Sudden changes in spasticity can be a sign of an underlying medical issue such as an ingrown toenail, constipation, or a UTI. It is important to remember though that the majority of women with SCI above T10 experience uterine contractions with only abdominal discomfort, an increase in spasticity, and AD [57]. Stretching and splints are important to prevent contracture formation. Medications, such as baclofen, are often used for the management of spasticity if symptoms are severe enough to affect sleep, function, hygiene, or to cause pain (see Table 24.7).

Breastfeeding Intact neurohormonal signaling is involved with successful breastfeeding. This may not be intact in women with SCI. Although women with SCI have successfully breastfed after delivery, Krassioukov et  al. found insufficient milk production, absent let-down reflex, and incidence of AD associated with high-level SCI. AD was triggered by 24% of

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women, more commonly in those women with injuries above T6. AD usually resolves when noxious stimulus is removed. Mothers with higher injuries may have difficulty in positioning baby or pump to successfully breastfeed on their own. Time needed for activities of daily living and sleep loss were the top reasons for cessation of breastfeeding  [75]. A candid conversation with the mother fully describing the obstacles and benefits of breastfeeding in this special population is needed, and adequate support provided to those mothers who would like to proceed.

­Rehabilitation A comprehensive multidisciplinary approach to rehabilitation and recovery is essential. Once medically stabilized the injured patient may benefit from transfer to an acute inpatient rehabilitation center that specializes in care of individuals with SCI. A team lead by a physiatrist (rehabilitation physician) and may be composed of occupational and physical therapist, speech language pathologist, nursing, psychology, case manager, social worker, and so on, combined with recommendations of an OB consultant are beneficial in meeting the unique needs of this patient population. The patient will need assessment for custom durable medical equipment and family training with special consideration to potential weight change due to pregnancy and how to care for baby once it arrives. Injuries to the spinal cord are characterized by completeness of injury (presence of sensory and/or voluntary motor sparing of rectum), and level of injury (last normal neurologic level) under the ASIA Impairment Scale using the International Standards for Neurological Classification of SCI Worksheet (ISNCSCI). This scoring can help describe the functioning of the spinal cord at the time of exam and may help indicate how much the patient will be able to do for herself versus how much assistance may be needed. A comprehensive neurologic exam using the ISNCSCI worksheet is recommended, if possible, between 3 and 7 days after injury to get a reliable picture of neurologic impairment and can help predict neurologic recovery [80]. This can be repeated depending on patient’s clinical presentation. Studies have found that most recovery occurs within the first 3–6  months of injury possibly corresponding with decreasing edema in the spinal cord, although some recovery of motor function has been documented up to 2 years after injury. This is commonly in the incomplete patients, who usually have a better recovery than the complete patients. Research has shown patients with complete injuries often regain one or two motor levels below level of injury. Based on the initial week neurologic exam, 80–90% of these patient’s injury will remain

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Table 24.6 Medications useful with pain management.

Drug name

Starting dose

Use

Side effects

Pregnancy risk

Lactation risk

Amitriptyline

25 mg qday Max: 150 mg daily

Neuropathic pain CI: Within 14 days of MAOI, with cisapride, following cute MI

Dry mouth, hypotension, dizziness, drowsiness

Adverse events observed in animal reproduction studies. CNS effects, limb deformities, developmental delay noted, but no causal relationship established

Excreted into breast milk, concentration similar to maternal plasma. Breastfeeding is not recommended by manufacturer, although literature does report use in breastfeeding mothers without adverse events

Duloxetine

30 mg qday Max: 60 mg qday

Neuropathic pain CI: Within 14 days of MAOI, use with linezolid or IV methylene blue

Nausea, headache, dry mouth, drowsiness, fatigue, weight loss

Adverse events observed in animal reproduction studies. SNRI exposure in third trimester may be associated with respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hyper- or hypotonia, jitteriness, irritability, constant crying, or tremor

Excreted into breast milk. Caution advised on US labeling; Canadian labeling recommends avoiding in nursing women

Gabapentin

30 mg TID Max: 3600 mg qday

Neuropathic pain

Dizziness, drowsiness, ataxia, fatigue

Excreted into breast Adverse events observed in animal reproduction studies. milk; no adverse events reported Crosses the placenta

Lidocaine patch 1 patch Max: 3 patches qday

Neuropathic pain

Local skin reaction

Adverse events not observed in animal studies using systemic injection. Crosses the placenta. Systemic absorption from patch varies based on location, but it is expected to be low

Excreted into breast milk. Oral bioavailability to the infant is expected to be low

Pregabalin

50 mg TID Max: 150 mg TID

Neuropathic pain

Somnolence, dizziness, ataxia, peripheral edema, weight gain, dry mouth, blurred vision

Adverse events observed in animal studies. Crosses the placenta. Outcome data in human use are limited

Excreted into breast milk at concentration of 76% of maternal serum. Breastfeeding is not recommended

Tapentadol

50 mg q4–6 h prn pain Max: 600 mg daily

Neuropathic pain

Nausea, dizziness, drowsiness, vomiting, constipation

Adverse events observed in animal studies. Opioids cross the placenta. Not represented during labor and delivery; neonate should be monitored for respiratory depression

May be excreted into breast milk. Possibility for infant sedation or respiratory depression. Breastfeeding is not recommended

CI: contraindicated; IV: intravenous; MAOI: monoamine oxidase inhibitor; MI: myocardial infarction; prn: as needed; SNRI: serotonin– norepinephrine reuptake inhibitor; TID: three times daily. Note: Medications for bowel management (Colace, Senna, and laxatives) are all commonly used during pregnancy and regarded as safe. Nociceptive and musculoskeletal pain medications, including opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen, should also be used as needed and per provider comfort. Source: Drug information obtained from Lexicomp, Inc.

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Summary

Table 24.7 Spasticity medications. Drug name

Starting dose

Use

Side effects

Pregnancy risk

Lactation risk

Baclofen

5 mg TID Max: 20 mg QID

Spasticity

Hypotonia, drowsiness, confusion, headache, nausea, vomiting

Adverse events observed in animal studies. Withdrawal symptoms have been noted in previous case reports upon delivery

Excreted into breast milk. Breastfeeding is not recommended

Dantrolene

25 mg qday Max: 100 mg QID

Spasticity

Drowsiness, dysphagia, nausea, muscle weakness

Adverse events observed in animal studies. Crosses the placenta; cord blood concentrations same as maternal

Excreted into breast milk. Breastfeeding is not recommended

Diazepam

2 mg TID Max: 10 mg QID

Spasticity

Hypotension, drowsiness, constipation, nausea, weakness

Adverse events observed in animal studies. Teratogenic effects have been observed. Exposure later in pregnancy may lead to hypoglycemia, respiratory depression, and floppy infant syndrome

Excreted into breast milk at 1/10 plasma concentration. Drowsiness, lethargy, and weight loss have been observed. Breastfeeding is not recommended

Tizanidine

2 mg TID Max: 36 mg daily

Spasticity CI: With ciprofloxacin or fluvoxamine

Hypotension, somnolence, dry mouth, weakness, dizziness

Adverse events observed in animal studies

Expected to be excreted into breast milk

Onabotulinumtoxina

Varies

Focal spasticity

Dysphagia, urinary retention, headache, local site reaction, weakness

Adverse events observed in animal studies

Unknown if excreted into breast milk. Caution advised

CI: contraindicated; QID: four times daily; TID: three times daily. Source: Drug information obtained from Lexicomp, Inc.

complete [81]. Incomplete injuries have better potential for ambulation compared to complete patients. According to the Consortium for Spinal Cord Medicine, patients with injuries at C7 may become independent with their care at a wheelchair level after participating in therapy. If injury is above C7, patient will likely need varying levels of assistance [81]. A rehabilitation physician with experience using the ISNCSCI worksheet and SCI can best discuss the neurologic exam and its implication for  neurorecovery and functional independence with the patient. Research searching for a cure to spinal cord injuries is being investigated, though there is currently none available. A popular focus of current research is stem cells. Consideration may be given to pregnant patients regarding saving their cord blood to be banked for stem cell research. Education is crucial for the pregnant patient with an SCI and her family. Numerous reliable resources are now available for free on the Internet. The Consortium for

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Spinal Cord Medicine has several Consumer Guides in clinically relevant topics available for patients to download, with topics including bowel, bladder, outcomes, sexuality, and so on  [82]. The Spinal Cord Injury Model System has several educational fact sheets and videos available for consumers, including a section specifically for the newly injured [83]. The United Spinal Association provides information regarding support groups and resources [84].

­Summary Care of the acute spinal cord injured patient requires an  awareness of commonly occurring serious or lifethreatening complications. Immediate care consists of initial stabilization, treatment of neurogenic shock, and the avoidance of secondary cord damage by minimizing physical manipulation and cord hypoxia. Extended antepartum and intrapartum care is focused on the prevention,

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recognition, and management of AD. Comprehensive management of pregnant SCI patients necessitates addressing the multitude of medical issues that accompany SCI, including urinary hygiene, frequent UTI, pressure sores, thromboembolic surveillance, pulmonary toilet, constipation, and the potential for unattended delivery secondary to unperceived labor. Additionally, pain and muscle spasms may require specific medications for control, as well as altering the mode of delivery, depending on their severity.

Attention to detail is crucial during the acute phase due to the potential rapid development of complications including PIs and contractures, which can lead to long-term complications. A multidisciplinary team approach is, therefore, essential for care of these complex patients, and referral to an appropriate rehabilitation center may be indicated once the patient is medically appropriate. A focus on patient and staff education is important to help the pregnant patient with successful adjustment to her disability.

­References 1 National Spinal Cord Injury Statistical Center. Facts and figures at a glance. Birmingham, AL: University of Alabama at Birmingham; 2020. 2 DeVivo MJ. Epidemiology of traumatic spinal cord injury: Trends and future implications. Spinal Cord. 2012;50:365–372. 3 Lin VW. Spinal cord medicine: Principles and practice. 2nd ed. New York: Demos Medical; 2010. 4 Bochicchio GV, Napolitano LM, Haan J, et al. Incidental pregnancy in trauma patients. J Am Coll Surg. 2001;192(5):566–569. 5 D’Arville A, Walker M, Lacey J, Lancman B, Hendel S. Airway management in the adult patient with an unstable cervical spine. Curr Opin Anaesthesiol. 2021;34(5);597–602. 6 Martini RP, Larson DM. Clinical evaluation and airway management for adults with cervical spine instability. Anesthesiology Clin. 2015;33(2015):315–327. 7 Munnur U, de Boisblanc B, Suresh MS. Airway problems in pregnancy. Crit Care Med. 2005;22(10):S259–S268. 8 Hegewald MG, Crapo RO. Respiratory physiology in pregnancy. Clin Chest Med. 2011;32(1):1–13. 9 Lapinsky SE. Acute respiratory failure in pregnancy. Obstet Med. 2015;8(3);126–132. 10 Ward KR. Trauma airway management. In: HarwoodNuss A, editor. The clinical practice of emergency medicine. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001; p. 433–441. 11 Donaldson WF III, Towers JD, Doctor A, et al. A methodology to evaluate motion of the unstable spine during intubation techniques. Spine. 1993;18(14):2020–2023. 12 Prasarn ML, Horodyski MB, Scott NE, et al. Motion generated in the unstable upper cervical spine during head tilt–chin lift and jaw thrust maneuvers. Spine J. 2014;14;609–614. 13 Singleton BN, Morris FK, Yet B, et al. Effectiveness of intubation devices in patients with cervical spine immobilization: A systemic review and network metaanalysis. Br J Anaesth. 2021;126(5):1055–1066.

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14 Kim YJ, Hur C, Yoon H-K, et al. Effects of external laryngeal manipulation on cervical spine motion during videolaryngoscopic intubation under manual in-line stabilization: A randomized crossover trial. J Clin Med. 2021;10:2931. 15 Jain V, Chari R, Maslovitz S, et al. Guidelines for the management of the pregnant trauma patient. J Obstet Gynaecol Can. 2015;37(6);553–571. 16 Schwaiberger D, Karcz M, Menk M, et al. Respiratory failure and mechanical ventilation in the pregnant patient. Crit Care Clin. 2016;32;85–95. 17 Bowton DL, Scott LK. Ventilatory management of the noninjured lung. Clin Chest Med. 2016;37:701–710. 18 Wong SL, Shem K, Crew J. Specialized respiratory management for acute cervical spinal cord injury: A retrospective analysis. Top Spinal Cord Inj Rehabil. 2012;18(4):283–290. 19 Consortium for Spinal Cord Medicine. Respiratory Management Following Spinal Cord Injury: A clinical practice guideline for health-care professionals. J Spinal Cord Med. 2005;28(3):259–293. 20 Hatton GE, Mollett PJ, Du RE, et al. High tidal volume ventilation is associated with ventilator-associated pneumonia in acute cervical spinal cord injury. J Spinal Cord Med. 2021;44(5):775–781. 21 Grindheim G, Toska K, Estensen ME, et al. Changes in pulmonary function during pregnancy: A longitudinal cohort study. BJOG. 2012;119(1):94–101. 22 Berrly M, Shem K. Respiratory management during the first five days after spinal cord injury. J Spinal Cord Med. 2007;30:309–318. 23 Lapinsky SE. Cardiopulmonary complications of pregnancy. Crit Care Med. 2005;33(7):1616–1622. 24 Aoyama K, Seaward PG, Lapinsky SE. Fetal outcome in the critically ill pregnant woman. Crit Care. 2014;18(3):307. 25 Oluyomia-Obi T, Avery L, Schneider C, et al. Perinatal and maternal outcomes in critically ill obstetrics patients with pandemic H1N1 influenza A. J Obstet Gynaecol Can. 2010;32(5):443–447.

References

26 Desjardins G. Management of the injured pregnant patient. Trauma.org. http://trauma.org/archive/resus/ pregnancytrauma.html 27 Consortium for Spinal Cord Medicine. Early acute management in adults with spinal cord injury: A clinical practice guideline for health-care professionals. J Spinal Cord Med. 2008;31(4):403–479. 28 Sanchez JAS, Sharif S, Costa F, et al. Early management of spinal cord injury: WFNS Spine Committee Recommendations. Neurospine. 2020;17(4):759–784. 29 Taylor MP, Wrenn P, O’Donnell AD. Presentation of neurogenic shock within the emergency department. EMJ. 2016;34(3):157–162. 30 Dave S, Cho JJ. Neurogenic Shock. [Updated 2022 Feb 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. Available from: https:// www.ncbi.nlm.nih.gov/books/NBK459361/ 31 Clark RB, Brown MA, Lattin DL. Neostigmine, atropine, and glycopyrrolate: Does neostigmine cross the placenta? Anesthesiology. 1996;84:450–452. 32 Gao F, Chu H, Chen L, et al. Factors associated with in-hospital outcomes of traumatic spinal cord injury: 10-year analysis of the US National Inpatient Sample. J Am Acad Orthop Surg. 2020;28(17):707–716. 33 Rose CH, Faksh A, Traynor KD, et al. Challenging the 4- to 5-minute rule: From perimortem cesarean to resuscitative hysterotomy. Am J Obstet Gynecol. 2015;213(5):653–656, 656.e1. 34 Marotta JT. Spinal injury. In: Rowland LP, editor. Merritt’s neurology. 10th ed. Philadelphia: Lippincott, Williams & Wilkins; 2000; p. 416–423. 35 Katx VL, Dotters DJ, Droegemueller W. Perimortem cesarean delivery. Obstet Gynecol. 1986;68(4):571–576. 36 Morris JA Jr, Rosenbower TJ, Jurkovich GJ, et al. Infant survival after cesarean section for trauma. Ann Surg. 1996;223(5):481–491. 37 Oxford CM, Ludmir J. Trauma in pregnancy. Clin Obstet Gynecol. 2009;52(4);611–629. 38 Gilson GJ, Miller AC, Clevenger FW, et al. Acute spinal cord injury and neurogenic shock in pregnancy. Obstet Gynecol Surv. 1995;50(7):556–560. 39 Baker ER, Cardenas DD. Pregnancy in spinal cord injured women. Arch Phys Med Rehabil. 1996;77(5):501–507. 40 International Commission on Radiological Protection. Protection of the patient in diagnostic radiology. ICRP Publication No. 34. Oxford: Pergamon; 1983. 41 Brent RL. The effect of embryonic and fetal exposure to X-ray, micro-waves, and ultrasound: Counseling the pregnant and nonpregnant patient about these risks. Semin Oncol. 1989;16(5):347–368. 42 McCollough CH, Schueler BA, Atwell TD, et al. Radiation exposure and pregnancy: When should we be concerned? Radiographics. 2007;27(4):909–917.

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43 Patel SJ, Reede DL, Katz DS, et al. Imaging the pregnant patient for nonobstetric conditions: Algorithms and radiation dose considerations. Radiographics. 2007;27(6): 1705–1722. 44 Wolf M, Weber MA. Neuroimaging of the traumatic spine. MRI Clin N Am. 2016;24(3):541–561. 45 American College of Obstetricians and Gynecologists. Guidelines for diagnostic imaging during pregnancy and lactation. Committee Opinion No. 656. Obstet Gynecol. 2016;127:e75–e80. 46 National Institutes of Health. Effect of corticosteroids for fetal maturation on perinatal outcomes. NIH Consensus Statement. 1994;12(2):1–24. 47 McGregor JA, Meeuwsen J. Autonomic hyperreflexia: Amortal danger for spinal cord-damaged women in labor. Am J Obstet Gynecol. 1985;151(3):330–333. 48 Gimovsky ML, Ojeda A, Ozaki R, et al. Management of autonomic hyperreflexia associated with a low thoracic spinal cord lesion. Am J Obstet Gynecol. 1985;153(2);223–224. 49 Helkowski WM, Ditunno JF, Boninger M. Autonomic dysreflexia: Incidence in persons with neurologically complete and incomplete tetraplegia. J Spin Cord Med. 2003;26(3):244–247. 50 Colachis SC III. Autonomic hyperreflexia with spinal cord injury. J Am Paraplegia Soc. 1992;15(3):171–186. 51 Greenspoon JS, Paul RH. Paraplegia and quadriplegia: Special considerations during pregnancy and labor and delivery. Am J Obstet Gynecol. 1986;155(4):738–741. 52 Lindan R, Joiner B, Freehafer AA, et al. Incidence and clinical features of autonomic dysreflexia in patients with spinal cord injury. Paraplegia. 1980;18(5):285–292. 53 Abouleish E. Hypertension in a paraplegic parturient. Anesthesiology. 1980;53(4):348. 54 Cross LL, Meythaler JM, Tuel SM, et al. Pregnancy, labor and delivery post spinal cord injury. Paraplegia. 1992;30(12): 890–902. 55 ACOG Committee Opinion. Obstetric management of patients with spinal cord injuries. Obstet Gynecol. 2020;135(5):e230–e236. 56 Crosby E, St-Jean B, Reid D, et al. Obstetrical anesthesia and analgesia in chronic spinal cord-injured women. Can J Anaesth. 1992;39(5 Pt. 1):487–494. 57 Pereira L. Obstetric Management of the patient with spinal cord injury. Obstet Gynecol Surv. 2003;58(10): 678–686. 58 Hughes SJ, Short DJ, Usherwood MM, et al. Management of the pregnant woman with spinal cord injuries. Br J Obstet Gynaecol. 1991;98:513–518. 59 Routh A. Parturition during paraplegia, with cases. Trans Obstet Soc Lond. 1897;39:191–229. 60 Bertschy S, Bostan C, Meyer T, et al. Medical complications during pregnancy and childbirth in

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63 64

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66

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women with SCI in Switzerland. Spinal Cord. 2016;54(3): 183–187. Ghidini A, Helaey A, Andreani M, et al. Pregnancy and women with spinal cord injuries. Acta Obstet Gynecol Scand. 2008;87(10):1006–1010. Byrne CM, Pager CK, Rex J, et al. Assessment of quality of life in the treatment of patients with neuropathic fecal incontinence. Dis Colon Rectum. 2002;45(11):1431–1436. Craig DI. The adaptation to pregnancy of spinal cord injured women. Rehabil Nurs. 1990;15:6–9. Consortium for Spinal Cord Medicine, Neurogenic bowel management in adults with spinal cord injury. J Spinal Cord Med. 2020. Anwar F et al. Gastrointestinal bleeding in spinal injuries patient: Is prophylaxis essential? Br J Med Pract. 2013;6(1):a607. Pannek J, Bertschy S, Mission impossible? Urological management of patients with spinal cord injury during pregnancy: A systematic review. Spinal Cord. 2011;49;1028–1032. Andretta E Landi L, Cianfrocca M, et al. Bladder management during pregnancy in women with spinalcord injury: An observational, multicenter study. Int Urogynecol J. 2019;30:2. Sterling L, Keunen J, Wigdor E, et al. Pregnancy outcomes in women with spinal cord lesions. J Obstet Gynaecol Can. 2013;35(1):39–43. National Advisory Pressure Ulcer Panel. National Pressure Ulcer Advisory Panel (NPUAP) announces a change in terminology from pressure ulcer to pressure injury and updates the stages of pressure injury. 2016. https://www.npuap.org/national-pressure-ulceradvisory-panel-npuap-announces-a-change-interminology-from-pressure-ulcer-to-pressure-injury-andupdates-the-stages-of-pressure-injury/ Kirshblum S, Campagnolo D. Spinal cord medicine. 2nd ed. Philadelphia: Lippincott, Williams & Wilkins; 2011. Consortium for Spinal Cord Medicine. Pressure ulcer prevention and treatment following spinal cord injury: A clinical practice guideline for health-care professionals. J Spin Cord Med. 2001;24(Suppl. 1):S40–S101.

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72 Consortium for Spinal Cord Medicine. Prevention of venous thromboembolism in individuals with spinal cord injury: Clinical practice guidelines for health care providers. 3rd ed. Washington, DC: Paralyzed Veterans of America; 2016. 73 Robinson-Whelen S, Taylor HB, Hughes RB, et al. Depression and depression treatment in women with spinal cord injury. Top Spinal Cord Inj Rehabil. 2014;20(1):23–31. 74 Lee A, Wen B, Walter M, et al. Prevalence of postpartum depression and anxiety among women with spinal cord injury. J Spinal Cord Med. 2021;44(2):247–252. 75 Krassioukov A, Ax L, Elliott S, et al. Women’s health after spinal cord injury: Focus on pregnancy and breastfeeding. J Musculoskelet Neuronal Interact. 2019;19(4):537. 76 Nosek MA, Howland C, Rintala DH. National study of women with physical disabilities: Final report. Sexual Disabil. 2001;19(1):5–39. 77 Westgren N, Levi R. Motherhood after traumatic spinal cord injury. Paraplegia. 1994;32:517–523. 78 Spinal Cord Injury Research Evidence. https://www. scireproject.com/rehabilitation-evidence/painmanagement/incidence-quality-and-significance/ incidence-of-pain-post-sc 79 Lance JW. Symposium synopsis. In: Feldman RG, Young RR, Koella WP, editors. Spasticity: Disordered motor control. Chicago: Year Book Medical; 1980; p. 485–494. 80 Hughes SJ, Short DJ, Usherwood MM, et al. Management of the pregnant woman with spinal cord injuries. Br J Obstet Gynaecol. 1991;98(6):513–518. 81 Maynard FM, Bracken MB, Creasey G, et al. American Spinal Injury Association. International Standards for Neurological and Functional Classification of Spinal Cord Injury. Spinal Cord. 1997;35(5):266–274. 82 Consortium for Spinal Cord Medicine. Outcomes following traumatic spinal cord injury: Clinical practice guidelines for health-care professionals. J Spinal Cord Med. 2000;23(4):289–316. 83 Spinal Cord Injury Model Systems. http://www.uab.edu/ medicine/sci/uab-scims-information 84 United Spinal Association. http://www.spinalcord.org

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25 Severe Acute Asthma Dharani K. Narendra and Nicola A. Hanania Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX, USA

Introduction Asthma is a chronic inflammatory disease of the airways characterized by airway hyper-responsiveness to various stimuli, resulting in partially or completely reversible airway obstruction. It is a major public health problem worldwide and is one of the most common chronic conditions to be reported in pregnant women. The prevalence of asthma in pregnancy increased in the United States from 5.5% in 2001 to 7.8% in 2007  [1], and it affects approximately 200,000–376,000 pregnancies every year  [2]. Episodes of acute asthma requiring emergency department (ED) visits or hospitalization have been reported in 9–11% of pregnant women managed by asthma specialists [3]. One in 10 pregnant women worldwide has asthma, and of these, 10% will have a severe exacerbation requiring oral corticosteroids (OCSs) in pregnancy [4]. Pregnancy can affect the course of asthma, and uncontrolled asthma is associated with adverse maternal and perinatal outcomes [5,6].

­ aternal and fetal physiologic M considerations during pregnancy The physiological changes in the respiratory system during pregnancy are remarkable and are essential to understand. As the blood volume and cardiac output increase in pregnancy, there is a relative increase in pulmonary blood flow and hyperemia in upper respiratory mucosa. In addition, there is marked hyperactivity of mucus glands and increased phagocytic activity and mucopolysaccharide content, all resulting in increased nasal congestion, stuffiness, and epistaxis. Progesterone-induced stimulation of the respiratory center leads to an increase in minute ventilation by

approximately 50%. This increase is primarily due to increased tidal volume with minimal change in the respiratory rate and results in respiratory alkalosis. Compensatory metabolic acidosis occurs with increased renal excretion of bicarbonate. The normal arterial blood gas values in pregnancy are pH, 7.40–7.44; PaCO2, 28–32  mmHg; PaO2, 72–110 mmHg; and bicarbonate, 18–22 mEq/L. Physiologic tests of airway function such as forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), the mean forced expiratory flow during the middle half of FVC (FEF25–75), FEV1/ FVC, and peak expiratory flow rate (PEFR) remain unchanged. Therefore, these measures remain useful indicators of airway function and may help assess asthma severity during pregnancy. With advancing gestation, the functional residual capacity (FRC), residual volume (RV), and expiratory reserve volume (ERV) decrease. Overall, there is a minimal decrease in total lung capacity (TLC). Table 25.1 lists a summary of normal respiratory physiological changes during pregnancy.

I­ nterrelationship between asthma and pregnancy Effects of pregnancy on asthma Although multiple physiological and biochemical changes in pregnancy may have a significant impact, the exact effects of pregnancy on asthma and its course remain unclear and unpredictable. Turner et al., summarizing large retrospective studies, reported that 22% of patients experienced improvement in their asthma, while 40% remained unchanged and another 20% had worsening disease [7]. In a prospective study of 568 pregnant women with asthma, Kircher et al. noted that asthma control improved in 34%, worsened in 36%, and remained unchanged in 26%  [8].

Critical Care Obstetrics, Seventh Edition. Edited by Luis D. Pacheco, Jeffrey P. Phelan, Torre L. Halscott, Leslie A. Moroz, Arthur J. Vaught, Antonio F. Saad, and Amir A. Shamshirsaz. © 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.

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Table 25.1 Physiologic respiratory variables in pregnancy. Unchanged

Increased

Decreased

FEV1

MV (30–50%)

FRC (17–20%)

FVC

TV (30–50%)

RV (20–25%)

FEV1/FVC FEF25–75 PEFR Respiratory rate

VO2 (20%)

ERV (5–15%)

ERV: expiratory reserve volume; FEV1: forced expiratory volume in first second; FRC: functional residual capacity; FVC: forced vital capacity; MV: minute ventilation; PEFR: peak expiratory flow rate; RV: residual volume; TV: tidal volume; VO2: oxygen consumption. Source: Guy et al. [10], Hardy-Fairbanks and Baker [11].

Table 25.2 Risk factors of asthma exacerbation during pregnancy. ●

Severity of asthma

●

Noncompliance with asthma control medications

●

Respiratory viral infections

●

African American race

●

Cigarette smoking

●

Comorbidities: rhinitis, gastroesophageal reflux disease, obesity, anxiety and depression, and socioeconomic status

In another study, reviewing the outcome of 198 pregnancies in 181 patients with asthma, Stenius-Aarniala et al. reported an improvement of asthma control in 18%, worsening in 42%, and no change in 40% of cases [9]. Pregnancy has significant effects on asthma-related healthcare utilization  [12]. Asthma exacerbation is more likely to occur during the second and third trimesters, with significantly fewer attacks in the last 4 weeks and during labor. In general, the course of asthma tends to be similar to that experienced in prior pregnancies [13]. Reported risk factors for asthma exacerbations during pregnancy are listed in Table 25.2 and include the following [14]: 1) Severity of asthma: The risk of asthma exacerbation during pregnancy correlates with the severity of the disease  [15]. Severe asthma is associated with more exacerbations and hospitalizations. In a large prospective observation cohort study by Dombrowski et al. [16], the severity of asthma was an important determinant of the rate of asthma exacerbations and asthma-related hospitalization (the rates of exacerbations in mild, moderate, and severe asthma were 12%, 25.7%, and 52%, respectively, and the rates of hospitalization were 2.3%, 6.8%, and 27%, respectively) [16]. 2) Noncompliance: Noncompliance and underutilization of asthma control medications have been shown to

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comprise an independent risk factor for exacerbation [17]. Despite sufficient evidence of safety of asthma control medication in pregnancy, mothers and healthcare providers are sometimes reluctant to use asthma controller medications during pregnancy. In addition, acceptance of illness, anxiety, and fear of teratogenicity from control medications are known to modify adherence to medication and, hence, lead to poor asthma control [14,18]. Stenius et al. found that the risk of exacerbation was reduced by 75% among women who were regularly using inhaled corticosteroids (ICSs) [17]. 3) Viral respiratory infection: Respiratory viral infections have been shown to be a risk factor for asthma exacerbation during pregnancy [19]. Influenza has been associated with worse outcomes in pregnant women with asthma. During the 2009 influenza A (H1N1) pandemic, 7% of hospitalized patients were pregnant, and 33% of these hospitalized women had asthma [20]. The impact of COVID pandemic affecting the pregnant women with asthma is emerging. A large prospective cohort study in Denmark of over 80,000 pregnancies found that asthma was a significant risk factor for COVID-19  infection with severe acute respiratory distress syndrome (odds ratio [OR]: 2.12; 95% confidence interval [CI]: 1.41–3.41)  [21]. The Centers for Disease Control and Prevention (CDC) has indicated that pregnant women with moderate to severe asthma may be at higher risk for severe illness from COVID-19 [22]. 4) Race: Carroll et  al.  [23] examined a cohort of 112,171 people for racial differences in the incidence of asthma exacerbation during pregnancy in a low-income US population. 43% were black, and 4% had asthma. They found statistically significant differences between black and white women, with black women requiring more rescue corticosteroids, more asthma-related ED visits, and increased hospitalizations. In a retrospective cohort study of 13,900 pregnant women with asthma, African American women were more likely to have preterm labor and infection of the amniotic cavity [24]. 5) Cigarette smoking: There is high prevalence of smoking during pregnancy worldwide: studies from the United Kingdom and Australia report more than 20% prevalence of smoking in pregnant women with asthma [25]. In general, pregnant women who are current or exsmokers are 4.5 times more likely to have uncontrolled asthma than never-smokers  [26]. Passive smoke exposure has also been shown to adversely affect lung function (decrease FEV1). Women with passive smoke exposure are 2.9 times more likely to have an episode of uncontrolled asthma during pregnancy compared with never-smokers without passive exposure [26]. Hence, it is evident that smoking in pregnancy has been shown to

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be associated with worsening asthma control and symptoms, and more frequent exacerbations [27]. 6) Comorbidities: Multiple comorbidities can complicate the course of asthma in pregnancy and need to be addressed. a) Rhinitis: Rhinitis is a common comorbidity associated with pregnant women with asthma. Powell et al. demonstrated that approximately 65% of pregnant women with asthma had rhinitis and were more likely to have worse asthma control, worse asthma-related quality of life, poor lung function, and higher anxiety levels  [28]. In addition, they noted that the rhinitis symptoms improved with advanced gestation, resulting in better asthma control. b) Gastroesophageal reflux disease (GERD): GERD is more common in women with asthma than in the general population. Harding et al. reported that 82% of people with asthma have an abnormal 24-h esophageal pH test, although asthma symptoms improved in 69% of patients after treatment of GERD  [29]. Increased progesterone in pregnancy and some asthma medication cause relaxation of smooth muscles in the lower esophageal sphincter, which may result in acid reflux. Gastroesophageal reflux is considered a potential trigger for asthma, as acid reflux has been associated with poor asthma control. Approximately 30–50% of pregnant women have heartburn [30]. If as-needed calcium carbonate is insufficient to control heartburn symptoms, firstline treatment for reflux during pregnancy is the H2antagonist famotidine. For patients with persistent symptoms, a proton-pump inhibitor (PPI) can be prescribed. A meta-analysis showed that PPIs are not associated with an increased risk for major congenital birth defects, spontaneous abortions, or preterm delivery [31]. c) Maternal obesity: The proportion of overweight and obesity has increased, and maternal obesity is associated with increased risk of many pregnancy complications  [32]. A recent Australian study showed that 24% of women were overweight and an additional 35% were obese  [27]. Hendler et  al. have shown that, after adjusting for potential confounding factors, obesity was an important predictor of the risk of asthma exacerbations in pregnant obese women (OR: 1.3; 95% CI: 1.1–1.7) [33]. d) Anxiety and depression: A recent study from Australia reported a 45% prevalence of self-reported anxiety and depression in pregnant women with asthma from a socially disadvantaged area. Maternal

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depression and anxiety were associated with an increased likelihood of uncontrolled asthma, although an increase in exacerbations was not observed [34]. e) Socioeconomic status: Grzeskowial et  al. followed 189 pregnant patients prospectively in a socially disadvantaged population. They found that 50% of asthmatic women experienced loss of control or moderate/severe exacerbation during pregnancy, and 22% of women had a moderate/severe exacerbation [27].

Effects of asthma on pregnancy Studies on the effects of asthma on maternal and fetal outcomes are inconclusive [35]. Some studies reported no significant difference in birth outcomes between asthmatic and nonasthmatic women  [3,17]; others reported increased adverse outcomes, including fetal growth restriction, preterm labor and delivery, and preeclampsia [36–38]. Other adverse outcomes reported include the increased incidence of transient tachypnea of the newborn, meconium staining, oligohydramnios, development of pneumonia during pregnancy, increased risk of cesarean delivery, and increased risk of spontaneous abortion  [39]. Among a cohort of 36,587 pregnancies in asthmatic women, Blais et  al. reported an increased risk for congenital anomalies among women with exacerbations requiring hospitalization in the first trimester  [40]. In another large cohort of 223,512 deliveries, pregnant women with asthma had higher odds of preeclampsia, gestational diabetes, placenta abruption, placenta previa, and preterm birth and were less likely to have spontaneous labor and vaginal delivery [41]. It is not clear whether these adverse outcomes associated with asthma are caused by asthma or the result of other confounding factors that share common mechanisms with asthma. Maternal inflammation, hypoxemia, smoking, and altered placental function are possible mechanisms that may contribute to poor pregnancy outcomes in women with asthma [6]. In general, factors that predict poor pregnancy outcomes include poor compliance with controller medications, severity of asthma, and delayed diagnosis. Schatz et  al. reported that women whose asthma was actively managed had maternal and fetal outcomes that were not different from those of a control group without asthma [3]. In a recent prospective study that enrolled 189 pregnant women with asthma who were followed during their pregnancy, Grzeskowiak et al. [27] demonstrated that the key for improving perinatal outcomes lies in improving asthma control as early as possible in pregnancy and monitoring it throughout pregnancy, rather than focusing on

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Table 25.3 Adverse pregnancy outcomes associated with severe uncontrolled asthma. ●

Perinatal complications

●

Preterm labor (8 mm size is preferred to reduce air flow resistance, and for easier suctioning of secretions and mucus plugs. The principles of mechanical ventilation in patients with severe acute asthma have been previously described  [66,67]. General principles of mechanical ventilation include the use of small tidal volumes (6–8  mL/kg predicted body weight), positive end-expiratory pressure (PEEP) starting at 5 cmH2O, and a respiratory rate of 10–12 breaths/min [68]. Every effort should be must to avoid hypotension during mechanical ventilation to prevent decreased fetal placental blood flow. Hyperventilation can lead to dynamic hyperinflation and can also lead to barotrauma. The risks and benefits of controlled hypoventilation or permissive hypercapnia in pregnant patients are poorly understood. The transfer of CO2 across the placenta depends on a PaCO2 gradient of approximately 10  mmHg between fetal and maternal circulation. This difference remains fairly constant over a wide range of CO2 tensions. Maternal hypercapnia could result in fetal respiratory acidosis and a shift of the fetal hemoglobin dissociation curve to the right, which would limit the ability of fetal hemoglobin to bind oxygen. These theoretical concerns about permissive

450

Severe Acute Asthma Oxygen supplementation Short-acting β2-agonists (inhaled) Systemic steroids

Poor response: PEFR 70%, sustained 1 hour improvement after last treatment, reassuring fetal status

Continue inhaled short-acting β2-agonists, oral steroids and monitor PEFR

Admission to a monitored unit or ICU Maternal and fetal monitoring Indications for mechanical ventilation Acute respiratory failure (PaO240), respiratory muscle fatigue, altered mental status, circulatory collapse

Ventilator settings AC mode, FiO2:1.0, RR:8–10/min, Inspiratory Flow: 100 L/min, Peep: 0–5 cmH2O

Clinical and physiologic objectives achieved Plateau pressure ≤ 30 cmH2O, Improvement in oxygenation, pH > 7.2

Yes

Continue ventilator support Start weaning as tolerated

No Increase sedation Consider: Terbutaline infusion, heliox, magnesium sulphate, termination of pregnancy

Figure 25.1 Management algorithm of acute asthma in pregnancy. AC: assist control; FiO2: fractional inspired oxygen; PaCO2: partial pressure arterial carbon dioxide; PaO2: partial pressure arterial oxygen; PEEP: positive end-expiratory pressure; PEFR: peak expiratory flow rate; RR: respiratory rate.

hypercapnia emphasize the need for further research prior to justifying its routine clinical application. Fetal heart rate monitoring may be considered to assess the fetal response to maternal interventions. For patients responding poorly to mechanical ventilation, a favorable outcome may be obtained with the use of helium–oxygen mixture [69]. Bronchoalveolar lavage using saline or metaproterenol has also been attempted, with a successful outcome in few case reports  [70,71]. On rare occasions, life-threatening asthma such as status asthmaticus and near-fatal asthma unresponsive to mechanical ventilation may necessitate delivery of the fetus or termination of pregnancy [72,73]. The fetal placental unit places a large demand on maternal oxygen delivery and removing these demands may be essential for maternal resuscitation.

­ anagement of asthma during labor M and delivery Acute asthma exacerbations during labor and delivery are  uncommon, but if they occur, they pose risk to both the  mother and the fetus. Current asthma guidelines

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recommend that all regularly scheduled asthma medications be continued during labor and delivery [74]. Patients experiencing an acute asthma exacerbation should be treated promptly as outlined in this chapter. Continuous fetal and maternal monitoring is recommended. A skilled airway management provider should be notified of a laboring patient who experiences an asthma exacerbation and be available should intubation be required.

­ bstetric management of the pregnant O asthmatic patient Lumbar epidural analgesia reduces oxygen consumption and minute ventilation and is considered an excellent choice during labor. Because morphine and meperidine may cause histamine release, their use should be avoided, and the use of fentanyl as a narcotic analgesic is preferred. If preterm labor occurs during pregnancy, tocolytic therapy may be considered. Indomethacin may induce bronchospasm, especially in aspirin-sensitive asthmatics, and thus should be avoided. Administration of magnesium sulfate for fetal neuroprotection is safe and may be considered. For labor

References

induction and management of postpartum hemorrhage, oxytocin, prostaglandin E1 (misoprostol), and prostaglandin E2 (dinoprostone) can be used safely. However, 15-methylprostaglandin F2-α (carboprost) can induce bronchospasm, and its use should be avoided in pregnant women with asthma. Caution should be used when administering labetalol to pregnant patients with a history of asthma, and labetalol should not be given to those with bronchospasm.

­Summary Asthma is common in pregnant women. While most women who have asthma during pregnancy have controlled disease, some may experience exacerbation of

their  disease necessitating immediate intervention. It is essential to continue asthma medications during pregnancy in order to reduce the risks of poor control and acute exacerbations. The usual medications prescribed for asthma control are safe during pregnancy, and step down is not recommended during or in anticipation of pregnancy. Patients with severe acute exacerbation should be managed in a monitored unit. Initial management should include the administration of repeated doses of inhaled β2agonists, systemic corticosteroids, and oxygen. Mechanical ventilation of patients with severe acute asthma should be  performed in a controlled monitored setting to avoid complications. Multidisciplinary management is essential when treating pregnant mothers with asthma exacerbation.

­References 1 Hansen C, Joski P, Freiman H, et al. Medication exposure in pregnancy risk evaluation program: The prevalence of asthma medication use during pregnancy. Matern Child Health J. 2013;17(9):1611–1621. 2 Bracken MB, Triche EW, Belanger K, et al. Asthma symptoms, severity, and drug therapy: A prospective study of effects on 2205 pregnancies. Obstet Gynecol. 2003;102(4):739–752. 3 Schatz M, Zeiger RS, Hoffman CP, et al. Perinatal outcomes in the pregnancies of asthmatic women: A prospective controlled analysis. Am J Resp Crit Care Med. 1995;151(4):1170–1174. 4 Murphy VE, Jensen ME, Gibson PG. Asthma during pregnancy: Exacerbations, management, and health outcomes for mother and infant. Sem Resp Crit Care Med. 2017;38(2):160–173. 5 Schatz M. Interrelationships between asthma and pregnancy: A literature review. J Allergy Clin Immunol. 1999;103(2 Pt. 2):S330–S336. 6 Murphy VE, Gibson PG, Smith R, Clifton VL. Asthma during pregnancy: Mechanisms and treatment implications. Euro Resp J. 2005;25(4):731–750. 7 Turner ES, Greenberger PA, Patterson R. Management of the pregnant asthmatic patient. Ann Intern Med. 1980;93(6):905–918. 8 Kircher S, Schatz M, Long L. Variables affecting asthma course during pregnancy. Ann Allergy Asthma Immunol. 2002;89(5):463–466. 9 Stenius-Aarniala B, Piirila P, Teramo K. Asthma and pregnancy: A prospective study of 198 pregnancies. Thorax. 1988;43(1):12–18. 10 Guy ES, Kirumaki A, Hanania NA. Acute asthma in pregnancy. Crit Care Clin. 2004;20(4):731–745.

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11 Hardy-Fairbanks AJ, Baker ER. Asthma in pregnancy: Pathophysiology, diagnosis and management. Obstet Gynecol Clin N Am. 2010;37(2):159–172. 12 Kim S, Kim J, Park SY, et al. Effect of pregnancy in asthma on health care use and perinatal outcomes. J Allergy Clin Immunol. 2015;136(5):1215–1223, e1211–e1216. 13 Schatz M, Harden K, Forsythe A, et al. The course of asthma during pregnancy, post partum, and with successive pregnancies: A prospective analysis. J Allergy Clin Immunol. 1988;81(3):509–517. 14 Ali Z, Ulrik CS. Incidence and risk factors for exacerbations of asthma during pregnancy. J Asthma Allergy. 2013;6:53–60. 15 Schatz M, Dombrowski MP, Wise R, et al. Asthma morbidity during pregnancy can be predicted by severity classification. J Allergy Clin Immunol. 2003;112(2):283–288. 16 Dombrowski MP, Schatz M, Wise R, et al. Asthma during pregnancy. Obstet Gynecol. 2004;103(1):5–12. 17 Stenius-Aarniala BS, Hedman J, Teramo KA. Acute asthma during pregnancy. Thorax. 1996;51(4): 411–414. 18 Kaptein AA, Hughes BM, Scharloo M, et al. Illness perceptions about asthma are determinants of outcome. J Asthma. 2008;45(6):459–464. 19 Murphy VE, Gibson P, Talbot PI, Clifton VL. Severe asthma exacerbations during pregnancy. Obstet Gynecol. 2005;106(5 Pt. 1):1046–1054. 20 Jain S, Kamimoto L, Bramley AM, et al. Hospitalized patients with 2009 H1N1 influenza in the United States, April–June 2009. New Engl J Med. 2009;361(20):1935–1944.

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21 Adhikari EH MW, Zofkie AC, et al. Pregnancy outcomes among women with and without severe acute respiratory syndrome Coronavirus 2 infection. JAMA Netw Open. 2020;3(11):e2029256. doi:10.1001/ jamanetworkopen.2020.29256. 2020. 22 Aabakke AJM KL, Petersen TG, et al. SARSCoV-2 infection in pregnancy in Denmark-characteristics and outcomes after confirmed infection in pregnancy: A nationwide, prospective, population-based cohort study. Obstet Gynecol Scand. 2021 Nov;100(11):2097–2110. doi: 10.1111/aogs.14252. Epub 2021 Aug 31. PMID: 34467518; PMCID: PMC8652723. 23 Carroll KN, Griffin MR, Gebretsadik T, et al. Racial differences in asthma morbidity during pregnancy. Obstet Gynecol. 2005;106(1):66–72. 24 MacMullen NJ, Tymkow C, Shen JJ. Adverse maternal outcomes in women with asthma: Differences by race. MCN. Am J Matern Child Nurs. 2006;31(4):263–268. 25 Charlton RA, Snowball JM, Nightingale AL, Davis KJ. Safety of fluticasone propionate prescribed for asthma during pregnancy: A UK population–based cohort study. J Allergy Clin Immunol. 2015;3(5):772–779.e773. 26 Grarup PA, Janner JH, Ulrik CS. Passive smoking is associated with poor asthma control during pregnancy: A prospective study of 500 pregnancies. PLoS One. 2014;9(11):e112435. 27 Grzeskowiak LE, Smith B, Roy A, et al. Patterns, predictors and outcomes of asthma control and exacerbations during pregnancy: A prospective cohort study. ERJ Open Res. 2016;2(1). 28 Powell H, Murphy VE, Hensley MJ, et al. Rhinitis in pregnant women with asthma is associated with poorer asthma control and quality of life. J Asthma. 2015;52(10):1023–1030. 29 Harding SM. The potential role of gastroesophageal reflux in asthma. Minerva Gastroenterol Dietologica. 2001;47(2):75–83. 30 Gerson LB. Treatment of gastroesophageal reflux disease during pregnancy. Gastroenterol Hepatol. 2012;8(11):763–764. 31 Gill SK, O’Brien L, Einarson TR, Koren G. The safety of proton pump inhibitors (PPIs) in pregnancy: A metaanalysis. Am J Gastroenterol. 2009;104(6):1541–1545; quiz 1540, 1546. 32 Poston L, Harthoorn LF, Van Der Beek EM. Obesity in pregnancy: Implications for the mother and lifelong health of the child. A consensus statement. Pediatr Res. 2011;69(2):175–180. 33 Hendler I, Schatz M, Momirova V, et al. Association of obesity with pulmonary and nonpulmonary complications of pregnancy in asthmatic women. Obstet Gynecol. 2006;108(1):77–82.

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34 Grzeskowiak LE, Smith B, Roy A, et al. Impact of a history of maternal depression and anxiety on asthma control during pregnancy. J Asthma. 2017:706–713. 35 Hanania NA, Belfort MA. Acute asthma in pregnancy. Crit Care Med. 2005;33(10 Suppl.):S319–S324. 36 Murphy VE, Schatz M. Asthma in pregnancy: A hit for two. Eur Respir Rev. 2014;23(131):64–68. 37 Namazy JA, Murphy VE, Powell H, et al. Effects of asthma severity, exacerbations and oral corticosteroids on perinatal outcomes. Euro Resp J. 2013;41(5): 1082–1090. 38 Johnston S, Said J. Perinatal complications associated with maternal asthma during pregnancy. Obstet Med. 2012;5(1):14–18. 39 Blais L, Kettani FZ, Forget A. Relationship between maternal asthma, its severity and control and abortion. Hum Reprod. 2013;28(4):908–915. 40 Blais L, Kettani FZ, Forget A, et al. Asthma exacerbations during the first trimester of pregnancy and congenital malformations: Revisiting the association in a large representative cohort. Thorax. 2015;70(7):647–652. 41 Mendola P, Laughon SK, Mannisto TI, et al. Obstetric complications among US women with asthma. Am J Obstetr Gynecol. 2013;208(2):127.e121–e128. 42 Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention, 2022. Available from www.ginasthma.org. 43 de Araujo GV, Leite DF, Rizzo JA, Sarinho ES. Asthma in pregnancy: Association between the Asthma Control Test and the Global Initiative for Asthma classification and comparisons with spirometry. Eur J Obstet Gynecol Reprod Biol. 2016;203:25–29. 44 Palmsten K, Schatz M, Chan PH, et al. Validation of the Pregnancy Asthma Control Test. J Allergy Clin Immunol. In practice. 2016;4(2):310–315, e311. 45 NAEPP Expert Panel Report. Managing asthma during pregnancy: Recommendations for pharmacologic treatment: 2004 update. J Allergy Clin Immunol. 2005;115(1):34–46. 46 Charlton RA, Hutchison A, Davis KJ, de Vries CS. Asthma management in pregnancy. PLoS One. 2013;8(4):e60247. 47 Lim AS, Stewart K, Abramson MJ, et al. Multidisciplinary Approach to Management of Maternal Asthma (MAMMA): A randomized controlled trial. Chest. 2014;145(5):1046–1054. 48 Powell H, Murphy VE, Taylor DR, et al. Management of asthma in pregnancy guided by measurement of fraction of exhaled nitric oxide: A double-blind, randomised controlled trial. Lancet (London, England). 2011;378(9795):983–990. 49 Murphy VE, Jensen ME, Mattes J, et al. The breathing for life trial: A randomised controlled trial of fractional

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exhaled nitric oxide (FENO)-based management of asthma during pregnancy and its impact on perinatal outcomes and infant and childhood respiratory health. BMC Pregnancy Childbirth. 2016;16:111. Nelson-Piercy C. Asthma in pregnancy. Thorax. 2001;56:325–328. Wendel PJ, Ramin SM, Barnett-Hamm C, et al. Asthma treatment in pregnancy: A randomized controlled study. Am J Obstetr Gynecol. 1996;175(1):150–154. Kallen B, Rydhstroem H, Aberg A. Congenital malformations after the use of inhaled budesonide in early pregnancy. Obstet Gynecol. 1999;93(3): 392–395. Norjavaara E, de Verdier MG. Normal pregnancy outcomes in a population-based study including 2,968 pregnant women exposed to budesonide. J Allergy Clin Immunol. 2003;111(4):736–742. Namazy J, Schatz M, Long L, et al. Use of inhaled steroids by pregnant asthmatic women does not reduce intrauterine growth. J Allergy Clin Immunol. 2004;113(3):427–432. The American College of Obstetricians and Gynecologists (ACOG) and the American College of Allergy, Asthma and Immunology (ACAAI). The use of newer asthma and allergy medications during pregnancy. Ann Allergy Asthma Immunol. 2000;84(5):475–480. Dombrowski MP, Schatz M, ACOG Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin: Clinical management guidelines for obstetriciangynecologists number 90, February 2008: Asthma in pregnancy. Obstet Gynecol. 2008; 111(2 Pt. 1):457. Beitins IZ, Bayard F, Ances IG, et al. The transplacental passage of prednisone and prednisolone in pregnancy near term. J Pediatr. 1972;81(5):936. Spector SL. Safety of antileukotriene agents in asthma management. Ann Allergy Asthma Immunol. 2001;86(6 Suppl. 1):18–23. Namazy J, Cabana MD, Scheuerle AE, et al. The Xolair Pregnancy Registry (EXPECT): The safety of omalizumab use during pregnancy. J Allergy Clin Immunol. 2015;135(2):407–412. Moretti ME, Caprara D, Coutinho CJ, et al. Fetal safety of loratadine use in the first trimester of pregnancy: A multicenter study. J Allergy Clin Immunol. 2003;111(3):479–483. Heinonen OP, Shapiro S, Monson RR, et al. Immunization during pregnancy against poliomyelitis

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and influenza in relation to childhood malignancy. Intl J Epidemiol. 1973;2(3):229–235. Cossette B, Beauchesne MF, Forget A, et al. Systemic corticosteroids for the treatment of asthma exacerbations during and outside of pregnancy in an acute-care setting. Respir Med. 2014;108(9):1260–1267. Seyal AM. Asthma in the hospitalized obstetrical patient. Clin Rev Allergy Immunol. 2001;20(3):327–339. Margulies JL, Kallus L. Terbutaline-induced hypotension in a pregnant asthmatic patient. Am J Emerg Med. 1986;4(3):218–221. Silverman RA, Osborn H, Runge J, et al. IV magnesium sulfate in the treatment of acute severe asthma: A multicenter randomized controlled trial. Chest. 2002;122(2):489–497. Jain S, Hanania NA, Guntupalli KK. Ventilation of patients with asthma and obstructive lung disease. Crit Care Clin. 1998;14(4):685–705. Oddo M, Feihl F, Schaller MD, Perret C. Management of mechanical ventilation in acute severe asthma: Practical aspects. Intens Care Med. 2006;32(4):501–510. Schwaiberger D, Karcz M, Menk M, et al. Respiratory failure and mechanical ventilation in the pregnant patient. Crit Care Clin. 2016;32(1):85–95. George R, Berkenbosch JW, Fraser RF 2nd, Tobias JD. Mechanical ventilation during pregnancy using a helium-oxygen mixture in a patient with respiratory failure due to status asthmaticus. J Perinatol. 2001;21(6):395–398. Munakata M, Abe S, Fujimoto S, Kawakami Y. Bronchoalveolar lavage during third-trimester pregnancy in patients with status asthmaticus: A case report. Respiration. 1987;51(4):252–255. Schreier L, Cutler RM, Saigal V. Respiratory failure in asthma during the third trimester: Report of two cases. Am J Obstetr Gynecol. 1989;160(1):80–81. Gelber M, Sidi Y, Gassner S, et al. Uncontrollable life-threatening status asthmaticus: An indicator for termination of pregnancy by cesarean section. Respiration. 1984;46(3):320–322. Shanies HM, Venkataraman MT, Peter T. Reversal of intractable acute severe asthma by first-trimester termination of pregnancy. J Asthma. 1997;34(2):169–172. National Asthma Education Program. Management of asthma during pregnancy: Report of the Working Group on Asthma in Pregnancy. NIH Publication No. 93–3279. Bethesda: National Institutes of Health; 1993.

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26 Acute Respiratory Distress Syndrome in Pregnancy Dharani K. Narendra, Munish Sharma, David Muigai, and Kalpalatha K. Guntupalli Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX, USA

Introduction Acute respiratory distress syndrome (ARDS) is an important cause of acute hypoxic respiratory failure in pregnancy. Current literature is sparse on ARDS in pregnant women, and no randomized controlled trials have been conducted on any management strategies in pregnant women to date, and many trials exclude pregnant women. Therefore, management strategies are derived mainly from studies in nonpregnant patients, case reports, case series, and, notably, experience in managing hypoxemic respiratory failure in pregnant patients during the 2009–2010 influenza A (H1N1) pandemic. More recently, the management of ARDS as a manifestation of coronavirus disease 2019 (COVID-19) in the pregnant population has posed further challenges to clinicians around the globe. This unprecedented scenario has compelled clinicians to manage ARDS in the pregnant population more frequently. It has also further emphasized the need for more concrete and focused guidelines in ARDS for this special patient population. This chapter discusses the definition, epidemiology, pathophysiology, clinical features, and management of ARDS in pregnant patients.

Definition The definition of ARDS has undergone significant changes since the clinical entity was first described by Ashbaugh et al. in 1967 [1], when they coined the term adult respiratory distress syndrome after they described 12 patients with acute hypoxic respiratory failure refractory to supplemental oxygen, with reduced lung compliance and diffuse

bilateral infiltrates on chest radiograph. Murray et  al.  [2] expanded the definition in 1988, using four-point lung injury scoring based on the (1) ratio of partial pressure arterial oxygen to fraction of inspired oxygen (PaO2/FiO2), (2) level of positive end-expiratory pressure (PEEP), (3) lung compliance, and (4) degree of lung infiltrates on chest imaging. A score of ≥2.4 was considered to be consistent with ARDS. In 1994, the American–European Consensus Conference (AECC) [3] developed a concise definition that included: acute onset of severe respiratory distress, bilateral infiltrates on chest radiograph, pulmonary artery wedge pressure 18  mmHg, and no clinical signs of left heart failure. A PaO2/FiO2 300  was diagnosed as acute lung injury (ALI), and PaO2/FiO2 200 as ARDS. In 2012, the Berlin definition of ARDS was adopted [4]. It incorporated the following: (1) timing of disease – within one week of known clinical insult (e.g., pneumonia, sepsis, or aspiration); (2) bilateral alveolar infiltrates on chest radiograph not explained by pleural effusions, masses, or consolidation; and (3) severity of ARDS categorized by PaO2/FiO2 with the use of at least PEEP of 5 cm H2O [4]. ARDS was graded as mild when PaO2/FiO2 was 200–300, moderate when PaO2/FiO2 was 100–200, and severe when PaO2/FiO2 100. There was no role of pulmonary artery wedge pressure in the Berlin definition; instead, a noninvasive measurement such as an echocardiogram is recommended to exclude heart failure as the cause of alveolar infiltrates. The classification by the Berlin definition was validated and correlated with mortality, ventilator-free days, and the number of mechanical ventilator days in survivors. Mortality in ARDS increases with severity. Table  26.1 shows the key differences in severity and mortality between the AECC and Berlin definitions.

Critical Care Obstetrics, Seventh Edition. Edited by Luis D. Pacheco, Jeffrey P. Phelan, Torre L. Halscott, Leslie A. Moroz, Arthur J. Vaught, Antonio F. Saad, and Amir A. Shamshirsaz. © 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.

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Table 26.1 Severity and mortality comparison between AECC and Berlin definitions. Parameter

AECC [2]

Berlin [3]

Year published

1994

2012

Severity

ALI: 300

Mild: 200–300

PaO2/FiO2

ARDS: 200

Moderate: 100–200

(no inclusion of PEEP level)

Severe: 100 (on minimal CPAP or PEEP of 5 cm H2O)

Mortality %

ALI: 26 (23–29)

Mild: 27 (24–30)

Mean (range)

ARDS: 37 (35–38)

Moderate: 32 (29–34), severe: 45 (42–48)

AECC, American–European Consensus Conference; ALI, acute lung injury; ARDS, acute respiratory distress syndrome; CPAP, continuous positive airway pressure; PaO2/FiO2, ratio of partial pressure arterial oxygen and fraction of inspired oxygen; PEEP, positive endexpiratory pressure.

Epidemiology ARDS occurs more frequently in pregnancy than the 1.5 cases per 100,000 per year reported for the general population  [5,6]. Though difficult to accurately determine, the incidence of ARDS in pregnancy was reported to range from 16 to 70 per 100,000 pregnancies in the pre-COVID-19 era  [7]. The current pandemic seems to have inflicted a higher burden with around 12.2–13.4% of ARDS incidences reported in pregnant patients with COVID-19  [8,9]. Furthermore, pregnant women’s mortality is much higher compared to the general population, ranging between 40% and 60%  [5,10]. Within the ARDS population, mortality increases further when the cause is direct injury to the lung and when there is more organ system failure. In most cases, death results from multi-organ failure rather than from respiratory failure alone [6].

Pathophysiology and etiology As noted in Chapter 4, the physiological changes in the respiratory system during pregnancy include: decreased functional residual capacity, reduced chest wall compliance, higher airway pressures, elevated diaphragm, increased minute ventilation, and hyperemia/edema of the airways. Superimposed on these physiological changes are the inflammatory changes that occur in ARDS. ARDS is an acute-onset, diffuse, inflammatory lung injury condition that leads to increased capillary permeability, resulting in interstitial edema and hyaline membrane formation on the alveolar sacs. The hallmark pathological findings of ARDS are diffuse alveolar damage

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and hyaline membrane formation. Infiltration by neutrophilic inflammatory cells, macrophages, and erythrocytes is seen, with exudative fluid in the alveoli and interstitium. Ware and Matthay [11] described the pathophysiology of ARDS. Briefly, there are two types of alveolar epithelial cells: type I cells constitute 95% of the epithelial cells that line the alveoli and form tight junctions, and type II cells, which comprise the remaining 5% of epithelial cells, produce surfactant and transport ions. The type II cells can also differentiate into type I cells to repopulate the damaged alveolar lining during recovery from ALI. Alveolar and capillary endothelial injury is the predominant mechanism in the pathogenesis of ARDS. The degree of damage to the alveolar epithelium correlates with the severity of ARDS. Injury to type I alveolar epithelium leads to increased permeability and alveolar flooding, while injury to type II cells causes decreased surfactant production and repair of epithelium. Injury to the endothelial cells results in increased vascular permeability and interstitial edema. Pro-inflammatory markers such as interleukin-8, interleukin-10, and interleukin-11 and tumor necrosis factor-α (TNF-α) are also increased in alveolar sacs. Three stages of ARDS are recognized: the acute, proliferative, and resolution stages. Alveolar damage, interstitial edema, and hyaline membrane formation are seen in the acute stage. It is followed by the proliferative stage, largely characterized by interstitial inflammation. In the resolution stage, healing and repair begin; dysfunctional repair may lead to fibrosis. Not all patients necessarily progress through the three stages (Figure 26.1a,b). In pregnant patients, experimental data suggest a two-hit model in which increased pro-inflammatory cytokines due to pregnancy and parturition constitute the first hit, and an inciting event constitutes the second hit  [12]. The most common risk factors for ARDS complicating pregnancy are sepsis, pneumonia, aspiration of gastric contents, and amniotic fluid embolism (AFE) [12–14]. Table 26.2 outlines the various risk factors related to both pregnancy and non-pregnancy states. Important causes are elaborated in the following text.

Sepsis Sepsis is the most common cause of ARDS, accounting for 50% of all cases [10,15,16]. Pregnant women are susceptible to infections due to suppressed cell-mediated immunity. Acute pyelonephritis is the most common cause of sepsis in obstetric patients, with 1–2.5% of pregnancies. Pregnancyrelated urinary system dilatation, increased urinary volume and frequency, and untreated bacteriuria contribute to the pathogenesis of acute pyelonephritis. Escherichia coli remains the most common organism, and endotoxinmediated tissue damage can result in multiple organ dysfunction. Pregnant women are also at increased risk of

Pattoptysiooogy and etiooogy

(a)

Figure 26.1 (a) The normal alveolus (left-hand side) and the injured alveolus in the acute phase of acute respiratory distress syndrome (ARDS). In the acute phase of the syndrome (right-hand side), there is sloughing of both the bronchial and alveolar epithelial cells, with the formation of protein-rich hyaline membranes on the denuded basement membrane. Neutrophils are shown adhering to the injured capillary endothelium and marginating through the interstitium into the air space, which is filled with protein-rich edema fluid. In the air space, an alveolar macrophage is secreting cytokines; interleukin-1, interleukin-6, interleukin-8, and interleukin-10 (IL-1, IL-6, IL-8, and IL-10, respectively); and tumor necrosis factor-α (TNF-α), which act locally to stimulate chemotaxis and activate neutrophils. Macrophages also secrete other cytokines, including IL-1, IL-6, and IL-10. IL-1 can also stimulate the production of extracellular matrix by fibroblasts. Neutrophils can release oxidants, proteases, leukotrienes, and other proinflammatory molecules, such as platelet-activating factor (PAF). A number of anti-inflammatory mediators are also present in the alveolar milieu, including IL-1-receptor antagonist, soluble TNF receptor, autoantibodies against IL-8, and cytokines such as IL-10 and IL-11 (not shown). The influx of protein-rich edema fluid into the alveolus has led to the inactivation of surfactant. MIF, macrophage inhibitory factor. Source: Ware and Matthay [11]. Reproduced with permission from NEJM.

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(b)

Figure 26.1 (Continued) (b) Mechanisms important in the resolution of acute lung injury and the ARDS. On the left side of the alveolus, the alveolar epithelium is being repopulated by the proliferation and differentiation of alveolar type II cells. Resorption of alveolar edema fluid is shown at the base of the alveolus, with sodium and chloride being transported through the apical membrane of type II cells. Sodium is taken up by the epithelial sodium channel (ENaC) and through the basolateral membrane of type II cells by the sodium pump (Na+/K+-ATPase). The relevant pathways for chloride transport are unclear. Water is shown moving through water channels, the aquaporins, located primarily on type I cells. Some water may also cross by a paracellular route. Soluble protein is probably cleared primarily by paracellular diffusion and secondarily by endocytosis by alveolar epithelial cells. Macrophages remove insoluble protein and apoptotic neutrophils by phagocytosis. On the right side of the alveolus, the gradual remodeling and resolution of intra-alveolar and interstitial granulation tissue and fibrosis are shown. Source: Ware and Matthay [11]. Reproduced with permission from NEJM.

non-pulmonary sepsis such as septic abortion in antenatal period, endometritis in postnatal period, pneumonia (most commonly due to streptococcus pneumonia and influenza), and other infections with bacterial, viral (varicella), fungal (blastomycosis, coccidioidomycosis), and parasitic agents, including malaria  [17]. Chorioamnionitis may present with fever, uterine tenderness, foul-smelling amniotic fluid, and fetal tachycardia. In the appropriate clinical

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scenario, a diagnostic amniocentesis may be considered in patients with an unexplained cause of ARDS.

Aspiration First described in pregnant patients by Mendelson in 1946  [18], aspiration of gastric contents is an important cause of acute respiratory failure and ARDS in pregnancy.

Pattoptysiooogy and etiooogy

Table 26.2

or steroids in aspiration pneumonitis  [19]. Aspiration pneumonia, in contrast, requires antibiotic therapy.

Risk factors for ARDS.

Non-pregnancy-related factors

Pregnancy-related factors

Sepsis

Tocolytic-induced pulmonary edema

Pneumonia bacterial and viral, including COVID pneumonia Aspiration of gastric contents

Preeclampsia or eclampsia

Acute pancreatitis

Amniotic fluid embolism

Lung contusion

Placental abruption

Inhalational injury

Retained products of conception

Multiple transfusions Transfusion-related acute lung injury

Septic abortion

Fat embolism

Chorioamnionitis

Maternal infections

Burns

Endometritis

Drug overdose

Acute fatty liver of pregnancy

Trauma

Venous air embolism

Factors contributing to increased risk of aspiration in pregnancy include a reduced lower esophageal sphincter tone, delayed gastric motility and emptying, and increased intra-abdominal and gastric pressure from the enlarged uterus. Supine position during delivery predisposes to aspiration. The incidence of aspiration is higher with cesarean section compared to vaginal deliveries and in those undergoing general anesthesia. Aspiration of gastric contents leads to chemical pneumonitis. Aspiration can occur as silent microaspiration or overt large-volume aspiration of gastric contents. The degree of lung injury depends on the volume, pH, and size of the particles aspirated. There are two phases of response to aspiration. The acute phase is characterized by intense coughing and bronchospasm. The inflammatory phase, typically seen after 6–12 h, is characterized by increased capillary permeability and loss of surfactant leading to lung infiltrates, atelectasis, and hypoxemia [12,16,19]. This phase may lead to rapid recovery or progress to ARDS. Bacterial superinfection leading to pneumonia, lung necrosis, or abscess may occur after a few days [20]. It is important to note that vomiting is not essential for the diagnosis of aspiration formation. Clinical features include sudden onset of cough, wheezing, chest pain, dyspnea, and hypoxemia. Chest radiograph may or may not reveal pulmonary infiltrates depending on the timing of the imaging in the disease process. Treatment is supportive with left lateral positioning, oropharyngeal suctioning, and head-of-bed elevation. Bronchodilators are useful in patients who are wheezing. There is no role for antibiotics

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Preeclampsia Preeclampsia is one of the most common causes of intensive care unit (ICU) admission in pregnant patients. It is defined as the new onset of hypertension (systolic blood pressure >140  mmHg or diastolic blood pressure >90  mmHg) and proteinuria (>0.3 g/day) or new-onset hypertension along with evidence of end-organ dysfunction with or without proteinuria in a previously normotensive pregnant patient who is >20  weeks gestational age [21]. Pulmonary edema is seen in about 3% of patients with preeclampsia [22]. Factors contributing to pulmonary edema in preeclampsia are a combination of reduced oncotic pressure, elevated vascular hydrostatic pressure, and increased permeability of capillary membranes in the pulmonary vasculature. Patients may present with tachypnea, tachycardia, chest pain, and hypoxemia. Management includes fluid restriction, diuretics, supplemental oxygen, and antihypertensive agents that are safe in pregnancy. Maternal mortality has been reported as high as 26% in patients with preeclampsia in Latin American and Caribbean populations, while 9% in African and Asian populations  [21]. Preeclampsia is a common cause of pulmonary edema, but not ARDS.

Tocolytic-induced pulmonary edema Tocolytic-induced pulmonary edema (TPE) is an important cause of ARDS in pregnancy. Use of tocolytics such as terbutaline and ritodrine has been implicated in the causation of pulmonary edema in as high as 25.5% cases in a review of 62,917 consecutive deliveries over a period of 10 years [23]. The exact mechanism of TPE is unknown, but several factors may play a role, including drug-induced tachycardia, hyperdynamic state, myocardial dysfunction due to prolonged exposure to catecholamines, increased capillary permeability due to infection, and aggressive fluid resuscitation in response to maternal hypotension or tachycardia. Risk factors for TPE are multiple gestation, infection, and corticosteroid therapy. Management of TPE includes stopping the drug, diuresis, and supportive care. This condition is uncommon in current practice, as β2agonists are no longer indicated for long-term use.

Amniotic fluid embolism AFE is believed to result from amniotic fluid elements entering the maternal circulation. AFE may occur after uterine manipulation, during labor, or delivery. Incidence is around

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7.7 per 100,000 pregnancies. Mortality rates, as high as 86%, have decreased to less than 25%. AFEs account for 14% of all maternal deaths [24]. Clinical features include sudden onset of dyspnea with hypoxia, followed by seizures, hypotension, cardiac arrest, and disseminated intravascular coagulation (DIC) [19]. Management is mainly supportive and is aimed at restoring hemodynamic stability.

Transfusion-related acute lung injury (TRALI) TRALI can occur after transfusion of blood products such as packed red blood cells, fresh frozen plasma, platelets, and cryoprecipitate. Clinical features include sudden or gradual onset of dyspnea and hypoxia a few hours after a blood or blood product transfusion (symptoms must occur within 6 h of administration of blood products). Management of TRALI includes diuresis, supplemental oxygen, and supportive care.

Venous air embolism Venous air embolism is a rare cause of ARDS. It may occur after cesarean delivery, after instrumentation during delivery, uterine manipulation, and, uncommonly, after orogenital sexual acts during pregnancy [25,26].

Figure 26.2 Chest radiograph of a 26-year-old woman at 32 weeks of gestation, with post influenza complicated by Staphylococcus aureus pneumonia, shows diffuse bilateral opacities with no cardiomegaly or pleural effusion. See the computed tomography (CT) of chest of the same patient in Figure 26.3.

(a)

Clinical features ARDS presents with a wide spectrum of signs and symptoms, including acute/subacute onset of shortness of breath, tachypnea, use of accessory muscles of breathing, confusion, tachycardia, and hypotension. Hypoxemia, in general, is refractory to supplemental oxygen. Physical examination may reveal overt respiratory distress and bibasilar crackles in the lungs without peripheral edema or elevated jugulovenous distension. An electrocardiogram may show normal heart rate or sinus tachycardia. Chest radiography typically shows bilateral diffuse alveolar and interstitial infiltrates without cardiomegaly and pleural effusions (Figure  26.2). Radiographic studies in pregnant patients should employ a protective shield to the abdomen. Computerized tomography (CT) of the chest without contrast may also be obtained and is generally considered safe in pregnancy. CT chest will show bilateral consolidation, air bronchograms with predominant involvement of dependent and dorsal areas, and decreased aerated tissue. The coronal view depicts the lung’s involvement better than the axial view (see Figure 26.3a,b). Arterial blood gas reveals hypoxemia with a wide A–a gradient. Serial blood gas analysis is often needed to assess response to therapy, and monitor for hypercapnia and acid– base status to further guide management. Bedside critical

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120 mm

(b)

Figure 26.3 (a) and (b) Axial and coronal views of computerized tomography of chest without contrast, showing bilateral extensive air space disease and air bronchograms with predominant dorsal and basal involvement, but no pleural effusion is seen.

Management

care ultrasound (CCUS) shows more than 3 B lines in multiple chest views (suggestive of alveolar/interstitial edema), absence of pleural effusion, and normal ejection fraction of the left ventricle that is useful to diagnose a noncardiogenic nature of pulmonary edema. Acute cor pulmonale with right ventricular pump failure and pulmonary hypertension are indicators of worse outcomes in ARDS [27].

Management The management of ARDS in pregnancy is complicated, as it requires a multidisciplinary approach that addresses both maternal and fetal aspects of care. Management should be in the ICU with a team consisting of intensivists, maternal–fetal medicine specialists, anesthesiologists, neonatologists (depending on the stage of gestation), critical care nursing, and respiratory therapists. Support from a clinical pharmacist, nutritionist, and physical therapist is also recommended  [28]. Where needed, arrangements should be made as early as possible to transfer the patient to an institution with the capacity, expertise, experience, and resources to manage high-risk pregnant patients and neonates. Such an institution would ideally have a wellestablished ARDS care escalation pathway. Throughout the patient’s care, there should be ongoing communication between the different clinical services about goals of care and triggers for further escalation. At all points of escalation, there should also be an ongoing discussion about the risk versus benefit of delivering the fetus. An example of an ARDS care pathway is shown in the adjunct algorithm. Clinical management of ARDS in pregnancy involves early recognition and diagnosis of ARDS, reversal of the inciting cause, and supportive care directed at avoiding hypoxemia without compromising the health of the mother and fetus. Under-recognition of ARDS has the potential to delay appropriate care, leading to harm to both mother and fetus. Adopting the 2012 Berlin definition of ARDS has made it easier to identify ARDS patients earlier by eliminating the ALI category. Any pregnant patient with a PaO2/ FiO2 ratio of 300 mmHg should at the very least be considered to have mild ARDS, among other causes, and should warrant increased acuity of care and serious consideration to entering the ARDS care pathway. Close monitoring of the mother in a critical care setting and fetal monitoring whose intensity is matched to gestation are essential. Maternal hypoxemia, which is detrimental to both mother and fetus, should be avoided and addressed aggressively. It is often necessary to have an indwelling arterial line to facilitate frequent blood gas sampling and hemodynamic monitoring to guide therapy. Maternal PaO2 is more reflective of fetal oxygenation than

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arterial oxygen saturation. In contrast to the nonpregnant ARDS population, the goal of maternal PaO2 is >70 mmHg (compared to PaO2 of 55–80 mmHg in the ARDSnet protocol). The goal of PaCO2 should match the pregnant physiologic 28–32 mmHg as much as possible. Mild hypercapnia, which may be associated with increased uterine blood flow,  may be tolerated for short periods, but excessive hypercapnia (PaCO2 > 60 mmHg) and hypocapnia (PaCO2 < 22  mmHg) are associated with reduced uterine blood flow, fetal hypoxemia, and acidosis. Specific therapies in the ARDS care pathway include those discussed in the following subsections.

High-flow oxygen therapy (HFOT) High-flow oxygen therapy, available under several proprietary names, refers to heated and humidified oxygen delivered via a blender by nasal cannula or prongs at higher than conventional flows (16–60 L/min). It has been shown in animal and limited clinical studies to reduce hypoxemia and work of breathing. Some of the mechanisms thought to be at play are: elimination of nasopharyngeal dead space, reduced dilution of inspired oxygen, increase in the reservoir of oxygen in the upper airways, application of positive airway pressure (estimated as 1 cm/H2O for every added 10 L/min flow), improved ciliary function, mucokinesis, and patient comfort [29]. Evidence from nonpregnant critically ill patients with acute respiratory failure from various causes shows that HFOT does not significantly lower the intubation rate in ARDS compared to oxygen delivered through face mask or noninvasive positive pressure ventilator. However, it has been associated with greater number of ventilator-free days and a higher 90-day survival compared to other noninvasive modes of supplemental oxygenation  [30,31]. Other recent studies have failed to demonstrate a benefit of HFOT compared to conventional oxygen therapy. HFOT may reduce heart rate, respiratory rate, subclavicular retraction, and thoracoabdominal asynchrony compared to conventional oxygen therapy [32]. It is more comfortable than an aerosol face mask [33]. It can also potentially allow patients to drink liquid, eat food, and have better mobility than positive pressure noninvasive ventilation. However, HFOT is more likely to fail in patients on vasopressors  [34], and when the duration between the time of initiation and admission to ICU is prolonged [35]. There are no formal studies on the use of HFOT in pregnancy, but the pregnant patient in acute hypoxemic respiratory failure, with baseline raised respiratory drive, fits the patient’s phenotype who might benefit from early use of HFOT. Extrapolating from the available evidence in the nonpregnant patient population, HFOT can improve

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oxygenation, decrease work of breathing, and possibly prevent intubation or noninvasive ventilation while minimizing discomfort. A trial of HFOT must be closely monitored to achieve a measurable clinical improvement within an hour of initiation. Evidence of clinical improvement includes improved oxygenation and decreased work of breathing, manifested as a reduction in respiratory and heart rates. If no improvement is seen within a reasonable period, endotracheal intubation is recommended. HFOT has been used as part of the strategy in the management of respiratory failure in pregnancy due to COVID. Concern for increased viral dissemination due to the high flows is reduced by placing a surgical mask over the nose and mouth.

Noninvasive positive pressure ventilation (NIPPV) Noninvasive ventilation in pregnancy was first used in patients with severe kyphoscoliosis or severe neuromuscular disease requiring respiratory support, particularly in the second and third trimesters when unable to sustain the required work of breathing [36]. Advancements in delivery technology and the first-line use of NIPPV in adults for acute exacerbations of chronic obstructive pulmonary disease (COPD) and acute cardiogenic pulmonary edema have made it more widely available in ICUs [37]. The use of NIPPV in ARDS remained sparse until the 2009–2010 H1N1 pandemic. A prospective multicenter study in 2012 that utilized early initiation of NIPPV during the H1N1 pandemic reported a 48% success rate in avoiding invasive ventilation  [38]. During and after H1N1 pandemic, more reports of the NIPPV rescue therapy began to be published in pregnant patients. Besides the H1N1 pandemic, few other authors have described case reports and series on utility of NIPPV in ARDS among pregnant patients caused by a multitude of causes such as sepsis, communityacquired pneumonia, all-trans-retinoic-acid syndrome, among others. In another such example, Al-Ansari et  al. described four cases of ARDS due to acute chest syndrome in four pregnant patients with sickle cell disease. Authors described avoidance of invasive ventilation with timely initiation of NIPPV [39]. Different noninvasive ventilation (NIV) delivery interfaces are available, including full head helmet, full face mask, nasal mask, and nasal pillows. Advantages of NIV include avoidance of intubation and intubationrelated injuries, decreased need for sedation, less immobility, and fewer ventilator-associated adverse events, including infection. The disadvantages of NIV include reduced secretion clearance, discomfort, and facial trauma from the mask. Because of the increased risk of aspiration due to physiological changes during pregnancy,

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it has traditionally been considered a contraindication to NIV. The risk of ongoing silent aspiration is greater with the use of the full face mask. Precautions employed to mitigate aspiration risk include using a nasal mask and nasal pillows allowing the mouth to be free to open if needed, keeping the patient NPO (nil per os, or nothing taken orally), and having an indwelling continuously decompressing gastric tube. Extrapolating from studies of nonpregnant adults with hypoxemic respiratory failure, NIV may have a role in decreasing work of breathing, improve gas exchange, and minimize the use of sedation. Similar to HFOT therapy, NIV should be considered an early trial therapy to be administered in a closely monitored ICU setting to achieve measurable clinical improvement within a short time. It is often helpful to define specific goals of improvement at the point of commencing the NIV trial. NIV is contraindicated where there is vomiting, excessive airway secretions, unsustainable work of breathing, and altered mental status. The COVID pandemic has allowed us experience with noninvasive ventilation in respiratory failure.

Positive pressure ventilation: invasive ventilation Invasive mechanical ventilation should be considered and implemented early, after either HFOT or NIV failure, or immediately if there is apparent unsustainable work of breathing, altered mental status, significant respiratory or metabolic acidosis, or life-threatening hypoxemia. At this point in the care pathway, if not already ongoing, serious consideration should be given toward the risk–benefit ratio of delivering the fetus. There can be potential difficulties in endotracheal intubation mainly due to the gravid uterus (decreased functional residual capacity) and alterations in upper airway anatomy (edema and mucosal friability). Thus, an experienced operator should attempt endotracheal intubation. The advantages of invasive ventilation include delivery of precise FiO2, minute ventilation, decreased work of breathing, and protection of the airway; it serves as a bridge to salvage therapy when conventional therapies fail to reverse severe refractory hypoxemia. Disadvantages unique to the pregnant population include risks in the peri-intubation period due to an anatomically and physiologically difficult airway, peri-intubation hypoxemia due to reduced respiratory reserve, and increased risk of aspiration. Once intubated, the challenge is to maintain physiologically adequate blood gases while minimizing ventilator-induced lung injury (VILI) and using the lowest dose of effective sedation. There are no randomized trials of mechanical ventilation in pregnant ARDS patients. However, the majority of the aspects of instituting and maintaining mechanical

Management

ventilation strategies are similar in pregnant and nonpregnant patients. Perhaps one of the stark differences lies in the target partial pressure of carbon dioxide (PaCO2) in arterial blood. In normal physiological milieu of pregnancy, due to respiratory stimulation by progesterone, arterial pH ranges from 7.40 to 7.47 with average PaCO2 around 32 mmHg. Thus, clinicians should adjust minute ventilation to maintain PaCO2 between 30 and 32 mmHg to mirror normal physiological state in pregnancy. The concept of permissive hypercapnia is detrimental and ensues fetal respiratory acidosis, while significant respiratory alkalosis (especially with PaCO2 < 30  mmHg) causes decreased uterine blood flow  [40,41]. Reducing mortality using a lung-protective low-tidal-volume ventilation strategy in nonpregnant patients would hold true for pregnant patients with ARDS. Lung-protective ventilation is thought to prevent VILI by avoiding overdistension of the alveoli and the repetitive opening and closing of atelectatic lung units. VILI can initiate a cascade of pro-inflammatory cytokines release, leading to systemic inflammatory response syndrome (SIRS) and multi-organ failure. In the landmark National Institutes of Health (NIH)–sponsored ARDS network randomized trial  [42], 861 patients with ALI and ARDS were randomized to tidal volumes of 12 mL/kg ideal body weight (high-tidal-volume group) and 6 mL/kg ideal body weight (low-tidal-volume group). Results demonstrated a 22% relative risk reduction in mortality favoring the low-tidal-volume group (absolute mortality rates 39.8% vs. 31%, p = 0.007). The trial employed a detailed algorithm to titrate FiO2 and PEEP, maintaining plateau pressures below 30  cm H2O (Table  26.3). However, a high-PEEP approach has not shown mortality benefits in the 2004 ARDSnet trial [43]. A 2010 meta-analysis confirmed similar results, with a subgroup of ARDS patients receiving higher PEEP showing a trend toward improved survival (mainly patients with a P/F ratio less than 200) [44]. PEEP may be selected according to the severity of the disease, as in mild ARDS: 5–10  cm H2O PEEP; moderate ARDS: 10–15  cm H2O PEEP; and severe ARDS: 15–20  cm H2O PEEP  [45]. Though optimal PaO2 and peripheral oxygen saturation in mechanically ventilated pregnant patients are not clearly established, it is reasonable to adjust PEEP and FiO2 to maintain PaO2 > 70 mmHg. The ARDSnet protocol recommends decreasing tidal volume by 1 mL/kg (lowest: 4 mL/kg) if plateau pressure is more than 30  cm H2O. However, plateau pressures less than 30 cm H2O may not be achievable in obese patients or those in late pregnancy due to the high intra-abdominal pressures. In such cases, monitoring transpulmonary pressures may be helpful. For respiratory acidosis with pH 7.15–7.3, the respiratory rate is increased to a maximum of 35 until pH is more than 7.3 or PaCO2 < 25. If pH 7.15 or sodium bicarbonate can be infused, though the benefit of which is debatable in pregnancy. Using a spontaneous breathing trial (SBT), weaning from mechanical ventilation should be attempted when FiO2 is 0.5 and PEEP 8 cm H2O. An SBT is performed with continuous positive airway pressure (CPAP) 5 cm H2O and pressure support 8. If tolerated well for 30 min, extubation may be considered. Successful parameters include no signs of respiratory distress, rapid shallow breathing index (RSBI; the ratio of spontaneous respiratory rate and tidal volume) 92%)

Absolute contraindications ⧠ Hemodynamic instability or life-threatening arrythmia ⧠ Non-reassuring fetal status requiring immediate delivery ⧠ Spinal instability ⧠ Increased intracranial pressure ⧠ Concern for acute respiratory decompensation requiring intubation (*awake only) ⧠ Unable to communicate or cooperate with the procedure (agitation, AMS) (*awake

Yes

only)

Relative contraindications

Continue supine

⧠ Recent

tracheal, thoracoabdominal surgery or trauma, or cesarean delivery within last 48 h injury, chest tubes, massive hemoptysis, cardiac pacemaker, ventricular assist device ⧠ Estimated gestational age ≥34 weeks ⧠ Facial

No

Intubated

Awake

Before prone positioning

Before prone positioning ⧠ If

possible, stop enteral feeds at least 1 h ⧠ Assemble the team (minimum 5 people, 2 per side, 1 at head for airway, plus 1 for directing and for feet, if available) ⧠ Sedate to RASS-4, give neuromuscular blockers, obtain ABG to optimize settings before positioning; monitor withh BIS or nerve stimulator; neuromuscular blockade precautions ⧠ Secure lines (Foley, arterial, peripheral and central lines, drains, chest tubes), remove ECG electrodes

⧠ If

possible, NPO at least 1 h ⧠ Explain procedure and goals, obtain patient assent ⧠ Introduce team (minimum 2 people, 1 per side) ⧠ Secure lines (Foley, arterial, peripheral and central lines, drains, chest tubes) ⧠ Confirm O delivery device well connected 2 and increase O2 to max setting (6 L for low flow nasal cannula) ⧠ Move ECG leads to back (mirror image)

Prone positioning procedure ⧠ Place

Prone positioning procedure ⧠ Have

patient lie on her side facing the O2 delivery device while placing padding ⧠ Place pillows or blankets to support head and neck and offload the breasts and uterus (e.g. 3 pillows at head, 2 chest, 2 pelvis, 2 under lower legs) ⧠ Have the patient turn over onto the pillows (recommend position on knees then lay down) ⧠ Adjust pillows for patient comfort (consider possible engorgement of breasts postpartum) ⧠ Position arms overhead or to the side, or 1 of each “swimmer’s position” (change every 2 hours) ⧠ Place bed in “reverse Trendelenburg” (~10°) ⧠ Adjust fetal monitors as needed ⧠ Confirm all lines and tubing not pressing against skin ⧠ Readjust O settings to pre-prone settings 2

YES

⧠ SpO ⧠ No

clean sheet under patient ⧠ Arm closest to ventilator is tucked underneath buttocks withh palm facing up ⧠ Place padding onto the patient (e.g. 2 pillows at the chest, pelvis, and under lower legs) ⧠ Clean bed sheet should be placed on top of pillows ⧠ Roll sides of bed sheets together encasing the patient (cocoon) ⧠ Slide patient horizontally to lie on the edge of bed away from vantilator ⧠ The person at the head holds ETT tube, counts, and directs move of patient 90° to lie on their side, facing the ventilator ⧠ Staff will change hand positions to hold the opposite side of the sheet and turn patient to prone position ⧠ Person at the head of bed ensures patient head and neck position, position of ETT and that CO2 present on capnography ⧠ Note the depth of the ETT at the teeth and review ventilator settings ⧠ Reattach the ECG electrodes to the back (mirror image) ⧠ Re-establish all monitoring (maternal and fetal) ⧠ Place pad under patient’s head to absorb secretions ⧠ Position arms in the “swimmer’s position” (change head and arm positions every 2 h) ⧠ Place bed in “reverse Trendelenburg” (~10°) ⧠ Confirm all lines and tubing not pressing against skin ⧠ ABG after 30 min, then after 2 h

Monitor O2 saturation for 15 min

≥95% (postpartum SpO2 >92%) signs of obvious distress or discomfort

Continue ⧠ Goal

NO

2

prone time 2 h (awake patients); may modify to shorter duration or lateral positions as needed; intubated patients–discuss prone time with ICU team ⧠ When not prone, aim to elevate head of bed 30° ⧠ Monitor O saturations after every position change 2 ⧠ Wean O requirements as able 2

If deteriorating oxygen saturations ⧠ Ensure

O2 is connected to patient inspired O2 patient’s position, consider return to supine

⧠ Increase ⧠ Change

Discontinue prone positioning ⧠ No

improvement with change of position ⧠ Cardiac arrest impending or occurring ⧠ Patient unable to tolerate position ⧠ Concern for acute respiratory decompensation requiring intubation (*awake only)

Tolcher MC, McKinney JR, Eppes CS, Muigai D, Shamshirsaz A, Guntupalli KK, et al. Prone positioning for pregnant women with hypoxemia due to coronavirus disease 2019 (COVID-19). Obstet Gynecol 2020;136. The authors provided this information as a supplement to their article. © 2020 American College of Obstetricians and Gynecologists.

Figure 26.4 A published practice guideline for prone positioning for pregnant women with hypoxemia due to coronavirus disease 2019. Published with permission.

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Acute Respiratory Distress Syndrome in Pregnancy Oxygenated blood

Figure 26.5 Extracorporeal membrane oxygenation cannulation: deoxygenated blood leaving from right femoral venous cannula and oxygenated blood entering into the right internal jugular venous cannula in a pregnant patient.

Pump oxygenator heater

Deoxygenated blood

cardiopulmonary failure between January 1, 2008 and December 31, 2017. Of these patients, 17% (9 patients) were pregnant or postpartum (350 IU/L AST >250 IU/L Within 48 h Decrease in hematocrit >10% Increase in BUN >5 mg/dL Calcium 6 L Gallstone pancreatitis On admission Age >70 years WBC >18,000/mm3 Glucose >220 mg/dL LDH >400 IU/L AST >250 IU/L Within 48 h Decrease in hematocrit >10% Increase in BUN >2 mg/dL Calcium 5 mmol/L Fluid deficit >4 L AST, aspartate aminotransferase; BUN, blood urea nitrogen; LDH, lactate dehydrogenase; WBC, white blood cells. Source: Refs. Scout et al. [45], Ranson [80], Ranson et al. [81].

An additional five variables were added to APACHE II, leading to the APACHE III [83]. Unlike Ranson’s criteria [79–81], the APACHE III [83] can be updated and the patient’s course monitored on a continuing basis. This system calculates scores based on deviation from normal values. A 5-point increase in score is independently associated with a statistically significant increase in the relative risk of hospital death within a specific disease category. Within 24 h of admission, 95% of patients admitted to the intensive care unit could be given a risk estimate for death within 3% of that actually observed  [83]. Although more complex and computer dependent, the APACHE scoring system appears more accurate than Ranson’s criteria in predicting morbidity [84]. The addition of body mass index seems to improve prediction, as obesity predicts severity [85].

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Acute Pancreatitis

Several single prognostic indicators have been investigated in order to achieve early identification of pancreatic necrosis. Paracentesis can be performed; return of dark, prune-colored fluid is characteristic of necrotizing pancreatitis. Utilizing color charts, Mayer and McMahon  [86] identified 90% of the patients who subsequently died and 72% of patients with severe morbidity. Biochemical indicators that have been evaluated as predictors of severity of disease include C-reactive protein  [87,88], trypsinogen activation peptide  [89–91], procalcitonin  [92,93], thrombomodulin  [87], and serum amyloid A [88]. Only C-reactive protein is currently used clinically, but it is limited in that it is predictive only after 48–72 h following onset of symptoms. While interleukin-6, trypsinogen activation peptide, and granulocyte nuclear elastase all show promise in acutely identifying patients destined for a severe clinical course, they await confirmatory trials and widespread acceptance into routine clinical use. Compared with scoring systems and laboratory markers, contrast-enhanced CT scans offer broader information regarding intra-abdominal anatomy. The location and extent of necrosis are identified and can be serially evaluated. Infection within pseudocysts is suggested by evidence of gas production. This test, however, may be limited in its availability and is difficult to obtain in severely ill patients. MRI has been shown to be as effective as CT for staging acute pancreatitis [94].

­Management Initial management A team approach involving the obstetrician, gastroenterologist with experience in ERCP, surgeon, and radiologist should be adopted in the management of acute pancreatitis in pregnancy. Treatment of acute pancreatitis in pregnancy is similar to that of non-pregnant individuals. However, additional measures during pregnancy include fetal monitoring and attention to positioning of the mother to avoid compression of the inferior vena cava. The initial treatment of acute pancreatitis is supportive medical management. Because most cases are mild and self-limiting, this approach is largely successful. Correction of any underlying predisposing factors, such as avoidance or cessation of exacerbating factors like alcohol or drugs, and reversal of hypercalcemia are basic principles to be observed. Assessment of prognostic indicators, as discussed in this chapter, permits appropriate surveillance. Patients with more severe disease should be transferred to an intensive

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care unit for continuous monitoring, because shock and pulmonary failure can present early in the course of disease and require prompt recognition and management. Medical therapy is composed of fluid and electrolyte management, adequate analgesia, and elimination of oral intake to suppress exocrine function of the pancreas, thereby preventing autodigestion of the pancreas. Intravenous fluid resuscitation is a vital component of treatment in both mild and severe cases. Restoration of intravascular volume and avoidance of hypotension are important for cardiovascular stability and renal perfusion. Early aggressive fluid resuscitation with isotonic crystalloid fluids (lactated Ringer’s) in the first 24 h of admission is recommended  [95]. In early severe acute pancreatitis, fluid requirements of 150–300 mL/h may be needed. Input should be titrated to target a urine output of 0.5 mL/kg/h [96]. Electrolyte abnormalities are common, including hypokalemia and metabolic alkalosis from severe vomiting and hypocalcemia from fat saponification. Serial assessment of electrolytes and appropriate replacement are essential. Parenteral analgesia is frequently necessary; morphine compounds, however, should be avoided secondary to their actions on the sphincter of Oddi. For nutrition, oral intake should be encouraged provided that pain is controlled and the patient is otherwise clinically improving [97]. However, oral intake is withheld in patients with hypertriglyceridemia-induced acute pancreatitis [98]. Most patients with mild pancreatitis, if unable to eat, can be managed with intravenous fluids since the clinical course is usually uncomplicated, and a low-fat diet can be started within 3–5  days. Nutrition should also be implemented early in the hospital course in patients with severe disease. Enteral feeding may have advantages over parenteral, because it has the potential benefit of maintaining the intestinal barrier (it is felt that bacterial translocation is probably the major source of infection). Enteral nutrition also avoids catheter-related complications of parenteral nutrition, such as line sepsis [99,100]. Nasogastric suction may be appropriate in a subset of patients with acute pancreatitis. Nasogastric suction, however, does not appear to influence duration of disease or its symptoms. Several studies have investigated the role of nasogastric suction in mild to moderate pancreatitis and found no difference in duration of abdominal pain, tenderness, nausea, and elevated pancreatic enzymes or time to resumption of oral feeding [101–103]. Therefore, nasogastric suction should be utilized on an elective basis for symptomatic relief for those patients with severe emesis or ileus. Prophylactic antibiotics also have been advocated in an  effort to prevent the development of infectious

Management

complications. Mild cases of pancreatitis do not appear to benefit from antibiotic prophylaxis, although studies are few  [104,105]. In contrast, severe cases with pancreatic necrosis have a high rate (40%) of bacterial contamination and represent a subset of patients that may benefit from antibiotic administration [106]. A study of 74 patients with acute necrotizing pancreatitis treated with prophylactic imipenem demonstrated a significantly decreased incidence of pancreatic sepsis (12% vs. 30%)  [107]. Similar results were observed by Sainio and colleagues  [108]. However, more contemporary reports recommend antibiotics only for patients with proven infections such as infected pancreatic necrosis [109,110]. Antienzyme and hormonal therapies have been designed to reduce the severity of disease by halting the production of pancreatic enzymes and the subsequent cascade activation of the complement, kallikrein–kinin, fibrinolytic, and coagulation systems. Studies evaluating atropine, calcitonin, glucagon, somatostatin, and the enzyme inhibitors aprotinin and gabexate, however, have not shown improved morbidity or mortality in severe acute pancreatitis [21,60]. Octreotide, a somatostatin analog, has received considerable attention as a means to improve the course of acute pancreatitis. Five randomized trials have been performed  [111–115] that failed to demonstrate a clinical benefit.

Management of underlying predisposing conditions Biliary pancreatitis

The goals of biliary surgery in cases of gallstone pancreatitis are to prevent recurrence and to decrease morbidity and  mortality by removing the instigating agent. Cholecystectomy and bile duct exploration are not performed, however, during the acute episode. Because nearly 95% of stones pass during the first week of illness, the utility of surgery early in the illness does not weigh heavily against the high mortality rates that have been reported for early biliary surgery [116]. While not indicated in the acute phase of illness, on resolution of acute pancreatitis, cholecystectomy is typically performed in a non-pregnant patient prior to discharge from the hospital. Pregnancy can pose limits to both diagnostic and surgical options. Expectant management during the pregnancy, once the norm [9,117], has been challenged by reports of higher recurrence rates among patients receiving expectant management for gallstone pancreatitis  [15,118]. A 20–30% relapse rate in the general population was noted  [12,13,119], whereas a high relapse rate of 50–70% during the same pregnancy was often encountered [12,15]. A report described the incidences of recurrent episodes of acute gallstone pancreatitis in pregnancy in patients who

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presented in the first, second, and third trimesters of 92%, 64%, and 44%, respectively  [120]. Surgical intervention decreases the incidence of relapse and the risk of systemic complications. In addition, good outcomes were noted among pregnant patients with acute pancreatitis who underwent laparoscopic cholecystectomy  [118,121–126], ERCP, and endoscopic sphincterotomy [127–129]. The management of acute pancreatitis in pregnancy with gallstones and common bile stones raises the issue of timing of surgery. There is no consensus on when to perform cholecystectomy, with some recommending intervention for worsening or recurrent pancreatitis and obstructive jaundice. Some suggest cholecystectomy in all trimesters [15,118], while others advocate intervening in the second trimester for presenting cases in the first or second trimesters and postpartum for cases presenting in the third trimester  [9,12]. Several studies support second-trimester cholecystectomy for pancreatitis [1,9,12,122,130]. The second trimester appears optimal in order to avoid medication effect on organogenesis and a possible increased rate of spontaneous abortion in the first trimester [1,9,12,122,130]. Third-trimester patients are best managed conservatively because they are close to the postpartum period when operative risks are reduced. Cholecystectomy may be performed by laparotomy or open laparoscopy. The open technique for the laparoscopic approach is often best, to avoid puncture of the gravid uterus with blind trocar insertion. Fetal loss following cholecystectomy was once reported to be as high as 15% [131]. Many earlier reports, however, included patients undergoing surgery in the first trimester and then suffering spontaneous abortion many weeks postoperatively. Because at least 15% of all pregnancies are now known to end in spontaneous abortion, and preterm labor is seen in up to 10% of all continuing pregnancies, it would appear that the actual rate of complications related to surgery probably approaches nil, a figure confirmed by several recent studies [12,132,133]. A review of studies from 1963 to 1987, evaluating fetal loss in patients undergoing cholecystectomy, revealed an 8% spontaneous abortion rate and an 8% rate of premature labor [132]. In a similar manner, laparoscopic cholecystectomy in the second trimester has been reported in a small number of patients, with no increase in fetal or maternal morbidity or mortality [134]. A literature review identified 197 pregnant patients in 20 studies who underwent laparoscopic cholecystectomy without any maternal deaths [14]. An alternative to open surgical removal of bile duct stones has been developed utilizing ERCP. ERCP with sphincterotomy and removal of bile duct stones is indicated in patients with cholangitis and severe acute pancreatitis, and in those who are post-cholecystectomy or poor candidates for surgical therapy [135]. It is also indicated for the

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prevention of recurrence of acute pancreatitis during the third trimester of pregnancy [77]. Choledocholithiasis that causes cholangitis and pancreatitis during pregnancy increases the risk of morbidity and mortality for both the fetus and mother. Combined with endoscopic sphincterotomy, ERCP offers both diagnostic and therapeutic advantages in the critically ill patient  [136,137]. If performed within the first 72 h of illness, this procedure has been shown to decrease morbidity and length of hospital stay in patients with severe pancreatitis [137,138]. ERCP has been used in a number of pregnant patients without complications and has been found advantageous in the avoidance of the potential risks of major surgery during pregnancy  [54,56,127–129,139]. ERCP is safe during pregnancy and may be performed with modified techniques to reduce radiation exposure to the fetus and without fluoroscopy  [54,56,140]. A maximum dose of 3 mGy to the fetus was noted during the 3 min of fluoroscopy [141]. If there is radiation exposure during ERCP, the dosimetry should be routinely recorded. The risk of ERCPinduced acute pancreatitis is approximately 5% without adverse outcome if the procedure is performed by an experienced surgeon. A recent multimodal approach to acute pancreatitis during pregnancy has been published [142] that recommends MRCP, ERCP, and sphincterotomy followed by laparoscopic cholecystectomy. In summary, there are no published standardized guidelines regarding the most effective management of acute biliary pancreatitis in pregnant women to lower the maternal and fetal morbidity and mortality. The following treatment strategy according to the gestation age has been proposed [143,144]: 1) First trimester: Conservative treatment, and laparoscopic cholecystectomy during second trimester. 2) Second trimester: Laparoscopic cholecystectomy. 3) Third trimester: Conservative treatment or ERCP with biliary endoscopic sphincterotomy, and laparoscopic cholecystectomy in the early postpartum period. However, concerns about fetal safety should not overshadow any decision to proceed with any invasive intervention when it is needed. Hypertriglyceridemia

Once the diagnosis of hypertriglyceridemia-induced acute pancreatitis in pregnancy is made, rapid lowering of triglyceride levels is crucial. 1) Therapeutic plasma exchange (TPE) It is recommended that TPE be used early in cases of severe pancreatitis [145]. TPE rapidly removes and lowers triglycerides and chylomicrons. TPE also serves to

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reduce inflammatory cytokines and replace deficient lipoprotein lipase or apolipoproteins when plasma is used as the replacement fluid [146]. 2) Insulin Intravenous insulin enhances lipoprotein lipase activity and increases chylomicron degradation, thus reducing triglyceride levels  [147]. To maintain euglycemia, the insulin should be infused with a dextrose infusion with close monitoring of the electrolytes [148]. 3) Heparin Heparin activates the release of lipoprotein lipase from endothelial cells  [149]. However, the potential benefit must be weighed against the risk of bleeding with hemorrhagic pancreatitis or other surgical procedures. In addition, long-term heparin may cause hypertriglyceridemia by depleting the lipoprotein lipase. [150]. 4) Diet and pharmacotherapy In the non-acute setting, omega-3 fatty acids, which increase lipoprotein lipase activity, are safe to use in pregnancy. Dietary modification includes a very-low-fat diet and avoidance of high-glycemic-index foods [18].

Management of complications Surgery for early and late complications of pancreatitis has also been the subject of considerable discussion. A few situations appear to be clear indications for surgical intervention, such as acute, life-threatening hemorrhage. However, the timing and type of surgical procedures for later complications, such as sterile necrosis, pseudocyst, and abscess, are less straightforward. Using the development or persistence of organ failure despite 72 h of intensive medical therapy as indications for surgery, Gotzinger and colleagues [151] reported on 340 patients who underwent surgical exploration for acute pancreatitis. Control of pancreatic necrosis (total removal of necrotic tissue) was accomplished in 73% of patients, requiring an average of 2.1 operations. Mortality was 100% in patients in whom surgical control of necrosis could not be accomplished versus 19% in those patients who did achieve surgical control of necrosis. Arterial hemorrhage occurs in 2% of patients with severe pancreatitis. Necrosis and erosion into surrounding arteries of the gastrointestinal tract result in massive intraabdominal or retroperitoneal hemorrhage. Arteriographic embolization followed by surgical debridement and artery ligation improved survival from 0 to 40% [152]. In contrast, the development of sterile pancreatic necrosis is not an automatic indication for surgery, because up to 70% of cases will resolve spontaneously. While few studies have been performed, no benefit for early debridement has been demonstrated [153,154].

References

The formation of pseudocysts may mandate surgical debridement based on clinical characteristics. Occurring in as many as 10–20% of patients with severe acute pancreatitis, pseudocysts resolve in approximately 50% of cases  [60]. Surgery is performed if symptoms of hemorrhage, infection, or compression develop or if the pseudocyst exceeds 5–6  cm or persists longer than 6  weeks. Internal drainage represents the superior surgical approach, although percutaneous drainage may temporize a critically ill patient. Fluid should be collected for culture to rule out infection. Finally, pancreatic abscess formation occurs in 2–4% of patients with severe pancreatitis and is 100% lethal if left undrained. Although percutaneous drainage may be temporizing, the catheter often becomes occluded secondary to the thick purulent effluent. With early and aggressive surgical debridement, mortality is reduced to 5% [155]. Either transperitoneal or retroperitoneal approaches may be

appropriate. Postoperatively, 20% will require reoperation for incomplete drainage, ongoing infection, fistulas, or hemorrhage [155].

­Conclusion Acute pancreatitis during pregnancy is a rare but severe disease with associated increased perinatal morbidity and mortality. Clinicians should understand the potential complications so that they can anticipate and monitor the patients as clinically indicated and counsel the patients as needed. There is no consensus in the literature regarding the management of acute pancreatitis during pregnancy. A team approach involving the obstetrician, gastroenterologist with experience in ERCP, surgeon, and radiologist should be adopted in the management of acute pancreatitis in pregnancy.

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106 Berger HG, Bittner R, Block S, Buchler M. Bacterial contamination of pancreatic necrosis: A prospective clinical study. Gastroenterology. 1986;91:433–438. 107 Pederzoli P, Bassi C, Vesentini S, Campedelli A. A randomized multicenter clinical trial of antibiotic prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem. Surg Gynecol Obstet. 1993;176:480–483. 108 Sainio V, Kemppainen E, Puolakkainen P, et al. Early antibiotic treatment in acute necrotizing pancreatitis. Lancet. 1995;346:663–667. 109 National Institute for Health and Care Excellence (NICE). Pancreatitis NICE guideline [NG104]. London: NICE; 2018 [https://www.nice.org.uk/guidance/ng104/ resources/pancreatitis-pdf-66141537952453] 110 Greenberg JA, Hsu J, Bawazeer M, et al. Clinical practice guideline: Management of acute pancreatitis. Can J Surg. 2016;59(2). 111 Beechey-Newman N. Controlled trial of high-dose octreotide in treatment of acute pancreatitis. Dig Dis Sci. 1993;38:644–647. 112 Paran H, Neufeld D, May A, et al. Preliminary report of a prospective randomized study of octreotide in the treatment of severe acute pancreatitis. J Am Coll Surg. 1995;181:121–124. 113 McKay C, Baxter J, Imrie C. A randomized, controlled trial of octreotide in the management of patients with acute pancreatitis. Int J Pancreatol. 1997;21: 13–19. 114 Karakoyunlar O, Sivrel E, Tani N, Denecli AG. High-dose octreotide in the management of acute pancreatitis. Hepatogastroenterology. 1999;46:1968–1972. 115 Uhl W, Buchler MW, Malfertheiner P, et al. A randomized, double-blind, multicentre trial of octreotide in moderate to severe acute pancreatitis. Gut. 1999;45:97–104. 116 Osborne DH, Imrie CW, Carter DC. Biliary surgery in the same admission for gallstone-associated acute pancreatitis. Br J Surg. 1981;68:758–761. 117 Langmade CF, Edmondson HA. Acute pancreatitis during pregnancy and the postpartum period; A report of nine cases. Surg Gynecol Obstet. 1951;92: 43–52. 118 Lee S, Bradley JP, Mele MM, et al. Cholelithiasis in pregnancy: Surgical versus medical management. Obstet Gynecol. 2000;95:S70–S71. 119 Debette-Gratien M, Yahchouchy E. Management of acute biliary pancreatitis. Gastroenterol Clin Biol. 2001;25(Suppl.):S225–S240. 120 Vilallonga R, Calero-Lillo A, Charco R, Balsells J. Acute pancreatitis during pregnancy: 7–year experience of a tertiary referral center. Cir Esp. 2014;92:468–471. 121 Lanzafame RJ. Laparoscopic cholecystectomy during pregnancy. Surgery. 1995;118:627–631.

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122 Martin IG, Dexter SP, McMahon MJ. Laparoscopic cholecystectomy in pregnancy: A safe option during the second trimester? Surg Endosc. 1996;10:508–510. 123 Friedman RL, Friedmen IH. Acute cholecystitis with calculous biliary duct obstruction in the gravid patient: Management by ERCP, papillotomy, stone extraction, and laparoscopic cholecystectomy. Surg Endosc. 1995;9:910–913. 124 Posta CG. Laparoscopic surgery in pregnancy: Report on two cases. J Laparoendosc Surg. 1995;5:203–205. 125 Weber AM, Bloom GP, Allan TR, Curry SL. Laparoscopic cholecystectomy during pregnancy. Obstet Gynecol. 1991;78:958–959. 126 Lu EJ, Curet MJ, El-Sayed YY, Kirkwood KS. Medical versus surgical management of biliary tract disease in pregnancy. Am J Surg. 2004;188:755–759. 127 Nesbitt TH, Kay HH, McCoy MC, Herbert WN. Endoscopic management of biliary disease during pregnancy. Obstet Gynecol. 1996;87:806–809. 128 Uomo G, Manes G, Picciotto FO, Rabitti PG. Endoscopic treatment of acute biliary pancreatitis in pregnancy. J Clin Gastroenterol. 1994;18:250–252. 129 Baillie J, Cairns SR, Putnam WS, Cotton PB. Endoscopic management of choledocholithiasis during pregnancy. Surg Gynecol Obstet. 1990;171:1–4. 130 Cosenza CA, Saffari B, Jabbour N, et al. Surgical management of biliary gallstone disease during pregnancy. Am J Surg. 1990;178:545–548. 131 Green J, Rogers A, Rubin L. Fetal loss after cholecystectomy during pregnancy. Can Med Assoc J. 1963;88:576–577. 132 McKellar DP, Anderson CT, Boynton CJ. Cholecystectomy during pregnancy without fetal loss. Surg Gynecol Obstet. 1992;174:465–468. 133 Kort B, Katz VL, Watson WJ. The effect of nonobstetric operation during pregnancy. Surg Gynecol Obstet. 1993;177:371–376. 134 Morrell DG, Mullins JR, Harrison PB. Laparoscopic cholecystectomy during pregnancy in symptomatic patients. Surgery. 1992;112:856–859. 135 Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 2006;101:2379–2400. 136 Venu RP, Brown RD, Halline AG. The role of endoscopic retrograde cholangiopancreatography in acute and chronic pancreatitis. J Clin Gastroenterol. 2002;34(5):560–568. 137 Adler DG, Baron TH, Davila RE, et al. ASGE guidelines: The role of ERCP in diseases of the biliary tract and the pancreas. Gastrointest Endosc. 2005;62:1–8. 138 Neoptolemos JP, Carr-Locke DL, London NJ, et al. Controlled trial of urgent endoscopic retrograde cholangiopancreatography and endoscopic sphincterotomy versus conservative treatment for acute pancreatitis due to gallstones. Lancet. 1988;2:979–983. 139 Buchner WF, Stoltenberg PH, Kirtley DW. Endoscopic management of severe gallstone pancreatitis during pregnancy. Am J Gastroenterol. 1988;83:1073.

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140 Akcakaya A, Koc B, Adas G, Kemik O. The use of ERCP during pregnancy: Is it safe and effective? HepatoGastroenterology. 2014;61:296–298. 141 International Commission on Radiological Protection (ICRP). Publication 84: Pregnancy and Medical Radiation. Ann ICRP. 2000;30(1). 142 Polydorou A, Karapanos K, Vezakis A, et al. A multimodal approach to acute biliary pancreatitis during pregnancy: A case series. Surg Laparosc Endosc Percutan Tech. 2012;22:429–432. 143 Ducarme G, Maire F, Chatel P, et al. Acute pancreatitis during pregnancy: A review. J Perinatol. 2014;34:87–94. 144 Hot S, Egin S, Gokeck B, et al. Acute biliary pancreatitis during pregnancy and in the post-delivery period. Ulus Travma Acil Cerrahi Derg. 2019;25(3):253–258. 145 Tan YH, Ong JY, Devendra K. Hyperglyceridaemiainduced acute pancreatitis in pregnancy: Experience from a tertiary hospital in Singapore. Med J Malaysia. 2021;76(4):591–593. 146 Stefanutti C, Labbadia G, Morozzi C. Severe hypertriglyceridemia-related acute pancreatitis. Ther Apher Dial. 2013;17:130–137. 147 Li J, Chen TR, Gong HI, et al. Intensive insulin therapy in severe acute pancreatitis: A meta-analysis and systematic review. West Indian Med J. 2012;61: 574–579. 148 Gupta N, Ahmed S, Shaffer L, et al. Severe triglyceridemia induced pancreatitis in pregnancy. Case Rep Obstet Gynecol. 2014;2014:485493. 149 Wong B, Ooi TC TC, Keely E. Severe gestational hypertriglyceridemia: A practical approach for clinicians. Obstet Med. 2015;8:158–167. 150 Watts GF, Cameron J, Henderson A, et al. Lipoprotein lipase deficiency due to long-term heparinization presenting as severe hypertriglyceridemia in pregnancy. Postgrad Med J. 1991;67:1062–1064. 151 Gotzinger P, Sautner T, Kriwanek S, et al. Surgical treatment for severe acute pancreatitis: Extent and surgical control of necrosis determine outcome. World J Surg. 2002;26(4):474–478. 152 Waltman AC, Luers PR, Athanasoulis CA, Warshaw AL. Massive arterial hemorrhage in patients with pancreatitis. Arch Surg. 1986;121:439–443. 153 Bradley EL, Allen K. A prospective longitudinal study of observation versus surgical intervention in the management of necrotizing pancreatitis. Am J Surg. 1991;16:19–25. 154 Karimigani I, Porter KA, Langevin RE, Banks P. Prognostic factors in sterile pancreatic necrosis. Gastroenterology. 1992;103:1636–1640. 155 Warshaw AL, Gongliang J. Improved survival in 45 patients with pancreatic abscess. Ann Surg. 1985;202:408–417.

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29 Pneumonia During Pregnancy (Bacterial and Viral) M. Ashley Cain and Judette M. Louis Department of Obstetrics and Gynecology, Division of Maternal–Fetal Medicine, The University of South Florida Morsani College of Medicine, Tampa, Florida, USA

Introduction Worldwide, pneumonia carries a significant morbidity and mortality burden. In 2018, pneumonia led to 1.5  million emergency department visits and over 40,000 deaths in the United States [1]. Among the pregnant population, pneumonia is a leading cause of antepartum admissions and maternal morbidity, accounting for approximately 4% of all antepartum admissions [2]. The incidence of pneumonia in pregnancy is approximately 0.5–1.5 per 1000 pregnancies  [3,4]. Comorbid asthma, tobacco use, anemia, antepartum steroid use, and the use of tocolytics are also risk factors for pneumonia in pregnancy [5–7]. Cohort studies note higher risk of small for gestational age infant and preterm delivery among patients who experience pneumonia in pregnancy [4,8,9]. Pneumonia develops following exposure to various infectious agents including bacterial, viral, and fungal pathogens. The infectious process then leads to inflammation in alveoli blocking oxygen exchange and causing hypoxia. Treatment recommendations in the pregnant population are derived from non-pregnant recommendations. Treatment guidance varies depending on infectious source and local resistances. Previously, bacterial pneumonias were subdivided based on community-acquired versus healthcare-associated and ventilator-associated. In 2018, the Infectious Diseases Society of America (IDSA) published guidelines regarding community-acquired pneumonia and recommended abandoning the terminology for healthcare-associated pneumonia. In place of prior nomenclature, the IDSA recommends treatment guidelines based on risk factors for methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa as well as

local epidemiology  [10]. We will focus on diagnosis and treatment of community-acquired pneumonia as well as viral and rarer subtypes of pneumonias.

­Respiratory changes in pregnancy While diagnosing and treating pneumonia in the pregnant patient, the impact of pregnancy and physiologic changes in the respiratory system must be taken into consideration (Table 29.1). Both anatomical and biochemical adaptations to pregnancy occur. These changes allow the patient to meet the demands of pregnancy and the physiologic needs of the fetus. The enlarging uterus and effects of relaxin hormone lead to an elevation of the diaphragm by approximately 4 cm on average [11,13]. Additionally, the subcostal angle increases from 68.5° to 103.5°  [13]. Further anatomic changes include a 5–7 cm increase in the chest circumference, and an up to 2  cm increase in chest diameter. These changes also impact lung capacities. The vital capacity, forced expiratory volume in 1 s (FEV1), diffusion capacity, and respiratory rate remain unchanged. Progesterone leads to increased respiratory drive resulting in a 30–50% increase in minute ventilation, mainly as a function of enlarged tidal volume, which addresses the physiological need for increased overall oxygen consumption; as a necessary anatomical compensatory response, functional residual capacity (FRC) decreases by 20% [11]. Elevation of the diaphragm and a decrease in lung compliance contribute to the decreased FRC (the amount of air remaining in lungs after exhalation) in pregnancy. Patients experiencing respiratory compromise can demonstrate rapid declines due to

Critical Care Obstetrics, Seventh Edition. Edited by Luis D. Pacheco, Jeffrey P. Phelan, Torre L. Halscott, Leslie A. Moroz, Arthur J. Vaught, Antonio F. Saad, and Amir A. Shamshirsaz. © 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.

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Table 29.1

Respiratory changes in pregnancy.

Total lung capacity

Decrease by up to 5%

Vital capacity

No change

Functional residual capacity

Decrease by 20%

Tidal volume

Increase by 40–50%

Residual volume

Decrease by up to 20%

Respiratory rate

No change

Oxygen consumption

Increase by 20%

Minute ventilation (tidal volume multiplied by breaths per minute)

Increase by 30–50%

Forced expiratory volume in 1 s (FEV1)

No change

Peak expiratory flow rate

No change

Diffusion capacity

No change

Source: Adapted from Bobrowski [11], LoMauro and Aliverti [12].

Table 29.2 Arterial blood gas changes in pregnancy.

Parameter

Non-pregnant adult

Pregnant (second– third trimester)

pH

7.35–7.45

7.40–~7.49

PaO2 (mmHg)

80–100

90–110

PaCO2 (mmHg)

35–45

25–33

Bicarbonate (mEq/L)

21–30

16–22

Source: Adapted from Carlin and Alfirevic [15]. PaO2 and PaCO2 refer to the partial pressure of each gas, respectively, in the arterial blood.

increased oxygen consumption coupled with decreased FRC and expiratory reserve volumes, limiting their ability to augment ventilation if oxygen demand outstrips supply or the relative converse of excess carbon dioxide occurs [11,14]. Additionally, as pregnancy progresses, airway edema increases and can cause increased difficulty with intubation [13]. Increases in minute ventilation can be attributed to an increased metabolic rate and increased oxygen consumption in pregnancy [11]. These changes also lead to decreases in arterial partial pressure of CO2 (PaCO2) and increased O2 (PaO2). The arterial pH remains within a normal to mildly alkalotic range due to increased renal excretion of bicarbonate as physiological compensation. This compensated respiratory alkalosis can be noted on an arterial blood gas evaluation (Table  29.2). Worsening respiratory status may be reflected in subtle changes in arterial blood gas

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values, which may appear in range with normal values for the non-pregnant adult, such as PaCO2 in the normal range for a pregnant patient may therefore represent a pathological retention of carbon dioxide and worsening respiratory status, whereas in the non-pregnant adult such a value may be indicative of adequate ventilation. These may have greater maternal and fetal impacts than are clinically evident, and due to this, discerning interpretation of these values may be a crucial aspect of care for such patients. The changes in minute ventilation and oxygen consumption also lead to physiologic dyspnea of pregnancy, increasing the challenge of diagnosing pathologic dyspnea [11]. When evaluating the pregnant patient with pneumonia, obstetricians must understand the normal physiologic changes in order to readily recognize worsening respiratory status themselves, as well as to help other consulting specialties appropriately understand these clinical scenarios. Increased rates of severe pneumonia may occur among pregnant patients, potentially due to anatomical as well as biochemical effects of pregnancy and the accompanying diminished respiratory reserve. In addition to these changes, immunologic alterations occur during pregnancy. Alterations in cellular immunity increase in the second and third trimester of pregnancy. Pregnancy changes lead to T-cell diminishment, particularly a decrease in helper T-cells. Natural killer cell levels are also lower and hormonal changes alter cellular-mediated immunity  [16,17]. These immunologic changes when taken together are likely to contribute to the increased severity of disease as well.

Pneumonia diagnosis Pneumonia develops following the inhalation or aspiration of infectious agents, including bacterial, viral, and fungal. The subsequent infection of distal bronchioles and alveoli leads to inflammation and direct lung injury. Ventilation and perfusion mismatch then occurs leading to hypoxia. Pregnant patients will present with similar symptoms to the non-pregnant population. These presenting symptoms in patients with pneumonia include cough (90%), sputum production and dyspnea (66%), and pleuritic chest pain (approximately half of patients). Additional symptoms may include fever, myalgias, nausea, and cough  [7,18]. Careful physical examination may reveal use of accessory muscles, dullness to percussion, rales, and diminished breath sounds  [19]. Vital signs assessment can indicate intravascular depletion and evaluate severity of tachypnea and fever. Respiratory status is further analyzed with pulse oximetry, arterial blood gas assessment, and chest X-ray; pregnancy is not a contraindication to indicated imaging

­AAeAAment oo Aeeerity

and a vital role in the care for such patients is to reassure the patients themselves as well as our colleagues as needed to accomplish this. When a patient presents with findings concerning for pneumonia, the differential diagnosis also includes other conditions that have pulmonary manifestations. These can include pulmonary embolism, aspiration (particularly related to the use of general anesthesia), pleural effusions postoperatively, sepsis (including that arising from other organs such as pyelonephritis), and airway constrictive disease, for example, asthma, allergic reactions, etc. The initial evaluation should include laboratory evaluations such as a complete blood count, serum chemistries including assessment of renal and liver functions, and consideration for arterial blood gas. Chest radiography (chest X-ray) should be used to look for lobar consolidations, cavitations, or pleural effusions which can be seen in bacterial pneumonias [9] (Figure 29.1). Chest radiograph in viral pneumonias is notable for diffuse involvement with nodular and interstitial infiltrates. Viral pneumonia may be complicated by bacterial superinfection complicating the diagnosis and imaging findings [9]. Chest X-ray can be completed safely in pregnancy with abdominal shielding and should not be deferred due to pregnancy [20]. Munn et al. reported positive chest X-ray findings in 98% of patients with pneumonia, making this evaluation modality more sensitive for pneumonia over physical exam alone [7]. The IDSA addresses the use of procalcitonin in the initial assessment of non-pregnant individuals with pneumonia. Prior studies evaluated the use of procalcitonin levels to distinguish between bacterial and viral etiologies of

pneumonia [21]. These findings were varied and therefore it is not recommended to use procalcitonin levels to guide the initiation of antibiotic therapy or decision to withhold antibiotic therapy [22,23]. In critically ill patients, early initiation of antibiotics is crucial to survival and should never be delayed [24].

­Assessment of severity Previous researchers proposed various methods of assessing severity of disease in the non-pregnant population. Despite differing biomarker and vital sign parameters in pregnancy, a pregnancy-specific severity assessment tool does not exist. In the absence of pregnancy-specific parameters, the IDSA recommends utilizing the pneumonia severity index (PSI) along with clinical judgment in the nonpregnant population to guide treatment and evaluation  [22]. This tool utilizes physical exam findings, comorbid conditions, and age and laboratory findings to assess the risk of death from pneumonia (Table  29.3). In 2007, the IDSA along with the American Thoracic Society developed criteria utilizing physical exam and laboratory findings to identify those patients with severe disease [22]. In the most recent guidelines, those criteria continue to be used [22]. While not specific to pregnancy, these resources can be used to guide management along with clinical judgment and underlying knowledge of physiologic changes to parameters in the pregnant population. Evaluating risk factors for severe disease may assist in decisions regarding inpatient versus outpatient management. Patients with

Figure 29.1 Chest radiographs in pneumonia: (left) bacterial pneumonia with consolidation predominantly in right middle lung; (right) viral pneumonia with bilateral, diffuse infiltrates.

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Table 29.3 Criteria for defining severe community-acquired pneumonia. 2007 Infectious Diseases Society of America/American Thoracic Society’s criteria for defining severe communityacquired pneumonia Validated definition includes either one major criterion or three or more minor criteria

Minor criteria Respiratory rate ≥ 30 breaths/min PaO2/FiO2 ratio 250 Multi-lobar infiltrates Confusion/disorientation Uremia (blood urea nitrogen level ≥20 mg/dL) Leukopenia* (white blood cell count 50,000/mm3), fibrinogen level (>50–100 mg/dL), and near-normal temperature, pH, and calcium levels  [189]. Thus, major sources of bleeding should be controlled, and blood products administered to correct major deficiencies before administering rFVIIa. The optimal dose needs to be clarified. Doses of 16.7–120 mcg/kg as a single bolus injection over a few minutes every 2 h until hemostasis is achieved have been reported effective and usually control bleeding within 10–40 min of the first dose [188,190]. It is preferable to start with a low dose (40 or 60  mcg/kg) to reduce the risk of thromboembolic events [191]; doses of 40–90 mcg/kg have been suggested for obstetric hemorrhage. The dose may be repeated once in 15–30  min if there is no response. Additional doses are unlikely to be effective. Repletion of clotting factors: Although FFP contains a small amount of fibrinogen, cryoprecipitate and fibrinogen concentrate are preferable for treating hypofibrinogenemia because they have a higher fibrinogen concentration per infused volume. Cryoprecipitate: Cryoprecipitate is primarily used for correcting fibrinogen deficiency (1000 mL, refractory to oxytocin, methylergonovine, and carboprost. Bilateral uterine artery ligation failed to control hemorrhage in only 10  women, giving a 96% success rate. An immediate effect was

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reported, with visible uterine blanching; myometrial contractions sometimes occurred, but even if the uterus remained atonic, hemorrhage was usually controlled [227]. No long-term effects on menstrual patterns or fertility have been reported  [228,229]. The uterine vessels appeared to have recanalized in women who have undergone repeat cesarean sections. Unilateral or bilateral ligation of the ovarian artery may be performed as an adjunct to ligation of uterine arteries. The ligature is tied medial to the ovary to preserve the ovarian blood supply [228]. Failure of this procedure is most associated with placenta previa with or without accreta. However, evidence supports that the concomitant use of tranexamic acid and bilateral uterine artery ligation in previa cases is associated with a reduction in total blood loss, the need for blood products, and the use of other uterotonics [230]. Low bilateral uterine artery ligation has been described for ongoing bleeding from the lower segment in these cases. A series of 103 patients involving stepwise uterine devascularization reported a 75% success rate with conventional uterine artery ligation  [229]. Success was highest with uterine atony and abruption. Of seven cases of placenta previa with or without accreta, hemorrhage continued in four women. A further bilateral ligation was performed 3–5 cm below the first sutures, following further bladder mobilization. Ligation includes the ascending branches of the cervicovaginal artery and the uterine artery branches supplying the lower segment and upper cervix. This procedure was effective in all cases. A vaginal route for uterine artery ligation has also been described, with moderate success [229]. This intervention includes incising the anterior cervix near the cervicovaginal fold with the bladder retracted. The uterus is gently pulled to the contralateral side of the intended suture placement. A single absorbable suture is placed around the vessels, including myometrial tissue. Although this technique may be quick and minimally invasive, more studies are required to prove its utility in PPH.

Bilateral internal iliac artery ligation Kelly first performed internal iliac artery ligation as a gynecologic procedure in 1894 [231]. He termed this “the boldest procedure possible for checking bleeding” and assumed that the blood supply to the pelvis would be completely arrested. From the 1950s, internal iliac ligation was increasingly performed for gynecologic indications, primarily for cervix carcinoma. Ligation was still considered to shut off the arterial flow, even though necrosis of pelvic tissues had not been observed. In the 1960s, Burchell reported cutting a uterine artery following bilateral internal iliac ligation to demonstrate the absence of flow. However, to the surprise of those present,

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blood still flowed freely. This observation led to extensive studies of the hemodynamic effects of internal iliac ligation. These were performed on gynecologic patients, but are quoted widely in the obstetric literature  [232,233]. Aortograms performed between 5 min and 37 months postligation demonstrated extensive collateral circulation, with blood flow throughout the internal iliac artery and its branches. Three collateral circulations were identified: the lumbar and iliolumbar arteries, the middle sacral and lateral sacral arteries, and the superior rectal and middle rectal arteries. Ligation above the posterior division resulted in collateral and therefore reversed flow in its iliolumbar and middle sacral branches (Figure 37.2). Ligation below (a)

Common iliac Interior iliac Iliolumbar Reversed flow Lateral sacral Middle hemorrhoidal

Normal flow

Exterior iliac

(b) Common iliac Interior iliac Iliolumbar Lateral sacral Middle hemorrhoidal

Normal flow

Reversed flow

Exterior iliac

Figure 37.2 Internal iliac artery ligation. (a) Ligation above the posterior diversion; collateral pathways result in reversed flow in the iliolumbar and lateral sacral arteries. (b) Ligation below the posterior diversion; collateral pathways result in reversed flow in the middle hemorrhoidal (middle rectal) artery. Source: Reproduced from Burchell [235], with permission from the American College of Obstetricians and Gynecologists.

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the posterior division caused collateral flow only in the middle hemorrhoidal artery, again in a retrograde direction. Flow to more distal branches of the internal iliac artery was normal. A second study involved intra-arterial pressure recordings before and after ligation [233]. Following bilateral ligation, distal arterial pulse pressure decreased by 85%, with a 24% reduction in mean arterial pressure. In addition, a 48% reduction in blood flow resulted following ipsilateral ligation. The authors concluded that internal iliac ligation controls pelvic hemorrhage mainly by decreasing arterial pulse pressure. The smaller diameter of the anastomoses of the collateral circulation was proposed to explain this phenomenon. The arterial system was considered to have transformed into a venous-like circulation, with clot formation able to arrest bleeding at the injury site. These studies have been extensively quoted, but similar studies have not been performed in postpartum women. A single case report found no change in uterine artery Doppler waveform velocity before and 2 days after bilateral internal artery ligation was performed to control hemorrhage due to uterine atony [234]. Internal iliac artery ligation is a more complex procedure than uterine artery ligation. The bifurcation of the common iliac artery is identified at the pelvic brim, and the peritoneum opened and reflected medially along with the ureter [107,236]. The internal iliac artery is identified, freed of areolar tissue, and a right-angled clamp passes under the artery. Two ligatures are tied 1–2 cm apart. The artery is not divided. The uterine and vaginal arteries are branches of the anterior division, and ligation should, if possible, be distal to the origin of the posterior division. This is more efficacious and does not compromise the blood supply to the buttocks and gluteal muscles. A retroperitoneal approach may be used when hemorrhage has followed vaginal delivery. Complications of this procedure include damage to the internal iliac vein and ureter. Tissue edema, ongoing bleeding, and a sizable atonic uterus may make identification of anatomy difficult and prolong operating time. Incorrect identification of the internal iliac artery may result in accidental ligation of the external or common iliac artery, resulting in the lower limb and pelvic ischemia. Femoral pulses should therefore be checked before and after the procedure. Recanalization of ligated vessels may occur, and successful pregnancy has been reported whether or not recanalization has taken place. Demonstration of the extensive collateral circulation explains why the efficacy of internal iliac ligation is lower than for uterine artery ligation. This may be worsened by cases of placenta accreta, where recruitment of additional collateral vascularity is the rule. Reverse filling of the internal iliac arteries has been reported beyond the point of

Surgical management of postpartum hemorrhage

ligation via branches of the external iliac artery (inferior epigastric, obturator, deep circumflex iliac, and superior gluteal arteries) [237]. Still, bilateral internal iliac ligation has been used as a prophylactic measure to reduce blood loss in placenta accreta cases, demonstrating an overall reduction in the need for blood and blood product replacement [107,238]. Overall success rates of internal iliac ligation are generally reported to be approximately 40%. A 1985 study reported a success rate of 42% in a series of 19 patients, with a hysterectomy necessary in the remainder [236]. Morbidity was higher than for patients in whom hysterectomy was performed as a primary procedure; mean blood loss was 5125  mL for patients with unsuccessful internal iliac artery ligation followed by a hysterectomy 3209 mL for those undergoing hysterectomy alone. In this series, complications associated with unsuccessful arterial ligation were associated with delay in instituting definitive treatment (hysterectomy) rather than as a consequence of arterial ligation. Successful and safe bilateral hypogastric ligation becomes even more difficult when attempted by a surgeon who rarely operates deep in the pelvic retroperitoneal space  [239]. For these reasons, uterine compression sutures and, less commonly, uterine artery ligation have primarily replaced this procedure. These authors consider that there is only a limited role for this procedure in treating PPH, being restricted to hemodynamically stable patients of low parity in whom future fertility is of paramount concern. Conversely, in another retrospective study, only 10% of women who underwent hypogastric artery ligation underwent a hysterectomy for hemorrhage [240].

Arterial embolization Uterine devascularization by selective arterial embolization has recently gained popularity in centers with expertise in interventional radiology. Access is via the femoral artery, and the site of arterial bleeding is located by injection of contrast into the aorta. The bleeding vessel is selectively catheterized, and pledgets of absorbable gelatin sponge are injected  [241]. These affect only a temporary blockade lasting 3–6 weeks. If the bleeding site cannot be identified, embolization of the anterior branch of the internal iliac artery or the uterine artery is performed. Gelfoam is often utilized if extravasation is not seen or there are multiple areas of injury to avoid excessive contrast and radiation dose. Embolization with coils is reserved for pseudoaneurysms or identified bleeding sources. In published studies, uterine atony and pelvic trauma are the primary indications for embolization, and overall success rates of 85–100% are reported  [242]. Higher failure rates are associated with placenta accreta and procedures performed following failed bilateral internal iliac artery

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ligation  [242]. Subsequent successful pregnancies have been documented. Compared to surgical devascularization, embolization has several advantages. It is less invasive and generally results in visualization of the bleeding vessel. Occlusion of distal arteries close to the bleeding site is possible, thereby reducing the risk of ongoing bleeding from collateral circulation [241]. The efficacy of embolization can immediately be assessed, and repeated embolization of the same or different arteries can be performed. Disadvantages are the need for rapid availability of specialist equipment and personnel and the need to transfer a hemorrhaging patient to the radiology suite. Embolization may also be a timeconsuming procedure, generally requiring between 1 and 3 h, but with hemostasis of the major bleeding vessel frequently established in 30–60  min. Pelage and colleagues evaluated the role of selective arterial embolization in 35  patients with unanticipated PPH  [243]. Bleeding was controlled in all except one who required a hysterectomy for rebleeding 5  days later. All women in this series who had successful embolization resumed normal menstruation. These findings have been reported in other studies  [244,245]. Patients with life-threatening hemorrhage have also been successfully treated with arterial embolization. In another study evaluating the efficacy of arterial embolization for PPH, 86% of women responded to embolization. In that analysis, over 50% of women received other therapies, including uterotonics, ligation sutures, or balloon, before the procedure  [218]. Failure is associated with shock, more significant blood loss, and an increased rate of transfusion [246,247]. In addition, embolization may be more successful in women with vaginal births compared to cesarean delivery  [247]. Historically, rates of hemorrhage control with pelvic artery embolization have been over 90%, but it is not proven to be more successful than other fertility-preserving treatments  [223]. In a comparative propensity-scorematched cohort study, there was no difference in the risk of peripartum hysterectomy or maternal death between women who had intrauterine balloon tamponade and women who underwent uterine artery embolization as initial management for persistent PPH after a vaginal delivery [248]. Uterine artery embolization has been associated with shorter hospital stays than hysterectomy in one national inpatient sample study but was used less often [249]. Embolization has also been 88% successful in secondary PPH  [250]. Fever, contrast-media renal toxicity, and leg ischemia are rare but reported complications of this procedure. Although well-designed trials are lacking, radiologic and surgical techniques for managing PPH do not appear to adversely affect future menstrual and fertility

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outcomes  [251,252]. In a meta-analysis and systematic review of studies including over 483 pregnancies with prior uterine artery embolization, pregnancies with prior uterine artery embolization were associated with higher rates of future PAS (odds ratio [OR] 20.82; 95% [CI] 3.27–132.41) and PPH (OR 5.32, 95% CI 1.40–20.16), but not with higher rates of hysterectomy (OR 8.93, 95% CI 0.43–187.06), placenta previa (OR 2.31, 95% CI 0.35–15.22), fetal growth restriction (OR 7.22, 95% CI 0.28–188.69), or preterm birth (OR 3.00, 95% CI 0.74–12.14)  [253]. Clark et  al.  [254] caution against using selective arterial embolization in hemodynamically unstable patients with ongoing severe hemorrhage; delay in hemorrhage control has been attributed to the cases of maternal cardiovascular collapse, possibly preventable by surgical intervention. Failed embolization requiring repeat procedures has been associated with patients experiencing PPH with DIC [255].

Internal iliac artery occlusion A variation on the theme of arterial embolization is temporary arterial occlusion using the prophylactic placement of inflatable balloon catheters into iliac arteries of patients who are expected to bleed excessively at the time of surgery, for example, elective cesarean delivery in a patient with placenta percreta. Balloon catheters are placed but not inflated prior to delivery. Following the delivery of the neonate, the catheters can be immediately inflated. Such catheters can be deflated at the completion of surgery and left in situ during the next 24–48 h to be re-inflated if required. The use of prophylactic occlusion balloons in the internal iliac arteries has shown mixed results. While initial results reported promise with this approach, most recent studies have failed to show significant benefit, with no differences found in operative time, blood loss, and the number of hospital days or transfused products with iliac balloon occlusion  [256–260] and an approximate rate of 7.5% for complications, including iliac artery rupture [261], thromboembolism, and organ injury [262].

Common iliac artery occlusion Bilateral common iliac artery occlusion using balloon catheters can control catastrophic hemorrhage from placenta percreta during cesarean hysterectomy, but evidence of safety and efficacy is limited to case reports. Like internal iliac occlusion techniques, the catheters are usually placed preoperatively by an interventional radiologist when the potential for massive hemorrhage is high. In situations where unanticipated intraoperative bleeding is there and sufficient time is available, common iliac catheters can be placed in the operating room via a femoral approach by an

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interventional radiologist [263,264]. In one report, occlusion of the common iliac arteries for 53  min dramatically reduced blood loss, and the patient tolerated the procedure without apparent lower limb damage  [265]. The oxygen saturation in the lower limbs remained between 85% and 92% during balloon occlusion. Other small case series also suggest benefit [266]. This procedure should only be done in lifesaving situations where death is imminent and likely without such interventions. Theoretically, occlusion of the common iliac arteries shuts down collateral flow between the internal and external iliac arteries. This results in more effective uterine perfusion reduction than internal iliac occlusion alone. None of the published cases have described ischemic limb injury despite occlusion times up to 70 min, presumably because collateral supply to the leg maintains adequate flow during common iliac occlusion. In the 2021 PASTTIME trial, a shift from using iliac balloon occlusion to multivessel embolization for placenta accreta surgery resulted in reduced blood loss and transfusion requirements, with no increase in postoperative complications [267].

Intermittent aortic occlusion Resuscitative endovascular balloon occlusion of the aorta (REBOA) catheters have been used to stabilize patients with life-threatening PPH in extreme emergencies and for selected cases of PAS, but evidence of safety and efficacy is limited to case reports and retrospective studies [268,269]. Emergent use of this procedure should only be done in extreme situations where death is imminent and likely without such interventions. In cases where the risk of massive hemorrhage is known (i.e., diagnosed percreta), the intra-aortic balloon catheter can be placed prophylactically prior to surgery and positioned by an interventional radiologist using fluoroscopy  [270]. In an extreme unanticipated intraoperative emergency when no interventional radiologist or vascular surgeon is available, a balloon catheter can be placed directly into the aorta at the bifurcation using a Seldinger technique (initial needle followed by a guidewire over which the balloon catheter is inserted). The catheter is advanced up the aorta, the balloon is positioned under direct vision and palpation, and then inflated. Consultation with a vascular surgeon is recommended before the removal of the catheter. Increased complication risks have been shown with emergent, compared to prophylactic use [270]. The balloon is preferably placed below the renal arteries and above the ovarian and inferior mesenteric arteries to ensure a substantial reduction in uterine blood flow. Placing the intra-aortic balloon just above the aortic bifurcation may not substantially reduce uterine blood flow

Surgical management of postpartum hemorrhage

because of the extensive collateral blood supply to the uterus. For example, the ovarian arteries supply the uterus via the utero-ovarian branches; therefore, if the ovarian arteries are not occluded, then uterine blood flow may not be substantially reduced despite uterine artery and even internal iliac artery ligation. Similarly, the inferior mesenteric artery is continuous with the uterine arterial collateral system via the superior rectal artery and its posterior collaterals (lumbar and median sacral arteries); therefore, uterine blood flow may not be substantially reduced if the inferior mesenteric artery is not occluded. In a study comparing bilateral common iliac artery occlusion to REBOA in women with extensive placenta accreta, the quantitated median intraoperative blood loss was significantly lower for the REBOA group (541 [IQR 300–750] mL) compared to the bilateral common iliac artery occlusion group (3331 [IQR 1150–4750] mL) (P = 0.001). The total volume of fluid and blood replacement therapy was also significantly lower in the REBOA group (P < 0.05), and none of the women with REBOA required a hysterectomy. In contrast, 8/16 women in the bilateral common iliac artery occlusion group underwent a hysterectomy (P = 0.008)  [269]. Invasive REBOA following non-compressible hemorrhage may result in significant ischemia–reperfusion injury (IRI) [271]. Adverse outcomes from IRI include organ dysfunction and can result in profound hemodynamic compromise. This risk must be balanced by the risk of shock, coagulopathy, and electrolyte derangements resulting from uncontrolled hemorrhage. To prevent this complication, the balloon is deflated intermittently, approximately every 30–60 min, and distal pulses are monitored frequently.

Hysterectomy Peripartum hysterectomy is the definitive surgical procedure for obstetric hemorrhage, but it is not without complications. In the long term, the loss of fertility may be devastating to the patient. In the emergency situation, the primary concern is that peripartum hysterectomy can be a complex procedure due to ongoing blood loss and grossly distorted pelvic anatomy due to edema, hematoma formation, and trauma. Pritchard showed an average blood loss of 1435  mL when a hysterectomy was performed during elective repeat cesarean section  [127]. At an emergency hysterectomy for postpartum bleeding, the mean blood loss attributed to the procedure was 2183 mL, with a mean loss of 2125 mL by the time of decision for hysterectomy [272]. Adequate hemostasis is not always achieved, and further procedures may be necessary. Uterine artery embolization has been performed for ongoing bleeding following hysterectomy, both with and without success  [240,244]. Relook laparotomy may also be required; this has been reported in

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up to 13% of patients  [273]. The incidence of febrile morbidity is high, with rates of 5–85% in different series. Hysterectomy is indicated if conservative procedures such as embolization or uterine devascularization fail to control bleeding. The most important prognostic factor is the time lapse between delivery and successful surgery. If the primary procedure fails, it is recommended that a hysterectomy is performed promptly, without attempts at another conservative measure  [240]. In patients with severe shock or life-threatening hemorrhage, a hysterectomy is, in most circumstances, the first-line treatment. Hysterectomy may be associated with higher mortality than other surgical procedures [240]. Uterine atony is the primary indication for peripartum hysterectomy, although other factors such as placenta accreta and abruption are frequently present [240]. Many studies have described the profound hemorrhage associated with placenta previa and accreta, with a recent analysis revealing blood loss greater than 3500  mL in 27% of patients and blood loss greater than 5500  mL in 10% of patients with this condition [108]. In this series, approximately 29% of patients required greater than four units of blood products, and 66% required a hysterectomy. Surgical re-exploration secondary to postoperative bleeding is needed in up to 7% of patients with placental invasion [274]. Other indications for peripartum hysterectomy include placenta previa, uterine rupture, and other genital tract lacerations. Trauma sustained at vaginal delivery may result in concealed bleeding and is therefore associated with a worse outcome; hemorrhage at cesarean section is more readily recognized and promptly remedied. A subtotal hysterectomy can generally be performed if bleeding is from the uterine body. It is usually simpler than a total hysterectomy – the cervix and vaginal angles can be challenging to identify in women who have labored to full dilation. There is also less risk of injury to the ureter and bladder. Urinary tract injury may be as high as 19.9–27%, with ureteral injury more common in the presence of placenta percreta  [126,275]. If placenta accreta is suspected, the use of prophylactic ureteral stents may help determine the location of the ureters and assist with complex dissection planes. In addition, perioperative intentional cystotomy may improve visualization of bladder invasion. If bleeding is from the lower segment (placenta previa, trauma), the cervical branch of the uterine artery may require ligation, and a total hysterectomy may be necessary. Anesthetic considerations include the need to convert to general endotracheal anesthesia in anticipation of prolonged surgical time and abdominal packing, placement of a lumbothoracic epidural catheter for postpartum pain relief, and readiness for massive blood transfusion. Prophylaxis for thromboembolism should also be

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considered. Compression stockings placed before induction of anesthesia, prophylactic low-molecular-weight heparin, or unfractionated heparin are also acceptable [106,276]. The importance of close postpartum observation cannot be overemphasized, and, in most cases, these patients should be recovered in an ICU setting. Frequently, because of prolonged operative time combined with massive transfusion, there is a risk for laryngeal edema, pulmonary edema, delayed extubation, and prolonged ventilation. Continuous vital sign determination, pulse oximetry, and hourly urine output measurement are warranted after significant hemorrhage and blood or product replacement. Patients with periods of prolonged hypotension during surgery should also be followed postoperatively for evidence of full Sheehan’s syndrome or forme fruste of this syndrome. Compared to other treatment modalities, women undergoing hysterectomy are more likely to have a cesarean delivery, coagulopathy, ICU stays, and more significant transfusion requirements. In a multivariate analysis, multiparity, placenta previa, primary PPH, and failed labor induction were significant risk factors for hysterectomy  [277]. Surgical antimicrobial prophylaxis should be adjusted for excessive blood loss.

Bleeding disorders Consumptive and dilutional coagulopathies secondary to extensive blood loss and crystalloid replacement are PPH’s most common bleeding disorders. Other obstetric causes of disseminated intravascular coagulopathy (acute fatty liver of pregnancy, abruption, and amniotic fluid embolism) or thrombocytopenia (HELLP syndrome and thrombocytopenic thrombotic purpura [TTP]) may cause or contribute to significant hemorrhage. Inherited and acquired bleeding disorders unrelated to pregnancy must also be considered. These include abnormalities of the coagulation system and qualitative or quantitative platelet disorders. The most common disorders are discussed in the remainder of this section.

Idiopathic thrombocytopenia purpura (ITP) The differential diagnosis of thrombocytopenia in the gravid patient includes gestational thrombocytopenia, autoimmune disorders such as systemic lupus erythematosus or antiphospholipid syndrome, HELLP syndrome, folate deficiency, cirrhosis, splenic sequestration, and viral illnesses, including human immunodeficiency virus (HIV)  [278,279]. Inherited thrombocytopenia should be considered in patients with long-standing thrombocytopenia and inadequate platelet count responses to glucocorticoids

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or intravenous immunoglobulin (IVIG). Certain anticonvulsants and analgesic agents can also cause thrombocytopenia. The most common cause in pregnancy is gestational thrombocytopenia, which accounts for 70% of cases when low platelets (50 IU/dL), but inactivation of the normal chromosome (lyonization) may result in low factor levels  [296]. The overall frequency of these disorders is approximately 1 in 100,000 births [297]. There is also an increased risk of primary and secondary PPH in hemophilia carriers, with reported rates of 19% and 11%, respectively, mainly occurring when factor levels are 50%, severe bleeding may occur with levels between 5% and 30% after surgery or delivery [299]. In small reports, hemophilia A and B had higher PPH rates than women with other bleeding disorders and required up to 4  days of factor replacement  [300]. Tranexamic acid appears promising in preventing secondary PPH for these individuals [301]. Carriers of hemophilia A generally experience a pregnancy-induced rise in factor VIII levels. However, factor IX levels are unaffected by pregnancy. Treatment is indicated for labor when factor levels are 4,000 g. Am J Obstet Gynecol. 2001;185(4):903–905. 86 Eden RD, Parker RT, Gall SA. Rupture of the pregnant uterus: A 53-year review. Obstet Gynecol. 1986;68(5). 87 Wylie JG, Gilbert S, Landon MB, et al. Comparison of transverse and vertical skin incision for emergency cesarean delivery. Obstet Gynecol. 2010;115(6). 88 Thakur A, Heer MS, Thakur V, et al. Subtotal hysterectomy for uterine rupture. Int J Gynaecol Obstet. 2001;74(1). 89 Ritchie EH. Pregnancy after rupture of the pregnant uterus. A report of 36 pregnancies and a study of cases reported since 1932. J Obstet Gynaecol Br Commonw. 1971;78(7):642–648. 90 Irving C HA. A study of placenta accreta. Surg, Gynecol Obstet. 1937;64:178–200. 91 Garmi G, Goldman S, Shalev E, Salim R. The effects of decidual injury on the invasion potential of trophoblastic cells. Obstet Gynecol. 2011;117(1). 92 Silver RM, Branch DW. Placenta Accreta Spectrum. N Engl J Med. 2018;378(16):1529–1536.

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93 Jauniaux E, Jurkovic D, Hussein AM, Burton GJ. New insights into the etiopathology of placenta accreta spectrum. Am J Obstet Gynecol. 2022;227(3). 94 Jauniaux E, Hussein AM, Elbarmelgy RM, et al. Failure of placental detachment in accreta placentation is associated with excessive fibrinoid deposition at the utero-placental interface. Am J Obstet Gynecol. 2022;226(2). 95 Einerson BD, Comstock J, Silver RM, et al. Placenta Accreta spectrum disorder: Uterine dehiscence, not placental invasion. Obstet Gynecol. 2020;135(5). 96 Jauniaux E, Jurkovic D. Placenta accreta: Pathogenesis of a 20th century iatrogenic uterine disease. Placenta. 2012;33(4):244–251. 97 Yagel S. The developmental role of natural killer cells at the fetal-maternal interface. Am J Obstet Gynecol. 2009;201(4):344–350. 98 Laban M, Ibrahim EA, Elsafty MS, Hassanin AS. Placenta accreta is associated with decreased decidual natural killer (dNK) cells population: A comparative pilot study. Eur J Obstet, Gynecol, Reprod Biol. 2014;181. 99 Bailit JL, Grobman WA, Rice MM, et al. Morbidly adherent placenta treatments and outcomes. Obstet Gynecol. 2015;125(3):683–689. 100 Fitzpatrick KE, Sellers S, Spark P, et al. Incidence and risk factors for placenta accreta/increta/percreta in the UK: A national case-control study. PLoS ONE. 2012;7(12):e52893. 101 Colmorn LB, Petersen KB, Jakobsson M, et al. The Nordic Obstetric Surveillance Study: A study of complete uterine rupture, abnormally invasive placenta, peripartum hysterectomy, and severe blood loss at delivery. Acta obstetricia et gynecologica Scandinavica. 2015;94(7). 102 Kaser DJ, Melamed A, Bormann CL, et al. Cryopreserved embryo transfer is an independent risk factor for placenta accreta. Fertil Steril. 2015;103(5):1176–1184.e2. 103 Modest AM, Toth TL, Johnson KM, Shainker SA. Placenta accreta spectrum: In vitro fertilization and non-in vitro fertilization and placenta accreta spectrum in a Massachusetts Cohort. Am J Perinatol. 2021;38(14). 104 Society of Gynecologic Oncology, American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, Cahill AG, Beigi R, et al. Placenta accreta spectrum. Am J Obstet Gynecol. 2018;219(6):B2–B16. 105 Jauniaux E, Ayres-de-Campos D, Langhoff-Roos J, et al. FIGO classification for the clinical diagnosis of placenta accreta spectrum disorders. Int J Gynaecol Obstet. 2019;146(1):20–24.

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106 Collins SL, Alemdar B, van Beekhuizen HJ, et al. Evidence-based guidelines for the management of abnormally invasive placenta: Recommendations from the International Society for Abnormally Invasive Placenta. Am J Obstet Gynecol. 2019;220(6):511–526. 107 Kingdom JC, Hobson SR, Murji A, et al. Minimizing surgical blood loss at cesarean hysterectomy for placenta previa with evidence of placenta increta or placenta percreta: The state of play in 2020. Am J Obstet Gynecol. 2020;223(3):322–329. 108 Schwickert A, van Beekhuizen HJ, Bertholdt C, et al. Association of peripartum management and high maternal blood loss at cesarean delivery for placenta accreta spectrum (PAS): A multinational database study. Acta obstetricia et gynecologica Scandinavica. 2021;100(Suppl. 1). 109 Tikkanen M, Paavonen J, Loukovaara M, Stefanovic V. Antenatal diagnosis of placenta accreta leads to reduced blood loss. Acta Obstet Gynecol Scand. 2011;90(10):1140–1146. 110 Shamshirsaz AA, Fox KA, Salmanian B, et al. Maternal morbidity in patients with morbidly adherent placenta treated with and without a standardized multidisciplinary approach. Am J Obstet Gynecol. 2015;212(2):218.e1–e9. 111 Shamshirsaz AA, Fox KA, Erfani H, et al. Outcomes of planned compared with urgent deliveries using a multidisciplinary team approach for morbidly adherent placenta. Obstet Gynecol. 2018;131(2):234–241. 112 Feiner D. Placenta accreta: Clinical consideration, pathology and management. Am J Obstet Gynecol. 1931;22(2):312–317. 113 Jauniaux E, Grønbeck L, Bunce C, et al. Epidemiology of placenta previa accreta: A systematic review and meta-analysis. BMJ Open. 2019;9(11):e031193. 114 Brown AD, Hart JM, Modest AM, et al. Geographic variation in management of patients with placenta accreta spectrum: An international survey of experts (GPASS). Int J Gynaecol Obstet. 2022;158(1). 115 Sentilhes L, Kayem G, Silver RM. Conservative management of placenta accreta spectrum. Clin Obstet Gynecol. 2018;61(4):783–794. 116 Zuckerwise LC, Craig AM, Newton JM, et al. Outcomes following a clinical algorithm allowing for delayed hysterectomy in the management of severe placenta accreta spectrum. Am J Obstet Gynecol. 2020;222(2). 117 Palacios-Jaraquemada JM, Fiorillo A, Hamer J, et al. Placenta accreta spectrum: A hysterectomy can be prevented in almost 80% of cases using a resectivereconstructive technique. J Matern Fetal Neonatal Med. 2020:1–8.

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118 Fox KA, Shamshirsaz AA, Carusi D, et al. Conservative management of morbidly adherent placenta: Expert review. Am J Obstet Gynecol. 2015. 119 Sentilhes L, Seco A, Azria E, et al. Conservative management or cesarean hysterectomy for placenta accreta spectrum: The PACCRETA prospective study. Am J Obstet Gynecol. 2022;226(6). 120 Clausen C, Lonn L, Langhoff-Roos J. Management of placenta percreta: A review of published cases. Acta Obstet Gynecol Scand. 2014;93(2):138–143. 121 Sentilhes L, Kayem G, Ambroselli C, et al. Fertility and pregnancy outcomes following conservative treatment for placenta accreta. Hum Reprod. 2010;25(11):2803–2810. 122 Gatta LA, Weber JM, Gilner JB, et al. Transfusion requirements with hybrid management of placenta accreta spectrum incorporating targeted embolization and a selective use of delayed hysterectomy. Am J Perinatol. 2022. 123 Collins SL, Sentilhes L, Chantraine F, Jauniaux E. Delayed hysterectomy: A laparotomy too far? Am J Obstet Gynecol. 2020;222(2). 124 Chandraharan E, Rao S, Belli AM, Arulkumaran S. The Triple-P procedure as a conservative surgical alternative to peripartum hysterectomy for placenta percreta. Int J Gynaecol Obstet. 2012;117(2):191–194. 125 Soleymani Majd H, Collins SL, Addley S, et al. The modified radical peripartum cesarean hysterectomy (Soleymani-Alazzam-Collins technique): A systematic, safe procedure for the management of severe placenta accreta spectrum. Am J Obstet Gynecol. 2021;225(2). 126 Erfani H, Salmanian B, Fox KA, et al. Urologic morbidity associated with placenta accreta spectrum surgeries: Single-center experience with a multidisciplinary team. Am J Obstet Gynecol. 2022;226(2). 127 Pritchard JA. Changes in the blood volume during pregnancy and delivery. Anesthesiol. 1965;26:393–399. 128 Reale SC, Easter SR, Xu X, et al. Trends in postpartum hemorrhage in the United States from 2010 to 2014. Anesth Analg. 2020;130(5). 129 Kramer MS, Berg C, Abenhaim H, et al. Incidence, risk factors, and temporal trends in severe postpartum hemorrhage. Am J Obstet Gynecol. 2013;209(5):449.e1–e7. 130 ACOG. ACOG educational bulletin. Postpartum hemorrhage. Number 243, January 1998 (replaces No. 143, July 1990). Int J Gynaecol Obstet. 1998;61(1). 131 Wetta LA, Szychowski JM, Sealse S, et al. Risk factors for uterine atony/postpartum hemorrhage requiring treatment after vaginal delivery. Am J Obstet Gynecol. 2013;209(1).

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285 Michel M, Ruggeri M, Gonazalez-Lopez TJ, et al. Use of thrombopoietin receptor agonists for immune thrombocytopenia in pregnancy: Results from a multicenter study. Blood. 2020;136(26). 286 Kouides PA, Phatak PD, Burkart P, et al. Gynaecological and obstetrical morbidity in women with type I von Willebrand disease: Results of a patient survey. Haemophilia. 2000;6(6). 287 Pierce-Williams RAM, Makhamreh MM, BlakeyCheung S, et al. Postpartum hemorrhage in patients with type 1 von Willebrand disease: A systematic review. Semin Thromb Hemost. 2022;48(2). 288 Kadir RA. Women and inherited bleeding disorders: Pregnancy and delivery. Semin Hematol. 1999; 36(3 Suppl. 4). 289 Ray JG. DDAVP. Use during pregnancy: An analysis of its safety for mother and child. Obstet Gynecol Surv. 1998;53(7). 290 Chediak JR, Alban GM, Maxey B. von Willebrand’s disease and pregnancy: Management during delivery and outcome of offspring. Am J Obstet Gynecol. 1986;155(3). 291 Reale SC, Farber MK, Lumbreras-Marque MI, et al. Anesthetic management of von Willebrand disease in pregnancy: A retrospective analysis of a large case series. Anesth Analg. 2021;133(5). 292 Castaman G, James PD. Pregnancy and delivery in women with von Willebrand disease. Eur J Haematol. 2019;103(2). 293 Lindoff C, Rybo G, Astedt B. Treatment with tranexamic acid during pregnancy, and the risk of thrombo-embolic complications. Thromb Haemost. 1993;70(2). 294 Roqué H, Funai E, Lockwood CJ. von Willebrand disease and pregnancy. J Matern-Fetal Med. 2000;9(5). 295 Kadir FA, Economides DL, Braithwaite J, et al. The obstetric experience of carriers of haemophilia. Br J Obstet Gynaecol. 1997;104(7). 296 Mannucci PM, Tuddenham EG. The hemophilias—from royal genes to gene therapy. N Engl J Med. 2001;344(23). 297 Kulkarni A, Draycott T. The use of serial betaHCG to plan surgical evacuation of retained placenta in a case of placenta accreta. J Matern Fetal Neonatal Med. 2005;17(4):295–297. 298 Togioka BM, Burwick RM, Kujovich JL. Delivery and neuraxial technique outcomes in patients with hemophilia and in hemophilia carriers: A systematic review. J Anesth. 2021;35(2). 299 Yang MY, Ragni MV. Clinical manifestations and management of labor and delivery in women with factor IX deficiency. Haemophilia: The Official Journal of the World Federation of Hemophilia. 2004;10(5).

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38 Septic Shock Sonya S. Abdel-Razeq Obstetrics, Gynecology, and Reproductive Sciences, Yale University, New Haven, CT, USA

Introduction

recognized, characterized by one of three primary physiologic derangements: (1) decreased preload (hypovolemic shock), (2) pump failure (cardiogenic shock), and (3) a severe drop in systemic vascular resistance with a compensatory increase in cardiac output (known as “distributive” or “vascular shock”) (Table 38.1). The primary pathophysiologic defect for each type of shock is highlighted. Septic shock is a type of vasodilatory or distributive shock. It is defined as sepsis with circulatory, cellular, and metabolic abnormalities associated with

Shock is best described as a life-threating disorder from acute circulatory failure as well as microcirculatory failure resulting in major tissue hypoxia and hypoperfusion leading to end-organ damage [1]. For these reasons, prompt recognition and appropriate management of shock states are crucial. Any classification scheme simplifies the complex pathophysiology underlying the many individual causes of shock states. Three broad types of shock states are

Table 38.1  Pathophysiology and hemodynamic profile of shock states. Physiologic variable Preload

Pump function

Afterload

Tissue perfusion

Clinical measurement

Type of shock

Pulmonary capillary wedge pressure

Hypovolemic shock

Cardiac output

Systemic vascular resistance

Mixed venous oxygen saturation

↓

↑

↓

Causes ● ●

Cardiogenic shock

↑

Distributive (vasodilatory) shock

↓ or ↔

↑ ↑

↓ ↑

● ● ● ● ● ● ● ● ● ● ●

Hemorrhage Fluid loss Cardiomyopathy Arrhythmias Valvular disease Obstruction Septic shock Toxic shock syndrome Anaphylaxis Drug or toxin reaction Myxedema coma Neurogenic shock Burn shock

Source: Adapted from Gaieski and Manaker [3]. Critical Care Obstetrics, Seventh Edition. Edited by Luis D. Pacheco, Jeffrey P. Phelan, Torre L. Halscott, Leslie A. Moroz, Arthur J. Vaught, Antonio F. Saad, and Amir A. Shamshirsaz. © 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.

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666

Septic Shock

Table 38.2  Terminology and international classification of diseases coding. Current guidelines and terminology

Sepsis

Septic shock

1991 and 2001 consensus terminology [4,5]

Severe sepsis Sepsis-induced hypoperfusion

Septic shock

2015 definition

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection.

Septic shock is a subset of sepsis in which underlying circulatory and cellular/ metabolic abnormalities are profound enough to substantially increase mortality.

2015 clinical criteria

Suspected or documented infection and an acute increase of >2 SOFA points (a proxy for organ dysfunction).

Sepsis and vasopressor therapy needed to elevate MAP >65 mmHg and lactate >2 mmol/L (>18 mg/dL) despite adequate fluid resuscitation [6].

995.92

785.52

R65.20

R65.21

Recommended primary ICD-9 codes Recommended primary ICD-10 codes Framework for implementation for coding and research

a

Identify suspected infection by using concomitant orders for blood cultures and antibiotics (oral or parenteral) in a specified period.b Within specified period around suspected infection:c 1) Identify sepsis by using a clinical criterion for life-threatening organ dysfunction 2) Assess for shock criteria, using administration of vasopressors, MAP 2 mmol/L (>18 mg/dL)d

ICD, International Classification of Diseases; MAP, mean arterial blood pressure; SOFA, Sequential (Sepsis-Related) Organ Failure Assessment [7]. a  Included training codes. b Suspected infection could be defined as the concomitant administration of oral or parenteral antibiotics and sampling of body fluid cultures (blood, urine, cerebrospinal fluid, peritoneal, etc.). For example, if the culture is obtained, the antibiotic is required to be administered within 72 h, whereas if the antibiotic is first, the culture is required within 24 h [8]. c  Considers a period as great as 48 h before and up to 24 h after onset of infection, although sensitivity analyses have tested windows as short as 3 h before and 3 h after onset of infection [8]. d  With the specified period around suspected infection, assess for shock criteria, using any vasopressor initiation (e.g., dopamine, norepinephrine, epinephrine, vasopressin, and phenylephrine), any lactate level >2 mmol/L (18 mg/dL), and MAP 2 mmol/L (>18 mg/dL) (Table 38.2) [2]. Septic shock is characterized by an inability of the host to maintain vascular integrity and fluid homeostasis, resulting in inadequate tissue oxygenation and circulatory failure. Even sepsis at the cellular level is a dysregulation of host response and is life-threatening. Although sepsis may not require vasoactive medications to maintain perfusion, sepsis is still the leading cause of death in the critically ill in the United States and worldwide [4–6]. Sepsis is a clinical syndrome with physiologic, biologic, and biochemical abnormalities caused by a dysregulated inflammatory response to infection. It has the most negative impact in extremes of age, comorbid conditions, and weakened immune systems. In 2019, there were approximately 200,000 sepsis-related cases with over 75% being over the age of 65 [4]. Although septic shock is an uncommon event in the United States, it is still a leader in maternal mortality worldwide [7].

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While improvements in care have led to a decrease in septic shock mortality rates over the past two decades [10,11], the overall number of patients dying from sepsis is growing as more patients are affected. Moreover, despite improvements in ICU care, the mortality rate from septic shock remains at 40–50% in most series [12], and an additional 20% of hospital survivors may succumb within the following year [13]. Short-term mortality appears to be related to the number of organ systems affected. The average risk of death increases by 15–20% with failure of each additional organ system  [14]. If there is evidence of renal, pulmonary, and cerebral dysfunction, mortality may be as high as 70% [15].

Screening tools for sepsis and septic shock Screening tools in sepsis are utilized to (1) appropriately identify patients at risk or diagnosed with sepsis; (2) allocate appropriate resources such as intravenous fluid resuscitation, culture data, and timely antibiotics; and (3) risk stratify to higher levels of care including intensive care unit and transfer to other centers. In all, there are a myriad

­Pathothyshohoh hofysoasic ythicc  667

of screening tools that can be used within and out of pregnancy, including systemic inflammatory response syndrome (SIRS), National Early Warning Signs (NEWS), Modified Early Warning Signs (MEWS), and the qSOFA and omqSOFA score [8]. SIRS is considered a clinical syndrome form of dysregulated inflammation. Its etiology is not limited to infection since burn injuries, trauma, and inflammatory conditions (such as pancreatitis) can elicit a similar clinical picture. It is characterized by two or more of the following cardinal signs: (1) a body temperature 38 °C; (2) a pulse rate >90 beats per minute (bpm); (3) tachypnea manifesting as a respiratory rate >20 breaths per minute or a PaCO2 10% immature forms on the differential count. In 1991, a consensus conference was convened by the American College of Chest Physicians and the Society of Critical Care Medicine to create a conceptual and practical framework to define the systemic inflammatory response to infection, a process that was incorporated under the generalized term sepsis [1,2]. In 2001, a second consensus conference revised the terminology for this syndrome, retaining the terms and concepts of SIRS, severe sepsis, and septic shock while expanding the criteria for sepsis. The most recent consensus conference, Sepsis-3, held in 2014, updated definitions and clinical criteria for sepsis syndrome and septic shock to be consistent with an improved understanding of the pathobiology. The original SIRS criteria were discarded as unhelpful, and laboratory assessment for sepsis toned down. The focus is again on clinical findings because the task force acknowledged the difficulty of defining a syndrome for which no diagnostic test remains. Only categories of sepsis and septic shock were retained. As one could surmise, SIRS criteria are present in many hospitalized patients who do not develop an infection, and their ability to predict death is poor when compared with other scores such as the Sequential (Sepsis-Related) Organ Failure Assessment (SOFA) score [7,16,17]. However, more recent evidence shows that it is no more favorable in diagnosing sepsis over qSOFA score, MEWS, and NEWS  [9]. For this reason, SCCM recommends against using any measure as single screening tool without clinical context. Sepsis-3 defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection [2]. The best clinical criteria that correlate with sepsis in infected patients outside the ICU are any two of the following: ● ● ●

Systolic blood pressure 22/min Altered mental status

Together, these constitute the Quick Sequential Organ Failure Assessment (qSOFA or Quick SOFA) score (Table 38.3). This measure provides simple bedside criteria

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Table 38.3  Quick Sequential Organ Failure Assessment (qSOFA or Quick SOFA) criteria. Systolic blood pressure 22/min Altered mental status Note: The qSOFA score is considered positive when at least two of the above three criteria are present. Source: Adapted from Singer et al. [2].

to identify adult patients with suspected infection who are likely to have a poor outcome. However, these parameters should be used with caution in singularity. Studies have shown that qSOFA is more specific but less sensitive in the diagnosis of sepsis and only 24% of infected patients will have qSOFA score of 2 or greater [15]. Even more concerning is that these patients accounted for 70% of septic patients with poor outcomes. Septic shock is now defined as a subset of sepsis in which underlying circulatory and cellular metabolism abnormalities are profound enough to substantially increase mortality [2]. Operationally, this equates to persistent hypotension (MAP 65  mmHg) requiring vasopressors, with a serum lactate level >2  mmol/L despite adequate volume resuscitation. Organ dysfunction can be identified as an acute change in total SOFA score ≥2 points consequent to the infection. Patients with a SOFA score of 2 or more have an overall mortality risk of approximately 10% in a general hospital population with presumed infection (Table 38.4) [8]. As mentioned in this chapter, the SOFA score is one of a number of severity-of-illness scoring systems in sepsis patients recommended by the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee as an adjunctive tool to assess mortality  [4]. The utility of the various scoring systems allows for comparison of different populations, for hospital planning, and as research tools for critical illnesses. The scoring systems are based on either physiologic variables or organ failure. The most widely used scoring systems include the Acute Physiology and Chronic Health Evaluation (APACHE) II, Simplified Acute Physiology Score (SAPS) II, Sequential Organ Failure Assessment (SOFA), and Multiple Organ Dysfunction Score (MODS). These tools have been validated for use in the general critical care population.

Pathophysiology of septic shock Infection with a pathogenic organism results in cellular activation of monocytes, macrophages, and neutrophils and induction of a pro-inflammatory cascade triggered by  interaction between the organism and a number of

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Table 38.4  Sequential (Sepsis-Related) Organ Failure Assessment score.a Score System

0

1

2

3

4

Respiration PaO2/ FIO2 (mmHg)

≥400 (≥53.3)

≥400 ( 25 mm/m2 Tetralogy of Fallot > 50 mm

Vascular Ehlers-Danlos Severe (re) coarctation Fontan Circulation with any complications Eisenmenger syndrome (cyanosis due to R-to-L intracardiac shunt) EF: ejection fraction, ASI: aortic size index. Source: Data from modified World Health Organization (WHO) IV.

Table 44.3 Risks of congenital heart disease to mother and fetus during pregnancy. Risk to the mother

Risk to the fetus

Pulmonary edema

Fetal growth retardation

Arrhythmias

Prematurity

Heart failure

Recurrence of congenital heart disease

Bleeding from anticoagulation

Teratogenic effect of drugs administered to the mother

Thrombosis and stroke

Intracranial hemorrhage

Death

Fetal loss

Table 44.4

With small shunts, right ventricular (RV) and pulmonary artery (PA) pressures are unchanged, and there is minimal change in pulmonary blood flow. With larger shunts, there is progressively increased pulmonary blood flow and increased RV and PA pressures. Ultimately, RV and left ventricular (LV) pressures equalize, leading to pulmonary vasoconstriction and irreversible vascular remodeling resulting in PH and Eisenmenger syndrome. The primary goal of anesthetic management is to avoid sudden increases in SVR and pulmonary vascular resistance (PVR) caused by pain, hypoxia, and hypercarbia [13]. Concomitantly, avoiding sudden decreases in SVR is also crucial because it exacerbates right-to-left (R-to-L) shunting and hypoxemia. Due to the hemodynamic stresses of labor and delivery, parturients with NYHA Class III and IV symptoms require invasive monitoring to denote the beatto-beat changes [13]. Therefore, continuous arterial blood pressure, electrocardiogram (ECG), and central venous pressure (CVP) monitoring may be useful during both labor and cesarean delivery [14]. Antibiotic prophylaxis for the prevention of bacterial endocarditis, particularly in patients with ASD for uncomplicated delivery, is not advocated by the American Heart Association (AHA) (see Table 44.5) [15,16]. In CHD parturients with L-to-R shunts, the primary consideration is the alleviation of pain during labor, so the use of a combined spinal–epidural (CSE) technique in early labor is particularly advantageous  [13]. An intrathecal lipophilic opioid such as fentanyl can be used to alleviate pain with minimal

Left-to-right shunts.

Size of defect

Hemodynamic alterations

Pregnancy complications

Prognosis

Small

RV and PA are unchanged

Increased risk of endocarditis

Usually uncomplicated course

Moderate

RV and PA pressures are increased but remain below systemic pressures. Increased pulmonary blood flow. Pulmonary vascular disease unlikely

LV volume overload and failure

CHF and arrhythmias are likely. High chance of cardiac decompensation during pregnancy

Large

RV and LV pressures equalize Eisenmenger syndrome. Pulmonary vascular disease likely

Heart failure, fetal hypoxemia

Mortality can reach as high as 50%; CI: Pregnancy

CHF: congestive heart failure; CI: contraindicated; LV: left ventricular; PA: pulmonary artery; RV: right ventricular.

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Table 44.5 Antibiotic prophylaxis for genitourinary and gastrointestinal procedures. Regimen (preferably treatment antibiotic 30–60 min before procedure

Treatment

Antibiotic

Intravenous therapy

Ampicillin or cefazolin or ceftriaxone*

2 g intravenously 1 g intravenously

Allergic to penicillin or ampicillin*

Cefazolin or ceftriaxone* or clindamycin

1 g intravenously * 600 mg intravenously

Oral

Amoxicillin

2g

Allergic to penicillin or ampicillin

Cephalexin Clindamycin Azithromycin

2g 600 mg 500 mg

* Cephalosporins should not be used in patients with a significant sensitivity to penicillins. These regimens do not cover enterococcus. Vancomycin can be used if enterococcus is concern

hemodynamics disturbances. This can then be followed with ultra-low-dose epidural infusion, thus providing continuous labor analgesia without adverse effects on hemodynamics or labor progression [17]. Epidural placement with loss of resistance to saline technique should be used to prevent air entry into an epidural vein, which can lead to paradoxical air embolism  [18]. Decompensation in the cardiac status is most likely to occur immediately after delivery due to autotransfusion from the uteroplacental unit; thus, close monitoring is paramount. Prevention of Valsalva maneuver in the second stage of labor is advised; instrumental delivery with the use of forceps or vacuum may be warranted. Supplemental oxygen is used to both increase oxygen reserves and enhance oxygen delivery in parturients with L-to-R shunting to prevent hypoxemia (see Table 44.6). Right-­to-­left shunts (cyanotic heart disease) Tetralogy of Fallot Pathophysiology Tetralogy of Fallot (TOF) is the most

common CHD associated with an R-to-L shunt; it consists of a VSD, RV hypertrophy, pulmonary stenosis with RV outflow tract obstruction, and an overriding aorta. Most women have correction in childhood and may present with residual defects. The degree of intracardiac shunting, severity of RV outflow obstruction, and RV function are primary determinants of outcome. Anesthetic considerations

ment include [13]:

Goals of peripartum manage-

1) Avoid decreases in SVR, thus minimize the magnitude of R-to-L shunt.

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Table 44.6 Anesthetic management principles in L-to-R intracardiac shunts. Management principles

Rationale

Supplemental oxygen

Increases oxygen reserves, especially in second stage of labor

Loss of resistance to saline technique for epidural anesthesia

Decreases risk of venous air embolism and paradoxical air embolism

Early combined spinal–epidural technique with intrathecal narcotics and ultra-low concentration of epidural infusion analgesia for good pain control throughout labor

Avoids increases in maternal catecholamines

Cut short second stage of labor with forceps or vacuum assist

Avoids Valsalva and hemodynamic changes associated with pushing

2) Maintain adequate intravascular volume and venous return. 3) Use α-agonist to counteract anesthetic-induced decreases of SVR. 4) Perform transthoracic echocardiography in awake patients to assess volume state and ventricular function. CSE is preferable among the neuraxial anesthesia techniques. Early establishment of CSE in labor with the use of intrathecal opioids followed by an epidural infusion of ultra-low concentration local anesthetic can provide excellent analgesia without decreasing the SVR  [13,14]. Phenylephrine is the drug of choice for managing hypotension in these patients. If general anesthesia becomes necessary, pharmacologic agents must be carefully titrated to avoid decreases in SVR or increases in PVR [13]. Following acid aspiration prophylaxis, controlled induction with ketamine and short-acting opioids such as remifentanil may be preferable to prevent large hemodynamic perturbations and to minimize adverse effects on the fetus. Consultation with the neonatologist and plans for neonatal resuscitation are a must. Eisenmenger syndrome Pathophysiology Eisenmenger’s complex is described as

PH with a reversible or bidirectional shunt through a large VSD. The systemic and pulmonary circulations are in open communication. When the PVR rises or SVR falls, severe hypoxemia ensues due to blood bypassing the lungs. When flow through the pulmonary vascular bed is increased, as in patients with congenital intracardiac (L-to-R) shunts, the vasculature is initially able to compensate for the increased volume. However, over a prolonged period, there is thickening of the vessel walls, resulting in an increase in

Congenital heart disease

PVR. Eventually, right-sided cardiac pressures become elevated, leading to reversal in the intracardiac shunt [12]. The conversion or reversal to an R-to-L shunt with a longstanding ASD/VSD or PDA results in Eisenmenger syndrome. A retrospective analysis showed that an increase in PA pressure and PVR was demonstrated in some patients who initially had moderate PH with CHD during gestation [19]. The maternal death rate was 36% in a series of 73 patients with Eisenmenger syndrome. Three women died during pregnancy, and 23 at delivery or within 1  month postpartum. Mortality was strongly associated with late diagnosis and late hospital admission, while the severity of PH was also found to be a contributing factor. Neither the mode and timing of delivery nor the type of anesthesia and monitoring correlated with maternal outcome. Most fatalities were described as sudden death or therapy-resistant heart failure [19]. Because maternal and fetal mortality can be as high as 50% in parturients with Eisenmenger syndrome, this condition is considered an absolute contraindication to pregnancy [11]. If the patient decides to continue pregnancy despite counseling, then the following modalities should be implemented: bed rest, hospital admission by the second trimester, continuous pulse oximetry, supplemental oxygenation, and prophylactic antithrombotic prophylaxis with heparin [12]. Anesthetic considerations

Important considerations in patients with Eisenmenger syndrome include [13]: 1) Avoidance of decrease in SVR and increase in PVR 2) Prevention of hypercarbia, hypoxemia, acidosis, and high airway pressures Invasive monitoring should include continuous blood pressure monitoring and CVP to assess hemodynamic status and right atrial pressure. Continuous supplemental oxygen should be used throughout labor. Perioperative risk in Eisenmenger syndrome is high for patients undergoing noncardiac surgery, and regional anesthesia is traditionally avoided because of the potential deleterious hemodynamic effects. Spinal or epidural anesthesia can cause sudden decrease in systemic afterload and increase to the R-to-L shunt. Nevertheless, a review of 57 articles describing 103 anesthetics in patients with Eisenmenger syndrome showed that overall perioperative mortality was 14%. Patients receiving regional anesthesia had a mortality of 5%, whereas those receiving general anesthesia had a mortality of 18%. This trend favored the use of regional anesthesia but was not statistically significant [19]. For labor, CSE is again the preferred technique in these high-risk patients. A combination of 10–15 mcg of fentanyl and 2.5 mg of bupivacaine intrathecally provides excellent

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analgesia with minimal hemodynamic perturbations. This is followed by an ultra-low concentration local anesthetic infusion. If operative delivery is needed, general anesthesia conventionally has been chosen to maintain cardiac output while carefully manipulating SVR/PVR [13]. The authors recommend ketamine as an induction agent and shortacting opioids such as remifentanil. Close monitoring in the intensive care unit postoperatively is recommended for at least 48 h after delivery due to increased risk of adverse maternal cardiac events and thromboembolism in these patients [20]. Stenotic lesions Aortic stenosis

Congenital aortic stenosis (AS) is usually associated with a bicuspid aortic valve  [21]. Women with AS lesions, functional NYHA Class >2, cyanosis, severe LV outflow obstruction (aortic valve area 40  mmHg) must be corrected before pregnancy. Severe AS carries a high risk of mortality during pregnancy. In a study of pregnancy outcomes in 49  women with congenital AS, cardiac complications occurred in 10% of pregnancies in women with severe AS (40% during follow-up)  [22,23]. Maternal death rarely occurs ( 4.5  cm  [25]. Numerous case series have reported favorable outcomes in the mother but not the fetus, especially if emergency surgery is involved [35,36]. Given the paucity of data, it seems logical that if the fetus is viable, then emergent delivery should be performed prior to surgery. In situations where fetal viability is unlikely, the mother’s condition takes priority, and emergent repair of the dissection should be performed with the knowledge that the fetus will poorly tolerate cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest. Fetal protection can be attempted with pulsatile perfusion and minimizing the circulatory arrest time. Anesthetic management is similar to those for non-pregnant patients who undergo emergent cardiac surgery and CPB (see Chapter 17).

Anesthetic considerations

­Acquired heart disease Rheumatic mitral stenosis Pathophysiology

Rheumatic mitral stenosis (MS) is the most frequently encountered rheumatic heart disease in the pregnant population worldwide  [1]. MS is also the lesion that most frequently requires therapeutic intervention during pregnancy. In severe MS, reduction in valve area decreases LV filling and causes a fixed cardiac output state, elevated left atrial and PA pressures, and eventually pulmonary edema [5]. During pregnancy and labor, the elevated cardiac demands further increase risk for arrhythmias and pulmonary edema. Chronic MS also can lead to PH and RV failure, all of which are further exacerbated by pregnancy. In addition to cardiopulmonary complications, parturients with MS can experience elevated risk of thromboembolism and fetal complications. Tolerance of pregnancy depends on the severity of valve disease, heart rate and rhythm, atrial compliance, circulating blood volume, and pulmonary vascular response [5,37]. Patients with a mitral orifice area >1.5 cm2 can usually be treated medically, whereas those with valve area 90% [38]. If PBMV is not available, open mitral commissurotomy under general anesthesia can be performed. The risk is higher in pregnant versus non-pregnant patients and even more risky for the fetus with high fetal mortality rates  [39]. Surgical mitral valve replacement is reserved only for those patients who have symptoms refractory to medical therapy in whom valvuloplasty is contraindicated [40,41]. Anesthetic considerations

Current recommendation for parturients with MS is vaginal delivery under epidural anesthesia unless obstetrically contraindicated. In a study by Goldszmidt et al., only 30% of the 522  women with heart disease required cesarean delivery and nearly 70% of them underwent successful vaginal delivery with epidural analgesia [42]. Proper pain control during labor will minimize tachycardia, excess blood flow across mitral valve, and pulmonary edema [13]. Some practitioners prefer CSE for labor analgesia with lipophilic opioid and ultra-low concentration local anesthetic infusion. If hypotension develops, phenylephrine is the vasopressor of choice rather than ephedrine, which causes tachycardia and decreases filling time [13]. Epinephrine-containing epidural solutions must be avoided because of the potential for accidental intravascular injection. Invasive blood pressure monitoring, continuous ECG, pulse oximetry, and supplemental oxygen are recommended for all laboring parturients [14]. Patients should avoid Valsalva maneuver during the second stage of labor and assistant delivery may be warranted. If cesarean delivery is required, gradual titration of an epidural block with continuous monitoring can be performed. NYHA Class III and IV patients are better managed under general anesthesia. Goals include maintaining hemodynamic stability, avoidance of tachycardia, fluid overload, and low SVR [13]. A balanced anesthetic with a high-dose titrated opioid induction and β-blockade has been done with success [32]. If expertise is available, perioperative transesophageal echocardiography may be invaluable in guiding clinical decisions [13].

Mitral regurgitation Pathophysiology

Mitral regurgitation (MR) is the second most common valvular disease in pregnancy [43]. LV is chronically overloaded eventually leading to CHF and pulmonary edema. Other potential complications include atrial fibrillation, thromboembolism, and bacterial endocarditis [5]. In general, MR is

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well tolerated in pregnancy. However, patients with LV dysfunction, moderate-to-severe PH, and/or NYHA Class III–IV are at increased risk for heart failure and arrhythmias during pregnancy [27]. Anesthetic considerations

For MR parturients, vaginal delivery is preferred, while cesarean delivery is reserved for obstetric indications [12]. Asymptomatic patients with good functional status likely will not need invasive monitoring. Goals of management include maintenance of sinus rhythm, high normal heart rate, and low normal SVR. Early epidural analgesia to prevent increases in SVR from pain and anxiety is paramount  [13]. Most patients tolerate vaginal delivery with good maternal and fetal outcomes  [12]. Patients with severe MR, LV failure, and pulmonary edema will need diuresis and afterload reduction  [14]. Invasive hemodynamic monitoring including PAC may be warranted. General anesthesia for severely symptomatic patients may be necessary, and transesophageal echocardiography (TEE) or newer noninvasive methods of cardiac output monitoring may facilitate managing these patients for cesarean delivery [13,14].

Aortic stenosis Pathophysiology

AS is rare in women of childbearing age. It is mostly seen with congenital bicuspid aortic valve or rheumatic heart disease [22]. Given bicuspid aortic valve frequently associates with aortic pathologies, they will need to be excluded as they can carry significant morbidity during pregnancy  [44]. Patients with mild-to-moderate AS typically tolerate hemodynamic changes of pregnancy well, whereas those with severe AS (valvular area 40  mmHg) may be at considerable risk for arrhythmias, myocardial decompensation, pulmonary edema, and LV failure. Fetal complications may include fetal growth restriction resulting in premature birth and low birth weight [45,46]. For patients who develop heart failure symptoms during pregnancy, medical management includes activity restriction, heart rate control, and diuresis. In case of therapy failure, percutaneous balloon valvuloplasty has good outcomes with low complication rate  [46,47]. Surgical valve replacement is usually the last resort, and if performed early in pregnancy, the risk of fetal mortality may be as high as 30% [48,49]. Anesthetic considerations

The mode of delivery for AS patients is strongly influenced by obstetric indications and disease severity. Labor and assisted vaginal delivery are preferred and may be safely pursued in asymptomatic patients. Overall management goals for AS

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include low normal heart rate, careful intravascular fluid balance, and maintenance of SVR [13]. Similar to MS patients, early implementation of epidural analgesia using an ultra-low concentration local anesthetic is key. The CSE technique using intrathecal opioid and dilute local anesthetic is also reasonable. If operative delivery is pursued, careful incremental extension of epidural anesthesia can be performed with good outcomes. Regardless of lesion severity, single-shot spinal anesthesia is contraindicated due to profound vasodilation, which can potentiate cardiovascular collapse [13]. In case of severe symptomatic AS, general anesthesia using a balanced technique may be the most appropriate choice. Invasive monitoring is advised, and TEE may be warranted to guide fluid resuscitation intraoperatively [14].

Aortic regurgitation Pathophysiology

Causes of aortic regurgitation (AR) in women of childbearing age include congenital bicuspid aortic valve, rheumatic heart disease, infective endocarditis, and aortic annular dilation [27,41]. In the absence of heart failure, AR is generally well tolerated in pregnancy due to naturally higher heart rate and lower SVR. Surgical intervention is rarely warranted except in the most severe cases with significant LV impairment. Symptomatic patients typically present with heart failure and/or arrhythmias, with medical therapy entails diuresis, afterload reduction, and heart rate control [12,41]. Dietary modifications and activity restrictions may also be helpful in mitigation of symptoms. Anesthetic considerations

In severe AR patients, vaginal delivery with a shortened second stage of labor is the preferred mode of delivery. Anesthetic goals include avoidance of aortocaval compression and myocardial depression, high normal heart rate (80–100 beats/min), and low normal SVR  [12]. Neuraxial analgesia is beneficial for laboring patients and should be sought early. If operatively delivery is warranted, both general and neuraxial anesthesia may be safely performed. A carefully titrated neuraxial technique is preferable because it decreases afterload while preventing increases in SVR and excessive LV volume [13]. The indirect-acting sympathomimetic ephedrine is the first-line pressor used in AR [13].

­Anticoagulation therapy in a parturient Venous thromboembolism (VTE) is a leading cause of maternal morbidity and mortality worldwide, and it accounts for 9.3% of all maternal deaths in the United

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States [50]. Pregnancy places women in a hypercoagulable state that increases the risk of VTE nearly 5× and lasts until the third month postpartum [51]. Many women enter pregnancy with a preexisting medical condition that requires anticoagulation like thrombophilia, atrial fibrillation, dilated cardiomyopathy, and mechanical heart valves. These women need to be closely monitored perinatally, while the risks and benefits of anticoagulation to the mother and fetus are carefully balanced. Unfractionated heparin and low-molecular-weight heparin (LMWH) and have been used in pregnancy for several decades because of their safety profile: they do not cross the placenta, do not have teratogenic effects, and are not heavily secreted in breast milk. Because the pharmacokinetic properties of LMWH allow for better reliability and ease of administration, it is recommended over unfractionated heparin for the prevention and treatment of VTE during pregnancy [52]. Therapy with unfractionated heparin needs to be closely monitored with activated partial thromboplastin time (aPTT) and therapy with LMWH by measuring peak and, in some cases, trough anti-Xa levels [52]. Oral anticoagulation with warfarin offers the best thromboembolic protection to the mother and is associated with the lowest maternal mortality  [52,53]. However, it does cross the placenta and can have detrimental effects to the growing fetus, such as warfarin embryopathy, neurologic abnormalities, fetal growth restriction, spontaneous abortion, premature birth, fetal and placental hemorrhage, and fetal loss [54]. Parturients with mechanical valves are particularly challenging as heparin is not as effective as warfarin and is associated with a high incidence of thromboembolic events. Despite the potential fetal complications, warfarin is the treatment of choice in this population. The AHA and the American College of Cardiology (ACC) recommend warfarin use in the second and third trimesters at 5 mg daily and then substitute with intravenous unfractionated heparin before planned delivery [52,53]. Warfarin can be used during the first trimester if the therapeutic dose is < 5 mg daily after a thorough explanation of the fetal risks. If higher doses are necessary, substitution with LMWH or unfractionated heparin is recommended. Warfarin is not recommended for the treatment of maternal arrhythmias; either unfractionated heparin or LMWH should be used [52,55]. There are limited data on direct thrombin and direct Xa inhibitors in the treatment and prevention of thromboembolism in pregnancy. They do cross the placenta and their effects on fetal development are currently unknown, so they are not recommended during pregnancy [52,54]. Aspirin is a mainstay therapy for pregnant women with artificial valves as it has not been shown to increase maternal/fetal bleeding risks or congenital abnormalities  [56].

Ischeeic heart disease

Table 44.7 Anticoagulants and their characteristics. Drug

Mechanism

Monitoring

Present in breast milk

Crosses placenta

Warfarin

Vitamin K antagonist

INR

No

Yes

Heparin

Potentiates ATIII

aPTT

Amount not clinically significant

No

Enoxaparin

Inhibits factor Xa and potentiates ATIII

Peak anti-Xa levels

No

No

Aspirin

Inactivation of COX enzyme

NA

Yes

Yes

Clopidogrel

Inhibits glycoprotein GPIIb/ IIIa complex

NA

Yes in animals

Unlikely

aPTT: activated partial thromboplastin time; INR: international normalized ratio; NA: not applicable. Source: Adapted from Alshawabkeh et al. [54].

Table 44.8

Anticoagulants and their management with neuraxial anesthesia.

Anticoagulant

Timing of neuraxial instrumentation

While epidural catheter is in place

Timing of epidural catheter removal

NSAIDS/aspirin

No restrictions

No restrictions

No restrictions

Clopidogrel

Stop drug for 7 days

Contraindicated while catheter in place

Can be restarted 6 h after catheter removed

Heparin (prophylactic dose)

Hold 4–6 h before placing epidural

Can restart immediately after epidural placed

Hold for 4 h before removing catheter; can restart immediately after catheter removed

Unfractionated Heparin (therapeutic dose)

Hold for 24 h and place epidural when aPTT 60–70 mmHg, hematocrit > 28%, normothermia > 35 °C, pulsatile flow, careful acid/base management, and/or tocolytic therapy, although evidence is limited to case reports and expert opinions [12]. Left lateral tilt is typically done to help improve arterial inflow to and venous outflow from the placenta. To ensure optimal patient outcomes, a multidisciplinary team involving cardiac anesthesiologist experienced in managing these patients intraoperatively is crucial.

­Summary Careful attention must be paid to detect cardiac diseases in women of childbearing age prior to pregnancy. While many patients may have known existing diseases, some will have de novo symptoms in previously undiagnosed pathologies. The gamut of cardiac diseases encountered in pregnancy can range from complex congenital lesions to acquired valvular and ischemic pathologies to aortic dissections and beyond. The anesthetic management of each is unique and often requires a large multidisciplinary team for coordinated care. Communication and team planning with the involvement of maternal–fetal medicine, obstetric anesthesiologists, cardiac anesthesiologists, cardiologists, cardiac surgeons, intensivists, and neonatologists are critical to ensure safe care and successful outcome to both the mother and the baby.

­References 1 Roos-Hesselink J, Baris L, Johnson M, et al. Pregnancy outcomes in women with cardiovascular disease: Evolving trends over 10 years in the ESC Registry of Pregnancy and Cardiac disease (ROPAC). Eur Heart J. 2019;40(47):3848–3855.

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2 Mehta LS, Warnes CA, Bradley E, et al. Cardiovascular considerations in caring for pregnant patients: A scientific statement from the American Heart Association. Circulation. 2020;141(23): e884–e903.

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3 Malhotra S, Yentis SM. Reports on confidential enquiries into maternal deaths: Management strategies based on trends in maternal cardiac deaths over 30 years. Int J Obstet Anesth. 2006;15(3):223–226. 4 Shime J, Mocarski EJ, Hastings D, et al. Congenital heart disease in pregnancy: Short- and long-term implications. Am J Obstet Gynecol. 1987;156(2):313–322. 5 Siu SC, Evans KL, Foley MR. Risk assessment of the cardiac pregnant patient. Clin Obstet Gynecol. 2020;63(4):815–827. 6 Windram J, Grewal J, Bottega N, et al. Canadian cardiovascular society: Clinical practice update on cardiovascular management of the pregnant patient. Can J Cardiol. 2021;37(12):1886–1901. 7 Silversides CK, Grewal J, Mason J, et al. Pregnancy outcomes in women with heart disease: The CARPREG II study. J Am Coll Cardiol. 2018;71(21):2419–2430. 8 Drenthen W, Pieper PG, Roos-Hesselink JW, et al. Outcome of pregnancy in women with congenital heart disease: A literature review. J Am Coll Cardiol. 2007;49(24):2303–2311. 9 Canobbio MM, Warnes CA, Aboulhosn J, et al. Management of pregnancy in patients with complex congenital heart disease: A scientific statement for healthcare professionals from the American Heart Association. Circulation. 2017;135(8):e50–e87. 10 Hirnle L, Lysenko L, Gerber H, et al. Respiratory function in pregnant women. Adv Exp Med Biol. 2013;788:153–160. 11 ACOG Practice Bulletin No. 212: Pregnancy and heart disease. Obstet Gynecol. 2019;133(5):e320–e356. 12 Elkayam U. Cardiac problems in pregnancy. 4th ed: Wiley-Blackwell; 2019; 560 p. 13 Arendt KW, Lindley KJ. Obstetric anesthesia management of the patient with cardiac disease. Int J Obstet Anesth. 2019;37:73–85. 14 Meng ML, Arendt KW. Obstetric anesthesia and heart disease: Practical clinical considerations. Anesthesiology. 2021;135(1):164–183. 15 ACOG Practice Bulletin No. 199: Use of prophylactic antibiotics in labor and delivery. Obstet Gynecol. 2018;132(3):e103–e119. 16 Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: Diagnosis, antimicrobial therapy, and management of complications: A scientific statement for healthcare professionals from the American Heart Association. Circulation. 2015;132(15):1435–1486. 17 Wong CA, Scavone BM, Peaceman AM, et al. The risk of cesarean delivery with neuraxial analgesia given early versus late in labor. N Engl J Med. 2005;352(7):655–665. 18 Saberski LR, Kondamuri S, Osinubi OY. Identification of the epidural space: Is loss of resistance to air a safe

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technique? A review of the complications related to the use of air. Reg Anesth. 1997;22(1):3–15. Martin JT, Tautz TJ, Antognini JF. Safety of regional anesthesia in Eisenmenger’s syndrome. Reg Anesth Pain Med. 2002;27(5):509–513. Leighton BL, DeSimone CA, Norris MC, Ben-David B. Intrathecal narcotics for labor revisited: The combination of fentanyl and morphine intrathecally provides rapid onset of profound, prolonged analgesia. Anesth Analg. 1989;69(1):122–125. Reimold SC, Rutherford JD. Clinical practice. Valvular heart disease in pregnancy. N Engl J Med. 2003;349(1):52–59. Silversides CK, Colman JM, Sermer M, et al. Early and intermediate-term outcomes of pregnancy with congenital aortic stenosis. Am J Cardiol. 2003;91(11):1386–1389. Windram JD, Colman JM, Wald RM, et al. Valvular heart disease in pregnancy. Best Pract Res Clin Obstet Gynaecol. 2014;28(4):507–518. Hameed A, Karaalp IS, Tummala PP, et al. The effect of valvular heart disease on maternal and fetal outcome of pregnancy. J Am Coll Cardiol. 2001;37(3):893–899. Chambers CE, Clark SL. Cardiac surgery during pregnancy. Clin Obstet Gynecol. 1994;37(2):316–323. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ ACC Guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(23):e521–643. Elkayam U, Goland S, Pieper PG, Silverside CK. High-risk cardiac disease in pregnancy: Part I. J Am Coll Cardiol. 2016;68(4):396–410. Hameed AB, Goodwin TM, Elkayam U. Effect of pulmonary stenosis on pregnancy outcomes – a case-control study. Am Heart J. 2007;154(5):852–854. Kan JS, White RI, Jr, Mitchell SE, Gardner TJ. Percutaneous balloon valvuloplasty: A new method for treating congenital pulmonary-valve stenosis. N Engl J Med. 1982;307(9):540–542. Loya YS, Desai DM, Sharma S. Mitral and pulmonary balloon valvotomy in pregnant patients. Indian Heart J. 1993;45(1):57–59. Ransom DM, Leicht CH. Continuous spinal analgesia with sufentanil for labor and delivery in a parturient with severe pulmonary stenosis. Anesth Analg. 1995;80(2):418–421. Deal K, Wooley CF. Coarctation of the aorta and pregnancy. Ann Intern Med. 1973;78(5):706–710. Ramlakhan KP, Tobler D, Greutmann M, et al. Pregnancy outcomes in women with aortic coarctation. Heart. 2020;107(4):290–298.

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49 Vahanian A, Beyersdorf F, Praz F, et al. 2021 ESC/EACTS guidelines for the management of valvular heart disease. Eur J Cardiothorac Surg. 2021;60(4):727–800. 50 Creanga AA, Syverson C, Seed K, Callaghan WM. Pregnancy-related mortality in the United States, 2011–2013. Obstet Gynecol. 2017;130(2):366–373. 51 Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: A 30-year population-based study. Ann Intern Med. 2005;143(10):697–706. 52 Pacheco LD, Saade G, Shrivastava V, et al. Society for Maternal–Fetal Medicine Consult Series #61: Anticoagulation in pregnant patients with cardiac disease. Am J Obstet Gynecol. 2022;227(2):B28–B43. 53 Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/ AHA guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2021;143(5):e72–e227. 54 Alshawabkeh L, Economy KE, Valente AM. Anticoagulation during pregnancy: Evolving strategies with a focus on mechanical valves. J Am Coll Cardiol. 2016;68(16):1804–1813. 55 Nishimura RA, Warnes CA. Anticoagulation during pregnancy in women with prosthetic valves: Evidence, guidelines and unanswered questions. Heart. 2015;101(6):430–435. 56 Yarrington CD, Valente AM, Economy KE. Cardiovascular management in pregnancy: Antithrombotic agents and antiplatelet agents. Circulation. 2015;132(14):1354–1364. 57 Horlocker TT, Vandermeuelen E, Kopp SL, et al. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines. 4th ed. Reg Anesth Pain Med. 2018;43(3):263–309. 58 James AH, Jamison MG, Biswas MS, et al. Acute myocardial infarction in pregnancy: A United States population-based study. Circulation. 2006;113(12):1564–1571. 59 Hayes SN, Tweet MS, Adlam D, et al. Spontaneous coronary artery dissection: JACC state-of-the-art review. J Am Coll Cardiol. 2020;76(8):961–984. 60 Tweet MS, Young KA, Best PJM, et al. Association of pregnancy with recurrence of spontaneous coronary artery dissection among women with prior coronary artery dissection. JAMA Netw Open. 2020;3(9):e2018170. 61 Ladner HE, Danielsen B, Gilbert WM. Acute myocardial infarction in pregnancy and the puerperium: A population-based study. Obstet Gynecol. 2005; 105(3):480–484.

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62 Tweet MS, Eleid MF, Best PJ, et al. Spontaneous coronary artery dissection: Revascularization versus conservative therapy. Circ Cardiovasc Interv. 2014;7(6):777–786. 63 Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53(1): 1801913. 64 Penning S, Robinson KD, Major CA, Garite TJ. A comparison of echocardiography and pulmonary artery catheterization for evaluation of pulmonary artery pressures in pregnant patients with suspected pulmonary hypertension. Am J Obstet Gynecol. 2001;184(7):1568–1570. 65 Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67–119. 66 Thomas E, Yang J, Xu J, et al. Pulmonary hypertension and pregnancy outcomes: Insights from the national inpatient sample. J Am Heart Assoc. 2017;6(10):e006144. 67 Sliwa K, van Hagen IM, Budts W, et al. Pulmonary hypertension and pregnancy outcomes: Data from the Registry of Pregnancy and Cardiac Disease (ROPAC) of the European Society of Cardiology. Eur J Heart Fail. 2016;18(9):1119–1128. 68 Bédard E, Dimopoulos K, Gatzoulis MA. Has there been any progress made on pregnancy outcomes among women with pulmonary arterial hypertension? Eur Heart J. 2009;30(3):256–265. 69 Martin SR, Edwards A. Pulmonary hypertension and pregnancy. Obstet Gynecol. 2019;134(5):974–987. 70 Low TT, Guron N, Ducas R, et al. Pulmonary arterial hypertension in pregnancy – a systematic review of outcomes in the modern era. Pulm Circ. 2021;11(2):20458940211013671. 71 Duggan AB, Katz SG. Combined spinal and epidural anaesthesia for caesarean section in a parturient with severe primary pulmonary hypertension. Anaesth Intensive Care. 2003;31(5):565–569. 72 Meng ML, Landau R, Viktorsdottir O, et al. Pulmonary hypertension in pregnancy: A report of 49 cases at Four Tertiary North American Sites. Obstet Gynecol. 2017;129(3):511–520. 73 Slomka F, Salmeron S, Zetlaoui P, et al. Primary pulmonary hypertension and pregnancy: Anesthetic management for delivery. Anesthesiology. 1988;69(6):959–961.

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74 Jaïs X, Olsson KM, Barbera JA, et al. Pregnancy outcomes in pulmonary arterial hypertension in the modern management era. Eur Respir J. 2012;40(4):881–885. 75 Bonnin M, Mercier FJ, Sitbon O, et al. Severe pulmonary hypertension during pregnancy: Mode of delivery and anesthetic management of 15 consecutive cases. Anesthesiology. 2005;102(6):1133–1137; discussion 5A-6A. 76 Breen TW, Janzen JA. Pulmonary hypertension and cardiomyopathy: Anaesthetic management for caesarean section. Can J Anaesth. 1991;38(7):895–899. 77 Thomas JS, Koh SH, Cooper GM. Haemodynamic effects of oxytocin given as i.v. bolus or infusion on women undergoing caesarean section. Br J Anaesth. 2007;98(1):116–119. 78 Arany Z, Elkayam U. Peripartum cardiomyopathy. Circulation. 2016;133(14):1397–1409. 79 Hoes MF, Arany Z, Bauersachs J, et al. Pathophysiology and risk factors of peripartum cardiomyopathy. Nat Rev Cardiol. 2022;19(8):555–565. 80 Hoevelmann J, Viljoen CA, Manning K, et al. The prognostic significance of the 12-lead ECG in peripartum cardiomyopathy. Int J Cardiol. 2019;276:177–184. 81 Hoevelmann J, Muller E, Azibani F, et al. Prognostic value of NT-proBNP for myocardial recovery in peripartum cardiomyopathy (PPCM). Clin Res Cardiol. 2021;110(8):1259–1269. 82 Sliwa K, Bauersachs J, Arany Z, et al. Peripartum cardiomyopathy: From genetics to management. Eur Heart J. 2021;42(32):3094–3102. 83 Bateman BT, Patorno E, Desai RJ, et al. Angiotensinconverting enzyme inhibitors and the risk of congenital malformations. Obstet Gynecol. 2017;129(1):174–184. 84 Hoevelmann J, Engel ME, Muller E, et al. A global perspective on the management and outcomes of peripartum cardiomyopathy: A systematic review and meta-analysis. Eur J Heart Fail. 2022;24(9):1719–1736. 85 Davis MB, Arany Z, McNamara DM, et al. Peripartum cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75(2):207–221. 86 Park K, Bairey Merz CN, Bello NA, et al. Management of women with acquired cardiovascular disease from pre-conception through pregnancy and postpartum: JACC Focus Seminar 3/5. J Am Coll Cardiol. 2021;77(14):1799–1812. 87 Saltzberg MT, Szymkiewicz S, Bianco NR. Characteristics and outcomes of peripartum versus nonperipartum cardiomyopathy in women using a wearable cardiac defibrillator. J Card Fail. 2012;18(1):21–27. 88 Kido K, Guglin M. Anticoagulation therapy in specific cardiomyopathies: Isolated left ventricular noncompaction and peripartum cardiomyopathy. J Cardiovasc Pharmacol Ther. 2019;24(1):31–36.

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89 Bauersachs J, König T, van der Meer P, et al. Pathophysiology, diagnosis and management of peripartum cardiomyopathy: A position statement from the Heart Failure Association of the European Society of Cardiology Study Group on peripartum cardiomyopathy. Eur J Heart Fail. 2019;21(7): 827–843. 90 Bauersachs J, Arrigo M, Hilfiker-Kleiner D, et al. Current management of patients with severe acute peripartum cardiomyopathy: Practical guidance from the Heart Failure Association of the European Society of Cardiology Study Group on peripartum cardiomyopathy. Eur J Heart Fail. 2016;18(9):1096–1105. 91 Elkayam U, Schäfer A, Chieffo A, et al. Use of Impella heart pump for management of women with peripartum cardiogenic shock. Clin Cardiol. 2019;42(10): 974–981. 92 Löwenstein BR, Vain NW, Perrone SV, et al. Successful pregnancy and vaginal delivery after heart transplantation. Am J Obstet Gynecol. 1988; 158(3 Pt. 1):589–590. 93 Coscia LA KD, McGrory C, Armenti DP, et al. Report from the National Transplantation Pregnancy Registry (NTPR): Outcomes of pregnancy after transplantation 2018 [available from: https://www.rtda.gov.rw/fileadmin/ templates/documents/Annual_Report_2017_2018_ FINAL.pdf]. 94 Khush KK, Cherikh WS, Chambers DC, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-fifth Adult Heart Transplantation Report-2018; Focus theme: Multiorgan transplantation. J Heart Lung Transplant. 2018;37(10):1155–68. 95 Costanzo MR, Dipchand A, Starling R, et al. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2010;29(8):914–956.

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96 DeFilippis EM, Haythe J, Farr MA, et al. Practice patterns surrounding pregnancy after heart transplantation. Circ Heart Fail. 2020;13(4):e006811. 97 Kim H, Jeong JC, Yang J, et al. The optimal therapy of calcineurin inhibitors for pregnancy in kidney transplantation. Clin Transplant. 2015;29(2):142–148. 98 Moritz MJ, Constantinescu S, Coscia LA, Armenti D. Mycophenolate and pregnancy: Teratology principles and National Transplantation Pregnancy Registry experience. Am J Transplant. 2017;17(2):581–582. 99 Punnoose LR, Coscia LA, Armenti DP, et al. Pregnancy outcomes in heart transplant recipients. J Heart Lung Transplant. 2020;39(5):473–480. 100 Cowan SW, Coscia LC, Philips L, et al. Pregnancy outcomes in female heart and heart–lung transplant recipients. Transplant Proc. 2002;34(5):1855–1856. 101 Vos R, Ruttens D, Verleden SE, et al. Pregnancy after heart and lung transplantation. Best Pract Res Clin Obstet Gynaecol. 2014;28(8):1146–1162. 102 Boscoe M. Anesthesia for patients with transplanted lungs and heart and lungs. Int Anesthesiol Clin. 1995;33(2):21–44. 103 Sepehripour AH, Lo TT, Shipolini AR, McCormack DJ. Can pregnant women be safely placed on cardiopulmonary bypass? Interact Cardiovasc Thorac Surg. 2012;15(6):1063–1070. 104 Arnoni RT, Arnoni AS, Bonini RC, et al. Risk factors associated with cardiac surgery during pregnancy. Ann Thorac Surg. 2003;76(5):1605–1608. 105 Lamb MP, Ross K, Johnstone AM, Manners JM. Fetal heart monitoring during open heart surgery. Two case reports. Br J Obstet Gynaecol. 1981;88(6):669–674. 106 Karahan N, Oztürk T, Yetkin U, et al. Managing severe heart failure in a pregnant patient undergoing cardiopulmonary bypass: Case report and review of the literature. J Cardiothorac Vasc Anesth. 2004;18(3):339–343.

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45 Thromboembolic Disease Martha Pritchett Mims and Arthur J. Vaught Department of Medicine, Division of Hematology and Oncology, Baylor College of Medicine, Houston, TX, USA

Venous thromboembolism (VTE) is an important cause of morbidity and mortality during pregnancy and delivery, but also in the puerperium. Pregnancy-related VTE has been reported to occur in 1–2 per 1000 pregnancies, with an antepartum risk of up to five times that observed in nonpregnant women  [1,2]. Although the incidence of VTE is  essentially the same ante- and postpartum, the much shorter length of the postpartum period makes the daily risk of VTE much higher in the puerperium [3,4]. Clinical symptoms should be confirmed with objective testing, with compression ultrasound (CUS) being the first test recommended for most patients  [5]. However, in the setting of diagnosing pulmonary embolism (PE), computed tomography (CT) angiography is preferred. When deep vein thrombosis (DVT) is diagnosed and treatment instituted, the incidence of PE and maternal mortality can be decreased by threefold and 18-fold, respectively. The goal of this review is to facilitate the recognition of the clinical signs and symptoms of VTE disorders, describe a rational approach to the workup of a suspected hypercoagulable state, and review the use of various diagnostic and treatment modalities.

­Incidence and risk factors Worldwide, from 2003 to 2009, VTE accounted for only about 3% of maternal deaths, with hemorrhage, infection, and cardiovascular disease accounting for a much higher proportion  [6]. In the developed world, where some of these issues are better addressed, VTE assumes a larger role in maternal morbidity and mortality, but inadequate reporting of maternal outcomes makes it hard to provide good estimates of incidence.

Although thromboembolic events, namely PE, account for a sizable portion of maternal mortalities in the United States, its mortal incidence is on the decline (see Table 45.1). Thromboembolic disease, hemorrhage, amniotic fluid embolism, and anesthesia complications have all decreased over the past several decades. These decreases in maternal mortality in these categories are secondary to advocacy, protocolization, and education through national societies. The traditionally held view is that the maternal risk for VTE is greater in the immediate puerperium, especially following cesarean delivery. Postpartum DVT has been reported to occur 3–5 times more often than antepartum DVT and 3–16 times more frequently after cesarean as opposed to vaginal delivery  [7,8]. In contrast, Rutherford and associates found that the highest incidence of pregnancy-related VTE was not in the puerperium but in the first trimester of pregnancy  [9]. These authors also found that the risk of DVT did not increase with advancing gestational age but stayed relatively constant. In contrast, PE (see Table 45.2) was almost twice as likely to occur in the postpartum patient and appeared to be related to the route of delivery. More recently, Gerhardt and colleagues reported on 119 women with a pregnancy-related VTE [10]. Approximately half (62 women) experienced a DVT during pregnancy: 14 (23%) in the first trimester, 13 (21%) in the second trimester, and 35 (56%) in the third trimester. The other half (57 women) experienced a DVT in the immediate puerperium: 38 (68%) following vaginal delivery and 19 (32%) following cesarean section. In summary, pregnancyrelated VTE may occur at any time during pregnancy or the immediate puerperium. A 30-year population-based study of trends in the incidence of VTE during pregnancy and postpartum found that the risk for first-time VTE is five

Critical Care Obstetrics, Seventh Edition. Edited by Luis D. Pacheco, Jeffrey P. Phelan, Torre L. Halscott, Leslie A. Moroz, Arthur J. Vaught, Antonio F. Saad, and Amir A. Shamshirsaz. © 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.

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832

Thromboembolic Disease

Table 45.1 Maternal mortality by cause and time. 1987–1990

1991–1997

1998–2005

TPE

11.9

11.3

10.2

9.6

9.2

Hemorrhage

28.7

18.2

12.5

11.4

11.4

AFE

7.6

8.6

7.5

5.3

5.5

Anesthesia

2.5

1.6

1.2

0.7

0.2

13.1

13.2

10.7

13.6

12.7

3.0

6.2

12.4

14.6

15.5

Infection CV conditions

2006–2010

2011–2013

Cardiomyopathy

5.6

7.7

11.6

11.8

11.0

Stroke

3.6

4.7

6.2

6.2

6.6

Other

8.7

12.0

13.2

12.7

14.5

Data are in percentage. TPE is thromboembolic pulmonary event, AFE is amniotic fluid embolism, and CV is cardiovascular. Green is improved, yellow is similar, and red is worse.

Table 45.2 Estimated incidence of first VTE in carriers of inherited thrombophilia.

Pregnancy, %/pregnancy (95% CI)

Antithrombin, protein C, or protein S deficiency

Factor V Leiden, heterozygous

Prothrombin 20210A mutation

Factor V Leiden, homozygous*

4.1 (1.7–8.3)

2.1 (0.7–4.9)

2.3 (0.8–5.3)

16.3

During pregnancy, % (95% CI)

1.2 (0.3–4.2)

0.4 (0.1–2.6)

0.5 (0.1–2.6)

7.0

Postpartum period, % (95% CI)

3.0 (1.3–6.7)

1.7 (0.7–4.3)

1.9 (0.7–4.7)

9.3

* Data are from family studies; thus, risk estimates in other settings may be lower.

times higher in the postpartum period than during pregnancy and the risk for PE is 15 times greater postpartum than during pregnancy [1]. Although the incidence of PE has decreased over time, the incidence of DVT is unchanged. Therefore, regardless of gestational age, the clinician should have a heightened awareness for the diagnosis when a gravid or postpartum woman presents with clinical symptomatology suspicious for VTE. Obesity, hemoglobinopathies, surgery, immobility, hypertension, and smoking are also risk factors that influence the development of VTE in pregnancy [11]. As noted above, prior history of a VTE confers the greatest risk for recurrence, especially if the initial event was idiopathic or associated with a hereditary or acquired thrombophilia. In the absence of pharmacologic thromboprophylaxis, the absolute risk of recurrent VTE is 2–10%  [12]. In two retrospective studies, the risk was higher for women whose first VTE was related to pregnancy or provoked by the use of oral contraceptives [13,14]. In a large retrospective study of women with previous history of VTE, those with a history of prior pregnancy-related VTE had a higher risk of recurrence than those with a history of unprovoked VTE (4.5% vs. 2.7%; relative risk [RR], 1.7; confidence interval [CI], 1.0–2.8) [15].

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As discussed in more detail in this chapter, inherited and acquired thrombophilias are additional risk factors for VTE. The inherited thrombophilias include deficiencies of protein C, protein S, antithrombin (AT), factor V Leiden, and prothrombin G20210A. 5,10-methylenetet-rahydrofolate reductase mutation (particularly the C677T mutation) has not been associated with an increased risk of VTE in pregnancy and should not be tested for VTE risk stratification [16]. In studies that evaluated the association between thrombophilias and VTE in pregnancy, the highest risks were associated with homozygosity for factor V Leiden or prothrombin G20210A (risk, ~4%). Heterozygosity for these mutations incurred lower risk, while deficiencies in antithrombin or in protein C or S demonstrated moderate risk. Family history of VTE increases the risk for VTE twoto fourfold; thus, thrombophilia patients with no personal or family history of VTE have lower risk than those with a positive family history. Table 45.2 summarizes the risk of a first episode of VTE in carriers of thrombophilia from family studies (i.e., at least one first-degree family member with VTE) [17,18]. There are less data for the acquired thrombophilias, but repeated positive tests for an antiphospholipid antibody does increase risk of VTE, although the risk of VTE in

Normal hemostasis

Table 45.3 embolism.

Factors associated with a higher risk of pulmonary

Maternal age Ethnic background Operative delivery Prior thromboembolism Prolonged immobilization Inherited or acquired coagulation disorders Trauma

pregnancy in women who have no previous history of VTE is not clear [19]. In summary, the risk of VTE varies among pregnant women; therefore, individualization of management must be emphasized. This risk will depend not only on the pregnancy, but also on additional clinical factors such as a prior history of thromboembolism, mode of delivery, prolonged immobilization, age, and ethnicity (see Table  45.3). The role of routine testing for inherited thrombophilias is unclear, as many guidelines are silent on the topic  [19]. The  most recent guidance from the American College of Obstetricians and Gynecologists suggests screening only when the results will affect management of the patient. Consideration for screening is recommended only with a personal history of VTE associated with a nonrecurrent risk factor such as a fracture, surgery, or prolonged immobilization or a first-degree relative with a high-risk thrombophilia  [20]. It should be noted that other guidelines actually recommend against testing for nonrecurrent risk factors and recommend testing for unprovoked VTEs [21]. If performed, testing is recommended when the patient is not pregnant, not taking anticoagulants or hormonal therapy, and remote from any thrombotic event.

­Normal hemostasis Few systems are more complex than hemostasis. Interactions among the vessel wall, platelets, and soluble molecules in the vicinity of an injury work to repair the vessel defect without sacrificing nearby vessel patency. The key processes are: 1) vasoconstriction; 2) formation of a platelet plug; 3) formation of a stable “seal” by coagulation factors; 4) prevention of spread of the clot along the vessel wall; 5) prevention of occlusion of the vessel by clots, when possible; and 6) remodeling and gradual degradation of the clot after it is no longer needed. The maintenance of normal blood flow requires intact, patent blood vessels. After an injury, the hemostatic and fibrinolytic systems work together to protect vascular

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integrity and assist in repair. Vessel wall integrity, platelet aggregation, normal function of the coagulation cascade, and fibrinolysis are all vital to this process. The initial response to injury is vasoconstriction, which reduces local blood flow and limits the size of the defect that the thrombus is required to seal [22]. After platelets begin to adhere to the exposed vessel wall, they change shape and secrete the contents of their granules. This action leads to further platelet accumulation or aggregation and results in the formation of a platelet plug. Proteolytic cleavage or conformational changes activate the circulating clotting factors at the site of injury. Factors II, VII, IX, and X require a vitamin-K-dependent reaction in the liver in which γ-carboxyglutamic acid residues are attached to the protein structure. This action provides a location to form a complex with calcium ion and phospholipid receptors on the platelet or endothelial cell membranes. Subsequent steps in the clotting cascade occur at those sites and include the formation of thrombin. Once formed, this is released into the fluid phase. The intrinsic and extrinsic pathways lead to the final common clotting pathway. Both pathways are activated by components of the vessel wall and lead to activation of progressive exponential increase in subsequent factors. In the intrinsic pathway, high-molecular-weight kininogen and kallikrein are cofactors for the initial step of the process, the activation of factor XII (XIIa). By catalyzing the formation of kallikrein from prekallikreins, factor XIIa also helps to initiate fibrinolysis, activate the complement system, and produce kinins [22]. Factor XI is activated by XIIa and then cleaves factor IX to form IXa. In comparison, the extrinsic pathway is so named because this pathway relies on tissue factor that is “extrinsic” to blood. Tissue factor is released into circulation following membrane damage or proteolysis  [22]. Factor VII is then activated to VIIa, which, with tissue factor, can activate factors IX or X. The common pathway begins with activation of factor X by either VIIa or IXa, in combination with the protein cofactor VIII:C (the antihemophilic factor) and the calcium ion, on the platelet surface (to form PF3) [23]. Factor Xa, assisted by cofactor Va, enzymatically divides prothrombin into thrombin and a peptide activation fragment, F1+2. Separation from this fragment liberates thrombin into the fluid phase. Thrombin catalyzes the formation of fibrin monomers from fibrinogen and, thus, releases fibrinopeptides A and B and facilitates activation of V, VIII:C, and XIII. A fibrin gel is created by the hydrophobic and electrostatic interactions of the fibrin α and γ chains. Subsequently, factor XIIIa forms covalent bonds linking nearby α and γ chains to form a stable polymerized fibrin clot into which water is also incorporated. Trapped within the clot are proteins that contribute to the enzymatic digestion of the fibrin matrix: plasminogen

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and plasminogen activators. A variety of substances can activate plasminogen. Plasma plasminogen activator is activated by factor XIIa. Release of tissue activators (tissue plasminogen activator) from blood vessel epithelium (especially venous) is stimulated by exercise, emotional stress, trauma, surgery, hypotensive shock, pharmacologic agents, and activated protein C (APC)  [22,24]. The fibrinolytic enzymes streptokinase and urokinase also activate plasminogen [25]. Having been activated from plasminogen, plasmin cleaves arginyl-lysine bonds in many substrates, including fibrogen, fibrin, factor VIII, and complement  [25,26]. The result of plasmin action on fibrin and fibrinogen is release of protein fragments, referred to as “fibrinogen degradation products” (or “fibrin split products”). The larger fragments, which may have slow clotting activity, are further divided by plasmin. These fragments have anticoagulant activity, in that they inhibit the formation and cross-linking of fibrin [22]. Measurement of fibrin degradation products provides an indirect measurement of fibrinolysis. Most laboratories now measure D-dimer levels, which are more specific fibrin degradation products that reflect clot breakdown. α2-antiplasmin, a specific plasmin inhibitor that binds to fibrin and fibrinogen, is found in serum, platelets, and within the clot, along with other inhibitors of plasmin or plasminogen activity [25,26]. As a potent inhibitor of thrombin, AT is important in the regulation of hemostasis. In decreasing affinity, AT binds and inactivates factors IXa, Xa, XIa, and XIIa. AT acts as a substrate for these serine proteases but forms stable intermediate bonds with the active portion and, thus, neutralizes the respective enzyme [25]. Heparin binds to AT and induces a conformational change that increases the affinity of AT for thrombin. The otherwise slow inactivation of thrombin by AT is accelerated greatly by even small amounts of heparin. After a stable thrombin-AT complex is formed, heparin is released and available for repetitive catalysis. Excess amounts of AT are normally present in the circulation, and some are bound to endothelial cell membranes via heparan, a sulfated mucopolysaccharide with a function similar to heparin. The presence of heparan on intact endothelial cell surfaces and its binding to AT, which neutralizes thrombin, help to prevent local extension of the thrombus beyond the sites of vessel injury [27]. Deficiency of AT leads to a substantially higher incidence of thrombotic events [28]. Proteins C and S are normally part of the protein C anticoagulant system. Like factors II, VII, IX, and X, their synthesis requires vitamin K and involves addition of γ-carboxyglutamic acid residues that enable binding, via calcium ions, to cell surfaces. Protein C is attached to endothelial cells, and protein S is attached to endothelial and platelet membranes. Endothelial cell surfaces also have a

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specific protein receptor for thrombin – thrombomodulin. The binding of thrombin to thrombomodulin, in the presence of protein S, activates protein C and promotes anticoagulation. Complexes of APC and adjacently bound protein S cofactor proteolyze the phospholipid-bound factors VIII:Ca and Va. This action results in a second mechanism to prevent extension of the thrombus beyond the area of vessel injury [27]. Deficiencies of either protein C or S are associated with an increase in thromboembolic events [27]. Homozygosity of protein C deficiency leads to fatal neonatal purpura fulminans [28].

Changes in hemostasis in pregnancy Estrogen stimulation of hepatic synthesis of several procoagulant proteins increases with pregnancy. Levels of von Willebrand factor; factors V, VII, VIII, and X; and fibrinogen all increase significantly in pregnancy, whereas prothrombin and factors V, IX, and XII are essentially unchanged (see Table 45.4) [29]. Factor XIII decreases in pregnancy. Levels of total and free protein S fall over the course of the pregnancy, while levels of protein C and antithrombin remain stable [30]. Venous stasis secondary to progesterone-mediated smooth muscle vascular relaxation and mechanical compression by the gravid uterus occurs. Placental separation and operative delivery can cause endothelial vascular damage. Recent studies suggest that while coagulation is favored over fibrinolysis during pregnancy, the fibrinolytic system is active. Plasminogen levels increase during pregnancy. Tissue-type plasminogen activator also increases during pregnancy, but plasminogen activator inhibitor type-1 (PAI-1), an antifibrinolytic protein secreted by endothelial cells, and PAI-2 (produced by the placenta) increase even more, maintaining the balance in favor of coagulation. While coagulation predominates over fibrinolysis, D-dimer Table 45.4

Hemostatic changes during pregnancy.

Hemostatic changes promoting thrombosis Increased levels of factors V, VII, VIII, X, and XII and fibrinogen Placental inhibitors of fibrinolysis Tissue factor released into the circulation at placental separation Venous stasis of the lower extremities Endothelial damage associated with parturition Hemostatic changes countering thrombosis Decreased levels of factor XIII Pregnancy-specific protein neutralizing AT

Thrombophilias

levels increase over the course of pregnancy  [31–33]. Following delivery, there are increased levels of fibrinogen and platelets, and fibrinolysis returns to normal within 1–2  days. Coagulation normalizes in the first 4–6  weeks postpartum, but the level of protein S can be low for as much as 8 weeks. Platelet counts appear to remain in the normal range during pregnancy, but have been documented to be significantly higher than predelivery on days 8 and 12 after vaginal delivery and continued to rise 16 days after a cesarean delivery [34]. The platelet count remained significantly higher than predelivery values for 24  days after cesarean delivery [34].

­Thrombophilias Approximately half of the women who have a pregnancyrelated VTE possess an underlying congenital or acquired thrombophilia [35]. In almost 50% of patients with a hereditary thrombophilia, the initial thrombotic event occurs in the presence of an additional risk factor such as pregnancy, oral contraceptive use, orthopedic trauma, immobilization, or surgery [36]. As per the most recent American College of Chest Physicians (ACCP) guidelines  [19], the highest risk of pregnancy-related VTEs was in subjects with homozygous mutation for factor V Leiden (odds ratio [OR], 34.4; 95% CI, 9.860–120.05) or prothrombin 20210  mutation (OR, 26.36; 95% CI, 1.24–559.20). Heterozygosity for these mutations resulted in lower risk for the factor V Leiden (OR, 8.32; 95% CI, 5.44–12.70) and prothrombin G20210A variant (OR, 6.80; 95% CI, 2.46–18.77). Deficiencies of antithrombin, protein C, and protein S resulted in moderate risk, with an OR of 3–5. Given the low background incidence of VTE in pregnancy, the absolute risk of VTE in women with no prior VTE is quite low. Thus, for patients with homozygous factor V Leiden mutation, the absolute risk of VTE in pregnancy is 9–16%, but for patients with antithrombin, protein C, or protein S deficiency, that number is about 4.1%.

Deep venous thrombosis Clinical diagnosis

In the gravid patient, DVT appears to occur more often in the deep proximal veins and has a predilection for the left leg [37,38]. The clinical diagnosis of DVT [39] is difficult and requires objective testing. Of those patients with clinically suspected DVT, half will not be confirmed by objective testing. Clinical symptomatology of VTE should usually be confirmed with objective testing before a diagnosis is rendered.

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Table 45.5 Clinical symptoms and signs of lower extremity deep venous thrombosis. Unilateral pain, swelling, tenderness, and/or edema Limb color changes Palpable cord Positive Homan’s sign Positive Lowenberg test Limb size difference >2 cm

Symptoms and signs of DVT are illustrated in Table 45.5. Swelling is considered whenever there is at least a 2  cm measured difference in circumference between the affected and normal limbs. Homan’s sign is present when passive dorsiflexion of the foot in a relaxed leg leads to pain, presumably in the calf or popliteal areas. The Lowenberg test is positive if pain occurs distal to a blood pressure cuff rapidly inflated to 180 mmHg. The presence of marked swelling, cyanosis or paleness, a cold extremity, or diminished pulses signals the rare obstructive iliofemoral vein thrombosis. DVT has also significant long-term implications, and a prior history of DVT may affect the patient’s symptomatology. Years after a severe obstructive DVT, patients may experience postphlebitic syndrome (skin stasis dermatitis or ulcers). An investigation of 104 women with a median post-thrombosis interval of 11 years revealed that 4% had ulceration, and only 22% were without complaints  [40]. Finally, it is important to remember that pregnant patients commonly complain of swelling and leg discomfort and, as such, do not require objective testing in every instance. It is important to remember that the first sign of DVT may be the occurrence of a PE. In a similar manner, silent DVT has been found in 70% of patients with angiographically proven PE [41]. During the initial evaluation in a pregnant patient with clinical symptomatology suspicious for a pregnancyrelated VTE, risk factors as described here should be sought.

Diagnostic studies Laboratory studies D-­Dimers and  thrombin assay

Recent evidence supports the utility of D-dimer and measurements of thrombin in the assessment of VTE in the non-pregnant setting. Studies examining D-dimer in pregnancy have been performed. A recent meta-analysis showed that D-dimer less than 500 ng/mL safely rule out VTE in pregnant women with an unlikely pretest probability (low-intermediate risk) [42]. However, more studies and consensus on utility during pregnancy are needed before relying on these assays in the obstetric population.

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D-dimer fragments are produced during degradation of thrombin-generated fibrin clots by plasmin. The presence of D-dimer is evidence that the blood-clotting cascade has been initiated. Three tests for the assessment of D-dimers exist: the enzyme-linked immunosorbent assay (ELISA), the latex agglutination assay, and whole-blood agglutination  [43]. The whole-blood agglutination assays involve monoclonal antibody that is specific for D-dimer linked to monoclonal antibody that binds to red cells. The advantage of this D-dimer assay is its high negative predictive value. Patients with a low clinical probability of DVT and a negative result on D-dimer testing could safely forgo additional diagnostic testing for DVT  [44,45]. Normal pregnancy has been shown to cause a progressive increase in circulating D-dimer. Thresholds for D-dimer levels to rule out VTE during each trimester of pregnancy are unavailable  [46]. Thrombin generation is additional evidence of ongoing hemostasis. Individuals with thrombin generations