Pediatric Surgery: General Pediatric Surgery, Tumors, Trauma and Transplantation 3662435586, 9783662435588

Citation preview

Prem Puri Editor

Pediatric Surgery General Pediatric Surgery, Tumors, Trauma and Transplantation

Pediatric Surgery

Prem Puri Editor

Pediatric Surgery General Pediatric Surgery, Tumors, Trauma and Transplantation

With 452 Figures and 207 Tables

Editor Prem Puri Beacon Hospital University College Dublin Dublin, Ireland

ISBN 978-3-662-43558-8 ISBN 978-3-662-43559-5 (eBook) ISBN 978-3-662-43560-1 (print and electronic bundle) https://doi.org/10.1007/978-3-662-43559-5 © Springer-Verlag GmbH Germany, part of Springer Nature 2021 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer-Verlag GmbH, DE part of Springer Nature. The registered company address is: Heidelberger Platz 3, 14197 Berlin, Germany

To my parents, with love and gratitude. Without their sacrifices, none of my academic accomplishments would be possible.

Preface

The specialty of pediatric surgery continues to grow and change rapidly. During the past two decades, major advances in prenatal diagnosis, imaging, anesthesia, and intensive care, as well as the introduction of new surgical techniques including minimally invasive surgery and robotic technology, have radically altered the management of newborns, infants, and children with surgical conditions. Although, these advances have undoubtedly decreased the incidence of morbidity and mortality in this vulnerable patient group, there are still many unsolved problems that require further study. In recent years, important basic science advances in the fields of regenerative medicine and tissue engineering, pharmacotherapy, genetics, immunology, embryology, and developmental biology offer hope of the translation of basic science discoveries to new clinical therapies for children in the future. Pediatric Surgery provides an authoritative, comprehensive, and up-to-date international reference on the surgical management of both common and rare diseases in infants and children, written by the world’s foremost experts. The authors are leaders in their respective fields and have been chosen in every case for their expertise and experience. The vast amount of information included in Pediatric Surgery is divided into three volumes, with a total of seven parts that focus on general principles, newborn surgery, general pediatric surgery, transplantation, trauma, tumors, and pediatric urology. There are three different publication formats of the reference works: (1) printed book, (2) a static e-version on SpringerLink that mirrors the printed book, and (3) a living reference also on SpringerLink that is constantly updateable, allowing the reader to rapidly find up-to-date information on a specific topic. Each chapter is organized in the form of a well-defined and structured review of the topic that allows readers to search and find information easily. General Principles and Newborn Surgery, which has 85 chapters, was published in early 2020. This volume has 70 chapters devoted to general pediatric surgery, transplantation, trauma, and tumors. The first 23 chapters are devoted to the management of general pediatric surgical conditions, each chapter providing a step-by-step detailed practical guide on the management including high-quality color illustrations to clarify and simplify various operative techniques. The part on transplantation includes principles of transplantation, complications of immunosuppression, and up-to-date reference on liver, intestinal, pancreatic, heart, and lung transplantation. The part on trauma deals with all different types of trauma in children including physical and vii

viii

Preface

sexual child abuse, worldwide control of childhood unintentional injury, major accident disasters, and nuclear disasters. The part on tumors has 21 chapters dealing with common and uncommon tumors in children. My hope is that Pediatric Surgery will act as a reference book for the management of childhood surgical disorders, providing information and guidance to pediatric surgeons, pediatric urologists, neonatologists, pediatricians, and all those seeking more detailed information on surgical conditions in infants and children. I wish to thank most sincerely all the contributors from around the world for their outstanding work in the preparation of this innovative international reference book on the management of surgical conditions in infants and children. I wish to express my sincere appreciation and special thanks to my dear friend and section editor, Professor Michael Hollwarth, who played an important role in the preparation of this volume. I also wish to express my gratitude to Dr. Anne Marie O’Donnell for her help in the preparation of this book. I wish to thank the editorial staff at Springer, particularly Ms. Audrey Wong-Hillmann, Ms. Nivedita Baroi, and Ms. Divya Rajakumar for all their help during the preparation, production, and publication of this important reference book. Dublin, Ireland January 2021

Prem Puri

Contents

Part I

General: Head and Neck

.............................

1

1

Thyroglossal and Branchial Cysts, Sinuses, and Fistulas . . . Michael E. Höllwarth

3

2

Lymph Node Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hugo A. Heij

11

3

Disorders of Salivary Glands . . . . . . . . . . . . . . . . . . . . . . . . . Douglas R. Sidell and Nina L. Shapiro

21

4

Torticollis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Spencer W. Beasley

31

Part II

General: Chest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

45

5

Gastroesophageal Reflux and Hiatal Hernia . . . . . . . . . . . . . Michael E. Höllwarth and Erich Sorantin

47

6

Achalasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Paul Kwong Hang Tam and Patrick Ho Yu Chung

73

7

Esophageal Replacement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Shilpa Sharma and Devendra K. Gupta

81

8

Chest Wall Deformities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 Robert C. Shamberger

9

Empyema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 Michael Singh and Dakshesh Parikh

10

Disorders of the Breast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 Steffi Mayer and Jan-Hendrik Gosemann

Part III General: Abdomen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

149

Hernias: Inguinal, Umbilical, Epigastric, Femoral, and Hydrocele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 Tomas Wester and Anna Svenningsson ix

x

Contents

12

Appendicitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 Alan E. Mortell and David Coyle

13

Intussusception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Shabnam Parkar and Amulya K. Saxena

14

Primary Peritonitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 Robert Baird and Jean Martin Laberge

15

Gastrointestinal Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 Pamela Choi, Josh Sommovilla, and Brad Warner

16

Gallbladder Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 Sohail R. Shah and George W. Holcomb III

17

Portal Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 Mark D. Stringer

18

Splenic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 Katherine A. Barsness

19

Ulcerative Colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 Risto J. Rintala, Mikko P. Pakarinen, and Antti Koivusalo

20

Crohn’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 Risto J. Rintala, Mikko P. Pakarinen, and Antti Koivusalo

21

Disorders of Anus and Rectum . . . . . . . . . . . . . . . . . . . . . . . . 293 Mikko P. Pakarinen, Risto J. Rintala, and Antti Koivusalo

22

Pilonidal Sinus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 Jason D. Fraser and Shawn D. St. Peter

23

Surgical Manifestations of Parasitic Disease . . . . . . . . . . . . . 311 Shilpa Sharma and Devendra K. Gupta

Part IV

Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

185

329

24

Principles of Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . 331 Evelyn G. P. Ong and Deirdre A. Kelly

25

Complications of Immunosuppression in Pediatric Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351 Markus G. Seidel

26

Pediatric Liver Transplantation . . . . . . . . . . . . . . . . . . . . . . . 363 Khalid Sharif and Deirdre A. Kelly

27

Intestinal Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393 Christophe Chardot

28

Pancreas and Islet Cell Transplantation Paul R. V. Johnson and Daniel Brandhorst

29

Heart Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421 Nagarajan Muthialu, Michael Burch, and Tain-Yen Hsia

. . . . . . . . . . . . . . . . 407

Contents

xi

30

Lung Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433 Charles B. Huddleston

Part V

Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

451

31

Fetal and Birth Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453 Piotr Hajduk, Hiroki Nakamura, Stephanie Ryan, and Prem Puri

32

Ingestion of Foreign Bodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 473 Sohail R. Shah and Megan E. Cunningham

33

Caustic Injuries of the Esophagus . . . . . . . . . . . . . . . . . . . . . 485 A. J. W. Millar, A. Numanoglu, and S. Cox

34

Facial Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501 Pedro Ferreira, Carlos Soares, and José Amarante

35

Ophthalmic Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535 Sarah Moran and Michael O’Keefe

36

Thoracic Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555 Howard I. Pryor II, Chiara Croce, and Paul M. Colombani

37

Abdominal Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571 Steven Stylianos, Katherine Bass, Barry Cofer, Barbara Gaines, and Robert Letton

38

Pediatric Genitourinary Trauma . . . . . . . . . . . . . . . . . . . . . . 597 Ofer Z. Shenfeld and Boris Chertin

39

Conservative Management of Severe Cerebral Trauma . . . . 611 Christoph Castellani and Hans-Georg Eder

40

Surgical Treatment of Severe Head Trauma . . . . . . . . . . . . . 627 Hans-Georg Eder

41

Burns in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641 H. Rode and A. D. Rogers

42

Therapeutic Principles of Bone Trauma in the Growing Skeleton . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663 Zacharias Zachariou

43

Pediatric Orthopedic Trauma . . . . . . . . . . . . . . . . . . . . . . . . . 693 Annelie-Martina Weinberg, Eva Elisa Amerstorfer, and Florian Amerstorfer

44

Soft Tissue Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735 Michael E. Höllwarth

45

Trauma to the Hands and Feet . . . . . . . . . . . . . . . . . . . . . . . . 745 Georg Singer

xii

Contents

46

Physical and Sexual Child Abuse . . . . . . . . . . . . . . . . . . . . . . 779 Michael E. Höllwarth and Erich Sorantin

47

Worldwide Control of Childhood Unintentional Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793 Brendan S. O’Brien and Martin R. Eichelberger

48

Major Accident Disasters and Their Management . . . . . . . . 805 Udo Rolle, Simon Meier, and Philipp Störmann

49

Nuclear Disasters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 813 Takeo Yonekura, Manabu Okawada, and Atsuyuki Yamataka

Part VI

Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

821

50

Genetics of Pediatric Tumors . . . . . . . . . . . . . . . . . . . . . . . . . 823 Jennifer Lynch and Raymond L. Stallings

51

Biopsy Techniques for Tumors . . . . . . . . . . . . . . . . . . . . . . . . 839 Christopher B. Weldon, Megan E. Anderson, and Robert C. Shamberger

52

Neuroblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 851 Andrew M. Davidoff

53

Renal Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 869 Thomas E. Hamilton and Robert C. Shamberger

54

Liver Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909 David G. Darcy, Joshua N. Honeyman, and Michael P. La Quaglia

55

Rhabdomyosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931 Amos Loh and Bhaskar Rao

56

Teratomas (All Locations) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 951 Thambipillai Sri Paran and David Coyle

57

Musculoskeletal Tumors (Osteosarcoma and Ewing’s Sarcoma) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 971 Andrea A. Hayes-Jordan and Valerae O. Lewis

58

Hodgkin and Non-Hodgkin Lymphoma . . . . . . . . . . . . . . . . . 989 Christian Urban and Herwig Lackner

59

Tumors of the Gastrointestinal Tract . . . . . . . . . . . . . . . . . . . 1001 Maureen J. O’Sullivan and Alan E. Mortell

60

Chest Wall Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015 Stephen J. Shochat and John A. Sandoval

61

Tumors of the Lung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1031 Stephen J. Shochat and John A. Sandoval

Contents

xiii

62

Ovarian Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1047 Daniel von Allmen and Mary E. Fallat

63

Testicular Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063 Jonathan H. Ross

64

Adrenal Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1073 Lynn Model, Michael G. Caty, and Emily R. Christison-Lagay

65

Thyroid and Parathyroid Tumors David E. Wesson

66

Pancreatic Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1103 Jun Tashiro, Casey J. Allen, and Juan E. Sola

67

Pediatric Brain Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1113 S. Ndoro, J. Caird, and D. Crimmins

68

Rare Malignant Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1135 Casey J. Allen, Jun Tashiro, and Juan E. Sola

Part VII

. . . . . . . . . . . . . . . . . . . . . 1089

Special Areas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1155

69

Congenital Nevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1157 Bruce S. Bauer and Sara R. Dickie

70

Hemangiomas and Other Vascular Anomalies David Coyle and Alan E. Mortell

. . . . . . . . . . . 1183

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1203

About the Editor

Prem Puri is the Newman clinical research professor at the University College Dublin School of Medicine and Medical Science and consultant pediatric surgeon and Director of surgical research at the Beacon Hospital. He is currently the secretary of the International Board of Pediatric Surgical Research. He is past President of the World Federation of Associations of Pediatric Surgeons (WOFAPS) and of the European Paediatric Surgeons’ Association (EUPSA). He is Editor-inchief of Paediatric Surgery International and also on the editorial board of several other journals. He was the Director of research (1989–2009) and President (2009–2016) of the National Children’s Research Centre, Our Lady’s Children’s Hospital, Dublin. Professor Puri has been awarded many honorary fellowships, including the American Surgical Association (ASA), American Academy of Pediatrics, American Pediatric Surgical Association, Canadian Association of Paediatric Surgeons, Japanese Society of Pediatric Surgeons, and also Argentinean, Austrian, Canadian, Czech, Croatian, Cuban, Indian, South African, and Ukrainian pediatric surgical associations. Professor Puri is known internationally for his research into underlying mechanisms causing birth defects and innovative treatments, which have benefited children all over the world. He is a multi-award-winning researcher whose previous awards include People of the Year Award (Highest Irish National Award), the prestigious Denis Browne Gold Medal by the British Association of Paediatric Surgeons, Abraham Colles Medal by the Royal College of Surgeons in Ireland, and Rehbein Medal by the European Paediatric xv

xvi

About the Editor

Surgeons’ Association for outstanding contribution to pediatric surgery. He has been a visiting professor to many leading universities all over the world and invited speaker at over 250 international scientific meetings. He has published 10 books, 147 chapters in textbooks, and over 700 articles including many in high impact factor journals, such as New England Journal of Medicine, Lancet, British Medical Journal, and Nature Genetics. Professor Puri is the editor of Newborn Surgery, regarded as the authoritative book in the field, and the fourth edition is now published, and also of the widely acclaimed Pediatric Surgery (Atlas Series), which is in its second edition. His research has been cited over 20,000 times in peer-reviewed articles.

About the Section Editor

Professor Michael Höllwarth is professor emeritus at the University Clinic for Pediatric and Adolescent Surgery, Medical University of Graz, Austria. He was the chairman and head of the Department of Pediatric Surgery at the University Clinic of Pediatric and Adolescent Surgery, Medical University of Graz from 1997 to 2012. Professor Höllwarth also served as the Vice Medical Director of the University Hospital of Graz and the General Director for medicine and nursing at hospitals in the Styrian region of Austria. His many accomplishments have been recognized by numerous awards and honors. He was the Founding President of the European Pediatric Surgeons Association (EUPSA) as well as President of the Austrian Association of Pediatric Surgeons and the Austrian Committee of Accident Prevention in Childhood. He has received several medals for outstanding contribution to pediatric surgery including the Great Honorary Medal of Gold of the Styrian Government and the Styrian Award for the Rights of Children. Professor Höllwarth received the Kafka Medal of the Czech Association of Pediatric Surgeons, the Rehbein Medal of the EUPSA, The Denis Brown Gold Medal of the British Association of Pediatric Surgeons, the Lifetime Achievement Award of the Indian Association of Pediatric Surgeons, and the Lifetime Achievement Award of the World Federation of Pediatric Surgical Associations. Professor Höllwarth is author and co-author of over 230 articles in peer-reviewed journals, over 40 chapters in pediatric surgical textbooks, and co-editor of four pediatric surgical books. He was co-founder of the Pediatric Surgery International

xvii

xviii

About the Section Editor

journal and is currently its review editor. His main clinical research interests are gastro-esophageal reflux in children and short bowel syndrome and accident prevention in children.

Contributors

Casey J. Allen Division of Pediatric Surgery, DeWitt-Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA José Amarante Department of Plastic Reconstructive, Aesthetic, Maxillofacial Surgery and Burn Unit, Centro Hospitalar de São João, Porto, Portugal Porto Medical School, Porto, Portugal Eva Elisa Amerstorfer Department of Pediatric and Adolescent Surgery, Medical University of Graz, Graz, Austria Florian Amerstorfer Department of Orthopedic Surgery and Traumatology, Medical University of Graz, Graz, Austria Megan E. Anderson Department of Orthopedic Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA Robert Baird Department of Pediatric Surgery, BC Children’s Hospital, Vancouver, BC, Canada Katherine A. Barsness Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Katherine Bass The State University of New York at Buffalo, Buffalo, NY, USA Bruce S. Bauer Section of Plastic and Reconstructive Surgery, University of Chicago, Pritzker School of Medicine, Chicago, IL, USA University of Chicago Hospitals, Illinois Dermatology Institute, Skokie, IL, USA Spencer W. Beasley Department of Paediatric Surgery, Christchurch Hospital and Christchurch School of Medicine, University of Otago, Christchurch, New Zealand Daniel Brandhorst Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK Michael Burch Departments of Cardiology, Great Ormond Street Hospital for Sick Children, London, UK xix

xx

J. Caird Temple St. Children’s University Hospital, Dublin, Ireland Christoph Castellani Pediatric Intensive Care Unit, Department of Pediatric and Adolescent Surgery, Medical University of Graz, Graz, Austria Michael G. Caty Yale School of Medicine, New Haven, CT, USA Christophe Chardot Hôpital Necker-Enfants Malades, Service de chirurgie pédiatrique viscérale, Université Paris Descartes, Paris, France Boris Chertin Department of Pediatric Urology, Shaare Zedek Medical Center, Faculty of Medical Science, Hebrew University, Jerusalem, Israel Pamela Choi Washington University, St Louis, MO, USA Emily R. Christison-Lagay Yale School of Medicine, New Haven, CT, USA Patrick Ho Yu Chung Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China Barry Cofer Children’s Hospital of San Antonio, San Antonio, TX, USA Paul M. Colombani Division of Pediatric Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA S. Cox Division of Paediatric Surgery, Faculty of Health Sciences, Red Cross War Memorial Children’s Hospital, University of Cape Town, Cape Town, South Africa David Coyle Department of Paediatric Surgery, Children’s Health Ireland at Crumlin, Dublin, Ireland D. Crimmins Temple St. Children’s University Hospital, Dublin, Ireland Chiara Croce Division of Pediatric Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA Megan E. Cunningham Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA David G. Darcy Department of Surgery, Pediatric Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA Andrew M. Davidoff St. Jude Children’s Research Hospital, Memphis, TN, USA Sara R. Dickie Section of Plastic and Reconstructive Surgery, University of Chicago, Pritzker School of Medicine, Chicago, IL, USA University of Chicago Hospitals, Illinois Dermatology Institute, Skokie, IL, USA Hans-Georg Eder Department of Neurosurgery, Medical University of Graz, Graz, Austria Martin R. Eichelberger Children’s National Medical Center, Washington, DC, USA

Contributors

Contributors

xxi

Mary E. Fallat University of Louisville, Kosair Children’s Hospital, Louisville, KY, USA Pedro Ferreira Department of Plastic Reconstructive, Aesthetic, Maxillofacial Surgery and Burn Unit, Centro Hospitalar de São João, Porto, Portugal Porto Medical School, Porto, Portugal Jason D. Fraser Children’s Mercy Hospital, Kansas City, MO, USA Barbara Gaines Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA Jan-Hendrik Gosemann Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany Devendra K. Gupta Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India Piotr Hajduk Department of Pediatric Surgery, Children’s Health Ireland at Temple Street, Dublin, Ireland Thomas E. Hamilton Department of Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA Andrea A. Hayes-Jordan Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA University of North Carolina School of Medicine, Chapel Hill, NC, USA Hugo A. Heij Pediatric Surgical Center, Amsterdam University Medical Center, Amsterdam, The Netherlands George W. Holcomb III University of Missouri – Kansas City School of Medicine, Children’s Mercy Hospital, Kansas City, MO, USA Michael E. Höllwarth Department of Paediatric and Adolescent Surgery, Medical University of Graz, Graz, Austria Joshua N. Honeyman Department of Surgery, Pediatric Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA Tain-Yen Hsia Departments of Cardiothoracic Surgery, Great Ormond Street Hospital for Sick Children, London, UK Charles B. Huddleston Saint Louis University School of Medicine, Saint Louis, MO, USA Paul R. V. Johnson Oxford Children’s Hospital, Oxford, UK Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK Deirdre A. Kelly The Liver Unit, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK Pediatric Hepatology, Birmingham Women’s and Children’s Hospital, University of Birmingham, Birmingham, UK

xxii

Antti Koivusalo Department of Pediatric Surgery, Children’s Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland Jean Martin Laberge Department of Pediatric Surgery, Montreal Children’s Hospital, McGill University Health Center, Montreal, QC, Canada Herwig Lackner Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria Michael P. La Quaglia Department of Surgery, Pediatric Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA Robert Letton Nemours Children’s Specialty Care, Jacksonville, FL, USA Valerae O. Lewis Department of Orthopaedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Amos Loh Department of Paediatric Surgery, KK Women’s and Children’s Hospital, Singapore, Singapore Duke-National University of Singapore Medical School, Singapore, Singapore Jennifer Lynch Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland National Children’s Research Centre, Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland Steffi Mayer Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany Simon Meier Department of Trauma, Hand and Reconstructive Surgery, Hospital of the Goethe University Frankfurt/Main, Frankfurt, Germany A. J. W. Millar Division of Paediatric Surgery, Faculty of Health Sciences, Red Cross War Memorial Children’s Hospital, University of Cape Town, Cape Town, South Africa Lynn Model Department of Surgery, Maimonides Medical Center, Brooklyn, NY, USA Sarah Moran Cork University Hospital/South Infirmary Victoria University Hospital, Cork, Ireland Alan E. Mortell Children’s Health Ireland at Crumlin, Dublin, Ireland Royal College of Surgeons in Ireland, Dublin, Ireland Department of Paediatric Surgery, Children’s Health Ireland at Temple Street, Dublin, Ireland Nagarajan Muthialu Departments of Cardiothoracic Surgery, Great Ormond Street Hospital for Sick Children, London, UK Hiroki Nakamura National Children’s Research Centre, Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland S. Ndoro Temple St. Children’s University Hospital, Dublin, Ireland

Contributors

Contributors

xxiii

A. Numanoglu Division of Paediatric Surgery, Faculty of Health Sciences, Red Cross War Memorial Children’s Hospital, University of Cape Town, Cape Town, South Africa Brendan S. O’Brien Children’s National Medical Center, Washington, DC, USA Michael O’Keefe Mater Private Hospital, Dublin, Ireland The National Maternity Hospital, Dublin, Ireland Maureen J. O’Sullivan Children’s Health Ireland at Crumlin, Dublin, Ireland University of Dublin, Trinity College, Dublin, Ireland Manabu Okawada Department of Pediatric Surgery, Juntendo University School of Medicine, Tokyo, Japan Evelyn G. P. Ong The Liver Unit, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK Mikko P. Pakarinen Department of Pediatric Surgery, Children’s Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland Thambipillai Sri Paran Children’s Health Ireland at Crumlin, Dublin, Ireland The National Children’s Hospital, Dublin, Ireland Dakshesh Parikh Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, UK Shabnam Parkar Paediatric Surgery, St George’s Hospital NHS Foundation Trust, London, UK Howard I. Pryor II Division of Pediatric Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA Prem Puri Department of Pediatric Surgery, Beacon Hospital, Dublin, Ireland University College Dublin, Dublin, Ireland Bhaskar Rao Department of Surgery, St Jude Children’s Research Hospital, Memphis, TN, USA International Outreach Program, St Jude Children’s Research Hospital, Memphis, TN, USA University of Tennessee Health Science Center, Memphis, TN, USA Risto J. Rintala Department of Pediatric Surgery, Children’s Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland H. Rode The Burns Unit, Division of Paediatric Surgery, Department of Surgery, Faculty of Health Sciences, Red Cross War Memorial Children’s Hospital, University of Cape Town, Cape Town, South Africa

xxiv

A. D. Rogers Division of Plastic Surgery, Department of Surgery, Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada Udo Rolle Department of Pediatric Surgery, University Hospital Frankfurt/ Main, Frankfurt, Germany Jonathan H. Ross Rush University, Chicago, IL, USA Stephanie Ryan Children’s Health Ireland at Temple Street, Dublin, Ireland John A. Sandoval Department of Surgery, St. Jude Children’s Research Hospital, Memphis, TN, USA Amulya K. Saxena Department of Paediatric Surgery, Chelsea Children’s Hospital, Imperial College London, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK Markus G. Seidel Division of Pediatric Hemato-/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria Sohail R. Shah Division of Pediatric Surgery, Texas Children’s Hospital / Baylor College of Medicine, Houston, TX, USA Robert C. Shamberger Department of Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA Nina L. Shapiro Department of Head and Neck Surgery, University of California-Los Angeles, Los Angeles, CA, USA Khalid Sharif The Liver Unit, Birmingham Women’s and Children’s Hospital, Birmingham, UK Shilpa Sharma Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India Ofer Z. Shenfeld Department of Urology, Shaare Zedek Medical Center, Faculty of Medical Science, Hebrew University, Jerusalem, Israel Stephen J. Shochat Department of Surgery, St. Jude Children’s Research Hospital, Memphis, TN, USA Douglas R. Sidell Department of Otolaryngology, Head and Neck Surgery, Division of Pediatric Otolaryngology, Stanford University, Stanford, CA, USA Georg Singer Department of Pediatric and Adolescent Surgery, Medical University of Graz, Graz, Austria Michael Singh Department Paediatric Surgery, Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, UK

John A. Sandoval: deceased.

Contributors

Contributors

xxv

Carlos Soares Porto Medical School, Porto, Portugal Department of Surgery, Centro Hospitalar do Tâmega e Sousa, Penafiel, Portugal Juan E. Sola Division of Pediatric Surgery, DeWitt-Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA Josh Sommovilla Washington University, St Louis, MO, USA Erich Sorantin Department of Pediatric Radiology, Medical University of Graz, Graz, Austria Philipp Störmann Department of Trauma, Hand and Reconstructive Surgery, Hospital of the Goethe University Frankfurt/Main, Frankfurt, Germany Shawn D. St. Peter Children’s Mercy Hospital, Kansas City, MO, USA Raymond L. Stallings Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland National Children’s Research Centre, Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland Mark D. Stringer Department of Paediatric Surgery, Wellington Children’s Hospital and Department of Paeddiatrics and Child Health, Wellington School of Medicine, University of Otago, Wellington, New Zealand Steven Stylianos Morgan Stanley Children’s Hospital, New York, NY, USA Anna Svenningsson Department of Pediatric Surgery, Karolinska University Hospital, Stockholm, Sweden Paul Kwong Hang Tam Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China Jun Tashiro Division of Pediatric Surgery, DeWitt-Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA Christian Urban Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria Daniel von Allmen Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Brad Warner Washington University, St Louis, MO, USA Annelie-Martina Weinberg Department of Orthopaedic Surgery, Medical University of Graz, Graz, Austria Christopher B. Weldon Department of Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA David E. Wesson Department of Surgery, Baylor College of Medicine, Houston, TX, USA

xxvi

Tomas Wester Department of Pediatric Surgery, Karolinska University Hospital, Stockholm, Sweden Atsuyuki Yamataka Department of Pediatric Surgery, Juntendo University School of Medicine, Tokyo, Japan Takeo Yonekura Department of Pediatric Surgery, Nara Hospital, Kinki University School of Medicine, Ikoma, Nara, Japan Zacharias Zachariou Medical School, University of Cyprus, Nicosia, Cyprus

Contributors

Part I General: Head and Neck

1

Thyroglossal and Branchial Cysts, Sinuses, and Fistulas Michael E. Höllwarth

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3

Thyroglossal Duct Remnants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Embryology (Sadler 2006) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Presentation and Diagnostic Workup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4 4 4 5 5

Branchial Cysts and Sinuses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Embryology (Sadler 2006) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Presentation and Diagnostic Workout . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6 6 6 7 8

Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Abstract

Keywords

Congenital fistulas, cysts, or sinuses in the neck region consist either of branchial anomalies which arise from incomplete obliteration of pharyngeal clefts and pouches during embryogenesis or from failure of obliteration of the thyroglossal duct that was formed during the descent of the thyroid gland. The most common clinical sign is infection of the remnants, and appropriate surgical therapy is needed.

Thyroglossal duct · Thyroglossal cyst · Hyoid bone · Thyroid gland · Foramen cecum · Branchial cysts · Branchial sinuses · Branchial cleft · Facial nerve · Hypoglossal nerve · Laryngeal nerve

M. E. Höllwarth (*) Department of Paediatric and Adolescent Surgery, Medical University of Graz, Graz, Austria e-mail: [email protected]

Introduction Abnormalities in the neck region are caused by a large variety of anomalies which may be congenital or acquired. Residuals from embryological structures in the neck derive either from the thyroglossal duct or from the branchial arches

© Springer-Verlag GmbH Germany, part of Springer Nature 2021 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43559-5_90

3

4

and constitute the most common congenital anomaly in this anatomical region accounting for up to 60% of all excised neck masses in children. Although they are congenital anomalies, they may only become evident months or years later due to local swelling discharge of fluid or inflammation. Knowledge of the embryology and neck anatomy is essential for safe surgical therapy and minimizing the risk of recurrence or unpleasant complications.

Thyroglossal Duct Remnants Thyroglossal duct remnants present usually as a midline neck cysts or mass below the hyoid bone. Sinuses drain into the foramen cecum of the tongue. Most commonly they cause clinical problems in the first decade of life, and more than half of the cases are diagnosed before the age of 5. Rarely may they cause problems in patients of a later age.

M. E. Höllwarth

tissue may be found anywhere along the path of the descent of the gland.

Pathology Thyroglossal duct remnants are slightly more common when compared with branchial cleft anomalies (55% vs. 45%) and account for more than half of all congenital anomalies in the neck region (El-Gohary and Gittes 2011). Three quarters present as cysts and 25% as sinus, with or without infection (Foley and Fallat 2006). Ectopic thyroid tissue may be found in the wall of the cysts. When elements of the duct persist, after the descent of the thyroid, most of them become clinically apparent before the age of 20. Infected cysts form a red and tender tumor in the middle of the neck (Fig. 1). Rarely, the duct cysts may either contain papillary carcinoma or squamous cell carcinoma (van Vuuren et al. 1994; Peretz et al. 2004; Amos and Shermetaro 2019). In cases with papillary cancer, additional nodes can exist within the

Embryology (Sadler 2006) The thyroid gland appears as an epithelial proliferation in the floor of the pharynx between the first pharyngeal arch and the second/third pharyngeal arch at a point later indicated as the foramen cecum. Subsequently, the thyroid descends in front, through, or behind the hyoid bone and reaches its final position in front of the trachea in the seventh week. During migration, the thyroid remains connected to the tongue by a narrow canal, the thyroglossal duct. The duct obliterates in the fifth gestational week, and the foramen cecum at the base of the tongue on one end and the pyramidal lobe of the thyroid at the other end are the normal remnants. However, if duct cells persist, they can form a cyst or a sinus which is connected to the foramen cecum but rarely a fistula with an external opening in the middle of the neck. The thyroglossal cyst may lie at any point along the thyroid gland migration but always near or in the midline. Approximately 50% of these cysts are close to or just inferior to the body of the hyoid bone. Aberrant thyroid

Fig. 1 Infected thyroglossal cyst in the middle of the ventral neck side (Höllwarth 2009)

1

Thyroglossal and Branchial Cysts, Sinuses, and Fistulas

thyroid gland, and/or regional affected nodes may be present.

Clinical Presentation and Diagnostic Workup In a large series, 60% of the cysts were located close to the hyoid bone, 24% behind the hyoid bone, 13% close to the pyramidal lobe of the gland, and 3% intra-lingual at the foramen cecum (Allard 1982). When located at the base of the tongue, they may cause respiratory distress or even sudden infant death (Diaz et al. 2005). During palpation, uninfected cysts are often ballotable and can be moved slightly from side to side, but not up or down. Due to their origin from the foramen cecum, the thyroid cysts move upward during swallowing or when the tongue protrudes. An ultrasound investigation is recommended as preoperative workup to prove the cystic structure of the pathology. Fluctuating cysts may drain the content into the mouth generating a foul taste (Foley and Fallat 2006). The differential diagnosis includes complete ectopic thyroid gland or parts of the thyroid, dermoid inclusion cysts, lipomas, sebaceous cysts, submental lymphadenitis, thymus cysts, or tumor (Amos and Shermetaro 2019). As mentioned above, the latter group of pathologies may be moved up and down with palpation but do not move during swallowing unless the pathology is in close connection with the hyoid bone or the thyroid gland. In particular, dermoid cysts may be located in close vicinity to the hyoid bone and should therefore be excised to avoid a recurrent pathology. If the clinical examination shows the typical upand-down movement of the pathology during swallowing but the ultrasound shows not a cystic but a solid structure, an ectopic thyroid gland may be present. The overall incidence is 1–2%, very rare, and most of these patients have hypothyroidism. Therefore, if the ultrasound shows a solid lesion and the TSH and T3/T4 estimations indicate hypothyroidism, scintiscanning is recommended to identify the amount of functional thyroid tissue and avoid surgical resection of the functioning part of the thyroid (Radkowski et al. 1991; Wadsworth and Siegel 1994).

5

Surgery Elective surgery is recommended to prevent infection and is followed by excellent results. However, the surgical resection of the cyst must always include resection of the middle part of the hyoid corpus, whether or not the surgeon has the feeling that the duct ends at the bone (Fig. 2). In order to resect the hyoid bone, the upper and lower rims have to be freed from the straight neck muscles – omohyoid and sternohyoid muscle – and the middle 1–2 cm can be excised with strong scissors. In some cases, a clear continuity of the duct behind the bone can be seen which then has to be resected up to the base of the tongue including high ligature of the fistula. Reconstruction of the straight neck muscles is recommended to form the anterior aspect of the neck. Recurrence only occurs when the middle part of the hyoid corpus has not been resected appropriately. Some authors recommend a small suction drain to reduce postoperative complications (Lillehei 2012). However, a recent dual institutional study found that a drain does not

Fig. 2 The surgical procedure of a thyroglossal cyst and duct must include resection of the middle part of the hyoid bone (Höllwarth 2019b)

6

reduce common complications (Brooks et al. 2019). If the pathology presents primarily as an abscess, a horizontal incision or antibiotic therapy is recommended. The use of a drain depends on the size of the abscess. Some authors recommend antibiotic therapy alone or an additional needle aspiration of the pus in order to avoid seeding of the ductal epithelium. The parents have to be informed that a second surgical procedure with excision of the duct will become necessary as soon as the local inflammation is under control.

Branchial Cysts and Sinuses Although branchial cysts and sinuses are most often operated on in childhood, sometimes they are not detected as a clinical problem before adulthood. They are located along the anterior border of the sternocleidomastoid muscle; however they drain into very different regions depending on their origin from one of the branchial clefts. Knowledge of the embryology and the anatomical variants is crucial to avoid surgical mistakes, thereby creating nerve lesions and significant morbidity.

Embryology (Sadler 2006) Pharyngeal or branchial arches appear in the fourth and fifth week of development. Initially they consist of bars of mesenchyme separated by deep clefts, the pharyngeal/branchial clefts (Fig. 3). Each pharyngeal arch is characterized by its own muscular components and cranial nerve and arterial component. The first pharyngeal arch has a dorsal portion, the maxillary process, and a ventral portion, the mandibular process that includes the anlage for the incus and malleolus of the middle ear. The second pharyngeal arch gives rise to a number of small bones among them the lesser horn und upper body of the hyoid bone. The third arch produces the lower body and the greater horn of the hyoid bone. The fourth to sixth pharyngeal arches form the laryngeal bones. Simultaneously, a

M. E. Höllwarth

1 Cleft

2 3 Clefts

Pouches

4

Fig. 3 Pharyngeal arches (1–4) with the clefts and internal pouches. (Modified from Sadler (2006))

number of outpocketings, the pharyngeal pouches, appear lateral to the pharyngeal gut. The first pharyngeal pouch is involved in the development of the external auditory meatus, the middle ear cavity, and the Eustachian tube. Parts of the second pouch remain and form the tonsillar fossa. The third and fourth pouches are characterized by forming a dorsal and a ventral wing. The dorsal wing of the third pouch forms the inferior parathyroid gland, and the ventral wing forms the thymus. The epithelium of the dorsal wing of the fourth pharyngeal pouch forms the superior parathyroid gland. The fifth pharyngeal pouch is considered to be a part of the fourth pouch and gives rise to parafollicular cells of the thyroid gland. These cells secrete calcitonin.

Pathology Treatment of branchial remnants requires knowledge of the related embryology. Cysts, sinuses, and fistulas result in persisting epithelial cells within the mesoderm and are lined by squamous or columnar epithelia (Waldhausen 2006). Between 75% and 90% of the anomalies derive from the second branchial cleft, while 8–20% arise from the first cleft. Although most branchial cleft anomalies are present at birth, they may not appear until a fluid-filled cyst is formed or becomes infected. Bilateral cysts or sinuses can be observed in 10–15% of patients.

1

Thyroglossal and Branchial Cysts, Sinuses, and Fistulas

Although the majority of branchial anomalies are singular events, some cases of coincidence in families point to a genetically determined abnormality. Simple cystic remnants present commonly in adolescence and adulthood, while sinuses and fistulas are usually diagnosed in infancy and early childhood. In principle, clinical manifestation should be taken as an indication for elective excision before infectious complications supervene.

Clinical Presentation and Diagnostic Workout Remnants of the first branchial cleft occur with an incidence of approximately 5–25% of all branchial anomalies (Golf et al. 2012). They form small cysts at the retroauricular and parotid region but may extend to the area below the mandible and above the hyoid. Parotid and retroauricular lesions present usually as enlarging masses. Within the parotid, the relation to the facial nerve is critical (D’Souza et al. 2002). The most common classification divides them according to Work in two types: Work type I is of ectodermal origin and occurs medial to the concha often extending into the postauricular crease and ending in a cul-de-sac at the osseous-cartilaginous junction of the external meatus. They are usually superficial to the main facial nerve trunk. Work type II anomalies may also contain cartilage. They may have a sinus opening below the angle of the mandible and extend upward through the facial nerve to the end in or around the external auditory meatus (Work 1972). Infection of the cysts or sinus is common and pus may be discharged from the ear. According to Olsen, cysts and sinuses are usually superficial, while fistulas are deep to the facial nerve (Olsen et al. 1980; Magdy and Ashram 2013). The remnants of the first branchial cleft need to be distinguished from the preauricular pits, cysts, and sinuses which are remnants of the auditory tubercles. They are located anterior to the tragus of the ear, are often bilateral, and tend to be inherited. Diagnosis as well as surgical therapy is difficult and must avoid any damage to the facial nerve. Magnetic resonance imaging and a high-resolution CT scan are helpful to show the extent and the

7

relationship to the external auditory canal and the middle ear, but these techniques cannot inform about the relationship of the anomaly to the facial nerve. Intraoperative continuous electrophysiological facial nerve monitoring has been shown to be useful for the location of the facial nerve and its branches (Magdy and Ashram 2013). Remnants of the second branchial cleft are with an incidence of 40–95% the most common branchial anomalies (Bajaj et al. 2011). They are typically located as a painless, smooth, slowly enlarging mass along the anterior border of the sternocleidomastoid muscle. Unilateral fistulae are found in 89% on the right side (Maddalozzo et al. 2012). The majority of the anomalies are cysts with or without an additional sinus tract. They may be painful and fluctuate in size from time to time. If a fistula of the second branchial cleft persists, saliva or pus is discharged periodically or continuously at the skin ventral to the sternocleidomastoid muscle (Fig. 4). The internal fistula enters the supratonsillar fossa and can be seen easily in adults. Injection of water-soluble contrast material into the neck fistula under X-ray control shows the extension of the tract up to the pharynx. From the supratonsillar fossa, the tract passes over the hypoglossal nerve and behind the bigastric muscle through the bifurcation of the carotid artery and in front of the superior thyroid artery. The most common complication is infection of the cyst leading to an abscess. More rare presentations are stridor, tumor feeling in the throat with dysphagia,

Fig. 4 Discharge of pus from the external opening of a second bronchial cleft fistula (Höllwarth 2009)

8

and hypoglossal nerve palsy. Differential diagnoses include suppurative lymphadenitis or dermoid cyst, vascular anomalies such as cystic hygroma, or subcutaneous hemangioma. Remnants of the third and fourth branchial anomaly are uncommon (Golf et al. 2012). The external presentation of both tracts is similar as the remnants of the second branchial cleft along the middle to lower third of the anterior border of the sternocleidomastoid muscle. The difference between both tracts is that the third sinus passes over the superior and recurrent laryngeal nerve and between the hypoglossal and glossopharyngeal nerves and posterior to the carotid artery to end finally within the upper piriform sinus, while the fourth sinus passes deep to the laryngeal nerve but superior to the recurrent nerve. Both anomalies are predominantly on the left side, and the classical presentation is a recurrent left abscess or acute thyroiditis in childhood (Nicoucar et al. 2010; Madana et al. 2011). Further typical symptoms are recurrent respiratory tract infection, hoarseness, and painful swallowing. If the anomalies present as recurrent abscesses at the lateral side of the thyroid gland or in close vicinity to the piriform sinus, they may cause life-threatening respiratory stridor in neonates and infants or acute unilateral thyroiditis in children and adults. The appropriate diagnosis is difficult, and the cyst may evoke a false impression of acute thyroiditis. Most often these anomalies are treated as they were harmless local lymphoid abscesses, a mistake that makes later surgical excision of the tract very difficult. CT scan of the neck helps to identify the origin of such lesions. In an acute suppurative phase, external pressure onto the mass may ensue in laryngoscopically visible evacuation of pus into the piriform fossa.

Surgery Surgery of the first branchial cleft remnants is difficult, and only symptomatic forms need to be treated by local excision. At the beginning of the procedure, it is essential to expose the facial

M. E. Höllwarth

nerve and all its horizontal and lower branches. The surgical procedure should start with the identification of the main trunk of the nerve by means of a retroauricular incision. The exit of the nerve from the stylomastoid foramen can be found in a triangle formed by the sternocleidomastoid muscle, the bigastric muscle, and the external ear canal. Once the branches are isolated, minor or major parts of the parotid gland must be resected to identify the tract. Intraoperative monitoring of both mechanically elicited activity and electrically evoked responses to facial nerve stimulation with a nerve integrity monitor is useful (Magdy and Ashram 2013). The opening of the fistula to the external ear canal should be included in the resection to avoid any recurrence. Rarely, the duct opens to the middle ear or runs parallel to the Eustachian tube. The whole procedure is even more difficult in cases with a previous infection. Surgery of a remnant of the second branchial cleft starts with the excision of the visible pathology at the anterior border of the sternocleidomastoid muscle. If an external opening exists, a probe may be inserted, and methylene blue can be injected to make the fistula easier visible (Fig. 5). The duct is then isolated carefully from the surrounding tissue avoiding any rough procedure which could damage the carotid arteries within the bifurcation or the hypoglossal nerve (Fig. 6). In order to isolate and ligate the duct close to the supratonsillar region in older children, it is useful to make a second step-ladder incision 3–5 cm above the first incision. As soon as the excision is close to the supratonsillar fossa, the anaesthetist is asked to push the fossa down with his finger in order to enable the surgeon to ligate the central part of the sinus/fistula as close as possible to the fossa (Höllwarth 2019a). Drainage of the wound is rarely necessary. Recurrences only occur when the duct ruptures during the procedure and cannot be closed by ligature. The special anatomy in the rare case of remnants of the third and fourth branchial cleft and the risk to damage the superior or the recurrent laryngeal nerve make the surgical procedure

1

Thyroglossal and Branchial Cysts, Sinuses, and Fistulas

difficult. Several approaches have been recommended, each of them bares its specific risks. Excision with hemithyroidectomy or combined approach including catheter insertion into the piriform opening has proven to be successful (Madana et al. 2011; Pereira et al. 2004). Recently, closure of the internal opening at the piriform sinus by cauterization or injecting sclerosing material (OK-432) endoscopically into the tract of the third and fourth branch anomalies has been recommended and may be an especially helpful

9

solution after previous repeated infections (Nicoucar et al. 2009; Nicoucar et al. 2010; Roh et al. 2006; Kim et al. 2009; Nixon and Healey 2011). In three patients with a fourth branchial pouch anomaly under 1 year of age, the sinus opening in the left piriform fossa was successfully endoscopically coagulated with a monopolar diathermy in order to seal the opening (Bajaj et al. 2011).

Conclusion and Future Directions

Fig. 5 If injection of methylene blue is possible, the fistula is easier to visualize during surgery (Höllwarth 2009)

Fig. 6 The fistula runs through the carotid bifurcation and close to the hypoglossal nerve. Therefore dissection must be close to the fistula (Höllwarth 2019a)

Branchial anomalies and thyroglossal duct cysts are common in children. Conservative observation is not indicated, but surgical therapy is most appropriate. However, detailed knowledge of the embryology and pathology of these anomalies is necessary not only for correct diagnosis but also to avoid unnecessary surgery and/or complications. In the difficult cases of the first or third and fourth branchial cleft fistulae and sinuses, a CT fistulography may provide additional information in regard to the surrounding structures. Intraoperative electrical stimulation of structures within the parotic gland might additionally be helpful to identify facial nerve branches.

10

Cross-References ▶ Disorders of Salivary Glands ▶ Lymph Node Disorders ▶ Thyroid and Parathyroid Tumors

References Allard RH. The thyroglossal cyst. Head Neck Surg. 1982;5:134–6. Amos J, Shermetaro C. Thyroglossal duct cyst. Treasure Island: StatPearls Publishing; 2019. Bajaj Y, Ifeacho S, Tweedie D, et al. Branchial anomalies in children. Int J Pediatr Otorhinolaryngol. 2011;75:1020–3. Brooks JA, Cunningham MJ, Koempel JA, et al. To drain or not to drain following a Sistrunk procedure: a dual institutional experience. Int J Pediatr Otorhinolaryngol. 2019;127:109645. D’Souza AR, Uppal HS, Zeitoun H, et al. Updating concepts of first branchial cleft defects: a literature review. Int J Pediatr Otorhinolaryngol. 2002;62:103–9. Diaz MC, Stormorken A, Christopher MC. A thyroglossal duct cyst causing apnea and cyanosis in a neonate. Pediatr Emer Care. 2005;21:35–7. El-Gohary Y, Gittes G. Congenital cysts and sinuses of the neck. In: Puri P, editor. Newborn surgery. 3rd ed. London: Hodder Arnold; 2011. Foley DS, Fallat ME. Thyroglossal duct and other congenital midline cervical anomalies. Sem Pediatr Surg. 2006;15:70–5. Golf CJ, Allred C, Glade RS. Current management of congenital branchial cleft cysts, sinuses, and fistulae. Curr Opin Otolaryngol Head Neck Surg. 2012;20:533–9. Höllwarth EM. Branchial cyst and sinus. In: Puri P, Höllwarth M, editors. Pediatric surgery. Springer Surgery Atlas series. Berlin/Heidelberg: Springer; 2019a. Höllwarth ME. Thyroglossal duct cyst. In: Puri P, Höllwarth M, editors. Pediatric surgery. Springer surgery atlas series. Berlin/Heidelberg: Springer; 2019b. Höllwarth ME. Thyreoglossal and branchial cysts, sinuses and fistulas. In: Puri P, Höllwarth M, editors. Pediatric surgery: diagnosis and management. Berlin/Heidelberg: Springer; 2009. Kim MG, Lee NH, Ban JH, et al. Sclerotherapy of branchial cleft cysts using OK-432. Otolaryngol Head Neck Surg. 2009;141:329–34. Lillehei C. Neck cysts and sinuses. In: Coran AG, Adzick NS, Krummel TM, Laberge J-M, Shamberger RC,

M. E. Höllwarth Caldamone AA, editors. Pediatric surgery. 3rd ed. Philadelphia: Elsevier; 2012. Madana J, Yolmo D, Kalaiarasi R, et al. Recurrent neck infection with branchial arch fistula in children. Int J Pediatr Otorhinolaryngol. 2011;75:1181–5. Maddalozzo J, Rastatter JC, Dreyfuss HF, et al. The second branchial cleft fistula. Int J Pediatr Otorhinolaryngol. 2012;76:1042–5. Magdy EA, Ashram YA. First branchial cleft anomalies: presentation, variability and safe surgical management. Eur Arch Otorhinolaryngol. 2013;270:1917–25. Nicoucar K, Giger R, Pope HG Jr, et al. Management of congenital fourth branchial arch anomalies: a review and analysis of published cases. J Pediatr Surg. 2009;44:5–10. Nicoucar K, Giger R, Jaecklin T, et al. Management of congenital third branchial arch anomalies: a systematic review. Otolaryngol Head Neck Surg. 2010;142:21. e2–8.e2. Nixon PP, Healey AE. Treatment of a branchial sinus tract by sclerotherapy. Dentomaxillofac Radiol. 2011;40:130–2. Olsen KD, Maragos NE, Weiland LH. First branchial cleft anomalies. Laryngoscope. 1980;90:423–36. Pereira KD, Losh GG, Oliver D, et al. Management of anomalies of the third and fourth branchial pouches. Int J Pediatr Otorhinolaryngol. 2004;68:43–50. Peretz A, Leibermann E, Kapelushnik J, et al. Thyroglossal duct carcinoma in children: case presentation and review of the literature. Thyroid. 2004;14:777–85. Radkowski D, Arnold J, Healy GB, et al. Thyroglossal duct remnants: preoperative evaluation and management. Arch Otolaryngol Head Neck Surg. 1991;117:1378–81. Roh JL, Sung NH, Kim H, et al. Treatment of branchial cleft cyst with intracystic injection of OK-432. Acta Otolaryngol. 2006;126:510–4. Sadler TW. Langman’s medical embryology. 10th ed. Philadelphia/Baltimore: Lippincott Williams & Wilkins; 2006. Van Vuuren PA, Balm AJ, Gregor RT, et al. Carcinoma arising in thyroglossal duct remnants. Clin Otolaryngol. 1994;19:509–15. Wadsworth DT, Siegel MJ. Thyroglossal duct cysts: variability of sonographic findings. Am J Roentgenol. 1994;163:1475–7. Waldhausen JHT. Branchial cleft and arch anomalies in children. Sem Pediatr Surg. 2006;15:64–9. Work WP. Newer concepts of the first branchial cleft defects. Laryngoscope. 1972;82:1581–93.

2

Lymph Node Disorders Hugo A. Heij

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Anatomy and Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Benign Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Malignant Causes of Lymphadenopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Diagnosis of Lymph Nodes Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical and Laboratory Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Invasive Diagnostic Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sentinel Lymph Node Biopsy (SLNB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14 14 15 16 17

Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Lymphadenitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Surgical Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Abstract

Enlarged lymph nodes (lymphadenopathy) are frequently a reason to consult the pediatric surgeon. The purpose of this chapter is to describe the various causes and methods to investigate a child with enlarged nodes. The increasingly important role of imaging, but

also its limitations, as well as various invasive procedures are discussed. The main issues for the pediatric surgeon are the indication for biopsy of enlarged nodes, the methods to assess lymph nodes in patients with malignancies and the need for radical lymph node dissection. Keywords

H. A. Heij (*) Pediatric Surgical Center, Amsterdam University Medical Center, Amsterdam, The Netherlands e-mail: [email protected]

Lymphadenitis · Lymphoma · Metastases · Lymph node biopsy · Lymph node dissection

© Springer-Verlag GmbH Germany, part of Springer Nature 2021 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43559-5_92

11

12

Introduction Enlargement of lymph nodes is called lymphadenopathy, and inflammatory disorders are called lymphadenitis. Because children have an active lymphatic system, enlarged lymph nodes are a frequent cause to seek medical and surgical consultation. Often the enlarged lymph nodes are in the cervical region, but they may occur anywhere in the body. A wide variety of diseases, both benign and malignant, can cause lymphadenopathy. The purpose of this chapter is not to provide an exhaustive list of these causes but rather to present guidelines for the pediatric surgeon regarding how to approach the child with enlarged lymph nodes and to help find answers to practical questions like: What is normal? When is there reason for concern and an indication to biopsy an enlarged lymph node? Which investigations can help to make a diagnosis, particularly the advantages and limitations of imaging procedures? How to assess the lymph node status in children with malignant tumors and what to do with lymph node metastases?

Anatomy and Physiology The lymphatic system consists of lymph vessels that drain into lymph nodes. Concentrations of lymph nodes are present in the regional basins in the neck, axillae, and groins. There are also lymph nodes in the face (parotid), knee region (popliteal), and around the elbow (epitrochlear). Lymph nodes are bean shaped and the long axis varies between several millimeters and 1 cm. If the long axis measures more than 1 cm, the node is considered enlarged. Microscopy of normal lymph nodes shows a germinal center with surrounding B- and T-cells, all enveloped in a connective tissue capsule. Various diseases cause microscopic changes, with partial or complete destruction of the microscopic structure. These changes can be reflected in

H. A. Heij

imaging studies, like ultrasound, and help to distinguish between so-called normal, reactive enlargement and pathologic changes (Gosche and Vick 2006). The function of lymph nodes is to act as filters of microorganisms that have entered the body, usually via skin or mucosal defects. Macrophages in the nodes phagocytose particulate material and the foreign proteins are bound to major histocompatibility (MHC) antigens. These form complexes with cellular signals (interleukins) that activate T-helper lymphocytes. These in turn, activate B-lymphocytes, which results in an inflammatory response with leukocyte chemotaxis and increased vascular permeability. So far, this is a normal, physiologic process to clear invaded microorganisms. The lymph nodes involved may be somewhat enlarged but usually this does not cause more than a mild discomfort. This is called reactive lymph node enlargement (Upperman and Ford 2005).

Pathology If the inflammatory lymph node process is not cleared in a few days or if the node enlarges to more than 1 cm and becomes tender, and the overlying skin hyperemic, one may speak of lymphadenitis. Many viral or bacterial invasions leading to acute lymphadenitis are over within 2 weeks. If the enlargement continues for more than 6 weeks, it points to specific infections (like tuberculosis) or malignant changes. Within the period of 6 weeks, bacterial lymphadenitis can progress to suppuration which may require drainage (Upperman and Ford 2005).

Benign Disorders Lymphatic Malformations: Lymphangioma, Lymphangiomatosis, and Absence of Lymph Vessels Lymphangioma is now considered as part of a spectrum of vascular malformations. Formerly called cystic hygroma or hygroma colli,

2

Lymph Node Disorders

congenital collections of encysted lymphatic fluid in the neck, axilla, or groin occur in the newborn. In some cases, these are small and do not manifest until bleeding or infection leads to rapid enlargement and concomitant anxiety of the parents. In other cases, huge cystic masses may lead to respiratory obstruction. Lymphangiomatosis refers to extensive and progressive malformations with proliferation of endothelium and secretion of large amounts of fluid. Congenital lymphedema is caused by an absence or paucity of lymph vessels. Iatrogenic lymphedema occurs after lymph nodes dissection and/or irradiation of lymph node basins (Fischer et al. 2005).

Infections (Lymphadenitis) Nonspecific Infections Many viruses that invade the upper respiratory tract cause lymph node enlargement of the cervical region. Viral lymphadenitis is usually bilateral and rarely suppurates. Symptoms subside within 2 weeks. Acute bacterial lymphadenitis leads to significantly enlarged (2–3 cm), tender, often solitary nodes that may suppurate. Causative organisms are mainly streptococcus and staphylococcus, but almost any type of bacteria has been reported as a culprit (Gosche and Vick 2006). Specific Lymphadenitis Mycobacterial lymphadenitis is probably the most common cause of specific pathologic lymph node enlargement worldwide. Tuberculous lymphadenitis is seen in many low-income countries where M. tuberculosis is still ubiquitous, and nontuberculous lymphadenitis occurs in children in Europe and the USA. Although tuberculous lymphadenitis is usually found in the cervical region, because of the entrance via the digestive tract (Waldeyer’s ring), abdominal tuberculosis in children can also be a nodal disease. After BCG vaccination, enlargement of regional lymph nodes (axillary, supraclavicular) is common, but two types of active lymphadenitis may occur. One type is the nonsuppurative that

13

subsides in a few weeks, and the other the suppurative type that may progress to perforation and sinus formation. Expectative management is indicated as antituberculous drugs are not effective. Needle aspiration in suppurative adenitis may prevent sinus formation and shorten the duration of the process. Nontuberculous mycobacteria like M. aviumintracellulare, M. Kansasii, and others are a relatively frequent cause of lymphadenitis, both in otherwise healthy children and in immunocompromised patients, in affluent countries (Gallois et al. 2019). Mycobacteria cause a lymphadenitis that progresses from an acute to subacute and chronic stage. Tuberculous infections are initially often difficult to distinguish from the nontuberculous on clinical grounds alone. After a rapid onset, the nodes enlarge to a size of 2–3 cm, then remain stable or grow slowly. They are usually nontender, rubbery, with blue discoloration of the skin. This condition can exist for several months, but many nodes perforate spontaneously leading to a fistula track that may continue to discharge. The difference between tuberculous and nontuberculous lymphadenitis is that the latter will gradually heal if left alone, whereas the former will usually progress. Another cause of specific lymphadenitis is cat-scratch disease, caused by Bartonella Henselae, which is also a self-limiting disease that may take several months to subside. Fungal and parasitic lymphadenitis may occur in immunocompromised patients. Nocardia, Actinomyces, Toxoplasma, Histoplasmosis, and Coccidioides species can be isolated in these cases.

Other Causes of Lymph Node Enlargement in Children A number of benign lympho-proliferative disorders may present with or accompanied by lymphadenopathy. Examples are: Kikuchi-Fujimoto, Kawasaki, Rosai-Dorfman, Castleman’s Disease (Dispenzieri et al. 2012), and Sarcoidosis. In most cases, the complete clinical picture is more relevant than the isolated finding of enlarged nodes.

14

Malignant Causes of Lymphadenopathy Primary Malignancies of Lymph Nodes Are Called Malignant Lymphoma (Thomas et al. 2011) Broadly speaking, two groups of malignant lymphoma are distinguished: Hodgkin disease and non-Hodgkin lymphoma (NHL). In general, NHL is eight times more common than Hodgkin disease and in children, Burkitt’s lymphoma (BL) is a relatively common subtype of NHL. Hodgkin disease is usually a nodal disease, whereas NHL may occur in lymph nodes but extranodal lymphoma is well known. Nodal lymphomas often expand rapidly. Mediastinal localizations can cause compression of the airway and large vessels, leading to respiratory and circulatory failure. General anesthesia for diagnostic procedures or insertion of a central venous catheter is fraught with danger and should never be undertaken without adequate supporting facilities. Preoperative corticosteroids may aid in shrinking the masses without losing diagnostic features. Although BL was first reported in Africa, it also occurs in Caucasians, where the primary focus is often an abdominal localization like the ileocoecal region, not infrequently presenting as intussusception. BL can also be localized in the retroperitoneum and ovaries. Kaposi sarcoma in children is always associated with HIV infection. It can be considered as the primary malignancy of lymph nodes, as 52% of the patients in a recent report form Malawi and Botswana present with nodal enlargement. This was usually in combination with skin lesions but isolated nodal disease was present in 10%. Multiple enlarged lymph nodes with diameter >2 cm at multiple sites were found in two-thirds and isolated inguinal nodes in one third of the children (Cox et al. 2013). Irira et al. recently reported the prevalence of HIV-associated malignancies in children and found that 70% of malignancies were Kaposi sarcoma (Irira et al. 2018). Secondary Malignancies (Lymph Node Metastasis) Many pediatric tumors can metastasize to lymph nodes. In general, lymph nodes metastases signify

H. A. Heij

advanced disease which requires more intensive treatment and carries worse prognosis. Careful and reliable staging is therefore of vital importance to guarantee optimal treatment. In the head and neck region, the most common primary tumors in children are thyroid carcinomas, and peri-orbital or para-meningeal rhabdomyosarcoma, whereas neuroblastoma and malignant teratoma are less common in this area. In certain, less privileged, parts of the world, nasopharyngeal carcinoma occurs in children. Thoracic neuroblastoma and malignant teratoma can metastasize to mediastinal and cervical nodes. The prognosis of the more common solid abdominal tumors in children, nephroblastoma and neuroblastoma, is determined by the involvement of lymph nodes and careful sampling of these nodes is essential for accurate staging and adequate treatment. The same is true for tumors of the extremities, particularly rhabdomyosarcoma. Lymph node status determines the stage of disease and therefore the treatment. Cutaneous melanoma, although rare in children, is another example of a tumor in which lymph node status is essential to guide adequate treatment and achieve good outcome.

Diagnosis of Lymph Nodes Disorders Clinical and Laboratory Examination History and physical examination are the corner stones of the diagnostic process, also in patients with lymph node disorders. A history of infection in the ENT-region is often elicited in children with enlarged cervical nodes. Similarly, wounds or infections of soft tissues of the lower limbs may explain the presence of inguinal lymphadenopathy. The duration, growth, and tenderness should be asked for. General symptoms, like fever, night sweats, and weight loss are relevant information. Other important items are the presence of animals in the house, recent travel abroad, or relatives with pulmonary TB. On physical examination, the localization, size, tenderness, and mobility are noted, as are the presence of inflammatory skin changes,

2

Lymph Node Disorders

fluctuation, or fistula (drainage). Wounds, skin infections, and masses in the extremities, breast, or abdomen are investigated. On the other hand, if the patient presents with a suspected malignant tumor, a careful search of the regional and in-transit lymph node basins should be made. Anatomical regions of cervical lymph nodes are: parotid; upper, middle, and lower cervical; posterior triangle; supraclavicular fossa; and submental and submandibular areas. Cervical nodes are present in up to 90% of children between 4 and 8 years, but supraclavicular nodes are often pathologic as are nodes larger than 10 mm (Ludwig et al. 2012). It is important to note that in children with obstructive sleep apnea (OSA), deep cervical, like retropharyngeal, lymph node hypertrophy has been demonstrated as the cause of the obstruction (Parikh et al. 2013). Laboratory tests towards bacterial and viral infections, including serologic titers (e.g., for Bartonella henselae) are indicated, as guided by the differential diagnosis made on the basis of history and examination. If a malignant lymphoma is suspected, LDH and ferritin are important markers.

Imaging Imaging studies have become very important in the diagnosis of lymph node disorders. Ultrasonography (US) is the first, and often only, method applied in children, because the risk of radiation in growing individuals makes CT-scanning less preferable whereas general anesthesia is often needed for MRI in young children. High-resolution US can demonstrate many details that will point to a diagnosis and aid in making the decision whether to proceed towards an invasive procedure (Ludwig et al. 2012). Normal lymph nodes: the following criteria are standard in adults, but also usually applied to children. Form 10 mm along long axis, reniform in shape. On US: fatty echogenic hilum and hypoechoic cortex relative to muscle. On color Doppler: avascularity or radial symmetric hilar vascularity. On CT: homogeneous enhancement

15

after contrast, circumscribed with preserved fat planes. On MRI: intermediate signal on T1 and T2-weighted image.

Imaging Findings in Common Clinical Entities Reactive nodes may result from viral, bacterial, fungal, or protozoal infections. As noted above, viral infections are common in children and nodal enlargement is typically mild and bilateral without periadenitis. Bacterial lymphadenitis due to Staphylococcus aureus and group A Streptococcus account for 50–90% of unilateral cervical adenitis, usually in children between 1 and 4 years of age. US may show suppurative changes, including anechoic regions, peripheral vascularity, and septations, with posterior acoustic enhancement. Mycobacterium tuberculosis infection of cervical nodes accounts for 15% of the extrapulmonary TB. In the acute phase, imaging shows nodal enlargement (long axis to short axis of more than 2) and strong internal echoes, whereas in the subacute phase suppuration with intranodal abscess formation occurs. Calcifications are seen in the chronic phase. Atypical nontuberculous mycobacterial infections show a similar picture with centrally necrotic mass with peripheral enhancement (Pandey et al. 2012). Other specific bacterial infections, like cat scratch disease, do not present with specific imaging characteristics and the diagnosis has to be made on the basis of clinical and laboratory findings. Lymphadenopathy associated with clinical syndromes, like SLE, juvenile rheumatoid arthritis, often lack specific imaging characteristics. Kawasaki disease can present with cervical lymphadenopathy, usually unilateral, with a diameter of more than 1.5 cm. US shows a coalescent nodal mass, resembling a bunch of grapes formed by multiple hypoechoic nodes, which is different from the vascular nodes in bacterial infection. In Castleman disease, nodal enlargement with hypervascularity is seen. Neoplasia In general, malignant lymph nodes are enlarged, round shaped, with absent or eccentric echogenic

16

hilum, hypoechoic parenchyma, and tendency of nodes to aggregate into a mass. Primary lymphoma shows similar features, whereby the distinction between Hodgkin and non-Hodgkin lymphoma cannot be made on the basis of imaging. Metastatic lymph nodes often show central nodal necrosis with a lack of periadenitis. Metastatic nodes of differentiated thyroid carcinoma are hyperechogenic (Restrepo et al. 2009). Mesenteric lymph nodes in children: what is normal? A few remarks on the issue of enlarged abdominal nodes in children. The discussion whether there is a separate entity of mesenteric lymphadenitis, a frequent finding at laparotomy for suspected appendicitis in children, can now be addressed with the help of modern imaging methods. It appears that there is little support for this clinical entity. Rathaus et al. (2005) analyzed mesenteric lymph nodes (MLN) on CT (in 99 children investigated for abdominal trauma) and US (in 189 children attending the uro-nephrology clinic), between 1 and 18 years, who were otherwise asymptomatic. Enlarged MLN were defined as follows: longitudinal diameter more than 4 mm on US, more than 5 mm on CT, and arranged in a cluster of 3 or more. Enlarged MLN were found on US and CT in resp 28% and 29%, with the highest incidence in the age group 7–10 years. This conclusion fits well with the finding that in Wilms’ Tumor patients a lymph node size of less than 7 mm has 89% negative predictive value (Lubahn et al. 2012).

The Role of PET-CT Scan of Lymph Nodes in Children with Malignant Tumors This new diagnostic method for the evaluation of malignant tumors is based on the increased metabolism of glucose by the cells in tumors. It has been found to be of great value in the evaluation of the lymph node status, particularly in children with soft tissue sarcomas. Baum et al. reported on 41 patients, aged between 1 and 20 years, with rhabdomyosarcoma in various locations. In eight patients, positive lymph nodes were found. PET-CT was more sensitive than MRI and more specific than US.

H. A. Heij

Invasive Diagnostic Procedures The modern imaging methods outlined above, have all but abolished the need for exploratory or staging laparotomy (often accompanied by splenectomy) in patients with primary lymphoma, particularly non-Hodgkin. Localized lesions can be approached by needle biopsy and there are few places nowadays that cannot be reached by an experienced interventional radiologist, working closely together with clinicians and cyto-pathologists.

Fine Needle Aspiration Cytology (FNAC) This procedure consists of aspirating cells with a fine (18G or smaller) needle and vacuum syringe. The technique requires experience in order to obtain sufficient cells for cytopathologic staining. FNAC can be performed under local anesthesia, e.g., after application of EMLA ointment, in most children thereby avoiding the need for general anesthesia. It is a well-established technique for the diagnosis of thyroid and breast masses and has also been used for the diagnosis of lymphadenopathy. Benign Lymphadenopathy Role of FNAC in diagnosis of TB lymphadenitis (Derese et al. 2013): aspiration of enlarged lymph nodes, suspected of tuberculosis was found to be an effective mode of diagnosis with PCR performing not better than cytology (highest sensitivity 81%) and ZN-stain (highest specificity 92.4%). In a study from the Central African Republic in 131 cases, it was found that 43% had a positive ZN-stain and that culture detected tuberculosis in 65% of the children with a negative ZN-stain (Fanny et al. 2012). FNAC in the Diagnosis of Lymphoma The role of FNAC in diagnosing malignant lymphoma has been the subject of much debate. Mitra et al. (2013) examined 81 lymph nodes, of which 8 were malignant: FNAC was accurate in 93% mainly in benign lymph nodes, but less accurate in malignant disease. FNAC is considered useful as screening tool before surgical biopsy (Iyer 2013).

2

Lymph Node Disorders

Surgical Biopsy If and when FNAC is not sufficient to make a certain diagnosis of enlarged lymph nodes, excisional or incisional biopsy is indicated. Preoperative localization with ultrasound may be very helpful in order to approach the most pathologic looking node. Although the procedure itself is not very difficult, the localization of the node(s) may put certain neighboring structures at risk. Blood vessels and nerves, particularly the accessory nerve in the posterior triangle of the neck, and the marginal branch of the facial nerve under the mandible can be adherent to the node and result in permanent loss of function if damaged. When in doubt, it is better to err on the safe side and perform an incisional biopsy by staying inside the capsule of the node.

Sentinel Lymph Node Biopsy (SLNB) In order to target the biopsy of regional lymph nodes in case of a primary malignant tumor, mapping of these nodes with radioactive and/or visible staining is a great help, also in children (Gow et al. 2008). One indication is the staging of malignant melanoma. Although melanoma is rare in children, its use is well established and warrants mention here. Out of 126 children younger than 21 years, 62 had SLNB, of which 18 were positive (29%). There was a positive correlation between Breslow thickness and positive SLNB result. SLNB positive patients had a worse prognosis with a 5-year RFS 59.5% versus 93.7% (Han et al. 2012).

Treatment Lymphadenitis Medical Treatment: Antibiotics for (Cervical) Lymphadenitis In the early phase of reactive lymph node swelling, the question often arises whether antibiotic treatment is indicated. The decision depends on the nature of the primary infection, which is often located in the oropharyngeal region. Obviously, there is no effect of antibiotics in viral lymphadenitis. There is a role for antibiotic treatment of bacterial lymphadenitis, albeit limited. The

17

majority of bacterial infections are self-limiting and liberal use of antibiotics will only increase the emergence of resistant strains. Even in specific infections, like Bartonella henselae, there is good evidence that a nonmedical strategy will be successful in the majority of healthy children. On the other hand, once suppuration takes place, as signified by redness, tenderness, and fluctuation, antibiotics will not reach the purulent matter in the necrotic center of the node and the old adagium: “uni pus, ibi evacua” has to be honored.

Surgical Treatment Although incision and drainage is the standard treatment of abscesses, there is evidence that suppurative cervical lymphadenitis can be managed by needle aspiration (Baek et al. 2010). A retrospective study in 38 children, aged 1 month to 10 years, showed that aspiration of pus with an 18 or 21 G needle under US guidance, under local anesthesia with EMLA, is an effective alternative to open surgical drainage.

Role of Surgical Excision in Benign Lymphadenopathy In benign forms of lymphadenopathy, such as Castleman disease, surgical excision of the lymph nodes is curative, provided this can be done without damage to surrounding structures. If there is multicentric or irresectable disease, chemotherapy should be considered in the symptomatic patient (Dispenzieri et al. 2012; Ludwig et al. 2012). Role of Surgical Treatment in Malignant Lymphadenopathy Primary Lymphoma In the era of very effective cytotoxic and radiotherapeutic treatment of primary lymphoma, particularly non-Hodgkin lymphoma, the role of the surgeon is very limited (Suh et al. 2019). Only if complete resection can be achieved, is there a place for excisional procedures and there is no place for debulking (Attarbaschi et al. 2002). Not infrequently, children with Burkitt lymphoma

18

present as an abdominal emergency with ileocaecal intussusception. Reduction is almost never possible, and primary resection with anastomosis will not only solve the acute problem but also reduce the tumor load considerably. Lymph Node Metastases and Regional Lymph Node Dissection The importance of adequate assessment of the lymph node status in children with malignancies for the purpose of staging and appropriate treatment has been emphasized above. In the following section, some remarks will be made on the role of radical excision of lymph node metastases in childhood tumors, so-called regional lymph node dissection (RLND). This can be performed at any lymph node basin: cervical, axially, iliac, inguinal, and femoral. The indication for the RLND depends on the type of primary tumor. Malignant melanoma is probably the best-known example where it has been shown that complete removal of nodal metastases can significantly contribute to survival in specific groups of patients. RLND may also lead to serious complications, particularly lymphedema. Therefore, a selection of patients that will benefit from the RLND is important. PET-CT scan and sentinel lymph node biopsy are the methods that are increasingly applied in children and adolescents. Examples of indications are: rhabdomyosarcoma, malignant germ cell tumor, particularly of the testis, malignant melanoma, and medullary thyroid carcinoma.

Conclusions and Future Directions Some practical issues in the diagnosis and management of enlarged lymph nodes for pediatric surgeons: 1. The child with enlarged lymph nodes: differentiation between infected and neoplastic nodes – (a) How long can we wait before further investigations are required? See algorithm in Gosche and Vick (2006)

H. A. Heij

(b) What is the role of imaging, FNAC and surgical biopsy? (i) Imaging initially comprises ultrasound. Characteristics of reactive, inflammatory, and suspicious lymph nodes can be applied, but imaging will never give 100% certainty. (ii) FNAC may be helpful to identify malignant cells in cases of lymphoma, but for further typing a tissue biopsy is usually required. (c) Specific question for mesenteric lymph nodes, MLN: as more than one quarter of asymptomatic children have enlarged mesenteric lymph nodes, this finding should be interpreted with caution. Only if the clinical condition raises suspicion, is further investigation warranted (Karmazyn et al. 2005). 2. Nontuberculous mycobacterial lymphadenitis – diagnosis and treatment (a) Since medical treatment of this selflimiting condition is not effective, the choice is between excision or expectative management. Excision can be performed in the early stages without risk to surrounding structures (like the marginal branch of the facial nerve) but once a spreading phlegmon has developed, observation is preferable. 3. A child with a known primary tumor – when, where, and how to look for lymph node metastases? (a) Adequate staging of solid malignant tumors includes assessment of the regional lymph nodes. This can be done by imaging (US, MRI), but a PET-CT scan is increasingly applied with superior results. (b) In abdominal tumors, like nephroblastoma, intraoperatve sampling of at least seven lymph nodes is required to allow reliable staging. 4. When is regional lymph node dissection indicated in malignant diseases? (a) SLNB is now standard care in the staging of melanoma and rhabdomyosarcoma and will help to select patients that need to undergo RLND

2

Lymph Node Disorders

(b) RLND is considered curative in melanoma although RCTs comparing identical patient groups with and without RLND have not yet been performed in children. The main area of progress is in the field of diagnosis. High-resolution imaging, improved MRI-techniques like perfusion MRI (Razek and Gaballa 2011), and nuclear techniques like PET will select patients with lymph node disorders that require biopsy and/or specific treatment. This applies particularly to nodal metastases and will help to define the role of RLND in pediatric tumors. FNAC and DNA-technology, like PCR, may reduce the need for surgical biopsy.

Cross-References ▶ Hodgkin and Non-Hodgkin Lymphoma ▶ Rhabdomyosarcoma

References Attarbaschi A, Mann G, Dworzak M, et al. The role of surgery in the treatment of pediatric B-cell nonHodgkin’s lymphoma. J Pediatr Surg. 2002; 37(10):1470–5. Baek MY, Park KH, We JH, Park SE. Needle aspiration as therapeutic management for suppurative cervical lymphadenitis in children. Korean J Pediatr. 2010; 53(8):801–4. Baum SH, Frühwald M, Rahbar K, et al. Contribution of PET/CT to prediction of outcome in children and young adults with rhabdomyosarcoma. J Nucl Med. 2011;52:1535–40. Cox CM, El-Mallawamy NK, Kabue M, et al. Clinical characteristics and outcomes of HIV-infected children diagnosed with Kaposi sarcoma in Malawi and Botswana. Pediatr Blood Cancer. 2013; https://doi. org/10.1002/pbc.24516. Derese Y, Hailu E, Assefa T, et al. Comparison of PCR with standard culture of fine needle aspiration samples in the diagnosis of tuberculosis lymphadenitis. J Infect Dev Ctries. 2013; 6(1). https://doi.org/10.3855/jidc2050. Dispenzieri A, Armitage JO, Loe MJ, et al. The clinical spectrum of Castleman’s disease. Am J Hematol. 2012;87:99701002. Fanny M-L, Beyam N, Gody JC, et al. Fine-needle aspiration for diagnosis of tuberculous lymphadenitis in

19 children in Bangui, central African Republic. BMC Pediatr. 2012;12:191–4. Fischer AC, Mitchell SE, Tufaro AP. Chapter 103. Lymphatic and venous vascular malformation. In: Oldham KT, Colombani PM, Foglia RP, Skinner MA, editors. Principles and practice of pediatric surgery. Philadelphia: Lippincott Williams & Wilkins; 2005. p. 1691–703. Gallois Y, Cogo H, Debuisson C, et al. Nontuberculous lymphadenitis in children: what management strategy? Int J Pediatr Otorhinolaryngol. 2019;122:196–202. Gosche JR, Vick L. Acute, subacute, and chronic cervical lymphadenitis in children. Semin Pediatr Surg. 2006;15:99–106. Gow KW, Rapkin LB, Olson TA, et al. Sentinel node biopsy in the pediatric population. J Pediatr Surg. 2008;43(12):193–8. Han D, Zager JS, Han G, et al. The unique clinical characteristics of melanoma diagnosed in children. Ann Surg Oncol. 2012;19:3888–95. Irira M, Ngocho JS, Youze J, et al. Prevalence and outcome of HIV-associated malignancies among HIV-infected children enrolled into Care at Kilimanjaro Christian Medical Center 2006 to 2014: a hospital-based retrospective analytical study. J Pediatr Hematol Oncol. 2018; https://doi.org/10.1097/MPH.0000000000001389. Iyer VK. Pediatric lymphoma diagnosis (review). Indian J Pediatr. 2013;80:756–83. Karmazyn B, Werner EA, Rejaie B, Applegate KE. Mesenteric lymphnodes in children: what is normal? Pediatr Radiol 2005;35:774–7 Lubahn JD, Cost NG, Kwon J, et al. Correlation between preoperative staging computerized tomography and pathological findings after nodal sampling in children with Wilms’ tumor. J Urol. 2012;188(4):1500–5. Ludwig BJ, Wang J, Nadgir RN, et al. Imaging of cervical lymphadenopathy in children and young adults. AJR. 2012;199:1105–13. Mittra P, Bharti R, Pandey MK. Role of FNAC in head and neck lesions in the paediatric age group. J Clin Diagn Res. 2013;7:1055–8. Pandey A, Kureel SN, Pandey J, et al. Chronic cervical lymphadenopathy in children: role of ultrasonography. J Indian Assoc Pediatr Surg. 2012;17(2):58–62. Parikh SR, Sadoughi B, Sin S, et al. Deep cervical lymph node hypertrophy: a new paradigm in the understanding of pediatric obstructive sleep apnea. Laryngoscope. 2013; https://doi.org/10.1002/lary.23748. Rathaus V, Shapiro M, Grunebaum M, Zissin R. Enlarged mesenteric lymph nodes in asymptomatic children: the value of the finding in various imaging modalities. Br J Radiol. 2005;78:30–3. Razek AA, Gaballa G. Role of perfusion magnetic resonance imaging in cervical lymphadenopathy. J Comput Assist Tomogr 2011;35:21–5 Restrepo R, Oneto J, Lopez K, Kukreja K. Head and neck lymph nodes: the spectrum from normal to abnormal. Pediatr Radiol. 2009;39:836–46.

20 Suh JK, Gao YJ, Tang JY, et al. Clinical characteristics and treatment outcomes of pediatric patients with non-Hodgkin lymphoma in East Asia. Cancer Res Treat. 2019; https://doi.org/10.4143/crt.2019.219. Thomas AG, Vaidhyanath R, Kirke R, Rajesh A. Extranodal lymphoma from head to toe: part I, The head and spine. AJR. 2011;197:350–6.

H. A. Heij Upperman JS, Ford HR. Chapter 14. Inflammation. In: Oldham KT, Colombani PM, Foglia RP, Skinner MA, editors. Principles and practice of pediatric surgery. Philadelphia: Lippincott Williams & Wilkins; 2005. p. 253–81.

3

Disorders of Salivary Glands Douglas R. Sidell and Nina L. Shapiro

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Anatomy of the Salivary Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Diagnostic Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radiographic Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laboratory Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sialoendoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

22 22 22 23 23 24 24

Salivary Gland Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Congenital Salivary Gland Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acquired Salivary Gland Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mucoceles and Mucous Retention Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sialorrhea and Ptialism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Salivary Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Malignant Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

24 24 24 26 27 27 28

Surgical Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Abstract D. R. Sidell (*) Department of Otolaryngology, Head and Neck Surgery, Division of Pediatric Otolaryngology, Stanford University, Stanford, CA, USA e-mail: [email protected] N. L. Shapiro Department of Head and Neck Surgery, University of California-Los Angeles, Los Angeles, CA, USA e-mail: [email protected]

Primary salivary gland disorders are uncommon in the pediatric population. Infectious, neoplastic, granulomatous, and systemic disorders can occur, thereby resulting in a broad differential diagnosis. Several advances have been made over the past decade with regard to minimally invasive diagnostic and therapeutic procedures aimed to treat salivary gland pathology.

© Springer-Verlag GmbH Germany, part of Springer Nature 2021 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43559-5_93

21

22

D. R. Sidell and N. L. Shapiro

Keywords

Salivary · Pediatric

Introduction This chapter aims to provide an overview of salivary gland pathology in children and to discuss current diagnostic and treatment modalities. A review of pertinent patient anatomy, physical examination findings, and surgical considerations is provided.

as the Wharton’s duct and exits the mouth adjacent to the lingual frenulum. This is easily seen on physical examination. The sublingual salivary gland is the smallest of the major salivary glands. The sublingual gland occupies the sublingual space and is bound superficially by the oral mucosa and anterior-laterally by the mandible. The mylohyoid is the deep border of the sublingual space. The sublingual gland empties its excretory product into the ducts of Rivinus or into tributaries of the submandibular duct. The ducts of Rivinus are multiple in number and are located posterior to the opening of the Wharton’s duct, adjacent to the lingual frenulum.

Anatomy of the Salivary Glands The parotid salivary glands are the largest of the major salivary glands. They are located on each side of the lateral neck, resting anterior-inferior to the external auditory meatus, posterior to the mandibular ramus, and posterolateral to the masseter muscle. Each gland is composed of a deep and superficial lobe. The superficial lobe rests just below the superficial muscular aponeurotic system (SMAS), and its depth extends to the plane of the facial nerve. The facial nerve serves as the anatomic dividing point between the superficial and deep parotid lobes. The deep lobe of the parotid extends from the plane of the facial nerve superficially to the level of the stylomandibular ligament as its deep border. Also known as Stensen duct, the primary parotid duct traverses the masseter and empties its contents into the oral cavity via a ductal papilla adjacent to the second maxillary molar. The submandibular glands are also paired and are located in the submandibular cervical triangle. This anatomic space is defined by the mandible superior laterally, the anterior digastric muscle anteriorly, and the posterior digastric muscle posteriorly. The roof of this space is the mylohyoid muscle and separates the submandibular triangle from the sublingual space. A portion of the submandibular gland extends around the posterior border of the mylohyoid, thus occupying a portion of the sublingual space. The submandibular duct is also known

Diagnostic Evaluation History A patient history should include the location, laterality, onset, and duration of the lesion. Pediatric salivary gland lesions may be congenital, appear shortly after birth, or manifest later in childhood. Congenital lesions include vascular anomalies such as lymphatic malformations and hemangiomas. Rapid growth or diffuse swelling in the setting of pain and fever suggests an inflammatory or infectious process and may present with bilateral tenderness and diffuse enlargement (Mehta and Willging 2006; Centers for Disease Control 1989; Cherry 2004). Other systemic disorders, including autoimmune disease, may also manifest with bilateral pathology. In contrast, slower growing, painless lesions that are isolated to a single salivary gland may indicate a neoplasm (Mehta and Willging 2006).

Physical Examination A thorough physical examination includes inspection of the face for swelling, asymmetry, and overlying skin changes. Facial asymmetry may be the result of gland enlargement, facial nerve weakness, or both. Facial nerve weakness should

3

Disorders of Salivary Glands

always be graded and documented, and an etiology elicited. Although uncommon, facial nerve weakness in the setting of a salivary gland mass should be considered malignancy until proven otherwise. Overlying skin changes may suggest a granulomatous process or malignancy; advanced malignancy with overlying skin changes is rare in the pediatric patient. The salivary glands should be palpated bimanually, and the salivary ducts should be compressed to express saliva. This technique allows the physician to identify isolated masses, assess tenderness, and identify obstruction or abnormal discharge from the salivary duct.

Radiographic Imaging Salivary gland pathology in children does not always require radiographic imaging to appropriately diagnose or manage. In contrast to the adult patient, some imaging modalities may require general anesthesia to perform. This should be taken into consideration when weighing the risks and benefits of each study (Ilgit et al. 1992). High-resolution ultrasonography has become increasingly popular as a painless, noninvasive technique for imaging head and neck pathology in children. Over the past decade, this has become the first-line imaging modality for evaluation of the parotid gland. The normal parotid gland has a homogeneous echogenicity. The facial nerve is not readily visualized, but its position can be deduced based on the location of the retromandibular vein. Lymph nodes present in the superficial parotid are easily visualized as oval or longitudinal hyperechoic masses; a longitudinal axis in excess of 6 mm or the lack of a hyperechoic hilum are abnormal findings and suggest a pathologic process (Garcia et al. 1998; Bialek et al. 2006). Inflammatory conditions, neoplastic processes, vascular anomalies, cystic lesions, sialadenosis, and salivary calculi can often be readily identified and characterized using high-resolution ultrasound (Sodhi et al. 2011). Due to the echogenicity of the mandible,

23

the sublingual and submandibular glands are more difficult to evaluate using this technique. High-resolution computed tomography (CT) with contrast enhancement is extremely effective in assessing salivary gland pathology and, in conjunction with magnetic resonance imaging (MRI), has effectively replaced plain radiographs and sialography. CT images allow one to distinguish lesions that arise within the salivary gland parenchyma from extrinsic pathology. CT imaging can also help characterize the behavior of a lesion by virtue of its involvement with surrounding structures such as the mandible or cervical vasculature. Magnetic resonance imaging provides the highest level of detail of soft tissue structures and is considered the imaging modality of choice for investigating the nature of the lesion and its extent (Inarejos Clemente et al. 2018). It serves as an important imaging modality for pathology involving the deep lobe of the parotid gland and can be enhanced with gadolinium contrast dye when evaluating neoplastic, inflammatory, or vascular pathology. High-resolution 3-tesla MRI may also provide valuable information with regard to potential nerve involvement in the setting of a salivary malignancy (Mehta and Willging 2006; Freling et al. 1992).

Laboratory Studies Laboratory studies are rarely necessary in the evaluation of salivary gland pathology. Serologic evaluation for the human immunodeficiency virus (HIV) can be performed in patients with bilateral parotid cysts (see “viral sialadenitis”). In the setting of suspected infection, material obtained by expressing ductal secretions may also be sent for culture and gram stain. Mumps titers may be performed if viral parotitis is suspected in the nonimmunized patient. Sjogren’s syndrome A and B antibodies (SS-A and SS-B, respectively) may be useful to evaluate for an autoimmune origin. Any patient with pulmonary symptoms or patients who are suspected of having extrathoracic tuberculosis may have a Mantoux TB test (also referred to as a purified protein derivative (PPD) test).

24

Biopsy In adult patients who present with salivary gland masses, fine needle aspiration (FNA) is often performed in the clinic setting. In children, this procedure requires sedation under most circumstances and is uncommonly performed. FNA allows the clinician to differentiate a salivary neoplasm from an inflammatory process and is capable of distinguishing benign pathology from malignant processes under most circumstances (Mehta and Willging 2006; Eisenhut et al. 1996).

Sialoendoscopy The endoscopic evaluation and treatment of salivary disorders has gained popularity following its introduction in the 1990s. Since this time, the applications of sialoendoscopy have become more widespread and have rapidly expanded to include the pediatric population. As a diagnostic instrument, sialoendoscopy can readily identify salivary stones, ductal strictures, and chronic inflammatory processes. In the pediatric patient, some of the more common indications for sialoendoscopy include juvenile recurrent parotitis (JRP) and salivary calculi. Sialoendoscopy is therapeutic for both processes, allowing for the extraction of calculi and the mechanical irrigation of debris within the salivary ducts (Hackett et al. 2012; Schwarz et al. 2018).

Salivary Gland Pathology Congenital Salivary Gland Pathology Branchial Cleft Anomalies Anomalies of the branchial apparatus that involve the salivary glands are most frequently branchial cysts, sinuses, or fistulae. Although a thorough discussion of branchial embryology is beyond the scope of this chapter, it is useful to note that branchial cleft anomalies are classified by the work classification. Work type I and type II first branchial cleft anomalies are capable of producing parotid masses. Work type I first branchial cleft cysts are often located within the preauricular soft

D. R. Sidell and N. L. Shapiro

tissues. These anomalies may run parallel to the external auditory canal and contain hair, skin, and sebaceous glands. They often lie in close proximity to the facial nerve. Work type II first branchial cleft cysts arise inferior to the preauricular soft tissues, commonly at the angle of the mandible. These cysts or fistulae may course superficial or deep to the facial nerve and have the potential to terminate within the external auditory canal at the bony-cartilaginous junction (Rosa et al. 2008). Branchial cleft anomalies are frequently asymptomatic until they become infected or are involved in a traumatic injury, after which they may enlarge rapidly and come to clinical attention. Management frequently involves treatment of the acute inflammatory episode with antibiotics, followed by surgical excision.

Vascular Malformations Vascular malformations are nonneoplastic, congenital vascular anomalies. Unlike vascular neoplasms such as hemangiomas, they have histologically normal endothelium and frequently grow commensurate with the child. Vascular malformations that involve the salivary glands include lymphatic malformations, venous malformations, and mixed malformations. Like branchial cleft cysts, vascular malformations are frequently asymptomatic until an infectious or inflammatory process ensues, after which they may rapidly enlarge. Treatment involves management of acute inflammatory episodes followed by nonsurgical therapy. Occasionally, complete excision is possible. Unfortunately, many vascular malformations are intimately involved with surrounding structures, thus precluding a purely surgical approach. Under many circumstances, serial partial excision or intralesional injections with sclerosing agents are the only suitable options. Recurrence or residual disease is common.

Acquired Salivary Gland Pathology Inflammatory Disease Bacterial Sialadenitis Bacterial infection of the salivary glands is associated with acute enlargement of the gland in

3

Disorders of Salivary Glands

concert with pain, fever, poor oral intake, and generalized malaise. The parotid glands are most commonly affected by bacterial infections, followed by the submandibular glands and sublingual glands. Unlike viral infections, bacterial sialadenitis is almost always unilateral. In the neonatal period, 40% of bacterial sialadenitis occurs in premature infants (Mehta and Willging 2006). Physical examination requires bimanual palpation of the gland while observing for purulent discharge from the duct. The pain associated with acute suppurative sialadenitis is often so severe that the child may not permit a thorough examination; however ductal discharge can be sent for culture if an uncontaminated specimen is obtained. Staphylococcus aureus and Streptococcus viridans are the most common organisms implicated in acute suppurative sialadenitis, and antibiotic treatment is therefore directed at these organisms. The majority of patients will see resolution of the infection with oral antibiotics in conjunction with adequate hydration and oral hygiene. Because salivary stasis commonly contributes to the development of sialadenitis, additional treatment involves massage of the infected gland and the use of sialagogues such as sour candy to increase salivary production. Young patients and patients with severe infection may require hospital admission for intravenous antibiotics. Rarely, an abscess develops in the salivary parenchyma that requires drainage. This should be suspected in the presence of gland fluctuance on physical examination or unresolving infection despite appropriate treatment. Confirmation of the abscess and the extent of fluid loculation can be obtained using ultrasonography. Large parotid abscesses that closely approximate the facial nerve should be drained using a nerve-identifying technique. Superficial abscesses may be drained via a standard preauricular incision with subsequent incision of the SMAS parallel to the orientation of the facial nerve. Under all circumstances, facial nerve preservation is of paramount importance, and the patient must be counseled preoperatively with regard to the risk of facial nerve injury. Submandibular abscesses can be approached via a standard submandibular incision placed inferior to the marginal mandibular branch

25

of the facial nerve. Blunt dissection can then be performed in an inferior to superior direction that is deep to the plane of the nerve, until all abscess contents are drained and abscess loculations are taken down. Fluid should always be sent for culture, and a drain should be placed under most circumstances (Mehta and Willging 2006; Rice 1991). Sialendoscopy is a well-tolerated and effective procedure for the treatment of recurrent sialadenitis in children. Sialendoscopy and salivary duct irrigation have been shown to improve the frequency and severity of sialadenitis in patients with juvenile recurrent parotitis (Ogden et al. 2016). Viral Sialadenitis Viral infection of the salivary glands is a common cause of acute inflammation in the pediatric patient. Viral sialadenitis most frequently involves the parotid glands; however, it is usually less tender on presentation and is infrequently associated with fever, anorexia, and malaise. Viral sialadenitis is a self-limiting process and often lasts less than 3 weeks in duration. Treatment is conservative. Although the echovirus, coxsackievirus, and Epstein-Barr virus are frequently implicated in viral sialadenitis, the mumps virus (paramyxovirus) and HIV (retrovirus) deserve special mention. In the late 1960s, the mumps vaccine was instituted as a component of a universal pediatric vaccination program. As a result, the virus has declined steadily in the United States over the past 50 years. Despite this, mumps remains one of the most common causes of viral sialadenitis worldwide. Other components of the disease include a spectrum of pancreatic, gonadal, and meningeal involvement (Centers for Disease Control 1989). The HIV virus must also be considered in patients with bilateral viral sialadenitis. With the advent of current antiretroviral therapies, patients with HIV are now surviving for decades with low levels of viral burden. As a result, HIV-associated disease manifestations are being seen more regularly in the chronically infected population. HIV parotitis manifests as bilateral cystic parotid disease that is nearly pathognomonic for HIV.

26

Fortunately, HIV parotitis is exceedingly rare in children. Treatment is conservative unless malignancy is suspected (Mehta and Willging 2006; Cvetinovic et al. 1991). Chronic Sialadenitis and Sialolithiasis Juvenile recurrent parotitis (JRP) is a form of chronic salivary inflammation that is thought to be one of the most common causes of sialadenitis in children. JRP is characterized by recurrent painful inflammation. Diagnosis requires two episodes of sialadenitis per year and is characterized by structural changes within the gland, including acinar destruction and ductal stenosis (Hackett et al. 2012). Although it has been noted to persist into adulthood, JRP frequently resolves following puberty and has been effectively treated using sialoendoscopy. Obstructive sialadenitis occurring secondary to salivary calculi is rare in children and occurs in the submandibular gland in the majority (80%) of cases. This predilection for the submandibular gland is due to the horizontal plane of the Wharton’s duct, the higher relative alkalinity of secretions, the greater viscosity of submandibular gland saliva, and the greater concentrations of calcium phosphate and calcium carbonate. As a rule of thumb, the majority of salivary stones in the submandibular gland are radiopaque, and the majority of salivary stones in the parotid gland are radiolucent. Management involves treating acute infection with antibiotics, adequate hydration, salivary gland massage, and the use of sialagogues. Surgical management often includes the use of sialoendoscopy with stone retrieval (Ogden et al. 2016). Submandibular stones in the floor of mouth may be retrieved by incision and extraction with marsupialization of the duct; however, ductal stenosis is a postoperative risk. In severe or recurrent cases, gland excision may be performed. Lithotripsy has also been used with some success in appropriately selected patients (McJunkin et al. 2009). Granulomatous Disease Mycobacterial sialadenitis may result from either Mycobacterium tuberculosis (TB) or an atypical mycobacterial infection. Extrathoracic TB with salivary involvement is uncommon in children,

D. R. Sidell and N. L. Shapiro

but should be included in the differential diagnosis for those children with parotitis and a positive Mantoux skin test. In contrast, atypical tuberculosis occurring secondary to Mycobacterium aviumintracellulare is a common source of sialadenitis in the pediatric population. Although the disease does not often originate in the salivary parenchyma, periparotid or submandibular lymph node involvement is common (Mehta and Willging 2006; Rieu et al. 1990). Mycobacterial lesions frequently have overlying skin breakdown (with occasional spontaneous drainage) and have minimal tenderness on examination. Surgical excision may be performed, as antituberculosis drugs often have little effect on the course of the disease. Unfortunately, operative management can be exceedingly difficult due to the necrotic and inflammatory nature of the disease and the proximity to critical structures. Observation may be elected when lesions do not appear to be at risk for secondary infection or drainage. Nonsurgical therapy often includes the use of antibiotics, including azithromycin and rifampin. Spontaneous resolution has been observed. Other granulomatous diseases affecting the salivary gland include sarcoidosis and actinomycosis. They are uncommon in children (Mehta and Willging 2006).

Mucoceles and Mucous Retention Cysts The term mucocele is often used interchangeably with the term mucous retention cyst. A mucocele differs from the mucous retention cyst in that it does not have an epithelial lining. Mucoceles result from minor salivary ductal obstruction (often secondary to trauma) with subsequent enlargement of the minor salivary gland. They most commonly occur on the lower lip and are painless masses; however, due to the proximity to the anterior dentition, the lesions are frequently involved in a cycle of growth and rupture. Ranulas are mucus retention cysts that arise secondary to obstruction of the sublingual gland. They result in a mass that occupies the floor of the mouth, often elevating the tongue. If the ranula enlarges, it may extend into the neck as a

3

Disorders of Salivary Glands

“plunging ranula” by traversing the mylohyoid. Plunging ranulas, oral ranulas, and labial mucoceles are each treated by surgical excision with removal of the surrounding salivary tissue. This is a minor undertaking in the case of the minor salivary tissue associated with the labial mucocele, but requires sublingual gland excision in the case of the ranula. Care must be taken to avoid injury to the lingual nerve or submandibular duct. With the exception of select revision procedures to remove recurrent plunging ranulas, almost all mucoceles, including primary plunging ranulas, can be removed via a transoral approach. Under some circumstances, recurrent plunging ranulas have been managed with sclerotherapy.

Sialorrhea and Ptialism Drooling can occur secondary to the overproduction of saliva (ptialism); however it is more commonly the result of the inability to control a normal quantity of saliva (sialorrhea). Ptialism can be the result of medications that stimulate the parasympathetic (or inhibit the sympathetic) nervous system, due to teething, or due to certain infectious processes. In contrast, sialorrhea is often the result of neuromuscular dysfunction. Under both circumstances, drooling can result in skin irritation and halitosis and also cause significant psychosocial problems (Kupferman et al. 2010; Crysdale 1994). Treatment is aimed at reducing the production of saliva and may include the use of systemic sympathomimetic medications or injections of botulinum toxin into the salivary glands. Surgical management may include parotid and submandibular duct ligation, submandibular gland excision, and tympanic neurectomy. All procedures have variable results, and a combination of treatments is frequently necessary to achieve success.

Salivary Neoplasms Salivary gland neoplasms are rare in children and represent fewer than 10% of all pediatric head and neck tumors (Dombrowski et al. 2019).

27

Benign Neoplasms Benign masses constitute the majority of salivary gland neoplasms in patients of all ages and represent more than 60% of salivary tumors in children (Bentz et al. 2000). Hemangiomas The most common salivary neoplasm in children is the hemangioma. Hemangiomas are a distinct form of vascular anomaly that is classified as a vascular neoplasm. Unlike the vascular malformation, vascular neoplasms arise shortly after birth, have histologically abnormal endothelium on microscopy, and have a nonlinear growth pattern. Overall, 80% of salivary hemangiomas occur in the parotid gland and comprise more than 90% of salivary neoplasms in the first year of life. An additional 18% of salivary hemangiomas arise in the submandibular gland, and the remaining 2% arise in the minor glands (Mehta and Willging 2006; Boyd et al. 2009). Overall, 20% of patients will have hemangiomas in multiple sites, and more than 50% of patients with a parotid hemangioma will also have a cutaneous hemangioma. Treatment is largely conservative. The natural growth pattern of the hemangioma dictates that most lesions proliferate during the first 6–9 months of life and involute gradually over the following 5–7 years. Lesions that cause functional or symptomatic impairments may be managed with nonsurgical systemic therapy aimed at inhibiting vascular proliferation. Over the past decade, the use of propranolol has revolutionized the management of infantile hemangiomas. Pleomorphic Adenoma (Benign Mixed Tumor) The pleomorphic adenoma is the most common nonvascular benign neoplasm to occur in pediatric salivary glands. Like hemangiomas, the vast majority of lesions arise in the parotid. Patients frequently present with a painless, firm, wellcircumscribed mass that is discovered incidentally on physical examination or after being visualized by the child’s parents. On histology, the neoplasm is comprised of myxoid, stromal, and epithelial components, earning it the name “benign mixed tumor.” Ultrasound or MRI will demonstrate a well-circumscribed, nondestructive lesion with

28

pushing borders. The neoplasm is most frequently unilateral and unifocal. The exception to this rule may occur following incomplete excision, after which tumor spillage may cause multifocal recurrence that can be exceptionally challenging to treat (Malata et al. 1997). Primary management includes complete surgical excision with a margin of normal salivary tissue to reduce the risk of recurrence. For superficial parotid lesions, a superficial parotidectomy with facial nerve preservation is performed to ensure excision of the neoplasm. Observation of the pleomorphic adenoma is not advised due to the increased risk of malignant degeneration that occurs over time (Mehta and Willging 2006).

D. R. Sidell and N. L. Shapiro

malignant epithelial neoplasms identified in children include mucoepidermoid carcinoma and acinic cell carcinoma. Morse et al. (2018) studied the epidemiology of pediatric salivary cancer in 588 children, and mucoepidermoid carcinoma was identified in 40% of the patients and acinar cell carcinoma in 37% of patients. Rhabdomyosarcoma is the most common mesenchymal lesion to affect children and is frequently diagnosed in the first 1–2 years of life.

Malignant Neoplasms

Mucoepidermoid Carcinoma Mucoepidermoid carcinoma is the most common salivary gland malignancy in children, constituting about half of all malignant salivary gland tumors found in the pediatric population (Dombrowski et al. 2019). The age of presentation is usually between 9 and 16 years (Mehta and Willging 2006). The neoplasm is usually located in the parotid gland; however, submandibular gland and minor salivary gland lesions are possible. The behavior of the lesion is determined by the histologic grade, and a treatment plan is established accordingly. The histologic grade is established by the level of cellular differentiation and by the presence of mucinous elements. Lowgrade, well-differentiated lesions have an abundance of mucinous elements. Treatment involves complete surgical excision with a margin of normal tissue. Adjuvant therapy is unnecessary, and overall survival is excellent (Batsakis et al. 1988). High-grade mucoepidermoid carcinoma is uncommon in children. Lesions are locally and regionally aggressive. They demonstrate a paucity of mucinous elements and resemble squamous cell carcinoma on histologic analysis. Treatment requires wide local excision with a selective neck dissection. Adjuvant chemoradiation is often required, and recurrence-free survival is drastically reduced when compared to low-grade neoplasms (Mehta and Willging 2006; Ethunandan et al. 2003; Shapiro and Bhattacharyya 2006).

Excluding vascular anomalies and infection, more than 50% of pediatric salivary masses are malignant. Fortunately, malignant salivary gland neoplasms are still rare in children, and the majority of malignancies are low-grade lesions. The most common

Acinic Cell Carcinoma Acinic cell carcinoma is the second most common salivary carcinoma in the pediatric population. Lesions often arise in a similar age group as mucoepidermoid carcinoma and are frequently

Warthin Tumor (Papillary Cystadenoma Lymphomatosum) The Warthin tumor is a benign neoplasm that may be seen in the parotid gland. It is an extremely rare lesion in the pediatric age group and frequently occurs in older, male patients. It is the most common benign salivary neoplasm to present bilaterally and may occur multifocally within the gland (Bentz et al. 2000). On physical examination, the mass is painless, slow-growing, and compressible due to the cystic component. Treatment includes complete surgical excision. Sialoblastoma Also known as “embryoma,” sialoblastoma is an embryonic neoplasm that is unique to children and frequently arises in the minor salivary glands. They are commonly diagnosed within the first year of life. Although they are histologically benign, they are locally aggressive, and a 25% incidence of malignant transformation with cervical metastases has been reported (Batsakis et al. 1988). Treatment includes wide local excision.

3

Disorders of Salivary Glands

low grade. Metastases are exceedingly rare; however bilateral and multifocal lesions are possible. Treatment includes wide local excision of the lesion. Recurrence is common (Sato et al. 2005).

Adenoid Cystic Carcinoma Adenoid cystic carcinoma is the second most common salivary malignancy in adults but is far less common in children. Like adults, it is characterized by neural and perineural invasion and is associated with a high recurrence rate. Management includes wide local excision, neck dissection for positive cervical disease, and adjuvant radiation therapy. Long-term surveillance is necessary due to the potential for distant metastases to arise decades after primary therapy has been completed (Mehta and Willging 2006). Rhabdomyosarcoma Rhabdomyosarcoma is the most common sarcoma to occur in the salivary glands. It is frequently diagnosed in the first year of life as a rapidly enlarging parotid mass. Histologically, the lesions are most often undifferentiated or embryonal types. Treatment is dependent on the tumor stage. Prognosis is improved significantly if complete excision is possible, including microscopic dissection.

Surgical Considerations Although a comprehensive description of operative techniques is beyond the scope of this chapter, the surgical management of salivary gland lesions is usually performed using a nerve-sparing technique. The decision to sacrifice surrounding structures is dependent on the pathology of the lesion being treated. Neurovascular structures are not sacrificed unless they are directly involved by a malignant neoplasm.

Conclusion and Future Directions The diagnosis and management of pediatric salivary disorders has made important advancements over the past decade. It is likely that innovations in

29

noninvasive imaging modalities and minimally invasive endoscopic interventions will continue to revolutionize the management of pediatric salivary gland disorders in the future.

Cross-References ▶ Rare Malignant Tumors ▶ Rhabdomyosarcoma

References Batsakis JG, Mackay B, Ryka AF, et al. Perinatal salivary gland tumours (embryomas). J Laryngol Otol. 1988;102:1007–11. Bentz BG, Hughes A, Ludemann JP, Maddalozzo J. Masses of the salivary gland region in children. Arch Otolaryngol Head Neck Surg. 2000;126:1435–9. Bialek EJ, Jakubowski W, Zajkowski P, Szopinski K, Osmolski A. Ultrasound of the major salivary glands: anatomy and spatial relationships, pathologic conditions & pitfalls. Radiographics. 2006;26:745–63. Boyd ZT, Goud AR, Lowe LH, et al. Pediatric salivary gland imaging. Pediatr Radiol. 2009;39:710–22. Centers for Disease Control. Mumps prevention. MMWR Morb Mortal Wkly Rep. 1989;38:338–92, 397–400 Cherry JD. Mumps virus. In: Feigen RD, Cherry JD, Demmler GJ, Kaplan SL, editors. Textbook of pediatric infectious diseases. 5th ed. Philadelphia: WB Saunders; 2004. p. 2305–14. Crysdale WS. Drooling. In: Gates G, editor. Current therapy in otolaryngology: head and neck surgery. Hamilton: B.C. Decker; 1994. p. 426–9. Cvetinovic M, Jovic N, Mijatovic D. Evaluation of ultrasound in the diagnosis of pathologic processes in the parotid gland. J Oral Maxillofac Surg. 1991;49:147. Dombrowski ND, Wolter NE, Irace AL, et al. Mucoepidermoid carcinoma of the head and neck in children. Int J Pediatr Otorhinolaryngol. 2019;120:93–9. Eisenhut CC, King DE, Nelson WA, et al. Fine-needle biopsy of pediatric lesions: a three-year study in an outpatient biopsy clinic. Dagn Cytopathol. 1996;14:43–50. Ethunandan M, Ethunandan A, Macpherson D, et al. Parotid neoplasms in children: experience of diagnosis and management in a district general hospital. Int J Oral Maxillofac Surg. 2003;32:373–7. Freling NJ, Molenaar WM, Verney A. Malignant parotid tumors: clinical use of MR imaging and histological correlation. Radiology. 1992;185:691. Garcia CJ, Flores PA, Arce JD, Chuaqui B, Schwartz DS. Ultrasonography in the study of salivary gland lesions in children. Pediatr Radiol. 1998;28:418–25. Hackett AM, Baranano CF, Reed M, Duvvuri U, Smith RJ, Mehta D. Sialoendoscopy for the treatment of pediatric

30 salivary gland disorders. Arch Otolaryngol Head Neck Surg. 2012;138(1):912–5. Ilgit ET, et al. Digital subtraction sialography techniques: advantages and results in 107 cases. Eur J Radiol. 1992;15:44. Inarejos Clemente EJ, Navallas M, Tolend M, et al. Imaging evaluation of pediatric parotid gland abnormalities. Radiographics. 2018;38:1552–75. Kupferman ME, de la Garza GO, Santillan AA, et al. Outcomes of pediatric patients with malignancies of the major salivary glands. Ann Surg Oncol. 2010;17 (12):3301–7. Malata C, Camilleri I, McLean N, et al. Malignant tumours of the parotid gland: a 12-year review. Br J Plast Surg. 1997;50:600–8. McJunkin J, Milov S, Jeyakumar A. Lithotripsy for refractory pediatric sialolithiasis. Laryngoscope. 2009;119 (2):298–9. Mehta D, Willging JP. Pediatric salivary gland lesions. Semin Pediatr Surg. 2006;15:76–84. Morse E, Fujiwara RJT, Husain Z, et al. Pediatric salivary cancer: epidemiology, treatment trends, and association of treatment modality with survival. Otolaryngol Head Neck Surg. 2018;159(3):553–63.

D. R. Sidell and N. L. Shapiro Ogden MA, Rosbe KW, Chang JL. Pediatric sialendoscopy indications and outcomes. Curr Opin Otolaryngol Head Neck Surg. 2016;24(6):529–35. Rice DH. Non-neoplastic diseases of the salivary glands. In: Paparella MM, et al., editors. Otolaryngology. Philadelphia: WB Saunders; 1991. Rieu PN, van den Broek P, Pruszczynski M, et al. Atypical mycobacterial infection of the parotid gland. J Pediatr Surg. 1990;25:483–6. Rosa P, Hirsch D, Dierks E. Congenital neck masses. Oral Maxillofac Surg Clin North Am. 2008;20:339. Sato T, Kamata SE, Kawabata K, et al. Acinic cell carcinoma of parotid gland in a child. Pediatr Surg Int. 2005;21:377–80. Schwarz Y, Bezdjian A, Daniel SJ. Sialendoscopy in treating pediatric salivary gland disorders: a systematic review. Eur Arch Otorhinolaryngol. 2018;275(2):347–56. Shapiro NL, Bhattacharyya N. Clinical characteristics and survival for major salivary gland malignancies in children. Otolaryngol Head Neck Surg. 2006;134(4): 631–4. Sodhi KS, Bartlett M, Prabhu NK. Role of high resolution ultrasound in parotid lesions in children. Int J Pediatr Otorhinolaryngol. 2011;75:1353–8.

4

Torticollis Spencer W. Beasley

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Definitions and Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Differential Diagnosis of Torticollis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Torticollis Due to a Tight Sternomastoid Muscle (Congenital Torticollis, Sternomastoid Tumor, Sternomastoid Fibrosis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Natural History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features (See Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Late Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Confirmation of Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Complications of Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Outcome Measures After Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

35 35 35 36 37 37 39 39 40 41 42 42

Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

Abstract

Torticollis, or wry neck, has a wide variety of causes in infants and children, including sternomastoid fibrosis, strabismus, cervical

S. W. Beasley (*) Department of Paediatric Surgery, Christchurch Hospital and Christchurch School of Medicine, University of Otago, Christchurch, New Zealand e-mail: [email protected]; [email protected]

hemivertebrae, intracranial malignancy, trauma, and inflammation of the soft tissues of the neck. When it presents at about 3 weeks of age, it is usually due to a sternomastoid tumor, with tightness and shortness of the sternomastoid muscle – demonstration of the tight and shortened sternomastoid muscle is the key clinical feature that distinguishes this condition from all other causes of torticollis. Sternomastoid tumor/ fibrosis is a benign condition that resolves spontaneously in the first year of life in about 90% of

© Springer-Verlag GmbH Germany, part of Springer Nature 2021 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43559-5_94

31

32

S. W. Beasley

cases, but sometimes produces secondary plagiocephaly and hemifacial hypoplasia. If it fails to resolve by 1 year of age, or where the shortened sternomastoid muscle presents later in childhood, surgical division of the lower end of the muscle is indicated. Keywords

Torticollis · Sternomastoid tumor · Sternomastoid fibrosis · Plagiocephaly · Hemifacial hypoplasia

Introduction Definitions and Terminology Torticollis (sometimes called “wry neck” or “head tilt”) is a term given to the situation where the head is consistently bent to one side. Literally, “torticollis” means twisted neck. The term “primary” or “congenital” torticollis is often given to its most common presentation, that of a shortened and tight sternomastoid muscle. Strictly speaking, it is not “congenital” in that it is not normally evident at birth: it usually becomes apparent at 2–3 weeks of age when a painless firm lump in the neck is first observed or it is noticed that the baby cannot turn the head to one side. Nor might it always be “primary,” as there is ongoing controversy as to its etiology (vide infra). This condition is frequently described as a “sternomastoid tumor,” when the muscle has a discrete lump localized to one part of the muscle (Fig. 1); on other occasions, it is referred to as “sternomastoid fibrosis” particularly when the whole muscle is involved. Sometimes “cleido” is added, such as in “sternocleidomastoid fibrosis” in recognition that both components of the muscle may be affected. Similarly, the terms “congenital muscular torticollis” and “congenital torticollis” are indicative of involvement of the sternomastoid muscle from infancy. However, some clinicians restrict the use of these terms to where the child with a tight sternomastoid muscle presents late or the torticollis does not resolve, mainly to

Fig. 1 Left sternomastoid tumour, clearly evident in this 3 week old infant. It appears as a discrete nontender lump within the sternomastoid muscle

distinguish these patients from those with a “pseudotumor of infancy” or “sternomastoid tumor.” This stems from a belief that those with a tumor may have a different etiology. It certainly seems that localized involvement (as in a “tumor”) is more likely to resolve than where the entire length of muscle is affected, or where the presentation is late. Unfortunately, the term is somewhat imprecisely applied which limits its usefulness. Torticollis is sometimes described as being “acute” when it appears suddenly (e.g., atlantooccipital subluxation) or has a short history (e.g., cervical lymphadenitis/abscess). In common parlance, “wry neck” is often used to describe rapid onset torticollis due to spasm of cervical muscles from minor trauma or adjacent inflammation, which is a more common cause in older children. “Chronic” is used to denote torticollis that is persistent (e.g., an unresolved sternomastoid tumor) or long-standing (e.g., caused by cervical hemivertebrae). These terms are not widely used but may sometimes serve a useful purpose.

4

Torticollis

33

Differential Diagnosis of Torticollis A range of conditions can produce torticollis in children: these are summarized in Table 1. In practice, the challenge is to distinguish sternomastoid tumor from other causes of torticollis, as a confident clinical diagnosis of sternomastoid fibrosis with muscle shortening means that unnecessary investigations can be avoided. The critical clinical feature that distinguishes sternomastoid tumor and sternomastoid fibrosis from the wide variety of other causes of torticollis is demonstration that the sternomastoid muscle is actually very tight and shortened and cannot lengthen adequately (Table 2). The muscle may feel hard and tight throughout its length or have a more localized and prominent swelling involving the middle or lower part of it, the so-called “sternomastoid tumor.” Either way, the muscle is clearly tight and short, and this usually restricts the range of movement of the head. Interpretation of the clinical features is made easier by an understanding of the anatomy of the sternomastoid muscle itself. The normal

Table 1 Causes of torticollis in infants and children Cause Sternomastoid tumor Abnormal position in utero Strabismus Cervical spine abnormalities Cervical lymphadenitis/ abscess Retropharyngeal abscess Posterior fossa tumors Acute atlanto-axial subluxation Atlantoaxial rotatory subluxation Spasmodic Postural

Comment Common; appears at 3 weeks of age Tends to improve with age Check eye movements Structural; confirmed on plain radiography Usually occurs in first 2 years of life

sternomastoid muscle has a complicated action as a result of it being attached to the manubrium of the sternum and medial end of the clavicle at one end, but being attached much more posteriorly and laterally, on the mastoid process and superior nuchal line of the occipital bone at the other (Fig. 2). Tightness and shortening reduces the distance between its medial and anterior origin to its more lateral and posterior insertion. Predictably then, contraction and shortening of the muscle causes the head to be flexed to the affected side and rotated to the contralateral shoulder: this demonstration of this feature is crucial in making the diagnosis (Fig. 3). There are a number of conditions in which the sternomastoid muscle clearly is not tight or shortened. Cervical hemivertebrae, cervical segmentation anomalies, and other structural abnormalities of the cervical spine do not cause any pain or other symptoms (other than the actual deformity of the cervical spine itself) (Figs. 4 and 5). The cervical bony deformity may be evident from birth on direct inspection, palpation of the dorsal cervical spines, and confirmed on plain radiology, CT scan, or MRI. Torticollis from intrauterine positioning is most pronounced at birth but resolves quite quickly thereafter: there is no shortening or tumor of the sternomastoid muscle, and no underlying bony defect, but there may be other features of intrauterine compression. Atlanto-occipital subluxation may be seen after tonsillectomy (Fig. 6), but its relationship to the surgery betrays the diagnosis, and again there is no tightness of the sternomastoid muscles. Atlanto-axial rotator subluxation (Grisel’s syndrome) is a nontraumatic subluxation of the atlanto-axial joint caused by inflammation of the

Acute; signs of toxicity Also cervical spinal cord tumors. Rare cause; look for neurologic signs May occur after tonsillectomy Diagnosed on dynamic CT Sandifer’s syndrome with gastroesophageal reflux Familial

Table 2 Critical points in the approach to assessing a child with torticollis In sternomastoid tumor/fibrosis, the muscle is tight, shortened and prominent, and restricts head movement The key discriminating clinical feature in the assessment of torticollis in infancy and childhood is whether the sternomastoid muscle is tight Where there is no prominence and tightness of the sternomastoid muscle another cause for the torticollis must be found

34

S. W. Beasley

Fig. 2 Anatomy of the right sternomastoid tumor

adjacent tissues (Goel 2019). Progressive cervical pain and neck stiffness can be followed by pain or numbness radiating to the arms (radiculopathies) (Bocciolini et al. 2005). It is a rare consequence of soft upper respiratory tract infections, and peritonsillar or retropharyngeal abscesses. It may occur after adenoidectomy, especially in children with Down syndrome, because of their inherently lax ligaments. The diagnosis is confirmed on plain Xrays and CT scan. Strabismus can cause head tilt as the toddler tries to compensate for the ocular imbalance (Fig. 7). The squint may become more apparent by straightening the head passively and can be confirmed by checking eye movements. Any child with head tilt suspected of being due to a squint should be referred at presentation for further assessment by a pediatric ophthalmologist. Surgical correction of congenital fourth cranial nerve palsy involves relatively straightforward repositioning of 1–2 extraocular muscles in most

cases. This corrects the child’s vertical diplopia, enabling binocular vision without the need for an abnormal head position. Surgery is effective at any age and is ideal from around 6 months. The torticollis then dramatically improves or resolves in the majority of cases. Posterior fossa tumors can compress the brain stem at the foramen magnum to produce acute stiffness of the neck. Usually the presence of the intracranial tumor is already known but rarely the torticollis can be its first symptom. Other signs including impairment of the lower cranial nerves and cerebellar function may be evident (Koumanidis et al. 2006). Prompt referral to the regional pediatric oncology service (which includes pediatric neurosurgery) is indicated. Unilateral inflammation of the neck can also produce head tilt from spasm of surrounding muscles, including the sternomastoid. The torticollis is of recent onset and there is usually pain and other features of inflammation.

4

Torticollis

35

Fig. 3 Upper row: normal anatomy. Lower row: contraction and shortening of the right sternomastoid muscle causes the head to be flexed to the affected side (right) and rotated to the contralateral shoulder

Torticollis Due to a Tight Sternomastoid Muscle (Congenital Torticollis, Sternomastoid Tumor, Sternomastoid Fibrosis) In sternomastoid fibrosis the muscle either is thickened and tight throughout its length or has a painless hard swelling (sternomastoid tumor) localized to one part of it. It is the most common cause of torticollis in infancy.

Incidence Sternomastoid tumors occur in approximately 0.4–2% of all newborns (Cheng et al. 2000; Do 2006). It is right sided in about 60% (Lin and Chou 1997) and bilateral in 2–8%, (Tufano et al. 1999; Thomsen and Koltai 1989). The majority of cases present at 3 weeks of age, although a few

patients first present and are diagnosed beyond a year of age.

Etiology The etiology of sternomastoid fibrosis is not well understood: possible causes include fetal malposition (Dunn 1973), birth trauma, intrauterine embryopathy, intrauterine sternomastoid compartment syndrome, and heredity (Beasley 2012; Davids et al. 1993). The etiology may be different in different infants. It is associated with a 20–30% incidence of forceps deliveries, and some form of obstetric difficulty occurs in 60% (Davids et al. 1993), but whether this is the cause or the result of the condition is argued. Recently, Kim et al. reported that 17% of congenital muscular torticollis patients presented in the breech

36

presentation, which is a much higher rate than that observed in the general population (3–4%) (Kim et al. 2019). The high incidence of breech

S. W. Beasley

deliveries might be a secondary effect of the limitation of head movement, although this would not explain why it is virtually never diagnosed before the third week of life.

Pathology

Fig. 4 Multiple cervical vertebral abnormalities causing torticollis

Fig. 5 This patient has a segmentation anomaly involving congenital vertebral fusions at C6/7. The plain film shows the disc space to be markedly narrowed, and on MRI it

There is some evidence that sternomastoid fibrosis may commence before birth, based on the appearance and maturity of the fibrous tissue. If this is so, it may account for the increased frequency of obstetric difficulty during delivery. The high incidence of breech deliveries may be because restricted head movement impedes the ability of the head to engage in the maternal pelvis. Endomysial fibrosis involving the deposition of collagen and fibroblasts around individual muscle fibers that then undergo atrophy has been observed (Jones 1967). The sarcoplasmic nuclei are compacted to form multinucleated giant cells. In older children, the histological features are consistent with disuse atrophy as a consequence of the limitation in movement caused by the tight muscle.

appears as just a black line, rather than the expected white of a normal intervertebral disc signal

4

Torticollis

37

Fig. 6 Torticollis caused by atlanto-occipital subluxation after tonsillectomy. Notice that there is no tightness of the sternomastoid muscle on either side. (From Beasley SWet al.: Pediatric Diagnosis. London, Chapman & Hall, 1994)

Natural History The mass usually increases in size until 1 month of age, remains static for 2–3 months, then gradually diminishes in size and disappears clinically within about a year in about 90% of cases. Even by 6 months, there is complete resolution in 50–70%. However, the resulting fibrosis of the sternocleidomastoid muscle may lead to a persistent torticollis in 10–20% of cases (Dunn 1973) and many of these will require surgical correction. Various classifications have been proposed to provide some prognostic indication of which lesions are more likely to resolve completely. In general, lesions localized to one part of the muscle, either clinically or on ultrasonography, are more likely to resolve completely than those involving the entire length of the muscle.

Clinical Features (See Table 3) Early It is with remarkable consistency that infants with sternomastoid tumors present in the third week of life. Typically, the parents first notice a lump on one side of the neck (Fig. 1), and subsequently become aware that the infant seems unable to turn the head to the affected side. There is a clear

Fig. 7 This child has a congenital left eye fourth nerve palsy with marked torticollis and head tilt to the left. The left eye is higher than the right. A vertical strabismus is the principle sign to elicit where a fourth cranial nerve palsy causing head tilt is suspected. (Photo courtesy A Bedggood with permission from parents)

preference for the baby to sleep with the head turned to the contralateral side. A history of breech presentation and a difficult labor is common. There is normally no family history. Clinical examination should include assessment of the following: 1. There is a hard, painless, yet discrete, spindleshaped lump within the body of one sternomastoid muscle in about 2/3 cases. The lump is about 1–3 cm in diameter. There are no signs of inflammation. In the other third, the whole muscle is prominent and hard, like a tight bow-string (Fig. 3). For this reason, the whole length of the sternomastoid muscle must be palpated. It should be recognized that sometimes in small infants in whom the neck is relatively short, the muscle may not be that easy to assess or compare with the other side. 2. Observation of the resting position of head: head tilt with lateral flexion to the affected side, and rotation of the head to the contralateral side.

38

S. W. Beasley

3. Assessment of range of head and neck movement: this involves assessment of both rotation and lateral flexion, but of the two, rotation is

Table 3 Key clinical features of torticollis due to sternomastoid shortening Infant

Older child

Hard painless lump in mid or lower third of sternomastoid muscle Tight shortened sternomastoid muscle Ipsilateral lateral flexion and rotation of head to contralateral side Limitation of head rotation to affected side Plagiocephaly Hemifacial hypoplasia Prominent tight sternomastoid muscle Elevation of ipsilateral shoulder Wasting of ipsilateral trapezius muscle Compensatory scoliosis Twisting of neck to keep eyes pointing forwards Hemifacial hypoplasia

Fig. 8 Restriction of rotation of the head secondary to shortening of the right sternomastoid muscle as viewed from above the head. The right sternomastoid muscle is

the more useful. Rotation is best assessed by placing the infant across-ways on the examining table and standing behind the head. The head is rotated in both directions passively, by controlling it between the examiner’s hands (Fig. 8). Changes in the range of movement can be used to monitor progress with time by recording the angle reached at the limit of movement. Lateral flexion is assessed by flexing the head laterally in each direction but is probably not accurate enough to reliably gauge change and can sometimes be difficult to demonstrate given the shortness of the infant’s neck. 4. Plagiocephaly, a deformation in which there is asymmetry of the head, reflects the effect of gravity on head shape of the infant: if the infant lies with the head facing in one direction repeatedly and for prolonged periods, the soft bones and unfused sutures of the skull are molded by the force of gravity against the surface on which the head lies. It has a predictable pattern (Fig. 9)

shortened: this inability to lengthen, limits rotation to the right. The head can be turned to the left easily

4

Torticollis

39

and is best observed looking down on the head from above. For example, when the head has been continuously turned to the left, the left occiput is flattened from direct pressure, and there is a corresponding flattening of the right frontal bone. It may give the false impression of one ear being forward of the other. Once the child is positioned in ways that more evenly distribute the pressure, the plagiocephaly tends to improve. And once walking, it tends to improve further; but as the child continues to grow, the malleability of the skull diminishes, so complete restoration of symmetry is unlikely. 5. Hemifacial hypoplasia: as the child grows, the immobility caused by restriction of head movement affects facial growth. There is progressive asymmetry of the face involving the mandible and maxilla, an illustration of an important principle in pediatrics: normal growth of the bones depends on normal muscular movement (Hutson and Beasley 2013). The hypoplasia can be demonstrated by comparing the plane of the lines between the eyes with that of the plane between the angles of the mouth (Fig. 10).

Late Presentation It is often assumed that children who present beyond infancy have had an unnoticed sternomastoid tumor as a baby, but that it has failed to resolve spontaneously, and only later recognized. The history is not always so clear: It may be that many of these children have a progressive fibrosis, called fibromatosis colli – in some respects, this has similarities to Dupuytren contracture and plantar fibromatosis. These children present with an elevated shoulder (to correct the lateral flexion that would otherwise occur), some wasting of the ipsilateral trapezius muscle (from disuse), compensatory scoliosis, and little or no head tilt (Figs. 11 and 12). This is because they try to keep their eyes horizontal – an important adaption once walking has commenced, given that the eyes are designed to be able to scan the horizon easily. The tight sternomastoid muscle is very prominent, like a tight band, and this confirms the diagnosis.

Fig. 9 Plagiocephaly. If the normal infantile skull is positioned the same way for prolonged periods (middle image) the bones flatten from the effects of pressure and gravity which appears as asymetry (lower image)

There may be hemifacial hypoplasia, secondary to the effects of the limitation of cervical movement over an extended period (Table 4).

Confirmation of Diagnosis No further investigation is required if the child clearly has a sternomastoid tumor or a prominent, tight, and shortened sternomastoid

40

muscle. However, even though ultrasonography is not required for diagnosis, it is sometimes obtained because the ultrasonographic appearance of sternomastoid fibrosis is used by some clinicians to predict the likelihood of spontaneous resolution (Dudkiewicz et al. 2005; Lin and

S. W. Beasley

Chou 1997). Torticollis can also be diagnosed on magnetic resonance imaging (MRI) (McGuire et al. 2002) and computed tomography (CT scan) (Parikh et al. 2004), but neither imaging modality is indicated as a routine. If the muscle is neither prominent nor shortened, the torticollis is assumed not to be caused by an abnormality of the sternomastoid muscle, and alternative diagnoses must be sought (see Table 1); and for these patients, the likely diagnosis determines the investigation required.

Treatment

Fig. 10 Facial hemihypoplasia on the right side in a child with unresolved shortening of the right sternomastoid muscle. The left side of the face has not grown at the same pace as the right

Fig. 11 Appearance of torticollis as a result of sternomastoid fibrosis in an older child. The eyes are kept horizontal, but the shortened sternomastoid muscle causes compensatory elevation of the shoulder. (Modified from Beasley SW et al.: Pediatric Diagnosis. London, Chapman & Hall, 1994)

Initial management is conservative. This is justified because even with no treatment about 90% resolve by 1 year of age. Despite there being little evidence that any measures significantly alter the natural history of the condition (Wright 1994), many clinicians still advise regular passive exercises to stretch the tight sternomastoid muscle in the belief that it contributes to the high rate of resolution (Cheng et al. 2001b; Tatli et al. 2006). It may have some benefit in the first year of life (Celayir 2000) and there is some evidence it may speed up the resolution of torticollis by several months (Din et al. 2003), thus shortening the time of restricted range of movement. The principle behind stretching exercises is to gently but firmly lengthen the muscle. This is done by a combination of flexion of the head to the contralateral

4

Torticollis

41 Table 5 Physiotherapy in torticollis due to a tight sternomastoid muscle Purpose of physiotherapy Reduce severity of plagiocephaly Reduce time before range of head movement restored Provide advice and reassurance to parents Positioning and postural advice to parents Position in cot with head facing affected side Hold in way that encourages head to be turned to affected side Place toys in position to encourage head to be turned to affected side Passive stretching of affected sternomastoid muscle Rotation in each direction Lateral flexion in each direction

Fig. 12 In an attempt to keep the eyes horizontal, there is compensatory elevation of the shoulder on the side of the tight sternomastoid muscle Table 4 Consequences of torticollis Infant

Older child

Plagiocephaly Hemifacial hypoplasia Parental anxiety Hemifacial hypoplasia Limitation in range of head movement affecting activities Social implications, self-esteem

side, and rotation of the chin to the affected side. Both these maneuvers effectively lengthen the sternomastoid muscle. Excessive force has been reported to cause unintentional rupture of the tendon, although this probably does not affect the long-term outcome (Cheng et al. 2001a). Conventional physiotherapy for sternomastoid tumors is summarized in Table 5. Physiotherapy and regular neck exercises appear to be safe and help make the parents feel that “something is being done” for their infant. Careful positioning of the head may also reduce the degree of secondary plagiocephaly that occurs. Plagiocephaly is a consequence of the severe restriction in the range of head movement that forces the infant to consistently hold the head turned to one side. Therefore, any measures which ensure the head is resting on a different part of the skull when the infant sleeps will prevent the deformity progressing.

Treatments not indicated: excessively forceful stretching of tendon, heat therapy, neck collars, botulinum toxin

Table 6 Indications for surgery 1. 2.

3.

Persistent sternomastoid tightness limiting head rotation beyond 12–15 months of age Persistent sternomastoid tightness with progressive facial hemihypoplasia and worsening plagiocephaly First presentation in children older than 1 year

Direct injection of Botulinum toxin type A into the sternomastoid muscle achieves little improvement (Collins and Jankovic 2006). Naturopathy, osteopathy, heat therapies, collars and chiropractic manipulation have no place in the treatment of sternomastoid fibrosis. Chiropractic manipulation is recognized as a cause of atlantoaxial rotatory subluxation in children (Kao et al. 2013).

Surgery Surgery is indicated where torticollis does not resolve spontaneously, and for older children who present late with a tight muscle with restricted head movements and who exhibit the secondary effects of prolonged torticollis (Table 6). Over the years, a variety of operative procedures have been described, although the best results appear to be achieved by low division of the sternomastoid muscle (Table 7). The standard

42

S. W. Beasley

Table 7 Surgical release of shortened sternomastoid muscle Anaesthesia General, with laryngeal mask or endotracheal intubation Anaesthesia Position Incision

Approach

Division sternomastoid Potential danger Closure Alternative procedures

Complications

Genral, with laryngeal mask or endotracheal intubatione Supine, with shoulders elevated and head turned to contralateral side 3–4 cm skin crease incision about 1 cm about the clavicle, overlying the sternal and clavicular heads of the muscle Division of platysma with monopolar diathermy dissection in the line of incision Division of both heads with diathermy, and release of cervical fascia across posterior triangle of neck Injury to the accessory nerve Platysma and skin closure, local anesthetic infiltration. No drain Division at its upper end, at both ends, or in its midportion endoscopic tenotomy of the muscle (Sasaki et al. 2000) Hematoma, incomplete division of tendon, recurrence

surgical approach has been through an open incision, but endoscopic tenotomy has also been described (Sasaki et al. 2000). A skin crease incision is made about 1 cm above the sternal and clavicular heads of the affected sternomastoid and the subcutaneous tissue and platysma divided in the line of the incision. The external jugular vein and other veins can be retracted. The two heads of the sternomastoid muscle are divided with diathermy. The investing cervical fascia, anterior and posterior to the muscle, must also be divided. The tight cervical fascia between the sternomastoid and trapezius is usually palpable and should be divided under direct vision to avoid damage to other structures, particularly the accessory nerve and branchial plexus. The wound is infiltrated with bupivacaine or another local anesthetic agent before the platysma and skin are closed with absorbable sutures. No drain is required if the operative field is dry. Full range of movement of the neck is normally achieved within 1 week of surgery, except in older children with long-standing torticollis: For these

patients, physiotherapy is usually offered postoperatively. The final cosmetic appearance in older children is less certain.

Complications of Surgery Postoperative bleeding is rare. Incomplete division of both heads of the sternocleidomastoid muscle or failure to divide the cervical fascia over the posterior triangle of the neck may result in persistent torticollis. Careful inspection and palpation of the neck for residual tightness and bands at the time of surgery should prevent this complication from occurring (Beasley 2012). Recurrent torticollis is seen in fewer than 3% of patients.

Outcome Measures After Surgery Key outcome measures after surgery include: 1. The torticollis has resolved completely. 2. There is full range of movement of the head and neck. 3. The sternomastoid muscle feels normal. Plagiocephaly tends to improve after release of the tendon and restoration of full head movements, but is unlikely to completely resolve. Hemifacial hypoplasia will tend to become less obvious with further growth. In an older child, secondary scoliosis and elevation of the shoulder may persist for several years.

Conclusion and Future Directions The most common cause of torticollis in infants is a shortened and tight sternomastoid muscle, which is referred to as a sternomastoid tumor or sternomastoid fibrosis, depending on its exact clinical characteristics. Clinical demonstration of a tight shortened muscle restricting head movement is diagnostic. This is a benign condition which usually resolves without treatment. Occasionally, surgery is required if it persists beyond a

4

Torticollis

year, particularly if it is producing secondary effects: plagiocephaly and hemifacial hypoplasia. Absence of a tight sternomastoid muscle suggests an alternative cause, of which there are many. The etiology is yet to be established. The paucity of quality clinical studies means that the influence of various treatment regimens on the natural history remains uncertain.

Cross-References ▶ Gastroesophageal Reflux and Hiatal Hernia ▶ Soft Tissue Trauma

References Beasley SW. Torticollis. In: Coran AG, Adzick NS, Krummel TM, Laberge J-M, Shamberger RC, Caldamone AA, editors. Pediatric surgery. 7th ed. Elsevier Saunders; 2012. p. 763–7. Bocciolini C, Dall’Olio D, Cunsolo E, Cavazzuti PP, Laudadio P. Grisel’s syndrome: a rare complication following adenoidectomy. Acta Otorhinolaryngol Ital. 2005;25:245–9. Celayir AC. Congenital muscular torticollis: early and intensive treatment is critical. A prospective study. Pediatr Int. 2000;42:504–7. Cheng JC, Tang SP, Chen TM, Wong MW, Wong EM. The clinical presentation and outcome of treatment of congenital muscular torticollis in infants: a study of 1,086 cases. J Pediatr Surg. 2000;35:1091–6. Cheng JC, Chen TM, Tang SP, et al. Snapping during manual stretching in congenital muscular torticollis. Clin Orthop. 2001a;384:237. Cheng JC, Wong MW, Tang SP, et al. Clinical determinants of the outcome of manual stretching in the treatment of congenital muscular torticollis in infants. A prospective study of eight hundred and twenty-one cases. J Bone Joint Surg Am. 2001b;83-A(5):679–87. Collins A, Jankovic J. Botulinum toxin injection for congenital muscular torticollis presenting in children and adults. Neurology. 2006;67(6):1083–5. Davids JR, Wenger DR, Mubarak SJ. Congenital muscular torticollis: sequelae of intrauterine or perinatal compartment syndrome. J Pediatr Orth. 1993;13:141. Din IU, Rahman F, Rahman IU. The role of physiotherapy in the management of sternocleidomastoid torticollis. Pediatr Surg Int. 2003;19:699. https://doi.org/10.1007/ s00383-002-0930-0.

43 Do TT. Congenital muscular torticollis: current concepts and review of treatment. Curr Opin Pediatr. 2006;18:26–9. Dudkiewicz I, Ganel A, Blankstein A. Congenital muscular torticollis in infants: ultrasound-assisted diagnosis and evaluation. J Pediatr Orthop. 2005;25:812–4. Dunn PM. Congenital sternomastoid torticollis: an intrauterine postural deformity. J Bone Joint Surg Br. 1973;55:877. Goel A. Torticollis and rotatory atlantoaxial dislocation: a clinical review. J Craniovertebr Junction Spine. 2019 Apr-Jun;10(2):77–87. Hutson JM, Beasley SW. The surgical examination of children. 2nd ed. Heidelberg: Springer; 2013. p. 101–7. Jones PG. Torticollis in infancy and childhood. Springfield: Charles C Thomas; 1967. Kao Y, Hsu S-K, Chang C-J, Hsieh C-T. Pediatric atlantoaxial rotation subluxation after minor trauma and chiropractic manipulation Fu-Jen. J Med. 2013;11:53–7. Kim SM, Cha B, Jeong KS, et al. Clinical factors in patients with congenital muscular torticollis treated with surgical resection. Arch Plast Surg. 2019 Sep;46(5):414–20. Koumanidis S, Per H, Gismos H, et al. Torticollis secondary to posterior fossa and cervical spine cord tumours: report of five cases and literature review. Neurosurg Rev. 2006;29:333–8. Lin JN, Chou ML. Ultrasonographic study of the sternocleidomastoid muscle in the management of congenital muscular torticollis. J Pediatr Surg. 1997;32:1648. McGuire KJ, Silber J, Flynn JM, et al. Torticollis in children: can dynamic computed tomography help determine severity and treatment. J Pediatr Orthop. 2002;22:766. Parikh SN, Crawford AH, Choudhury S. Magnetic resonance imaging in the evaluation of infantile torticollis. Orthopedics. 2004;27:509–15. Sasaki S, Yamamoto Y, Sugihara T, Kawashima K, Nohira K. Endoscopic tenotomy of the sternocleidomastoid muscle: new method for surgical correction of muscular torticollis. Plast Reconstr Surg. Apr 2000;105(5):1764–7. Tatli B, Aydinli N, Caliskan M, et al. Congenital muscular torticollis: evaluation and classification. Pediatr Neurol. 2006;34:41–4. Thomsen JR, Koltai PJ. Sternomastoid tumour of infancy. Ann Otol Rhinol Laryngol. 1989;98:955. Tufano RP, Tom LW, Austin MB. Bilateral sternocleidomastoid tumors of infancy. Int J Pediatr Otorhinolaryngol. 1999;51:41. Wright JE. Sternomastoid tumour and torticollis in infancy and childhood. Pediatr Surg Int. 1994;9:172.

Part II General: Chest

5

Gastroesophageal Reflux and Hiatal Hernia Michael E. Höllwarth and Erich Sorantin

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 The Normal Esophagus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Innervation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Peristalsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lower Esophageal Sphincter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reflux . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Upper Esophageal Sphincter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

49 49 49 49 50 50 51

Diagnosis of Reflux . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Esophageal Passage on the X-ray . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Twenty-Four-Hour pH-Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Combined Impedance Measurement/pH-Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Manometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endoscopy and Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Nuclear Medicine Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

51 51 53 53 54 55 56

Development of Esophageal Function in Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Pathological Reflux and Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Newborns and Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

M. E. Höllwarth (*) Department of Paediatric and Adolescent Surgery, Medical University of Graz, Graz, Austria e-mail: [email protected]; [email protected] E. Sorantin Department of Pediatric Radiology, Medical University of Graz, Graz, Austria e-mail: [email protected] © Springer-Verlag GmbH Germany, part of Springer Nature 2021 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43559-5_95

47

48

M. E. Höllwarth and E. Sorantin Treatment of GERD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Conservative Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Drug Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Surgical Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fundoplication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Complications of Fundoplication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Surgical Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

60 60 61 62

Barrett’s Esophagus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 Associated Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laryngopharyngeal Reflux . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reflux-Associated Respiratory Tract Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reflux and Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reflux and Apnea Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

64 64 64 64 65

Eosinophilic Esophagitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Hiatus Hernia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Axial Hiatus Hernia (Fig. 12) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Para-esophageal Hiatal Hernia (Fig. 13) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Abstract

Gastroesophageal reflux, caused by transient relaxation of the lower esophageal sphincter, is the term used to describe the backflow of gastric content into the esophagus. Pathological reflux disease is a situation in which reflux causes major symptoms and complications such as failure to thrive, disturbances of sleep, recurrent aspiration and cough predominantly in young infants and epigastric pain, esophagitis, stenosis, or Barrett’s esophagus in older children. A variety of diagnostic investigations are necessary to evaluate the extent and consequences of pathological reflux. Conservative management with different medications is widely used. However, in children with chronic gastroesophageal disease, surgical therapy by fundoplication is the treatment of choice. Keywords

Gastroesophageal reflux · Esophagitis · Barrett’s esophagus · Fundoplication · Hiatus hernia · Eosinophilic esophagitis · Sandifer syndrome

Introduction Gastroesophageal reflux (GER) is a physiological phenomenon. It occurs in persons of all age groups and more frequently after the ingestion of liquid food (soup) or other fluids (soft drinks, coffee, alcohol, etc.). A pathological reflux or gastroesophageal reflux disease (GERD) is considered to exist when the number and/or duration of reflux events exceeds normal ranges. The incidence of GERD in the population is difficult to determine, because the majority of refluxes are asymptomatic. The disease becomes clinically evident only when complications and their accompanying symptoms occur. Epidemiologic data in adults show that approximately 20% of the Western population is affected, and GERD is now the most common gastrointestinal disorder in the Western world (Dent et al. 2005). In an Italian study, 12% of more than 2000 infants (less than 1 year old) had clinical symptoms of reflux, but only 1 of 210 infants older than 24 months of age developed reflux disease (Vandenplas et al. 1991; Campanozzi et al. 2009). The significance of gastroesophageal reflux or reflux disease is reflected by 300–400 publications each year on the subject, focused

5

Gastroesophageal Reflux and Hiatal Hernia

49

on diagnostic and therapeutic aspects. In the following, we discuss the normal function of the esophagus; the development of esophageal function in newborns and infants; symptoms, investigation methods in patients with pathological reflux; therapeutic options and complications of reflux disease; and its potential late sequelae.

The Normal Esophagus Anatomy The esophagus is a muscular tubular organ in the dorsal mediastinum, responsible for transporting food from the mouth or the pharynx into the stomach. The esophagus is about 8 cm long in the newborn infant and about 25 cm long in the adult. Striated muscles are found in the upper half of the esophagus and smooth muscles in the lower half. The lumen covers a non-keratinizing multilayered squamous epithelium with a papillary type of basal layer. The transition to the single-layered columnar epithelium of the cardia is seen on endoscopy as an irregular line, the socalled Z-line, which partly extends in tonguelike fashion into the esophagus and, in terms of its location, often does not exactly correspond with the anatomical barrier of the lower esophageal sphincter. Within the diaphragmatic hiatus, the esophagus is fixed to the diaphragm by the phrenicoesophageal membrane. While the medial wall of the esophagus continues directly into the lesser curvature of the stomach, a type of incisure arises on the lateral circumference in the direction of the fundus – the so-called angle of His. The latter tends to be flat on the X-ray of a newborn – because of the inferior position of the diaphragm, but in adults, it is clearly sharp-angled. At this site, there is a mucosal fold within the gastric lumen (the flutter valve), which is pressed passively against the esophagus when the gastric fundus is filled, and thus prevents reflux (Fig. 1) (Edwards 1982). The flatter the angle of His, the less developed the mucosal valve mechanism; reflux can occur more easily in this setting.

Fig. 1 Typical mucosal “flutter valve” at the site of the His angle within the stomach (arrow). Opposite one can see a part of the cardia epithelia (star)

Innervation Parasympathetic innervation of the esophagus is achieved by the vagus nerve, which courses along the esophagus and sends its fibers to the latter. Sympathetic innervation is achieved by postganglionic neurons of the sympathetic trunk. The myenteric plexus and the submucosal plexus contain non-adrenergic and non-cholinergic nerves and initiate the complex activity of the esophagus through a number of neurotransmitters. Central regulation is achieved in the deglutition center located in the brainstem and core areas of peristalsis connected in a serial fashion. In infants with central sleep apnea and in cerebral disabled patients, disorders in the central coordination of motor functions of the esophagus play a major role in the etiology of reflux.

Peristalsis Once food enters the esophagus, it is passed on to the stomach by means of an orderly propulsive peristaltic wave (pressure between 60 and 100 mmHg, velocity 2–4 cm/s) (primary peristalsis; Fig. 2). After localized distension of the esophagus, as happens during reflux of gastric content, a propulsive peristaltic wave is generated locally that returns the refluxed volume back to the stomach (secondary peristalsis). Isolated and disorderly non-propulsive contractions are described as “tertiary peristalsis” or “pathological contractions.”

50

M. E. Höllwarth and E. Sorantin

Lower Esophageal Sphincter Backward flow of the contents of the stomach into the esophagus is prevented by the lower esophageal sphincter (LES). The LES pressure is between 12 and 15 or 25 mmHg, not only in adults but also in neonates and infants. The length of the LES in the newborn is about 1.0 cm; in the adult, it is about 2.5–3.5 cm (Table 1) (Höllwarth 1979; Höllwarth et al.

1986; Omari et al. 2002). While the pressure zone can easily be demonstrated by manometry, a special anatomical technique of preparation is required to detect thickening of the sphincter muscle at the esophagogastric transition (Liebermann-Meffert et al. 1979). On manometry, the pressure zone makes it easy to exactly determine the position of the LES – and thus the position of the lower end of the esophagus. The LES lies exactly within the esophageal hiatus, and the lower portion of the pressure zone is attributed to the abdominal pressure region while the upper portion is assigned to the chest pressure cavity (Fig. 3). The frequently described condition of an abdominal esophagus does clearly not exist in a normal person. The diaphragmatic pinch within the hiatus also contributes to the overall tone of the esophagogastric junction. It can be distinguished by manometry in cases of a fixed hiatal hernia.

Reflux

Fig. 2 Primary propulsive peristalsis after swallowing. One single irregular tertiary contraction in the distal esophagus (Höllwarth 2009)

An essential characteristic of the LES is that its tone becomes relaxed by propulsive peristalsis when food enters the esophagus. Even in a healthy person, and even without any other motor activity in the esophagus, spontaneous relaxations occur regularly and persist for 5–10 s (transient sphincter relaxation) (Mittal and Balaban 1997). Nitric oxide is involved in the timing of human esophageal peristalsis and is one of the neurotransmitters involved in the reflex arc mediating the triggering of transient LES relaxations (Hirsch et al. 1998). Physically,

Table 1 Results of esophageal manometry: the LES pressure values in newborn babies and infants are already normal. PS is the response of propulsive peristaltic waves in the esophagus after 10 induced swallows. The results

show that the response is significantly lower within the first 10 days of life, but thereafter it is normal with nearly 8 propulsive responses out of 10 induced swallows (Höllwarth and Uray 1985)

n Prematures (GA 30–36) Newborns Newborns Infants 

p < 0.05

7 24 19 20

Age (d) 7–28 1–10 11–28 >28

LES-tone (mm HG) x  SD

LES-length (mm) x  SD

23.0  3.6 20.4  8.0 21.8  10.0 18.0  7.0

1.0  1.1 10.7  0.8 11.0  0.5 11.3  1.1

PS (n = 10) – 5.2 7.3 7.9

5

Gastroesophageal Reflux and Hiatal Hernia

51

relaxations as well as the acid clearance time rise significantly in a person GERD, as will be described later on.

Upper Esophageal Sphincter Pressure values in the upper esophageal sphincter (UES; 40–80 mmHg) are much higher than those in the LES, which indicates that reflux into the esophagus may occur more easily than reflux into the pharynx or the oral cavity. The UES relaxes during the propulsion of food from the oral cavity, and strong contraction of the hypopharynx passes the bolus with great velocity into the esophagus. However, even when reflux approaches from below, the UES might relax and reflux can reach the hypopharynx, larynx, and eventually the mouth.

Fig. 3 Slow pull-through manometry through the LES in a newborn child. DU indicates the pressure inversion from a typical stomach tracing to a typical esophageal tracing. Thus, the DU is located within the diaphragmatic hiatus and one part of the LES belongs to the abdomen and the other part to the thorax. There is no other intra-abdominal esophagus (Höllwarth 2009)

this causes a shared space between the stomach and the esophagus, with the occurrence of a typical abdominal pressure curve in the esophagus on manometry, the “common cavity phenomenon” (Fig. 4) (Butterfield et al. 1972). Due to greater abdominal pressure on the one hand, and the thoracic suction effect during inspiration on the other, these spontaneous relaxations are usually accompanied by a reflux of the contents of the stomach and – depending on the pH of the contents of the stomach – to a drop, a rise, or no change in pH levels in the esophagus (Fig. 5). The refluxed volume is rapidly returned to the stomach by secondary propulsive peristalsis (volume clearance). However, the pH drop is neutralized in a stepwise manner by saliva during subsequent acts of swallowing (acid clearance) (Fig. 6). In contrast to a healthy person, the number and duration of spontaneous

Diagnosis of Reflux Esophageal Passage on the X-ray X-rays with contrast material are mainly used to investigate the morphology and peristaltic function of the esophagus. The primary benefits of an X-ray investigation include visualization of the esophagogastric junction or evidence of a sliding or fixed hiatal hernia, assessment of the angle of His, the presence of an orderly or pathological pharyngoesophageal act of swallowing, the course of esophageal peristalsis, and any irregularities of the epithelium as signs of inflammation. Evidence of aspiration of contrast medium during the investigation is another important finding. Actual evidence of reflux episodes, on the other hand, is of lesser significance because the duration of a barium esophagogram is short and an obvious reflux may occur or not occur during the few minutes of fluoroscopy. However, indirect signs of a GERD are several: frequent air reflux during the investigation, a positive water siphon test (reflux after drinking a large sip of water to provoke reflux), and in the case of a reflux events, it will be recorded to which height these refluxes reach in the esophagus (lower/middle/upper esophagus).

52 Fig. 4 Spontaneous pressure inversion of the esophageal tracing to an abdominal tracing indicates the opening of the LES due to a transient relaxation. This is the manometric sign of reflux – the “common cavity phenomenon” (CCP). It is always terminated by a secondary propulsive peristalsis pushing the refluxed volume back into the stomach (volume clearance) (Höllwarth 2009)

M. E. Höllwarth and E. Sorantin

Upper esophagus

Lower esophagus

Stomach

Respiration

Fig. 5 Common cavity phenomenon with reflux and simultaneous rise of the intraesophageal pH. This reflux cannot be detected with simple pH-monitoring

Upper esophagus

Lower esophagus

Stomach

Stomach

pH

Respiration

5

Gastroesophageal Reflux and Hiatal Hernia

53

can be correlated with the pH of the stomach, and the number of refluxes that reach the esophagus are analyzed (Semeniuk and Kaczmarski 2007). All drops in pH below 4 with a duration of at least 15 s (number of refluxes), the time taken for pH levels to normalize or rise back to pH 4 (reflux clearance), the number of refluxes with clearance time longer than 5 min, and the longest reflux time are analyzed. The type and the ingestion time of food as well as the length of time the person lies in supine position or is upright are also registered. Regrettably, laboratories use different cut-off values, which are partly influenced by standard values in adults (Table 2). The low threshold value of 3% in infants largely fed with milk takes the buffer effect of milk and the consequent lower numbers of acid refluxes (accompanied by a pH drop to below 4) into account. There is no doubt of the fact that 24-h pHmonitoring still is the most frequently used method to detect acid reflux. The weakness of the method, however, is that it does not demonstrate refluxes with neutral pH or mildly alkaline refluxes accompanied by a rise in pH.

Fig. 6 Common cavity phenomenon with reflux in the upper esophagus and pH drop 10

Fig. 7 Combined impedance and pHmonitoring. It shows a short reflux episode with a decrease of the pH in the esophagus and a small increase of the pH with the next swallow (Höllwarth 2009)

significantly related to MII baselines, although they did not correlate exactly with the endoscopic findings (van der Pol et al. 2013). However, the results of this study might have been influenced by the difficult macroscopic estimation of a grade of esophagitis, especially with lower grades. Recurrent cough due to microaspiration of nonacidic refluxes may play a significant role in respiratory tract infection and is a diagnostic domain of pH/MII (Blondeau et al. 2011). Furthermore, MII/pH results have an influence on the choice of medical treatment since it is possible to discriminate patients with primarily acid refluxes from those with nonacid refluxes needing a different neuromodular therapy (Jodorkovsky et al. 2014). Therefore, combined impedance measurement and pHmonitoring will probably soon replace pure pHmonitoring as the gold standard.

Manometry Manometric investigation of esophageal function was a diagnostic method introduced in the late 1960s, primarily to record the pressure in the LES. The general assumption at that time was that primarily a low LES pressure is the responsible factor to allow reflux. Initial manometric investigations in newborns and infants appeared to confirm that the LES pressure in this age group is extremely low. However, only when low-compliance perfusion pumps have been introduced, investigators were able to register relevant pressures values. As mentioned earlier, investigations in the 1970s already showed that normal LES pressures are present in neonates and infants (Höllwarth 1979). Furthermore, manometry is highly suitable to analyze the motor functions and peristalsis of the

5

Gastroesophageal Reflux and Hiatal Hernia

esophagus. Due to the longitudinal contraction of the esophagus during peristalsis, special sleeve devices have been developed for sphincter pressure measurement (Dent 1976). Manometry shows that reflux of gastric contents is rendered possible not due to low pressures but due to spontaneous transient relaxations of the LES. These occur much more often in patients with GERD and persist for a significantly longer time. These relaxations of the LES are the socalled “common cavity phenomenon” (CCP), because the manometry tracings in the thoracic esophagus are of the abdominal type and return to normal only after a secondary peristalsis and closure of the LES (Fig. 4) (Butterfield et al. 1972). The refluxed volume is returned to the stomach by secondary peristalsis, whereas the drop in pH is normalized in a stepwise manner by swallowing saliva. Simultaneous pH-monitoring permits demonstration of the pH of refluxes being nonacidic, neutral, or alkaline. Thus manometry allows the investigator to draw conclusions similar to those obtained by impedance measurement. However, the drawback of manometry is the fact that, in contrast to pH-monitoring and impedance investigation, it is motion dependent. It requires calm conditions. Therefore, it is not a suitable method for 24-h examinations.

Endoscopy and Histology Investigations with flexible fiberoptic endoscopes are part of the standard investigation of reflux disease. The device is introduced into the esophagus under direct vision, usually down to the duodenum. Biopsy specimens are taken from the duodenum and the antrum of the stomach. In the stomach, the tip of the device is inverted to view the esophagogastric junction from below. In normal cases, the device is closely encircled by the esophagus. At the lateral circumference, one sees the flap valve mentioned above (Fig. 1). In contrast, in a hiatal hernia, the diaphragmatic pinch is a little open and one obtains a clear upward view towards the higher positioned LES. By withdrawing the

55

device further, one is able to inspect the esophagogastric junction and the Z-line with the cardia monolayer epithelium more closely. The typical esophageal squamous epithelium is smooth and of milky red color (Grade 0). According to Savary-Miller, the grades in the presence of esophagitis are: Grade 1: single erosion or exudative lesion on only one longitudinal fold; Grade 2: multiple erosions on more than one longitudinal fold; Grade 3: circular erosion or exudative lesion; Grade 4: ulcers, strictures, or short esophagus; and Grade 5: Barrett’ epithelium (Ollyo et al. 1986). The more sophisticated Los Angeles Classification of the severity of reflux esophagitis can also be used in children; it describes four grades of mucosal damage, depending on the extension between mucosal folds (Genta et al. 2011). It must be emphasized that the macroscopic grading, especially with exudative lesions of the Grades 1 and 2, is affected by the impression of the observer and does often not well correlate with the histological results. Therefore, it is mandatory to take several biopsy specimens, starting 1–2 cm proximal to the Z-line and extending upward into the upper esophagus. It is advisable to place the biopsy specimens on a piece of cork, in appropriate direction, immediately after taking the specimen, and then inserting it in formalin. An optimal specimen consists of the entire layer of epithelium, including the basal cell layer. Thickening of the basal layer and relative elongation of the papilla (due to a thinner epithelial zone) are regarded as signs of greater cell turnover and pathological reflux. Evidence of intraepithelial eosinophils then confirms the presence of evident esophagitis, even in the absence of corresponding symptoms (Sherman et al. 2009). Erosions and ulcerations are, by their very nature, signs of severe chronic esophagitis. However, the latter is not always associated with unequivocal symptoms in children. The presence of more than 20 eosinophils per “high-power” field, on the other hand, is a sign of another non-reflux-related allergic or atopic disease, i.e., so-called eosinophilic esophagitis (Furuta et al. 2007).

56

Diagnostic Nuclear Medicine Investigations Scintigraphic investigation methods permit observation of the moving bolus through the esophagus, any aspiration of tracer into the lungs due to reflux, and measurement of gastric emptying time after standardized meals. The latter consist of a solid and a liquid portion, such as a meal consisting of egg and water. 99mTc sulfur colloid is used as tracer. The act of swallowing is visualized on dynamic sequences. After setting regions of interest (ROI), refluxes are registered and the mean gastric emptying rate is documented on a time/activity curve. Investigations after 24 h permit the detection of tracer in the lung, provided aspiration has occurred.

Development of Esophageal Function in Childhood Minimal spitting, flaccid flow, or vomiting of milk – as signs of frequent gastroesophageal reflux – are observed in approximately one-half of all newborns and young infants and are rightly deemed normal if the child’s development is otherwise uneventful and satisfying. As fluids cause frequent episodes of reflux even in adults, it is no surprise that the largely liquid diet in this phase of life may give rise to frequent reflux. The child’s subsequent development shows usually that these symptoms become rare after the first 4–6 months and are no longer observed at the end of 12 months. Switching to pulpy and later solid food obviously plays an important role in this development. As mentioned above, previously it was believed that frequent reflux in this early phase of life is caused by the absence or a very low tonus in the LES, and when these structures mature as the child develops, the enhanced LES tonus prevents reflux. In contrast, newborns and preterm infants have normal pressures (similar to those in adults) in the LES, and that reflux in this age group is not caused by the absence of tonus in the LES but by too frequent and prolonged transient relaxations in the LES (Höllwarth et al. 1986). As those frequent

M. E. Höllwarth and E. Sorantin

LES relaxations are often associated with a delay of normal propulsive peristalsis in the esophagus, reflux in this age group has been regarded as the consequence of a central delay in the development of motor coordination of the esophagus. An especially high incidence of reflux in infants with central apnea also indicates that immature central regulatory structures are responsible for frequent transient relaxations in this setting (Landler et al. 1990). Most infants experience an abatement of typical symptoms of reflux by the end of 12 months and also experience effective normalization of esophageal function as confirmed by 24-h pHmonitoring (Orenstein et al. 2006). However, the resolution of the clinical symptoms of reflux around the age of 1 year is not necessarily a sign of better function and spontaneous normalization of function may occur at the much later age of 3–5 years, evidenced by long-term follow-up pHmonitoring (Pesendorfer et al. 1993). The problem is that clinical signs of reflux after the age of 1 year are rare and mild and are therefore not given attention until several years later, when the late sequel of chronic pathological reflux become evident. Recent investigations in adults have shown that about one-half of young adults with GERD had marked symptoms in childhood (Martin et al. 2002; Gold 2006; El-Serag et al. 2007).

Pathological Reflux and Symptoms Gastroesophageal reflux disease (GERD) in children is different in several aspects from adults. In 2009, an International Consensus was published on the definition of GERD in the pediatric population (Sherman et al. 2009). The symptoms of GERD depend on the patient’s age.

Newborns and Infants In newborns and infants, reflux is a common phenomenon as long as they are fed mainly with liquid food. A moist pillow is a typical sign that reflux reached the mouth. However, GERD has to be suspected when the infant fails to thrive,

5

Gastroesophageal Reflux and Hiatal Hernia

57

Spitting and vomiting are common signs of reflux but become increasingly rare after the infantile age. This may mimic normalization of function. Typical symptoms include recurrent pain in the upper abdomen, but retrosternal burning, such as that known in adults, is very rare in children. Intolerance of acid or sweet food, a sour mouth odor, gurgling sounds in the chest after eating, recurrent respiratory

tract infection, and hoarseness are further characteristic symptoms (Chang et al. 2006; Semeniuk and Kaczmarski 2007). Asthmatic symptoms may also be caused by chronic microaspiration. A very rare but characteristic symptom of reflux is the Sandifer syndrome, which is accompanied by recurrent tic-like sideways inclination of the head to the left; this may be interpreted as support of passive prevention of reflux (Lee et al. 1999). The primary complication of gastroesophageal reflux is esophagitis, which is caused by frequent and excessively long relaxations of the LES with chronic acid exposure of the esophagus. The resulting inflammation leads to microhemorrhage of mucous membranes and, in chronic cases, hemorrhagic anemia. A significant aspect of the subsequent course of the disease is the fact that inflammation of the esophagus sets a vicious circle into motion, characterized by a disturbance of secondary peristalsis and consequent prolongation of acid clearance. Furthermore, the inflammation causes more numerous relaxations of the LES due to reflux. Subsequently the inflammation spreads to deeper layers of the wall, eventually leading to stenosis because of simultaneous scar formation (Fig. 9).

Fig. 8 Combined manometric study and pH-monitoring after a typical milk meal in a 4-month-old child. The lines indicate reflux episodes of different duration. The result

shows that refluxes are accompanied by a pH decrease only 90 min after feeding (CCP = common cavity phenomenon)

experiences recurrent respiratory infection due to microaspiration, shows greater irritability, restlessness, especially restless sleep interspersed by wake-up phases or screams, and near-miss sudden infant death events (Rosen et al. 2018; Slocum et al. 2007). Feeding difficulties, which frequently accompany this condition, may disturb the interaction between mother and child (Mathisen et al. 1999). Recurrent vomiting or regurgitation of food causes malnutrition and insufficient weight gain. Histologic evidence of esophagitis is rare at this age because the infant is largely fed on milk and gastric acid is sufficiently buffered over a period of 1–2 h after the meal (Fig. 8).

Childhood

58

M. E. Höllwarth and E. Sorantin

The symptoms of evident esophagitis in children include, in addition to recurrent pain in the upper abdomen, frequent bouts of vomiting partly tinged with blood. Chronic blood loss might lead to anemia, and the presence of a significant stenosis can cause swallowing difficulties and regurgitation of food. Such grave complications are rare at the present time; however, it should be noted that children with mental disabilities constitute an exception. Grave sequelae of reflux are often discovered late in these children because the patients are unable to articulate their difficulties. Investigations have shown that the symptom of autoaggression may be an important sign of painful esophagitis in these children and should always be taken as a reason to investigate the presence of reflux (Gössler et al. 2007).

Treatment of GERD Pathological reflux may be treated by conservative means or surgery. Conservative therapy is mainly considered in infants and young children, because the probability of spontaneous normalization of reflux is very high. Conservative treatment is also indicated if one wishes to gain time and when a severe esophagitis or reflux-related stenosis has to be treated before a planned operation. Furthermore, it is used in those rare patients who are unable to undergo surgery.

Conservative Therapy In Infants At this age, a pathological reflux is believed to exist when the child has recurrent bouts of vomiting and fails to thrive, cannot be fed orally, experiences recurrent respiratory tract infection and/or pain, restlessness at night, or reflux-related near-miss attacks. As the risk of esophagitis is very low at this age, one may well dispense with an endoscopic investigation in the absence of specific indications. However, in addition to 24h pH-monitoring or impedance investigation, an

Fig. 9 Esophageal stenosis due to chronic reflux with esophagitis

X-ray of the esophagus (and ultrasound investigation of the pylorus) will be necessary to exclude any pathology that may hinder spontaneous healing of the reflux, such as hiatus hernia, organo-axial gastric volvulus, gastric outlet stenosis, or hypertrophic pyloric stenosis. Investigations have shown that lying in prone position, possibly with a raised torso, prevents reflux most effectively. However, it also involves a much greater risk of sudden infant death due to vomiting in sleep and apnea events. Therefore, the supine position with a raised torso and frequent meals with lesser quantities of food and thickening the food with rice gruel is generally recommended (Carroll et al. 2002; Corvaglia et al. 2007; Horvath et al. 2008). In most cases,

5

Gastroesophageal Reflux and Hiatal Hernia

the symptoms abate within the next few months. Some food manufacturers offer special formula milk to prevent reflux. At the end of 12 months, control pH-monitoring should be performed even after the symptoms have apparently returned to normal, in order to rule out the persistence of a pathological reflux pattern. As mentioned earlier, due to altered food habits, the reflux may rarely reach the mouth and therefore remain invisible, thus mimicking the resolution of reflux. For the same reason, parents’ compliance with prescribed control investigations is usually poor. Just about 10% of children still have marked symptoms of reflux and require, in addition to treatment, follow-up controls every year. Spontaneous normalization of esophageal function may occur between the age of 4 and 5 years but cannot be expected to occur after this time (Pesendorfer et al. 1993).

In Older Children As the child’s food starts to resemble that of adults, there is an increasing quantity of acid secretion from the stomach after meals. Therefore, the majority of postprandial refluxes are now accompanied by a pH reduction to below 4 and, in cases of GERD, the possibility of esophagitis is increased. In addition to esophageal passage on X-rays and pH-monitoring/impedance measurement, a comprehensive investigation must include endoscopy and biopsy. Long-term conservative treatment is meaningful only when spontaneous normalization is anticipated. However, spontaneous healing, even in small babies, is unlikely to occur after esophageal atresia, diaphragmatic hernia, as well as in patients with severe mental disabilities. Thus, conservative maintenance therapy is advisable only in a few exceptional cases of these types. When no esophagitis is seen on biopsy, a suitable diet may be sufficient – such as avoiding acidic and sweet food or other foods causing reflux (coffee, tea, soft drinks), taking less fluids in the evening – and mucosal protection (e. g., Ulsal or Gaviscon). Nonacidic reflux episodes may still occur and may lead to aspiration and chronic respiratory infection particularly in sleep. Therefore, impedance measurement is an

59

excellent measure to determine the extent of nonacidic reflux in these patients. In the presence of esophagitis, preoperatively the patient should always be given drug-based reflux treatment. In reflux-related esophageal stenosis, it is advisable to perform bougienage under treatment with antacids until the condition has normalized. Surgery should be planned after these measures have been performed and the patient’s local condition has been stabilized. Preoperatively, the successful treatment of the stenosis should be verified by performing esophageal barium investigation in order to avoid postoperative bougienage.

Drug Therapy The aim of drug therapy is to reduce acid exposure of the esophagus and thus avoid or treat esophagitis. A distinction should be made here between drugs that protect the mucosal surface and those that reduce or hinder the production of gastric juices. Sucralfate is an aluminum complex in the form of a gel and belongs to the former group. It improves the symptoms of esophagitis and reduces signs of inflammation. The latter groups of drugs that block the production of gastric juices include H2 receptor antagonists or proton pump inhibitors (PPI). H2 receptor antagonists reduce acid secretion by blocking the H2 receptor on the surface of parietal cells in the stomach but might fail in the presence of gastric juice secretion induced by meals (Donnellan et al. 2004). Thus, today the efficacy of H2 receptor antagonists is considered to not be as effective as proton pump inhibitor therapy in GERD children (Ummarino et al. 2012). Proton pump inhibitors inhibit H+/K+-ATpase in parietal cells. Omeprazole and lanzoprazole are approved for children (Rudolph 2003; Castellani et al. 2014). The latter drug may even be administered during the first 12 months. However, longterm treatment with PPI is associated with a higher risk of gastrointestinal infection because it inhibits gastric acids (Berni Canani and Terrin 2010; Lo and Chan 2013).

60

Infants: Most milk-fed infants do not require drug-based treatment of reflux. However, if recurrent unquietness, disturbed sleep, and pain are the symptoms, PPI therapy is indicated. Studies in infants 80%; 35% have a score of 40–80% (Burgos et al. 2010)

more in the fundus, while the gastrin is secreted from near the antrum, the majority of surgeons routinely use the reversed gastric tube as it would have less acid in the neck and thus less chances of leak. In the isoperistaltic tube, the food is deposited directly near the pylorus bypassing the stomach body, thus resulting in dumping-like symptoms (Ionescu 2008).

89

Technique Through a midline epigastric laparotomy, the stomach is approached and the gastrostomy site is separated from the abdominal wall. The left triangular ligament of the liver is divided, and the lower esophageal stump is carefully dissected. The vagus nerves are identified and separated from esophagus; often the posterior nerve is not clearly visible. The proposed gastric tube is marked with stay sutures. The proximal end of the antiperistaltic gastric tube starts 2–5 cm away from the pylorus, on the antral segment. The course of the gastroepiploic vessels is identified but not yet divided; till the ideal procedure, isoperistaltic or reversed is decided. For an antiperistaltic tube, the gastrocolic ligament is progressively divided from right to left; the greater omentum is left attached to the colon and the gastroepiploic arcade to the stomach. The width of the tube after double suturing should be almost the same caliber as the native esophagus. For modeling the tube, a red rubber catheter of approximately #18-22Fr is used. A 2 cm transverse incision is made on the antrum at the chosen level; the tube is inserted retrogradely within the stomach and placed close to the greater curvature. The gastric tube is then separated from the greater curvature. Whether a reversed or isoperistaltic tube is to be fashioned is decided and the gastroepiploic vessel ligated and divided at the right or left end of the gastroepiploic arcade accordingly. The proximal 3–5 cm of the tube should be approximated with interrupted sutures in double layer and should be larger than the rest and a little funnel-shaped for good cervical anastomoses. The rest of the tube and stomach may be sutured as per the surgeon’s choice by continuous, running or interrupted, double-layer sutures or sutured with staplers. However, it should be waterproof to avoid blood loss and also risk of leak from the suture line. Only the short gastric vessels are divided. The gastrostomy tube is reposited, most commonly through the same site or a new one. Often the gastrostomy could be comfortably included in the long suture line. A feeding jejunostomy may be added for early feeding.

90

S. Sharma and D. K. Gupta

Fig. 4 Barium study (a, b) showing a long and tight post corrosive beaded stricture involving the pharynx and the esophagus. (c) Mobilized colon used for esophageal

replacement for a high anastomosis with the pharyngeal wall

After the gastric tube is fashioned, the route for the replacement, transhiatal or retrosternal, is developed. The long suture line should be kept in the anterior position. About 2–5 cm of the length of the neo tube should be left in the abdomen to prevent gastro-neoesophageal reflux. A drain may be left in the posterior mediastinum. The cervical anastomosis is the most important part of the operation. The proximal tube is trimmed of 1–2 cm and examined for a good vascular supply. The cervical anastomoses is made end-to-end, in one layer, with interrupted 5/0 absorbable sutures. The operation ends by repositioning the gastrostomy and closure of the abdomen. The removal of the damaged esophagus for esophageal stricture is recommended to avoid any risk of malignancy. The esophagectomy can be performed as a separate operation, by right or left thoracotomy, or as a transhiatal esophagectomy, by blunt digital dissection combined from above and below, performed concomitantly with the esophageal replacement. Some surgeons still prefer the isoperistaltic gastric tube believing it facilitates a better passage of the food (Table 5).

Table 5 Complications of gastric tube Immediate Leak in the neck (50–60%)

Early Leak in the neck

Mediastinitis due to leakage from the long suture line

Respiratory symptoms usually due to aspiration secondary to a stricture in the neck

Necrosis of the graft

Aspiration of gastric contents

Late Stricture of the tube is quite common (20–30%) Broncho-gastric tube fistula Stringer and Pablot (1985)

Mild sacculation or tortuosity of the gastric tube, though rare Diaphragmatic herniation and obstruction Gastric tube ulceration and hemorrhage

A leak in the neck is the most common complication, mostly closing spontaneously in due course of time. The second most common complication is a stricture that mostly resolves with

7

Esophageal Replacement

dilatations. The severe ones may require resection and redo anastomosis.

Long-Term Outcome and Follow-Up The long-term results following gastric tube have been quite satisfactory in the first few decades after the procedure in most children once they have survived the initial turmoil of the postoperative period (Ein 1998). However, complications may arise later. Lee et al. compared delayed primary anastomosis and esophageal replacement with gastric tube in patients with long-gap esophageal atresia and found that gastric tube replacement had more long-term complications (86%) compared to delayed primary anastomosis (30%) (Lee et al. 2014). There have been reports of acid secretion from the gastric tube and cervical Barrett’s esophagus above the anastomosis indicating the need for lifelong endoscopic follow-up for these patients (Borgnon et al. 2004). On comparing QoL scores and general life status patients who underwent gastric tube esophagoplasty with colon tube esophagoplasty, there was no difference (Gavrilescu et al. 2013).

Isolated Isoperistaltic Gastric Tube Interposition A new procedure involving isoperistaltic isolated gastric tube interposition with favorable shortand long-term functional results has been reported (Gounot et al. 2006).

Jejunal Graft A jejunal graft for esophageal replacement has been described way back in 1947 (Sharma and Gupta 2017). The procedure is the most technically demanding of all the four procedures and most time-consuming: it can take up to 24 h. Hence there is limited experience and a risk of life-threatening vascular compromise. Thus the usage of the jejunum as a substitute for the esophagus has not become very popular. Moreover, it involves discarding some length of jejunum to make a sufficient length of vascular pedicle due

91

to arcades. The jejunum also has a short mesentery and may involve the need of microvascular anastomosis of the jejunal vessels with the neck vessels, with a chance of failure, graft loss, and leaks in the neck. Some experts believe that the disadvantage of a longer operation time is easily compensated by less chances of dilatation of the graft and better quality of life of the patients, as the function of the jejunal segment is much better than the other substitutes of the esophagus, and believe the jejunum is the most appropriate substitute for the esophagus in infants and children (Hashizume and Dessanti 2008). The most disastrous complication is total necrosis of the interposed jejunum due to vascular insufficiency, i.e., arterial thrombosis or venous occlusion. Hence, it is not advisable to perform jejunum interposition in neonates with friable mesenteric arteries and veins. An age of 6 months or a minimal weight of 6 kg is considered adequate.

Technique The abdomen is opened with an upper midline incision, to approach the esophageal hiatus. The first jejunal artery with accompanying vein is preserved. The second and third jejunal arteries are usually divided and ligated near their origins, and the fourth artery is preserved and is used as part of vascular pedicle of the jejunal loop. With this, one can get adequate length of the vasculature pedicle. The distal end of divided jejunum is then placed on the anterior chest wall to ensure that this part can be brought to the level of the place designated for the upper anastomosis. The arcade is then ligated and divided just distal to the point of the confluence with the fourth jejunal artery. A longer length of the jejunal loop is usually redundant so the part is resected. The continuity of the jejunum is restored. The jejunal loop, so prepared, is brought to the upper abdomen through a small hole in the mesocolon. Concerning the route to the thoracic cavity, if the length of the lower esophagus is long enough to permit the lower anastomosis done in the right thoracic cavity, the loop should be

92

S. Sharma and D. K. Gupta

brought anterior to the stomach and through a hole in the diaphragm. However, if the length of the lower esophagus is not adequate enough and the anastomosis should be done in the abdomen, the jejunal loop should be brought to the right thorax through a retrogastric route and through the esophageal hiatus. Maximum precision is necessary to avoid kinking and torsion of the vascular pedicle. The end-to-side anastomosis of the upper esophagus and the jejunal loop is preferred to avoid undue tension to the vascular pedicle. The anastomosis of the interposed jejunum and the lower esophagus is accomplished in an end-toend fashion. A thoracic drain is inserted into the right thorax and a penrose or suction drain near the esophageal hiatus. A feeding jejunostomy distal to the anastomosis may be considered.

Complications If there is a leak, parenteral nutrition or enteral feeding through a gastrostomy should be initiated. Usually the leak heals spontaneously after 2 weeks (Table 6).

Long-Term Outcome and Follow-Up There is little experience reported with the use of jejunum to replace the esophagus. A recent meta-analysis of adult experience with jejunal grafts reported up to 10% mortality, 36% Table 6 Complications of jejunal graft Immediate Graft necrosis Perforation of the graft Anastomotic leak

Early Anastomotic leak Cervical fistulas Necrosis of tip of graft

Late Cervical stricture Gupta et al. (2004) Peptic strictures Cervical dysphagia Esophageal diverticulum Redundancy of the jejunum Delayed swallowing

anastomotic leak rate, and 5–11% graft loss frequency (Gaur and Blackmon 2014). Ring et al. reported the results of 32 staged jejunal interpositions with no failures of the jejunum to reach the neck, no loss of graft, and no deaths (Ring et al. 1982). On long-term follow-up (range 18–33 years; mean 27 years), all patients could eat a regular diet at normal speeds. Saeki et al. reported their long-term results with transient stagnation of swallowed barium at the lower esophagus was observed in 7/12 cases (58%) (Saeki et al. 1988). Comparing the results after the reconstruction of esophagus using colon, the long-term results of jejunal interposition seem to be extremely good, possibly due to less chances of anastomotic stricture formation due to good vasculature, better peristalsis of the jejunum, less tendency of dilatation even after several years, and less intrinsic problems compared to colon such as diverticulum formation and development of adenoma. In addition, the children after jejunal interposition have fewer problems, and they show normal growth as the influence of resection of redundant part of the jejunum on growth is nil or minimum. Jejunal interposition has also been used for a failed colon interposition (Ho et al. 2014). Gallo et al. compared long-term outcomes of gastric pull-up and jejunal interposition for longgap esophageal atresia and found functional obstruction in 46% after jejunal interposition versus none after gastric pull-up ( p = 0.02) (Gupta et al. 2007).

Gastric Transposition Gastric transposition was first done in children only about four decades ago, although the procedure has been extensively used in adults for esophageal carcinoma. As the colon interposition was associated with complications like redundancy, reflux, stricture, and rarely graft loss, pediatric surgeons sought alternate procedures. The gastric transposition as a primary procedure for replacing the esophagus in children was popularized by Prof. Lewis Spitz, from the Institute of Child Health, Great Ormond

7

Esophageal Replacement

Street, London, in 1981, after noting the unacceptably high complication rate with the use of colon interposition (Spitz et al. 2004). The authors have been using this technique for 25 years (Gupta and Sharma 2008a). After the initial experience with the use of stomach in infants and children, its use was extended even to newborns. Being a simple surgical procedure comparatively, with very good vascularity, there has recently been a wider interest in using the stomach to replace the esophagus in children. Thus, several surgeons have now switched over from using colon interpositions to gastric transpositions for esophageal replacement in children, and now many large series have reported satisfactory early and long-term results in newborns, infants, and children (Ludman and Spitz 2003).

Neonatal Gastric Transposition The stomach is considered the best option available in newborns requiring esophageal replacement as the vascular supply to the colon and the jejunum is very precarious and limits the length of the intestinal segments to reach the neck without tension. Also, the size of the stomach in newborns and in infants less than 6 months of age is quite small and unfit for preparing the gastric tube. Moreover, the gastric wall is also quite vascular and muscular to withstand mediastinal infection if any. Thus, gastric transposition is the only option to replace the esophagus in the neonatal period following major postoperative leaks and also with the long- or wide-gap esophageal atresia and tracheoesophageal fistula to avoid diversion and offer definitive procedure even in the newborn stage to avoid repeated visits to the hospital (Gupta and Sharma 2011; Soccorso and Parikh 2016) (Table 7). The advantages and disadvantages of gastric transposition are mentioned in Table 3.

Technique The abdomen is opened with a supraumbilical midline incision. Access is gained to the

93 Table 7 Merits and demerits of gastric transposition (Gupta and Sharma 2008a) Merits Technically easier operation

Stomach has a thick muscular wall with reliable vascular supply Adequate length is possible for anastomosis without tension. If needed, duodenum can be kocherized A single anastomosis is required in the neck

There is no suture line in the chest, except the closure sites of the gastrostomy and the esophageal hiatus Least short-term morbidity and mortality

Demerits Bulk of stomach in mediastinum/thorax can cause respiratory distress and may decrease venous return Reflux in the bulky stomach is common and can cause aspiration pneumonitis As vagotomy is part and partial with the procedure, gastric emptying may be delayed despite pyloromyotomy As the reservoir function of the stomach is lost, there may also be rapid gastric emptying leading to dumping Loss of gastric reservoir function effects the growth and development of the patient Bile gastritis may result in change in gastric mucosa in the long term

gastroesophageal junction. The anterior and the posterior vagus nerves have to be invariably sacrificed while delivering the esophageal stump in pure esophageal atresia cases in the abdomen. The stomach is mobilized, starting from right to left through the gastrocolic ligament (Fig. 5). The right gastroepiploic vessel, the gastroepiploic arcade, and the right gastric vessels are preserved. The 4–5 short gastric vessels running between the stomach and the spleen are ligated away from the stomach individually to avoid any vessel spasm or even thrombosis. The left gastric vessels are identified and ligated securely close to their origin. Kocherization of the second part of the duodenum is performed to gain length and bring the duodenum and the pylorus in a straight line. The spleen is preserved in all. The esophageal stump is transected from its junction with the stomach, and the defect is closed in two layers (Fig. 6). The site of the gastrostomy is also closed in two layers. Two stay sutures are

94

S. Sharma and D. K. Gupta

Fig. 5 (a) Mobilization of the cervical esophagostomy. (b) Assessing the length of the mobilized stomach in a newborn

Fig. 6 Gastric pull-up in a boy with a pure esophageal atresia showing. (a) The mobilized stomach with the esophageal stump. (b) The sutured site of the stomach after resection of the esophageal stump on the left and the sutured gastrostomy site on the right; the stay sutures are applied at the fundus which is the proposed site of anastomosis to the esophagus

applied to the highest point in the fundus of the stomach with a right and left side mark, for taking it up to the neck for the anastomosis, taking due care to avoid any rotation (Fig. 6). The appropriate route is now chosen. No thoracotomy is performed. The mediastinal route is quite feasible and preferred in all neonates. If the creation of the tunnel is found

difficult due to previous thoracotomy adhesions, the attempt is abandoned, and the substernal route is favored. In that case, the hiatus will be closed with a couple of Fig. 8 sutures. The substernal route can be created easily by a blunt finger dissection starting just behind the xiphisternum. The stomach is mobilized completely and taken up to the neck (Fig. 6).

7

Esophageal Replacement

95

Fig. 7 Skiagram chest in a patient with gastric transposition, depicting (a) gastric aspiration and (b) improving chest after a week of ventilation

A single-layer esophagogastric anastomosis is made at the highest point of the stomach using 5–0 polyglactin sutures. Pyloromyotomy or pyloroplasty is always performed to provide a drainage procedure as bilateral vagotomy has invariably been done. The pyloric antrum is fixed to the diaphragmatic edges at the hiatus. The stomach is also hitched to the prevertebral fascia in the neck to prevent any tension on the anastomosis. A soft glove drain is used to drain the neck wound. The stomach is decompressed with a nasogastric tube, the tip of which is carefully placed in the mid-thoracic region. A feeding jejunostomy is useful, especially for the critically ill patients who might take a longer time to recover from surgery and require prolonged nutritional support. In children with corrosive injuries, the stricture part is completely excised to have a pliable anastomosis with the upper esophagus. The esophagectomy is feasible and performed in the same sitting.

Complications Gastric transposition has relatively few complications compared to other procedures when done repeatedly (Table 4). An aspiration may result from gastric stasis or inadequate

swallowing reflex (Fig. 7). Anastomotic leaks in the neck are not uncommon, but most of them are minor and resolve within a few days. Major leaks result in stricture formation and thus need regular follow-up, including endoscopy at regular intervals. Most of these respond to dilatation. Few may however need a surgical correction. Anastomotic strictures are more common in patients with caustic esophageal injury. A contrast study is done in the follow-up period to evaluate for any leak or stricture (Fig. 8) (Table 8). Gastric transposition for esophageal substitution has been associated with a mortality rate of 3–5% of patients in the best hands. Most of the deaths in children have been reported in the early postoperative period due to ongoing sepsis and associated congenital heart disease besides chest aspiration that is preventable with close monitoring (Spitz 1992). Vomiting and aspiration pneumonitis is also seen frequently. The most common indication for redo surgery is following stricture formation in the neck. Others include mechanical obstruction such as compression of the stomach at the diaphragm level and at the neck and jejunostomyrelated complications besides the intestinal obstruction due to adhesions.

96

S. Sharma and D. K. Gupta

Fig. 8 (a–c): Barium swallow study showing the good emptying of the stomach used for esophageal replacement in the chest

Symptoms mimicking obstruction have been reported due to stasis of food in the thoracic stomach (functional obstruction due to vagotomy) without any evidence of mechanical obstruction. This needs careful assessment for the need of jejunostomy to provide nutrition. It may also lead to aspiration pneumonia during sleep.

Long-Term Outcome and Follow-Up In a large series of 173 children reported by Spitz et al., more than 90% had a good to excellent outcome in terms of absence of swallowing difficulties or other gastrointestinal symptoms (Spitz et al. 2004). Many, however, preferred to eat small frequent meals. The authors also have similar experience during the follow-up studies of patients who had undergone gastric transposition 10 years ago or more. The majority of the patients learned the habit of eating and swallowing in time (Jain et al. 2012). There has been no deterioration in the function of the stomach in those patients followed up for more than 10 years. There is no evidence of peristalsis in the thoracic stomach; however, it responds well to the food bolus by gravity. The manometric studies performed after gastric pull-up documented mass contractions

without any propulsive or peristaltic waves (Gupta et al. 2004). The baseline pressure was a little higher in newborns compared to that in children. Also, the pressure increased by over 120%, both in newborns and children, in response to the food bolus (Gupta et al. 2004). The response was irrespective of the age at surgery and the route adopted. The gastric emptying has been shown to be delayed in more than half and hurried in one third in another study (Ravelli et al. 1994). The emptying pattern was extremely irregular, suggesting that gastroesophageal as well as duodenogastric reflux episodes occurred in all patients (Ravelli et al. 1994). The quality of life for patients following gastric transposition was good with fewer disease-specific symptoms in the medium term compared with patients who had undergone previous unsuccessful attempts at reconstruction or replacement of their esophagus (Ludman and Spitz 2003). It has now been shown that gastric transposition is compatible with normal life, though the growth and development remained subnormal in children followed up for 5–10 years in some series. Anemia has been found in 70% of the cases during long-term follow-up (Jain et al. 2012).

7

Esophageal Replacement

97

Table 8 Complications following gastric transposition (Sharma and Gupta 2017; Gupta and Sharma 2008a; Ludman and Spitz 2003; Davenport et al. 1996) Immediate Leak Vascular compression in neck Chest infection Lung collapse Acute gastric dilatation Ventilation dependency Cardiac compression Twist of the stomach Perforation during pyloromyotomy Bleeding Pneumothorax Aspiration pneumonitis Recurrent laryngeal nerve palsy Sepsis

Mortality

Early Anastomotic leak in neck [15–35%] Neck or abdominal wound infection

Late Stricture in the neck Intestinal obstruction due to adhesions

Recurrent aspiration Delay in feeding Jejunostomy complications, leak, perforation

Dyspnea Uncoordinated swallowing Reflux gastritis

Pulmonary compression

Graft loss – rare

Dumping

Dumping syndrome

Vomiting

Functional obstruction due to vagotomy

Adhesive intestinal obstruction

Anemia

Gastroesophageal reflux in the neck Duodenogastric reflux in the abdomen Perforation due to jejunum through the feeding tube Broncho-gastric fistula

Loss of reservoir function and poor growth Pulmonary function compromise Problems during swallowing

Ischemia of the fundus of the stomach, if the diathermy has been used to divide the short gastric vessels, leading to a floppy stomach Mortality

Para-neo esophageal Hernia

The authors have noted the decreased functional capacity of the lungs especially in those patients who had undergone previous thoracotomies. This may be secondary to the pulmonary compression or recurrent aspirations. Gastric transposition has been reported to have excellent results, in terms of both surgical technique (simplicity, reproducibility, complication rate) and clinical follow-up (good oral feeding of young patients, normal social life, and regular growth curves) (Angotti et al. 2017). Surgical experience has been a great factor in lowering the complication rates. The mortality rate in Spitz series reduced from 5.2% in 173 cases reported in 2004 to 2.5% in 236 gastric transpositions in 2014 (Spitz et al. 2004; Spitz 2014). However, the leak rate of 12% and stricture rate of 20%

Malabsorption

Mediastinal abscess secondary to esophageal perforation as a result of dilatation procedure for stricture

remained the same. The follow-up of 236 gastric transpositions in 2014 showed a satisfactory outcome in over 90% patients (Spitz 2014).

Ileal Graft The pedicled ileum graft has also been successfully used in children (Sharma and Gupta 2017; Bax and Van Renterghem 2005). It has also been used for esophageal replacement in redo cases who had endured from one to four attempts of esophageal replacements by different methods, with good results (Ivanov et al. 2012). Minimally Invasive Esophageal Replacement Esophagectomy has been successfully performed thoracoscopically. This has been combined

98

with laparoscopy for either colonic interposition or gastric transposition (Esteves et al. 2010; Ng et al. 2014; Chokshi et al. 2009). Laparoscopic gastric transposition by minimally invasive techniques avoids the trauma of open access. On comparing outcomes of minimally invasive versus open gastric transposition in children, minimally invasive gastric transposition has been reported as a safe and acceptable alternative to open surgery in children (Ng et al. 2014).

S. Sharma and D. K. Gupta

Regenerative medicine and tissue engineering is the new ray of hope for a biologically functional esophagus. However, this will take at least two decades more for reality.

Cross-References ▶ Caustic Injuries of the Esophagus

References Conclusion and Future Directions The repair of the long-gap esophageal atresia still remains a challenge. Though it has been believed since ages that the native esophagus is the best esophagus, it may not always be a feasible option. In tertiary care centers worldwide, there has been a drift to preserve the native esophagus by promoting a delayed primary repair, but this has been found to be associated with high rate of postoperative strictures and gastro-neoesophageal reflux, requiring repeated surgeries, prolonged hospitalization, and the high costs. It may take many years to resume normal feedings orally with the need for balloon dilatations, gastrostomy closure, and antireflux surgery and even redo surgeries (Sharma and Gupta 2017). The skill for esophageal replacement has to be mastered by focused surgeons in tertiary centers so that the best possible care can be given to these children who undergo major surgery. Colon is the most preferred and safest organ for replacement. Stomach is a vascular and muscular organ with lower risk of ischemia. Gastric tube is a demanding technique. Jejunum and ileum are good alternatives for redo cases. With the advent of minimally invasive surgery, the morbidity of these complex procedures may be reduced. However, laparoscopy may not be feasible in presence of dense adhesions. Thoracoscopy is a feasible option for esophagectomy reducing the risk for malignancy in the redundant esophagus especially following corrosive injury. Robotic surgery may help in the future to perform in vivo anastomosis in the abdomen for colonic interposition in suitable cases.

Abou Zeid AA, Zaki AM, Safoury HS. Posterior cologastric anastomosis: an effective antireflux mechanism in colonic replacement of the esophagus. Ann Thorac Surg. 2016;101:266–73. AbouZeid AA, Zaki AM, Radwan AB et al. Colonic replacement of the esophagus: towards standardization of the technique. J Pediatr Surg. 2019. pii: S0022-3468 (19)30785-7. Angotti R, Molinaro F, Noviello C, et al. Gastric transposition as a valid surgical option for esophageal replacement in pediatric patients: experience from three Italian medical centers. Gastroenterol Rep (Oxf). 2017;5 (1):47–51. Baggaley A, Reid T, Davidson J, et al. Late life revision surgery for dilated colonic conduit in long gap oesophageal atresia. Ann R Coll Surg Engl. 2018 Sep;100(7):e185–7. Bax NM, Van Renterghem KM. Ileal pedicle grafting for esophageal replacement in children. Pediatr Surg Int. 2005;21:369–72. Borgnon J, Tounian P, Auber F, al e. Esophageal replacement in children by an isoperistaltic gastric tube: a 12year experience. Pediatr Surg Int. 2004;20:829–33. Burgos L, Barrena S, Andrés AM, Martínez L, Hernández F, Olivares P, Lassaletta L, Tovar JA. Colonic interposition for esophageal replacement in children remains a good choice: 33-year median follow-up of 65 patients. J Pediatr Surg. 2010;45:341–5. Burrington JD, Stephens CA. Esophageal replacement with a gastric tube in infants and children. J Pediatr Surg. 1968;3:24–52. Chen HC, Tang YB. Microsurgical reconstruction of the esophagus. Semin Surg Oncol. 2000;19:235–45. Chen H, Lu JJ, Zhou J, Zhou X, Luo X, Liu Q, Tam J. Anterior versus posterior routes of reconstruction after esophagectomy: a comparative anatomic study. Ann Thorac Surg. 2009;87:400–4. Cheng BC, Chang S, Huang J, Mao ZF, Wang ZW, Lu SQ, Wang TS, Wu XJ, Hu H, Xia J, Kang GJ, Xiao YG, Lin HQ. Surgical anatomy of the colic vessels in Chinese and its influence on the operation of esophageal replacement with colon. Zhonghua Yi Xue Za Zhi. 2006;86:1453–6. Chokshi NK, Guner YS, Ndiforchu F, Mathis R, Shin CE, Nguyen NX. Combined laparoscopic and

7

Esophageal Replacement

thoracoscopic esophagectomy and gastric pull-up in a child. J Laparoendosc Adv Surg Tech A. 2009;19 (Suppl 1):S197–200. Coopman S, Michaud L, Halna-Tamine M, Bonnevalle M, Bourgois B, Turck D, Gottrand F. Long-term outcome of colon interposition after esophagectomy in children. J Pediatr Gastroenterol Nutr. 2008;47:458–62. Davenport M, Hosie GP, Tasker RC, Gordon I, Kiely EM, Spitz L. Long-term effects of gastric transposition in children: a physiological study. J Pediatr Surg. 1996;31:588–93. Ein SH. Gastric tubes in children with caustic esophageal injury: a 32-year review. J Pediatr Surg. 1998;33:1363–5. Elshafei H, Elshafei E, ElDebeiky M, Hegazy N, Zaki A, Abdel Hay S. Colonic conduit for esophageal replacement: long-term endoscopic and histopathologic changes in colonic mucosa. J Pediatr Surg. 2012;47:1658–61. Ergün O, Celik A, Mutaf O. Two-stage coloesophagoplasty in children with caustic burns of the esophagus: hemodynamic basis of delayed cervical anastomosis–theory and fact. J Pediatr Surg. 2004;39:545–8. Esteves E, Sousa-Filho HB, Watanabe S, Silva JF, Neto EC, da Costa AL. Laparoscopically assisted esophagectomy and colon interposition for esophageal replacement in children: preliminary results of a novel technique. J Pediatr Surg. 2010;45:1053–60. Gallo G, Zwaveling S, Van der Zee DC, Bax KN, de Langen ZJ, Hulscher JB. A two-center comparative study of gastric pull-up and jejunal interposition for long gap esophageal atresia. J Pediatr Surg. 2015;50:535–9. Gaur P, Blackmon SH. Jejunal graft conduits after esophagectomy. J Thorac Dis. 2014;6(Suppl 3): S333–40. Gavrilescu S, Hanganu E, Sarbu I, Aprodu SG. Quality of life of patients with esophageal replacement for congenital and acquired esophageal anomalies. Rev Med Chir Soc Med Nat Iasi. 2013;117:334–6. Glasser JG, Reddy PP, Adkins ES. Treatment of colon conduit redundancy in a child with esophageal atresia. Am Surg. 2006;72:260–4. Gounot E, Borgnon J, Huet F, Sapin E. Isolated isoperistaltic gastric tube interposition for esophageal replacement in children. J Pediatr Surg. 2006;2006 (41):592–5. Gupta DK, Sharma S. Gastric transposition. In: Gupta DK, editor. Pediatric surgery diagnosis and management: Jaypee; 2008a. p. 409–21. Chapter 34. Gupta DK, Sharma S. Esophageal replacement with colon. In: Gupta DK, editor. Pediatric surgery diagnosis and management: Jaypee; 2008b. p. 382–90. Chap 32. Gupta DK, Sharma S. Primary gastric pull up in pure esophageal atresia: technique, feasibility and outcome. A prospective observational study. Pediatric Surg Int. 2011;27:583–5, 17. Gupta DK, Charles AR, Srinivas M. Manometric evaluation of the intrathoracic stomach after gastric transposition in children. Pediatr Surg Int. 2004;20:415–8.

99 Gupta DK, Sharma S, Arora MK, Agarwal G, Gupta M, Grover VP. Esophageal replacement in the neonatal period in infants with esophageal atresia and tracheoesophageal fistula. J Pediatr Surg. 2007;42:1471–7. Hamza AF, Abdelhay S, Sherif H, et al. Caustic esophageal strictures in children: 30 years’ experience. J Pediatr Surg. 2003;38:828–33. Hashizume K, Dessanti A. Jejunal interposition as a substitute of esophagus. In: Gupta DK, editor. Pediatric surgery diagnosis and management: Jaypee; 2008. p. 422–5. Chapter 35. Hernández F, Rivas S, Avila LF, Luis AL, Martínez L, Lassaletta L, Murcia FJ, Tovar JA. Early esophageal replacement in patients with esophageal atresia. Cir Pediatr. 2003;16:112–5. Ho AC, Yeo MS, Ciudad P, Chen HC. 2-stage free and pedicle jejunum for esophageal replacement after failed colon interposition for caustic injury in a 5 year-old child. J Plast Reconstr Aesthet Surg. 2014;67:417–9. Ionescu GO. Gastric tube esophageal replacement. In: Gupta DK, editor. Pediatric surgery diagnosis and management: Jaypee; 2008. p. 391–408. Chap 33. Ivanov AP, Nabokov VV, Miroshnikov BI, Galkina NV. Repeated plasty of the esophagus in children with the application of transplant from the ileum. Vestn Khir Im I I Grek. 2012;171:54–60. Jain V, Sharma S, Kumar R, Kabra SK, Bhatia V, Gupta DK. Transposed intrathoracic stomach: functional evaluation. Afr J Paediatr Surg. 2012;9:210–6. Lee HQ, Hawley A, Doak J, Nightingale MG, Hutson JM. Long-gap oesophageal atresia: comparison of delayed primary anastomosis and oesophageal replacement with gastric tube. J Pediatr Surg. 2014;49:1762–6. Lima M, Destro F, Cantone N, Maffi M, Ruggeri G, Dòmini R. Long-term follow-up after esophageal replacement in children: 45-year single-center experience. J Pediatr Surg. 2015;50:1457–61. Lobeck I, Dupree P, Stoops M, et al. Interdisciplinary approach to esophageal replacement and major airway reconstruction. J Pediatr Surg. 2016;51:1106–9. Ludman L, Spitz L. Quality of life after gastric transposition for oesophageal atresia. J Pediatr Surg. 2003;38:53–7; discussion 53–7. Ng J, Loukogeorgakis SP, Pierro A, Kiely EM, De Coppi P, Cross K, Curry J. Comparison of minimally invasive and open gastric transposition in children. J Laparoendosc Adv Surg Tech A. 2014;24:742–9. Prabhu R, Kantharia C, Bapat R, Shukla A, Bhatia S, Supe A. Morphological and functional changes in colon after coloplasty for management of corrosive esophageal strictures. Indian J Gastroenterol. 2013;32:165–71. Ravelli AM, Spitz L, Milla PJ. Gastric emptying in children with gastric transposition. J Pediatr Gastroenterol Nutr. 1994;19:403–9. Ring WS, Varco RL, L'Heureux PR, Foker JE. Esophageal replacement with jejunum in children: an 18 to 33 year follow-up. J Thorac Cardiovasc Surg. 1982;83:918–27. Saeki M, Tsuchida Y, Ogata T, Nakano M, Akiyama H. Long-term results of jejunal replacement of the esophagus. J Pediatr Surg. 1988;23:483–9.

100 Saldaña-Cortés JA, Larios-Arceo F, Prieto-Díaz-Chávez E, De Buen EP, González-Mercado S, Alvarez-Villaseñor AS, Prieto-Aldape MR, Fuentes-Orozco C, GonzálezOjeda A. Role of fibrin glue in the prevention of cervical leakage and strictures after esophageal reconstruction of caustic injury. World J Surg. 2009;33:986–93. Sharma S, Gupta DK. Surgical techniques for esophageal replacement in children. Pediatr Surg Int. 2017;33:527–50. Sharma S, Gupta DK. Colonic interposition for esophageal replacement in children. In Redkar R. IAPS texbook of Pediatric Surgery. Jaypee Brothers. 2020. Chapter 36:352–356 Sherman CD, Waterston DJ. Esophageal reconstruction in children using colon. Arch Dis Child. 1957;32:11.

S. Sharma and D. K. Gupta Soccorso G, Parikh DH. Esophageal replacement in children: challenges and long-term outcomes. J Indian Assoc Pediatr Surg. 2016;21:98–105. Spitz L. Gastric transposition for esophageal substitution in children. J Pediatr Surg. 1992;27:252–9. Spitz L. Esophageal replacement: overcoming the need. J Pediatr Surg. 2014;49:849–52. Spitz L, Kiely E, Pierro A. Gastric transposition in children–a 21-year experience. J Pediatr Surg. 2004;39:276–81; discussion 276–81. Stringer DA, Pablot SM. Broncho-gastric tube fistula as a complication of esophageal replacement. J Can Assoc Radiol. 1985;36:61–2.

8

Chest Wall Deformities Robert C. Shamberger

Contents Pectus Excavatum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

101 104 105 111

Pectus Carinatum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Operative Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nonoperative Correction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

111 112 113 114 114

Poland’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 Surgical Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

Abstract

A broad spectrum of anomalies occur in the chest wall, ranging from pectus carinatum, a protrusion anomaly, to pectus excavatum, a depression anomaly, to actual absence of the ribs and pectoral muscle in Poland’s syndrome. These deformities, which are the most frequent to occur, will be discussed in this chapter including their physiologic implications for the patient as well as frequent approaches to treatment. The devastating deformities of

R. C. Shamberger (*) Department of Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA e-mail: [email protected]

ectopia cordis and sternal defects are much rarer and as such will not be discussed. Keywords

Pectus Excavatum · Pectus Carinatum · Poland’s Syndrome

Pectus Excavatum Pectus Excavatum is a congenital deformity of the anterior chest wall. It consists of two primary elements. The first component is posterior depression of the body of the sternum, generally beginning at the level of the insertion of the second or third costal cartilages. The second component is

© Springer-Verlag GmbH Germany, part of Springer Nature 2021 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43559-5_98

101

102

R. C. Shamberger

Fig. 1 Age at appearance of the pectus excavatum configuration. (Reprinted from Journal of Pediatric Surgery, Vol. 23, Robert C. Shamberger, Kenneth J. Welch, Surgical repair of pectus excavatum, 615–622, Copyright (1988), with permission from Elsevier)

posterior depression of the attached costal cartilages. This depression generally involves ribs 3–7 and sometimes will extend to the level of the second costal cartilage. In older teenagers, the posterior depression of the ribs will involve part of the osseous as well as the cartilage component. This is a congenital deformity and in greater than 90% of children it will be apparent within the first year of life (Fig. 1). It has an increased frequency of occurrence in families with a history of chest wall deformity and has been estimated to have an incidence of 1 in 300 to 1 in 400 births. Multiple methods of grading the severity of the depression have been devised. The most widely accepted and utilized is that of Haller which is depicted in Fig. 2 (1987). While it was originally developed for use with a computed tomogram (CT scan), it has been adapted for use from standard radiographs as well to minimize radiation exposure to the patient. Individuals with an index of greater than 3.25 may be appropriate for repair (Fig. 3). The physiologic implications of pectus excavatum have been evaluated over the last four decades. It has been demonstrated that a “restrictive” defect occurs in individuals with pectus excavatum. The total lung capacity and the vital capacity are decreased relative to normative values. The values for an individual often do

Fig. 2 The Haller index is obtained by dividing the transverse diameter of the chest by the sternovertebral distance. These measurements can be obtained from a CT scan of the chest or a standard chest radiograph

not fall out of the “normal range,” but taken as a group, individuals with pectus excavatum do have decreased pulmonary volume compared with normals. The extent of this impairment is variable and it depends upon the severity of the depression and the depth of the chest. Recent results from a multicenter study of patients with pectus excavatum demonstrated a relatively small decrease in their lung function preoperatively with improvement in postsurgical correction of approximately 6–10% (Kelly et al. 2007). The second physiologic impairment which has been demonstrated is a decrease in the filling capacity of the heart, in particular the right ventricle. This is produced by anterior compression from the depressed sternum.

8

Chest Wall Deformities

Fig. 3 (a) Photograph of a 15-year-old male with a symmetric pectus excavatum. (b) Postoperative photograph 4 years later demonstrates excellent correction of the depression and a durable result. (c) Transverse image from the preoperative CT scan on this patient. (d) Similar image from his postoperative study obtained 2 years after correction reveals significant improvement in the contour of the chest wall and of the sternovertebral distance. Haller index has gone from 4.4 to 3.5

103

104

Studies dating back to those of Beiser have shown a decreased stroke volume, particularly in the upright position, associated with significant chest wall deformity (Beiser et al. 1972). While subsequent studies have shown variable results when using radioisotope techniques, this impairment is clearly one of the components of decreased cardiopulmonary function in patients with severe pectus excavatum. Workload studies have demonstrated that individuals with pectus excavatum develop symptoms of fatigue earlier in gaited exercise protocols than normal controls do. Two studies, by Cahill (1984) and Peterson (1985), have also demonstrated that following repair of the chest wall deformity, the level of the exercise tolerance has increased. Determination of the subject’s appropriateness for repair is dependent upon multiple considerations. These include the degree of psychologic distress created by the deformity, the extent of impairment of physical activity by cardiopulmonary symptoms, and results of pulmonary function and physiologic exercise studies.

Surgical Repair Techniques for repair of pectus excavatum have evolved significantly since it was first repaired in 1911. Modern approaches date to, when Ravitch (1949) first reported a technique which involved excision of all deformed costal cartilages with the perichondrium, and division of the xiphoid and the intercostal bundles from the sternum. A sternal osteotomy was created and the sternum was secured anteriorly with Kirschner wire fixation. This approach was modified by Baronofsky (1957) and Welch (1958) when they stressed the need for preservation of the perichondrial sheaths to allow optimal cartilage regeneration for durability of the repair. Fixation with metallic struts anterior to the sternum was the next modification developed by Rehbein and Wernicke (1957). Retrosternal strut fixation was described by Adkins and Blades (1961). While recent innovations for strut fixation have included the use of such materials as bioabsorbable struts, Marlex mesh, or Dacron vascular graft, no evidence

R. C. Shamberger

demonstrates that these are better than traditional metallic struts. In 1998, Donald Nuss first described a method for repair of pectus excavatum utilizing a heavy metal strut to anteriorly displace the sternum and depressed costal cartilages. It did not require resection or remodeling of any of the costal cartilages. In this chapter, I will present both the current open technique with its modifications which I utilize as well as the innovative Nuss technique which is also known as the minimally invasive repair of pectus excavatum (MIRPE). The latter technique has been shown to be quite durable and result in excellent correction of the posterior depression of the sternum and costal cartilages. A subsequent report by Croitoru (2002), utilizing this method, included a larger and older cohort of 303 patients. The primary complication encountered in this study was late bar displacement requiring bar repositioning in 8.6% of cases which included a high proportion (50%) of patients in whom a stabilizer was not utilized. Allergic reactions to the metal strut were also recognized, often with rash and erythema overlying the bar or with pleural effusions. The importance of placing the bars and stabilizers in a subcutaneous and not a submuscular position to avoid extra osseous bone formation around the strut was also identified. The occurrence of “over-correction” of the deformity was seen infrequently, primarily in children with connective tissue disorders (Marfan’s and Ehler-Danlos syndromes). Kelly et al. have recently summarized their large experience with 1,215 patients with the MIRPE and reviewed the changes they have made to the procedure (Kelly et al. 2010). One bar was placed in 69% and two bars were required in 30% of their patients. Good or excellent surgical outcome at the time of bar removal was seen in 95.8% of the patients. Complications with bar displacement decreased from 12% in the first decade to 1% in the second. An allergy to nickel was identified in 2.8% of patients, the vast majority prior to surgery. Wound infection occurred in 1.4% (17 patients) of whom four required surgical drainage. During the duration of this study, the median age at surgery went from 6 years to 14 years and modifications of the

8

Chest Wall Deformities

105

technique occurred including: routine use of unilateral or bilateral thoracoscopy, techniques to minimize the risk of dissection between the sternum and heart in patients with severe depressions including elevation of the sternum manually through an infraxiphoid incision or first placing a more superior transmediastinal tunnel and leaving the introducer in place elevating the sternum while dissecting the lower tunnel, use of titanium bars when a metal allergy is identified, using a bar length which is 1 inch shorter than the measurement from right to left midaxillary line, more frequent use of two bars in patients with severe depressions or in older patients, and use of a metal stabilizer to decrease the risk of rotation of the bar. Recently, Goretsky and McGuire (2018) and Notrica (2019) described early and late complications of the Nuss procedure and preventative strategies to minimize them.

Surgical Technique

Fig. 4 Demonstration of the osseous ribs, costal cartilages, and sternum creating the pectus excavatum configuration (a). The transverse incision in males is placed below and within the nipple line. In females it is placed in the inframammary crease to avoid a scar tethering between the

breasts. (b) The pectoralis major muscle inserts by a fascial attachment to the midline sternum. (From P. Puri and M. Höllwarth Eds, Pediatric Surgery, Springer Surgery Atlas Series, by permission Springer-Verlag)

Open Repair A transverse skin crease incision is placed below and within the nipple lines (Fig. 4). In females, it is of particular importance to see that this is placed in the future inframammary crease to avoid unsightly tethering of a scar between the two breasts. The skin flaps are then elevated superiorly to the level of the apex of the deformity and inferiorly to the tip of the xiphoid. The flaps are developed just anterior to the pectoral fascia to keep them well vascularized. The pectoral muscles are then elevated off the sternum being cautious to preserve all of the muscle and overlying fascia intact. To facilitate identification of the appropriate plane of dissection, the muscle is first elevated just anterior to one of the costal cartilages (Fig. 5). When this plane is defined, an empty knife handle is then inserted anterior to the costal cartilage and passed laterally. It is then replaced with a

106

right angle retractor to elevate the muscle anteriorly. This step is then repeated anterior to the next costal cartilage just above or below the first rib defined. Elevation of the muscle flap in between the two right angle retractors facilitates identification of the correct plane of dissection. The origin of the salmon-colored pectoral muscles is divided with electrocautery making certain to stay out of the intercostal bundles, which are covered with a glistening white fascia. Injury of the intercostal bundles can result in significant bleeding. The muscle flaps are mobilized laterally to the

Fig. 5 The pectoral muscle is divided from its insertion on the sternum overlying a costal cartilage. Once a plane is created, the empty knife handle is inserted to further develop the plane followed by a right angle retractor. This process is then repeated anterior to another adjacent costal cartilage. When the two retractors are then elevated, the pectoral muscle between them can be safely divided from the sternum and laterally the plane between the pectoral muscle and the intercostal muscles can be more readily defined. (From P. Puri and M. Höllwarth Eds, Pediatric Surgery, Springer Surgery Atlas Series, by permission Springer-Verlag)

R. C. Shamberger

costochondral junction or to the lateral extent of the deformity. Generally, cartilages 3–7 are involved, but sometimes the second cartilage is as well. Incisions are then placed through the perichondrial sheaths, parallel with the axis of the cartilage (Fig. 6). It is helpful to keep the incision on the flat anterior aspect of the rib. The perichondrial sheaths are dissected off the costal cartilage utilizing Welch perichondrial elevators (Codman and Shurtleff, Inc., Randolph, MA). Freeing the edge of the perichondrium from the medial aspect of the rib provides better visualization of the posterior aspect of the cartilage facilitating this process. The cross-sectional shape of the ribs must be remembered. Ribs 2 and 3 are fairly flat. Ribs 4 and 5 are round, and ribs 6 and 7 have a narrow width and greater depth.

Fig. 6 The perichondrium is dissected from the anterior surface of the costal cartilage. (From P. Puri and M. Höllwarth Eds, Pediatric Surgery, Springer Surgery Atlas Series, by permission Springer-Verlag)

8

Chest Wall Deformities

The medial aspect of the cartilage is then incised from the sternum (see insert), with the posterior aspect protected by the Welch perichondrial elevator (Fig. 7). Incising the cartilage directly adjacent to the sternum will also minimize the risk of injury to the internal mammary vessels which are generally a centimeter to a centimeter and a half lateral to the margin of the sternum. To minimize any impairment of subsequent growth of the ribs, a centimeter to a centimeter and half of

Fig. 7 The costal cartilage is divided sharply from the sternum with an instrument behind the cartilage to prevent injury to the posterior perichondrium and the deeper internal mammary vessels (inset). The cartilages are divided sharply from the osseous ribs leaving the costochondral junction intact with a segment of cartilage. (From P. Puri and M. Höllwarth Eds, Pediatric Surgery, Springer Surgery Atlas Series, by permission Springer-Verlag)

107

the costal cartilage is preserved with the costochondral junction. The wedge osteotomy is then created on the anterior surface of the sternum at the apex of the deformity (Fig. 8). The Hall air drill (Zimmer USA, Inc, Warsaw, IN) is used to create the osteotomy. The segment of bone is then mobilized using one of the wings of the perichondrial elevators, but without entirely dislodging it from the sternum. Leaving it partially in place will facilitate rapid healing of the fracture. The sternum is then elevated with a towel clip and posterior pressure is applied to the upper portion of the sternum to fracture the posterior sternal plate (Fig. 9). While in the past the xiphoid was divided along with the rectus muscle from the tip of the sternum, this step can currently be avoided. This minimizes the occurrence of an unsightly depression at the base of the sternum. Using a posterior sternal strut, it is also

Fig. 8 The anterior plate of the sternum is divided with a Hall air drill. (From P. Puri and M. Höllwarth Eds, Pediatric Surgery, Springer Surgery Atlas Series, by permission Springer-Verlag)

108

R. C. Shamberger

Fig. 10 This transverse image depicts the original configuration of the costal cartilages and the sternum and its final position being supported by the strut following surgery. (From P. Puri and M. Höllwarth Eds, Pediatric Surgery, Springer Surgery Atlas Series, by permission SpringerVerlag)

Fig. 9 The lower portion of the sternum is elevated using a large towel clamp to fracture the posterior plate of the sternum at the site of the anterior osteotomy and allow its anterior displacement. This will create a space between the back wall of the sternum and the pericardium so that a clamp can be safely passed behind the sternum to grasp the strut and pull it behind the sternum. (From P. Puri and M. Höllwarth Eds, Pediatric Surgery, Springer Surgery Atlas Series, by permission Springer-Verlag)

unnecessary to divide the lower perichondrial sheaths, as was done in the past. This division of the lower perichondrial sheaths also contributed to the depression below the sternum. If the xiphoid produces an unsightly protrusion when the sternum is in its corrected position, it can be divided from the sternum using a lateral approach with cautery. This avoids taking down the rectus attachment. Figure 10 depicts the retrosternal strut which is tunneled posterior to the sternum. This retrosternal tunnel is made by partially dividing one of the perichondrial sheaths directly adjacent to the sternum. A tunnel is then created posterior to the sternum with a Schnidt clamp, which is brought out directly adjacent to the sternum on the contralateral side to avoid injury to the internal mammary vessels. Prior to passing the strut behind the sternum, it is preformed so that there

is a slight depression in which the sternum will sit and the strut is curved somewhat posteriorly on each end to allow it to conform to the shape of the ribs and avoid any unsightly protrusions into the skin and the muscle. The Schnidt clamp is then used to draw the strut behind the sternum with the concave portion of the strut anterior. Once it is behind the sternum and in an appropriate position just anterior to the ribs on each side, it is rotated 180 . It is important in this step to make certain that the strut is deep to the pectoral muscle flap to provide adequate soft-tissue coverage over the strut. The strut is then secured to the periosteum laterally with two heavy #0 absorbable sutures. This will secure the strut in position. Figure 11 depicts the position of the retrosternal strut from an anterior perspective with the strut secured to the ribs on each side. The pectoralis major muscle flaps are then approximated over the sternum. The flaps are advanced inferiorly to cover the previously bare lower portion of the sternum with soft tissue. At the inferior aspect, the flap is attached to the rectus muscle with interrupted absorbable sutures.

The Nuss Minimally Invasive Repair of Pectus Excavatum (MIRPE) Two incisions are made at the anterior axillary line at the level of maximal sternal depression (Fig. 12).

8

Chest Wall Deformities

Fig. 11 The strut is shown in position behind the sternum elevating it anteriorly. It is important that the strut has significant overlap with the osseous rib to securely hold it in position. The strut is sutured to the underlying periosteum of a rib with an absorbable suture to prevent lateral displacement during the early stages of healing. (From P. Puri and M. Höllwarth Eds, Pediatric Surgery, Springer Surgery Atlas Series, by permission Springer-Verlag)

A pectus tunneler (Biomet Microfixation, Inc., Jacksonville, FL), or long clamp, is then passed through one lateral incision along the chest wall and enters into the pleural cavity at the inner aspect of the pectus ridge. It is tunneled behind the sternum and anterior to the pericardium, and it is brought out the contralateral side. The point of exit from the thorax is also aimed at the inner aspect of the pectus ridge. Thereafter, it is passed along the outside of the chest wall and out through the skin at the anterior axillary line. An umbilical tape is then grasped by the clamp or pectus tunneler and brought through the tunnel. Two tapes are often used in case one breaks. Several adaptations have been utilized to minimize the risk of cardiac injury from this maneuver. The first adaptation now widely utilized involves a thoracoscope to monitor the passage of the

109

Fig. 12 The pectus tunneler is shown with the preoperative configuration of the chest. It is passed from the most anterior site of the right chest under direct vision with a thoracoscope anterior to the pericardium and out the corresponding anterior position of the left side of the chest. (From P. Puri and M. Höllwarth Eds, Pediatric Surgery, Springer Surgery Atlas Series, by permission Springer-Verlag)

tunneler behind the sternum. A second adaptation less frequently used is to make a small incision at the tip of the sternum through which a bone hook can be inserted. The sternum is elevated anteriorly as the clamp is passed across the chest to broaden the retrosternal space. The preformed strut is shown in Fig. 13 (Biomet Microfixation, Inc., Jacksonville, FL). It has been premeasured and bent, to make sure that it fits the breadth of the patient’s chest, and is then brought through the chest and passed so that the concave surface is anterior. Once the bar is in position (Fig. 14), it is rotated 180 with a special “Pectus Flipper” (Biomet Microfixation, Inc., Jacksonville, FL) to elevate

110

Fig. 13 A cord is drawn through the chest cavities and anterior mediastinum and out the left side. (From P. Puri and M. Höllwarth Eds, Pediatric Surgery, Springer Surgery Atlas Series, by permission Springer-Verlag)

R. C. Shamberger

Fig. 15 Strut stabilizers are used to prevent rotation of the struts following surgery. They are secured to an underlying rib. (From P. Puri and M. Höllwarth Eds, Pediatric Surgery, Springer Surgery Atlas Series, by permission SpringerVerlag)

Fig. 16 Transverse view of the chest depicts the strut in its initial position. (From P. Puri and M. Höllwarth Eds, Pediatric Surgery, Springer Surgery Atlas Series, by permission Springer-Verlag)

Fig. 14 The preformed pectus strut is then pulled through the chest using the cord in an anterior concave position. (From P. Puri and M. Höllwarth Eds, Pediatric Surgery, Springer Surgery Atlas Series, by permission SpringerVerlag)

the sternum and costal cartilages. During this maneuver, the skin and muscle flaps are elevated over the end of the bar so that the bar sits directly along the chest wall.

The most frequent complication of this procedure when it was initially performed was rotation of the pectus strut. To reduce this risk, a “stabilizer” may be attached to both sides of the strut with heavy #3 wire or suture (Fig. 15). Once attached to the strut, it is then sutured to the soft tissues of the chest to provide secure fixation and prevent rotation of the bar and loss of correction of the deformity. Figure 16 shows the pectus strut in position prior to rotation, and Fig. 17 shows the bar in the final position displacing the sternum and costal

8

Chest Wall Deformities

Fig. 17 Transverse view of the chest depicts how the strut, when it is rotated 180 degrees, corrects the posterior displacement of the sternum and costal cartilages. (From P. Puri and M. Höllwarth Eds, Pediatric Surgery, Springer Surgery Atlas Series, by permission Springer-Verlag)

cartilages anteriorly to correct the pectus excavatum deformity. The bar is electively removed in 2–3 years.

Results The overall results of repair of pectus excavatum should be excellent. The perioperative risks must be limited. The most significant complication is a major recurrence, which has been described in large series as occurring in 5–10% of patients. A limited pneumothorax requiring aspiration is infrequent and rarely requires a thoracostomy tube. Wound infection should be rare with the use of perioperative antibiotic coverage and protective coverage of the skin during the operative procedure to minimize any contamination by skin flora. The long-term outcome of the Nuss procedure in teenagers is well documented. The most frequent complication described in early use of the minimally invasive procedure was rotation of the strut. Lateral stabilizers have significantly decreased the incidence of this complication. Other complications described include pneumothorax, pericarditis, and hemothorax. Complications unique to the minimal access procedure which have not occurred with the standard open technique include thoracic outlet syndrome and the rare occurrence of a carinate deformity after repair. Occurrence of an allergic reaction to the metal Lorenz struts has also occurred in 1% of patients who present with rashes along the area of the bar requiring replacement with bars composed

111

of other alloys. Older patients encounter significant pain equivalent to that of the open repair (Kelly 2007). Both techniques appear to achieve excellent correction of the deformity (Kelly et al. 2008). Complication rates of each technique were equivalent in a multi-institution study (Kelly et al 2013). Repair of pectus excavatum is important for children who are either psychologically distressed or physiologically impaired by their deformity.

Pectus Carinatum Pectus carinatum, an anterior protrusion of the sternum or chest wall, is much less frequent than pectus excavatum: 16.7% of all chest wall deformities in the Boston Children’s Hospital experience. The anterior protrusion occurs in a spectrum of configurations often divided into four categories (Shamberger and Welch 1987). The most frequent form, termed “chondrogladiolar,” consists of anterior protrusion of the body of the sternum with protrusion of the lower costal cartilages (Fig. 18). It is described as appearing as if a giant hand had pinched the chest from the front, forcing the sternum and medial portion of the costal cartilages forward and the lateral costal cartilages and ribs inward. Asymmetric deformities with anterior displacement of the costal cartilages on one side and normal cartilages on the contralateral side are less common (Fig. 19). Mixed lesions have a carinate deformity on one side and a depression or excavatum deformity on the contralateral side, often with sternal rotation. Some authors classify these as a variant of the excavatum deformities. The least frequent deformity is the chondromanubrial or “pouter pigeon” deformity with protrusion of the upper chest involving the manubrium and second and third costal cartilages with relative depression of the body of the sternum (Fig. 20). A clear-cut increased family incidence suggests a genetic basis. In a review by the author and colleagues of 152 patients, 26% had a family history of chest wall deformity and 12% of scoliosis (Shamberger and Welch 1987). It is much

112

R. C. Shamberger

Fig. 18 (a) Photo of a 19-year-old male with a symmetric chondrogladiolar pectus carinatum configuration. (b) Appearance of the patient following surgical correction

childhood, particularly in the period of rapid growth at puberty. The chondromanubrial deformity, in contrast with the chondrogladiolar form, is often noted at birth and is associated with a truncated, comma-shaped sternum with absent sternal segmentation or premature obliteration of the sternal sutures (Fig. 21). Currarino and Silverman (1958) described its association with an increased risk of congenital heart disease. Subsequently, Lees and Caldicott (1975) reviewed 1,915 thoracic radiographs and identified 135 children with sternal fusion anomalies. Eighteen percent of these children had documented congenital heart disease.

Fig. 19 A 12-year-old boy with an asymmetric pectus carinatum protrusion in which the right-sided costal cartilages produce a keel-like configuration

more frequent in boys than in girls by a three to one ratio. Scoliosis and other deformities of the spine are the most common associated musculoskeletal anomalies. Pectus carinatum is rarely present at birth, and in almost half of patients, the deformity was not identified until after the eleventh birthday. The deformity often progresses during early

Surgical Repair Correction of carinate deformities has had a colorful history, beginning with the first repair by Ravitch (1952) of an upper chondromanubrial deformity. He removed multiple costal cartilages and performed a double sternal osteotomy. In 1953, Lester reported two methods of repair for a lower chondrogladiolar deformity. The first approach, resection of the anterior portion of the sternum, was abandoned because of excessive blood loss and unsatisfactory results. The second

8

Chest Wall Deformities

113

Fig. 20 (a) Preoperative photo of a 15-year-old boy with a chondromanubrial pectus carinatum in which the superior second and third costal cartilages create the protrusion and

there is a relative depression of the more inferior body of the sternum. (b) Postoperative photo shows remarkable degree of correction of the configuration

method, which was subperiosteal resection of the entire sternum, was a no less radical technique. Chin and later Brodkin (1957, 1958), in a technique called the xiphosternopexy, advanced the transected xiphoid and the attached rectus muscles to a higher site on the sternum. This produced posterior displacement of the sternum in younger patients with a flexible chest wall. Howard combined this method with subperichondrial resection of the costal cartilages and a sternal osteotomy (1958). Ravitch reported repair of the chondrogladiolar deformity by resection of costal cartilage in a one- or two-stage procedure, with placement of “reefing” sutures to shorten and posteriorly displace the perichondrium (1960). A sternal osteotomy was used in one of three cases. Robicsek and associates described repair by subperichondrial resection of costal cartilages, combined with a transverse sternal osteotomy, and resection of the protruding lower portion of the sternum (1963). The xiphoid and rectus muscles

were reattached to the new lower margin of the sternum, pulling it posteriorly. In 1973, Welch and Vos reported an approach to these deformities that continues to be used by many today for open repair (1973).

Surgical Technique The placement of the skin incision, mobilization of the pectoral muscle flaps, and subperichondrial resection of the involved costal cartilage are identical to the method described for pectus excavatum. Management of the sternum is shown in Fig. 22 for the various deformities. In the chondromanubrial deformity, the costal cartilages must be resected from the second cartilage inferiorly (Shamberger and Welch 1988). A single-limb medium Hemovac drain (Snyder Laboratories, Inc., New Philadelphia, OH) is brought through the inferior skin flap, as for excavatum

114

R. C. Shamberger

Operative Results Results are overwhelmingly successful in these patients. In a review of 152 cases, postoperative recovery was generally uneventful (Shamberger and Welch 1987). Blood transfusions are rarely required, and none was given in the last 10 years of the report. There was a 3.9% rate of complications. Only three patients required revision, each having additional lower costal cartilages resected for persistent unilateral malformation of the costal arch.

Nonoperative Correction

Fig. 21 Lateral view of the chest radiograph of a male with the chondromanubrial configuration demonstrates the truncated and comma-shaped sternum

patients, with the suction ports placed in a parasternal position up to the level of the highest resected costal cartilage. The pectoralis muscle flaps and skin flaps are closed. Perioperative antibiotics are used as in pectus excavatum. Abramson has reported a minimally invasive operation for pectus carinatum (Abramson et al. 2009). The technique involves placement of a subcutaneous curved steel bar via lateral thoracic incisions. Subperiosteal wires attach small fixation plates to the ribs laterally and the convex bar is secured to the small fixation plates with screws. Satisfactory results have been reported. Best results are seen in younger patients who have a flexible chest wall. Other critical factors for success are insertion of the bar deep to the pectoral muscles and use of a strong pericostal wire.

Attempts to treat pectus carinatum by orthotic bracing have been reported since 1992 (Haje and Bowen 1992). Evolution of bracing devices has led to increased success of this method, and presently, several reports suggest that 65–80% of children and adolescents will have resolution with brace treatment alone (Egan et al. 2000; Frey et al. 2006; Lee et al. 2013). Compliance in the use of the brace is clearly the rate limiting factor for success in older patients. Recent efforts have focused on making the brace easy to conceal and more comfortable to wear. Bracing strategies which work toward incremental correction over several months have been met with better success than previous efforts. In teenagers, poor compliance with bracing programs can be addressed by peer pressure at a bracing clinic. This approach works optimally in patients with a symmetric deformity, but has been shown to have acceptable results even in those with an asymmetric configuration. Colozza recently reported on a quality of life questionnaire survey on patients who had treatment by bracing (Colozza and Bütter 2013). It revealed that the majority of patients were satisfied with their appearance after treatment, experienced minimal pain from the bracing, and would use the brace again. Their self-esteem increased significantly after bracing.

8

Chest Wall Deformities

Fig. 22 (a) For the chondrogladiolar configuration, a single osteotomy is created at the apex of the protrusion of the sternum following subperichondrial resection of the costal cartilages below that level. This allows posterior displacement of the sternum into an orthotopic position. (b) For patients with a mixed pectus deformity in which there is protrusion on one side of the sternum and depression on the second side, correction is achieved by symmetric resection of the deformed costal cartilages followed by a transverse wedge-shaped osteotomy which is wider on the depressed side of the sternum. Closure of the osteotomy achieves both anterior displacement and rotation of the sternum. This repair generally requires support of a retrosternal strut as in the open repair of pectus excavatum to support the sternum in its new position. (c) In patients with a chondromanubrial configuration, costal cartilages are resected up to the level of the second costal cartilage. A

115

broad osteotomy is then created at the apex of the protrusion and the posterior plate of the sternum is fractured with posterior pressure at this site. As the sternum is now attached at only the first costal cartilage, posterior displacement of the upper half of the sternum is achieved in conjunction with anterior displacement of the lower portion of the sternum correcting both components of the deformity. ((a) and (b) Reprinted from Journal of Pediatric Surgery, Vol. 22, Robert C. Shamberger, Kenneth J. Welch, Surgical correction of pectus carinatum, 48–53, Copyright (1987), with permission from Elsevier. (c) Reprinted from Journal of Pediatric Surgery, Vol. 23, Robert C. Shamberger, Kenneth J. Welch, Surgical correction of chondromanubial deformity (Currarino Silverman syndrome), 319–322, Copyright (1988), with permission from Elsevier)

116

Poland’s Syndrome Poland Alfred (1841), while a medical student, described an individual with congenital absence of the pectoralis major and minor muscles associated with syndactyly. Despite a prior report of this entity by Froriep (1839), the eponym Poland’s syndrome has been used in conjunction with this entity since Clarkson (1962), when first applied it to a group of similar patients. Subsequent reports have described additional components of the syndrome, including absence of ribs, chest wall depression, and abnormalities of the breasts. Each component of the syndrome occurs with variable severity. The extent of thoracic involvement may range from hypoplasia of the sternal head of the pectoralis major and minor muscles with normal underlying ribs to complete absence of the anterior portions of the second to fifth ribs and costal cartilages (Figs. 23 and 24). Breast involvement is frequent, ranging from mild hypoplasia to complete absence of the breast (amastia) and nipple (athelia), Abnormalities of the breast can be defined at birth by absence of the underlying breast bud and the hypoplastic nipple, which is often superiorly displaced. Minimal subcutaneous fat and an absence of axillary hair are additional components of the syndrome. Hand deformities may include hypoplasia of the fingers (brachydactyly) and fused fingers (syndactyly), involving the central three digits primarily. The most severe expression of the hand anomaly, mitten or claw deformity, (ectromelia) is fortunately rare. An extensive classification system of the associated hand anomalies has been developed (Al-Qattan 2002; Catena et al. 2012). Poland’s syndrome may also occur in combination with Sprengel’s deformity, in which there is decreased size, elevation, and winging of the scapula. Poland’s syndrome is associated with a second rare syndrome, the Möbius syndrome: bilateral or unilateral facial palsy and abducens oculi palsy. An unusual association between Poland’s syndrome and childhood leukemia has also been reported. The etiology of Poland’s syndrome is unknown. Poland’s syndrome is present at birth and has an estimated incidence of 1 in 30,000 to 1 in 32,000. The Boston Children’s Hospital

R. C. Shamberger

experience with Poland’s syndrome from 1970 to 1987, included 41 children and adolescents, of whom 21 were males (Shamberger et al. 1989). The lesion was right sided in 23 patients, left sided in 17 patients, and bilateral in one patient. Hand anomalies were noted in 23 (56%) patients and breast anomalies in 25 (61%) patients. In 10 children, the underlying thoracic abnormality required reconstruction, and in three children, rib or cartilage grafts were needed for complete repair.

Surgical Repair Assessment of the extent of involvement of the musculoskeletal components is critical for optimal thoracic reconstruction. If the deformity is limited to the sternal component of the pectoralis major and minor muscles without underlying chest wall deformity, little functional deficit and repair is unnecessary, except to facilitate breast augmentation in females. If the underlying costal cartilages are depressed or absent, repair must be considered to minimize the concavity, to eliminate the paradoxical motion of the chest wall if ribs are aplastic, and in girls to provide an optimal base for breast reconstruction. Ravitch reported correction of posteriorly displaced costal cartilages by unilateral resection of the cartilages; a wedge osteotomy of the sternum allowing rotation of the sternum; and fixation with Rehbein struts and Steinmann pins. Suitable repair can be achieved in most cases with bilateral costal cartilage resection and an oblique osteotomy, which corrects both the sternal rotation and posterior displacement, as in the patients with mixed pectus carinatum and excavatum deformity (Fig. 25). The sternum is then displaced anteriorly and is supported with a retrosternal strut, which allows correction of the posteriorly displaced costal cartilages. An unappreciated carinate deformity is often present on the contralateral side, which accentuates the ipsilateral concavity (Fig. 24b). Absence of the medial portion of the ribs can be managed with split rib grafts taken from the contralateral side. These must be secured to the sternum medially and to the “dagger point” ends

8

Chest Wall Deformities

Fig. 23 Individuals with Poland’s have a varied presentation which is dependent upon the components of this syndrome which they have. (a) This 17-year-old male has absence of the pectoralis major and minor muscles with hypoplasia of the nipple but with a normal contour of the chest wall and no hand anomalies. (b) This 8-year-old boy has aplasia of the third, fourth, and fifth ribs as well as obliquity of the sternum and ectromelia of the ipsilateral hand. (c) A 14-year-old female manifests aplasia of the

117

anterior third through fifth ribs and amastia and athelia of the breast on her right side. The clavicular component of the pectoralis major muscle was absent as well as the more commonly involved costal component. (Reprinted from Journal of Pediatric Surgery, Vol. 24, Robert C. Shamberger, Kenneth J. Welch, Joseph Upton, Surgical treatment of thoracic deformity in Poland’s syndrome, 760–766, Copyright (1989), with permission from Elsevier)

118

R. C. Shamberger

Fig. 24 The spectrum of the chest wall abnormality seen in individuals with Poland’s syndrome is depicted in this diagram. (a) An entirely normal rib cage is seen most frequently with only absence of the costal portion of the pectoral muscles. (b) Depression of the ribs on the involved side with rotation of the sternum and contralateral protrusion of the ribs and costal cartilages is the second most common configuration seen. (c) Hypoplasia of the ribs on the involved side is also seen without significant

depression. This configuration does not require surgical correction. (d) Aplasia of one or more of the ribs is much less frequently seen, but when present is often associated with depression of the adjacent ribs and rotation of the sternum. (Reprinted from Journal of Pediatric Surgery, Vol. 24, Robert C. Shamberger, Kenneth J. Welch, Joseph Upton, Surgical treatment of thoracic deformity in Poland’s syndrome, 760–766, Copyright (1989), with permission from Elsevier)

of the hypoplastic ribs laterally. The grafts can be covered with a prosthetic mesh if needed for further support. In these cases, it must be remembered that there is little tissue present between the endothoracic fascia and the fascial remnants of the pectoral muscles. Soft tissue coverage of the area can be augmented with transfer of a latissimus dorsi muscle flap. This is particularly helpful in girls who will require breast augmentation (Haller et al. 1984). Flap rotation is seldom, if ever,

required in boys and has the disadvantage of adding a second posterior thoracic scar and decreasing the strength of the latissimus dorsi muscle. Customized silicone prostheses can be utilized to correct both the chest wall depression as well as absence of the breast (Saour et al. 2008). Other recent innovations in repair include use of Surgisis ® and a “swinging rib” or of a Vertical Expandable Prosthetic Rib system.

8

Chest Wall Deformities

Fig. 25 (continued)

119

120

Conclusion and Future Directions Significant advances have been made in the management of children and adolescents with chest wall abnormalities. The minimally invasive repair of pectus excavatum avoids the anterior thoracic scar in exchange for two lateral axillary incisions and preserves the costal cartilages, which may be critical to the repair of younger children with significant residual chest wall growth. The physiologic impact of the standard open versus the MIRPE appears to be equivalent as is the postoperative pain in adolescents. It is now recognized that Pectus carinatum can be treated, in many cases, with orthotic bracing and does not require open repair. Enhancements of the braces continue to optimize results and minimize the discomfort of wearing the device. Poland’s syndrome is best treated with a clear focus on the components of the abnormality which are quite variable between individuals. Attempts should be made to return the chest wall to as normal a contour as possible, for both esthetic considerations and to minimize the adverse physiologic impact of any chest wall depression.

References Abramson H, D’Agostino J, Wuscovi S. A 5-year experience with minimally invasive technique for pectus carinatum repair. J Pediatr Surg. 2009;44:118–24. Adkins PC, Blades B. A stainless steel strut for correction of pectus excavatum. Surg Gynecol Obstet. 1961;113:111–3.

R. C. Shamberger Al-Qattan M. Classification of hand anomalies in Poland’s syndrome. Br J Plast Surg. 2002;54:132–6. Baronofsky ID. Technique for correction of pectus excavatum. Surgery. 1957;42:884–90. Beiser GD, et al. Impairment of cardiac function in patients with pectus excavatum, with improvement after operative correction. N Engl J Med. 1972;287:267–72. Brodkin H. Pigeon breast – congenital chondrosternal prominence. Arch Surg. 1958;77:261–70. Cahill JL, et al. A summary of preoperative and postoperative cardiorespiratory performance in patients undergoing pectus excavatum and carinatum repair. J Pediatr Surg. 1984;19:430–3. Catena N, Divizia MT, Calevo MG, et al. Hand and upper limb anomalies in Poland syndrome: a new proposal of classification. J Pediatr Orthop. 2012;32:722–6. Chin E. Surgery of funnel chest and congenital sternal prominence. Br J Surg. 1957;44:360–76. Clarkson P. Poland’s syndactyly. Guys Hosp Rep. 1962;111:335–46. Colozza S, Bütter A. Bracing in pediatric patients with pectus carinatum is effective and improves quality of life. J Pediatr Surg. 2013;48:1055–9. Croitoru DP, et al. Experience and modification update for the minimally invasive Nuss technique for pectus excavatum repair in 303 patients. J Pediatr Surg. 2002;37:437–45. Currarino G, Silverman F. Premature obliteration of the sternal sutures and pigeon-breast deformity. Radiology. 1958;70:532–40. Egan J, DuBois J, Morphy M, et al. Compressive orthotics in the treatment of asymmetric pectus carinatum: a preliminary report with an objective radiographic marker. J Pediatr Surg. 2000;35:1183–6. Frey A, Garcia V, Brown R, et al. Nonoperative management of pectus carinatum. J Pediatr Surg. 2006;41:40–5. Froriep R. Beobachtung eines Falles von Mangel der Brustdruse. Notizen Geb Natur Heilkunde. 1839;10:9–14. Goretsky MJ, McGuire MM. Complications associated with the minimally invasive repair of pectus excavatum. Semin Pediatr Surg. 2018;27(3):151–5.

ä Fig. 25 Correction of Poland’s syndrome with aplasia of the ribs is shown here. (a) A transverse incision is placed below the nipple lines and in females in the site of the future inframammary crease. (b) Schematic depiction of the deformity with rotation of the sternum, depression of the ipsilateral cartilages, and a carinate protrusion of the contralateral cartilages. (c) The endothoracic fascia is encountered directly below the attenuated subcutaneous tissue and pectoral fascia in patients with aplasia of the ribs. The pectoral muscle flap is elevated on the contralateral side and if present, the attenuated pectoral fascia is elevated on the involved side to expose the sternum and costal cartilages. Subperichondrial resection of the costal cartilages is then performed as shown by the dashed lines. Rarely this must be carried to the level of the second costal

cartilage. (d) A transverse offset wedge-shaped sternal osteotomy is then created as in a mixed-deformity case. The sternum is then supported in position with a retrosternal bar (not depicted). (e) In cases in which ribs are aplastic, rib grafts are harvested from the contralateral fifth or sixth ribs and then secured medially with wire sutures to previously created notches into the sternum and with wire to the native ribs laterally. Ribs are generally split as shown along their short axis to maintain maximum mechanical strength. (Reprinted from Journal of Pediatric Surgery, Vol. 24, Robert C. Shamberger, Kenneth J. Welch, Joseph Upton, Surgical treatment of thoracic deformity in Poland’s syndrome, 760–766, Copyright (1989), with permission from Elsevier)

8

Chest Wall Deformities

Haje S, Bowen J. Preliminary results of orthotic treatment of pectus deformities in children and adolescents. J Pediatr Orthop. 1992;12:795–800. Haller JJ, Colombani P, Miller D, et al. Early reconstruction of Poland’s syndrome using autologous rib grafts combined with latissimus muscle flap. J Pediatr Surg. 1984;19:423–9. Haller JJ, et al. Use of CT scans in selection of patients for pectus excavatum surgery: a preliminary report. J Pediatr Surg. 1987;22:904–6. Howard R. Pigeon chest (protrusion deformity of the sternum). Med J Aust. 1958;45:664–6. Kelly RJ, et al. Prospective multicenter study of surgical correction of pectus excavatum: design, perioperative complications, pain, and baseline pulmonary function facilitated by internet-based data collection. J Am Coll Surg. 2007;205:205–216. Kelly R, et al. Surgical repair of pectus excavatum markedly improves body image and perceived ability for physical activity: Multicenter Study. Pediatrics. 2008;122:1218–22. Kelly R, et al. Twenty-one years of experience with minimally invasive repair of pectus excavatum by the Nuss procedure in 1215 patients. Ann Surg. 2010;252:1072–81. Kelly R, et al. Multicenter study of pectus excavatum, final report: complications, status/exercise pulmonary function, and anatomic outcomes. J Am Coll Surg. 2013;217:1080–9. Lee R, Moormon S, Schneider M, et al. Bracing is an effective therapy to pectus carinatum: interim results. J Pediatr Surg. 2013;48:184–90. Lees R, Caldicott J. Sternal anomalies and congenital heart disease. Am J Roentgenol Radium Therapy, Nucl Med. 1975;124:423–7. Lester C. Pigeon breast (pectus carinatum) and other protrusion deformities of the chest of developmental origin. Ann Surg. 1953;137:482–9.

121 Notrica DM. The Nuss procedure for repair of pectus excavatum: 20 error traps and a culture of safety. Semin Pediatr Surg. 2019;28(3):172–7. Nuss D, et al. A 10 year review of a minimally invasive technique for the correction of pectus excavatum. J Pediatr Surg. 1998;33:545–52. Peterson RJ, et al. Noninvasive assessment of exercise cardiac function before and after pectus excavatum repair. J Thorac Cardiovasc Surg. 1985;90:251–60. Poland A. Deficiency of pectoralis muscles. Guy’s Hospital Rep. 1841;6:191–3. Ravitch MM. The operative treatment of pectus excavatum. Ann Surg. 1949;129:429–44. Ravitch M. Unusual sternal deformity with cardiac symptomsoperative correction. J Thorac Surg. 1952;23:138–44. Ravitch M. The operative correction of pectus carinatum (pigeon breast). Ann Surg. 1960;151:705–14. Rehbein F, Wernicke HH. The operative treatment of the funnel chest. Arch Dis Child. 1957;32:5–8. Robicsek F, Sargar P, Taylor F, et al. The surgical treatment of chrondrosternal prominence (pectus carinatum). J Thorac Cardiovasc Surg. 1963;45:691–701. Saour S, Shaaban H, McPhail J, et al. Customised silicone prostheses for the reconstruction of chest wall defects: technique of manufacture and final outcome. J Plast Reconstr Anesthet Surg. 2008;61:1205–9. Shamberger R, Welch K. Surgical correction of pectus carinatum. J Pediatr Surg. 1987;22:48–53. Shamberger RC, Welch KJ. Surgical Repair of Pectus Excavatum. J Pediatr Surg. 1988;23:615–622. Shamberger R, Welch K, Upton J III. Surgical treatment of thoracic deformity in Poland’s syndrome. J Pediatr Surg. 1989;24:760–5. Welch KJ. Satisfactory surgical correction of pectus excavatum deformity in childhood: a limited opportunity. J Thorac Surg. 1958;36:697–713. Welch K, Vos A. Surgical correction of pectus carinatum (pigeon breast). J Pediatr Surg. 1973;8:659–67.

9

Empyema Michael Singh and Dakshesh Parikh

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Investigation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Blood Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Computed Thermography (CT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

125 125 125 125 125

Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Supportive Medical Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intercostal Drainage and Fibrinolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fibrinolysis Versus Thoracoscopic Debridement of Empyema . . . . . . . . . . . . . . . . . . . . . . . . Debridement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Decortication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thoracoscopic (Video-Assisted Thoracoscopic VATS) Debridement . . . . . . . . . . . . . . . . . . Mini Thoracotomy and Debridement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thoracotomy and Decortication (Parikh 2009) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

126 126 126 127 129 129 129 129 131 131

Complicated Empyema Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 Necrotizing Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 Pneumatocele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 Bronchopleural Fistula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

M. Singh (*) Department Paediatric Surgery, Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, UK e-mail: [email protected] D. Parikh Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, UK e-mail: [email protected]; [email protected] © Her Majesty the Queen in Right of United Kingdom 2021 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43559-5_100

123

124

M. Singh and D. Parikh Operative Procedure for Serratus Muscle Digitation Flap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

Abstract

The incidence of pediatric empyema is increasing globally. It is usually a complication of pneumonia, with Streptococcus pneumoniae the most common organism identified. If untreated, the effusion progresses through three stages: exudative, fibropurulent, and organization. Early medical management may halt the progression. Chest X-ray and ultrasound are useful initial investigations, with CT of the chest reserved for complicated patients. The mainstay of treatment includes intravenous antibiotics and effusion drainage. Intrapleural fibrinolysis has improved the outcome. A mini thoracotomy or thoracoscopic debridement can produce effective drainage and lung re-expansion with a low recurrence. Thoracotomy and decortication is reserved for an organized empyema, with or without a bronchopleural fistula. Keywords

Empyema · Fibrinolysis · Decortication · Thoracoscopic · Thoracotomy · Empyema thoracis · Parapneumonic effusion · Pleural empyema

Introduction Empyema of the chest is the accumulation of pus in the pleural cavity. The most common etiology in childhood is secondary to an underlying pneumonia. The incidence is 3.3 per 100,000 children (Balfour-Lynn et al. 2005; Rees et al. 1997; Playfor et al. 1997; Hardie et al. 1996). Globally, there is an increasing incidence (Liese et al. 2019), with the under 5 year olds (53%) most commonly affected (Li and Tancredi 2010).

While the mortality from empyema is low, the morbidity and burden on health care systems is significant.

Etiology The majority of pediatric empyema is secondary to acute bacterial pneumonia. However, it can complicate viral infections (chicken pox and measles). Other predisposing factors include: chronic lung disease, steroid and immunosuppressive drugs, diabetes, transplantation, esophageal perforation, and peritonitis. The most common causative bacteria is Streptococcus pneumoniae. Other associated bacteria include: Group A Streptococcus, Streptococcus viridans, Streptococcus anginosus, Staphylococcus aureus, Haemophilus influenza, Streptococcus milleri, and the anaerobic Peptostreptococcus. However, due to prior antibiotic therapy, the yield from pleural fluid culture is low (17–42%) (Saglani et al. 2005; Bishay et al. 2009). The introduction of broad range polymerase chain reaction (PCR) has increased the ability to identify many species in a single assay. The advantages include: time and cost savings, identifying unexpected organisms, such as anaerobes, and improving targeted therapy. PCR combined with pleural fluid culture increases the bacterial identification rate up to 75% of patients (Saglani et al. 2005).

Pathology The pathology of empyema is a continuum over three stages: stage 1 exudative, stage 2 fibropurulent, and stage 3 organization (Table 1) (Balfour-Lynn et al. 2005; Parikh 2009). Its progression is influenced by: organism virulence, host resistance, antibiotic use,

9

Empyema

125

Table 1 The different phases of an empyema and their characteristics Stage I Exudative phase Stage II Fibropurulent phase

Stage III Organization phase

Initial post inflammatory response to an underlying pneumonia. Clear or cloudy fluid, high protein, low number of white cells, and sugar within the pleural space Advanced inflammatory process results in the deposition of fibrin within the parapneumonic effusion causing loculations. The effusion becomes thicker containing gelatinous material and pus. The visceral and parietal pleura get covered with pyogenic material. As the process advances more fibroblast mature to form fibrosis The fibrinous tissue matures and causes fibrosis which covers both visceral and parietal pleura. The consolidated lung gets trapped under this fibrous peel. Failure of re-expansion of the collapsed lung inevitably results in loss of function, a focus for a recurrent infection and bronchiectasis

and drainage procedures. Inevitably, the disease progresses if inappropriately managed. A large untreated empyema can spontaneously drain alongside a perforating vessel to the surface of the chest wall and is called empyema necessitans. If untreated, it can spontaneously drain externally and can cause an open pneumothorax (Pleuro-cuteneous fistula). Infection can cause a pericardial effusion or empyema. Spontaneous drainage into the airways or hematogenous spread to the bone and brain is possible.

Clinical Presentation The initial clinical presentation is of pneumonia: cough, fever, tachypnea, and anorexia. Empyema should be suspected when there is worsening or recurrence of the fever and tachypnea, despite appropriate antibiotic therapy. An older child may complain of pleuritic chest pain or abdominal pain. Examination of the chest will reveal poor air entry and stony dullness over the affected area. In advanced cases, there is reduced movement, loss of volume, and scoliosis on the affected side of the chest. A large effusion will result in marked tachypnea and mediastinal shift with a deviated trachea.

Investigation

Radiology A chest x-ray will give the typical appearance of an effusion with the meniscus sign (Fig. 1). There will also be signs of lung consolidation. In complicated cases, the presence of an air fluid level could indicate a lung abscess or bronchopleural fistula (Fig. 2).

Ultrasound Chest ultrasonography can provide very useful information about the nature of the effusion, avoiding the need for Computed Tomography (CT) scan and unnecessary irradiation. An ultrasound can identify if the effusion is clear, contains debris, and fibrin septation consistent with a loculated effusion (Fig. 3a, b). An ultrasound is superior to CT in identifying pleural septation. It can also be used to mark the site of chest drain insertion (Kurian et al. 2009). One advantage of ultrasound is that it is portable and can be done at the patient’s bedside without sedation. The disadvantages of ultrasound include: poor identification of mediastinal and lung pathology as well as tumors. Homogenous solid lesions may be misdiagnosed as advanced empyema (Sharif et al. 2006). The extent of necrotizing pneumonia is also difficult to quantify on ultrasound.

Blood Investigations Computed Thermography (CT) The following tests are indicated: full blood count, C reactive protein, and blood cultures. Serial measurements of the inflammatory parameters can be useful in monitoring the response to therapy.

Although CT scans of the chest offers no real advantage over ultrasound in the management of uncomplicated empyema, it gives better anatomical

126

M. Singh and D. Parikh

procedure, lung abscess, pneumatocele, bronchopleural fistula, and necrotizing pneumonia. Parenchymal necrosis appears as low-density areas within consolidated lung, with reduced enhancement relative to the adjacent parenchyma (Kurian et al. 2009). CT is particularly useful for patients who have had a poor response to fibrinolysis or complications following surgery, including recurrence (Fig. 4a, b).

Management

Fig. 1 Chest X-ray showing a complete whiteout of the right chest from a large effusion

The management of early empyema should be aimed at achieving adequate drainage and full expansion of the lung (Flowchart 1). Failure of management should be recognized early and prompt referral to a specialized pediatric thoracic surgery center. The aims of both the medical and surgical management of empyema are as follows: • Control of sepsis with appropriate antibiotics • Encourage lung expansion: chest drain, fibrinolysis, or surgery • Manage complications: conservative or surgery

Supportive Medical Therapy Supportive medical therapy includes: oxygen, rehydration with intravenous fluids, analgesia, antipyretics, physiotherapy, and nutritional supplementation.

Antibiotics Fig. 2 Chest X-ray showing a right pneumothorax with effusion and collapse and consolidation of the upper, middle and lower lobes of the lung. These findings indicate a bronchopleural fistula

definition to a surgeon. The use of CT with intravenous contrast can be selective where surgery is considered (Balfour-Lynn et al. 2005). It can image the lung parenchyma and therefore has a role in persisting pyrexia following a drainage

In the early exudative phase, high doses of appropriate antibiotics can result in improvement. However, in the fibrinopurulent phase, antibiotics alone are unlikely to result in improvement. The antibiotics used should ideally follow the local antibiotic policy and known sensitivities but must cover S. pneumoniae, S. pyogenes, and S. aureus. For community-acquired pneumonia, the following antibiotics will be appropriate: Coamoxiclav, Cefuroxime, Penicillin and

9

Empyema

Fig. 3 (a) Ultrasound of the right chest showing a clear effusion. The arrow is pointing to the diaphragm. (b) The empyema has progressed to the Fibropurulent Phase.

127

Septations can be seen on the ultrasound (arrow). EFF is effusion

Fig. 4 (a, b) CT showing a recurrent effusion and abscess cavity () in the right middle lobe post thoracoscopic debridement

Flucloxacillin, Amoxicillin and Flucloxacillin, and Clindamycin. Gram negative and anaerobic cover should be included if the empyema is as a result of hospital-acquired infection, aspiration, peritonitis, or surgery. If the patient has a small effusion and has had a good clinical response to 48 h of intravenous antibiotics, then conservative management should continue. Oral antibiotics should be continued for up to 4 weeks post discharge to allow for complete resolution (BalfourLynn et al. 2005). A recent study of pleural tapguided 14 day antimicrobial treatment yielded excellent results in children with empyema (Meyer Sauteur et al. 2019).

Intercostal Drainage and Fibrinolysis Drainage of the effusion should be considered if there is persistent pyrexia, worsening respiratory signs or a loculated empyema. The intrapleural instillation of a fibrinolytic agent has been shown to improve the outcome in pediatric empyema (Islam et al. 2012). A randomized trial of intrapleural urokinase versus saline for pediatric empyema showed a shorter hospital stay in the urokinase group (Table 2). The patients who had urokinase and a small size 10 (1.7 Fr) chest drain had a shorter hospital stay. The only adverse event reported was discomfort on instillation of both

128 Flowchart 1 A flowchart illustrating the management of a parapneumonic effusion or empyema

M. Singh and D. Parikh

Parapneumonic Empyema

•Supportive medical management •Intravenous antibiotics •Chest X-Ray, Ultrasound

Clinical and radiological improvement after 48 hours

Yes

Continue conservative management

Yes

Oral antibiotics for 4 weeks

No •Drainage and Fibrinolysis •Thoracoscopic debridement •Thoracotomy debridement

Clinical and radiological improvement No

Manage as complicated Empyema

urokinase and saline. Five of the 60 patients required surgical debridement (3 placebo, 2 urokinase) (Balfour-Lynn et al. 2005). It is recommended that the chest drain should be inserted by someone who is appropriately trained, preferably under ultrasound guidance. A small-size drain can be just as effective as a large one. The small-size drain can be easily inserted under ultrasound guidance with a Seldinger technique (Laws et al. 2003). In children, a small-size Seldinger

Table 2 British Thoracic Society dosing schedule for intrapleural urokinase (Balfour-Lynn et al. 2005) British Thoracic Society Guidelines for intrapleural urokinase (Balfour-Lynn et al. 2005) >10 kg – 40,000 Units in 40 ml normal saline, twice per day for 3 days 15 1 1–4.9 2 >5 0–4 Low probability 5–8 Indeterminate 9–12 High probability

>38  C

2 1

>37.5  C

>75%

2 1

>70%

2 1

>10

1

>10

2

6 Likely

1 1

0–4 Unlikely 5–6 Possible 7–8 Probable >9 Very probable

12

Appendicitis

of 80–100%. Neonatal appendicitis presents similarly to NEC with irritability, lethargy, abdominal distension, vomiting, cardiovascular and temperature instability, and palpable mass (Rothrock and Pagane 2000). It is often only diagnosed at laparotomy or even at autopsy and is associated with mortality rates of 25–35%, although rates of up to 100% have been recorded according to recent evidence (Rothrock and Pagane 2000; Karaman et al. 2003). Typical features of appendicitis in older preschool children include vomiting, abdominal pain, fever, irritability, and anorexia, although atypical symptoms such as cough, diarrhea, and urinary symptoms are relatively common. Abdominal tenderness tends to be more localized to the RLQ in older preschool children, whereas it can be quite diffused in toddlers (Rothrock and Pagane 2000). Presentation and diagnosis in this age group are frequently delayed, and symptoms can be frequently attributed to conditions that occur far more commonly in preschool children – gastroenteritis, upper respiratory tract infection, otitis media, and intussusception (Rothrock and Pagane 2000; Naiditch et al. 2013). Perforation rates increase with decreasing age, with an overall perforation rate of 56–62% for this group of patients (Mallick 2008; Bansal et al. 2012). This ranges from 49% in those over 4 years to 89% in those under 1 year of age (Bansal et al. 2012). In this age group, perforated appendicitis is associated with a significant burden on morbidity, ranging from surgical site infection, pneumonia, bowel obstruction, incisional hernia, and enterocutaneous fistula (Mallick 2008; Bansal et al. 2012). Bansal et al. (2012) noted that while younger preschool children presented with more advanced appendicitis, their postoperative complication rate was lower than in older children (Bansal et al. 2012). In view of the frequency of atypical presentation and the increased incidence of advanced appendicitis, a high index of suspicion is necessary in preschool children presenting with acute abdominal pain. Early diagnosis is the key to reducing morbidity in the preschool child with appendicitis.

171

Laboratory Investigations Laboratory investigations have proved neither sensitive nor specific in the diagnosis of appendicitis. Urinalysis is an essential investigation in children presenting with abdominal pain, although it must be borne in mind that pyuria or microscopic hematuria may be present in 7–25% of children with appendicitis (Rothrock and Pagane 2000). White cell count is probably the most widely available laboratory investigation utilized in the diagnosis of appendicitis. It can be raised in 70% of patients who have RLQ pain that is not due to appendicitis, and multiple studies have found it to be of limited utility in the diagnosis of appendicitis (Yu et al. 2013). C-reactive protein is synthesized in the liver in response to inflammatory conditions. Its diagnostic accuracy is highest in appendicitis complicated by perforation or abscess; its sensitivity in early appendicitis is poor, inferior to that of white cell count. Much attention has recently been given to procalcitonin, a precursor of calcitonin, as a promising marker of bacterial infection. While its diagnostic accuracy in diagnosing appendicitis is lower than that with C-reactive protein or white cell count, it is useful as a marker of severity of appendicitis (Yu et al. 2013). Several studies have also identified interleukin-6 as a useful marker of disease severity, with moderate diagnostic accuracy for appendicitis, similar to C-reactive protein (Sack et al. 2006). Despite these advances, most authors agree that normal inflammatory markers cannot exclude a diagnosis of appendicitis in a child presenting with RLQ pain.

Radiological Investigations In many cases, the diagnosis of appendicitis can be reliably made without the use of laboratory or radiological investigations; however, their use in selected patients can serve to reduce the rate of negative appendectomy or clarify appendicitis severity and suitability for early or interval appendectomy. Plain radiography of the abdomen, which exposes the patient to the equivalent radiation dose of 35–50 chest x-rays, may demonstrate

172

A. E. Mortell and D. Coyle

Fig. 3 Plain abdominal x-ray showing rounded density (tip of white arrow) in right lower quadrant in a child with appendicitis and an appendicolith. (Image courtesy of Children’s University Hospital, Dublin 1, Ireland)

Fig. 4 Transverse ultrasound image of noncompressible appendix with mural thickening. (Image courtesy of Children’s University Hospital, Dublin 1, Ireland)

a radio-opaque appendicolith in 7–15% (Environment 2000; Weissleder et al. 2007) (Fig. 3). Despite its relatively frequent utilization in the work-up of children with acute abdominal pain, its diagnostic value for appendicitis has been questioned by numerous studies, which have shown it to be neither sensitive nor specific, and sometimes misleading (Rao et al. 1999). Its use is therefore not recommended in the routine evaluation of children with suspected appendicitis, unless there is suspicion of bowel obstruction or an alternative diagnosis of urolithiasis based on clinical features. Contrast enemas are no longer seen to be of clinical value due to poor sensitivity and specificity.

Ultrasound is portable, fast, of modest incremental cost, useful in delineating gynecologic disease, and free of irradiation exposure. It is, however, highly operator-dependent. The appendix can be identified on ultrasound in approximately 24% of patients, although this rate is higher with dedicated pediatric sonographers (Fig. 4). Typical findings suggestive of appendicitis on ultrasound include a non-compressible appendix with appendiceal maximal outer diameter >6 mm enlargement, appendiceal wall thickness >3 mm, echogenic edematous mesenteric fat stranding, hypoechoic periappendiceal halo with associated wall edema, wall hyperemia on color Doppler, and the presence of an appendicolith

12

Appendicitis

173

Fig. 5 Thickened tubular structure seen on ultrasound in right lower quadrant with surrounding fat stranding in a child with appendicitis. (Image courtesy of Children’s University Hospital, Dublin 1, Ireland)

(Goldin et al. 2011) (Fig. 5). A multivariate analysis carried out by Trout et al. (2012) found inflammation of the periappendiceal fat to be the only significant independent predictor of appendicitis (Trout et al. 2012). A meta-analysis of the performance of ultrasound in children with appendicitis demonstrated a sensitivity and specificity of 88% and 94%, respectively (Doria et al. 2006). In a series of 2763 patients, Park et al. (2013) report positive and negative predictive values of 96.5% and 97.7%, respectively (Park et al. 2013). Many authors are now recommending ultrasound as a preferable first-line investigation to computed tomography (CT) in children, given the advantages discussed above, with the exception of obese children, in whom ultrasound detection rates are reduced (Park et al. 2013). There has been a dramatic increase in the use of cross-sectional imaging with CT in the evaluation of children with abdominal pain over the past 10–15 years. The principal advantages of CT are its operator independency and enhanced delineation of disease extent in perforated appendicitis (Fig. 6). It has established itself as a highly sensitive and specific imaging modality in the diagnosis of appendicitis, with studies quoting sensitivity and specificity in the order of 96% and 97%, respectively, and positive and negative predictive values of up to 100% and 100%,

Fig. 6 Coronal computed tomography imaging demonstrating retrocecal appendicitis. The appendix appears thickened and fluid filled. (Image courtesy of Children’s University Hospital, Dublin 1, Ireland)

respectively (Toorenvliet et al. 2010). These findings seem to be independent of body mass index, a major advantage over ultrasound. However, the radiation dose associated with nonselective CT of the abdomen or pelvis is

174

equivalent to approximately 500 chest x-rays (Environment 2000). The risk of radiationinduced cancer in a 5-year-old who has a CT abdomen is 26.1 per 100,000 in girls and 20.4 per 100,000 in boys (Doria 2009). This has led to efforts on the part of many institutions to try and limit the use of CT in the evaluation of abdominal pain, where appendicitis is suspected, to a more selected population in whom clinical, laboratory, and sonographical findings are equivocal. Some centers have employed the use of a risk stratification protocol to aid in better patient selection for CT, mindful that careful history and examination by an experienced surgeon can have comparable diagnostic accuracy. In patients with an uncertain diagnosis of acute abdominal pain, a policy of active observation in hospital is usually practiced (Surana et al. 1995). A repeated structured clinical examination is simple and noninvasive. However, the argument against this policy is that it may lead to a delay in specific management of these patients and may result in a high incidence of perforation. Conversely, numerous studies have found that active observation is not associated with higher rates of complicated appendicitis or morbidity and in many cases it improves accuracy of diagnosis and reduces the rate of negative appendectomy (Surana et al. 1995; Cavusoglu et al. 2009).

Management Non-operative Management of Uncomplicated Appendicitis An appendicectomy is currently considered the gold standard treatment for acute appendicitis. Recently, the need for surgery has been challenged both in adults and children. Several studies have recently reported that the non-operative treatment of uncomplicated appendicitis in children is safe and that this modality of treatment is gaining ground around the world (Knaapen et al. 2019). A number of multicenter randomized trials comparing non-operative treatment with appendicectomy for acute uncomplicated appendicitis are currently ongoing and should provide,

A. E. Mortell and D. Coyle

in the near future, evidence regarding the potential of this treatment modality (Hutchings et al. 2018; Hall et al. 2017).

Preoperative Management Once a child has been diagnosed with appendicitis, the principles of management are broadly similar, irrespective of disease severity. Opioid or non-opioid analgesia has been shown to be effective in reducing the pain associated with appendicitis, without obscuring clinical findings that allow a diagnosis of appendicitis to be made (Friday 2006). Intravenous fluid resuscitation is almost always indicated due to vomiting, poor oral intake, and increased insensible losses due to pyrexia. Resuscitation is guided by the degree of sepsis and dehydration on assessment. Broad-spectrum intravenous antibiotics therapy should be commenced at the time of diagnosis, with the choice of agent (s) determined by local antibiotic susceptibility patterns and hospital-specific antimicrobial usage guidelines. Antibiotic coverage should take account of the common organisms isolated from peritoneal swabs and be directed against gram-negative bacteria, anaerobes, and skin flora. Expeditious surgical treatment within 6–24 h has been traditionally accepted as the standard operative management for nonphlegmatous appendicitis. However, there is a mounting body of evidence suggesting that conservative management of appendicitis with antibiotics, with or without an interval appendectomy, may be an acceptable alternative to this approach.

Operative Technique Open Appendectomy McBurney described a muscle-splitting incision over what came to be known as McBurney’s point in 1893; this landmark lies at a point 2/3 of the way along a line from the umbilicus to the anterior superior iliac spine. The use of McBurney’s point as the anatomical landmark

12

Appendicitis

for this incision is based on the assumption that the base of the appendix lies below this point in the majority of patients. This incision has in recent times been largely superseded in children by the Lanz incision, an RLQ transverse skin crease incision, which, while still centered on McBurney’s point, runs along Langer’s lines and gives a more cosmetically acceptable result. Anthropometric studies carried out by Karim et al. (1990) demonstrated the appendix to lie inferior to the interspinous line and McBurney’s point in 70% of patients, and in practice the Lanz incision may be modified to be higher or lower depending on surgeon preference (Karim et al. 1990). Dissection should proceed with splitting of the muscular layers in the direction of their fibers. On opening the peritoneum, a sample of peritoneal fluid can be taken for culture. While this may help direct postoperative antibiotic therapy in a small number of patients, the majority will receive adequate coverage from a standard broad-spectrum antimicrobial regimen. The mesoappendix is divided and the appendiceal base clamped and ligated. Inversion of the stump is a controversial practice. Best clinical evidence available presently suggests no benefit over simple ligation regarding rates of postoperative surgical site infection and the potential for distortion of cecal anatomy leading to the false impression of a cecal tumor on future radiological studies (D’Souza 2011). Any free pus should be suctioned and irrigation with saline may be performed. The abdominal wall is closed in layers. The skin is usually closed by subcuticular absorbable sutures even in the cases complicated by perforation. Primary wound closure after perforated appendicitis is safe, economical, and advantageous in pediatric practice (Henry and Moss 2005). The placement of peritoneal drains in children, even in complicated perforated appendicitis, is not recommended (Tander et al. 2003).

Laparoscopic Appendectomy While it is almost 30 years since the first laparoscopic appendectomy was described, it is only in the last decade that its use has become commonplace, in some places superseding the open

175

approach. A standard three-port laparoscopic appendectomy begins with insertion of an infraumbilical port. Access for this port should be gained using an open Hasson’s technique rather than a percutaneous technique. Following attainment of carbon dioxide pneumoperitoneum, two 5 mm infraumbilical incisions are placed under direct vision, either on each side of the midline or in the left iliac fossa and suprapubic regions. An additional RLQ incision is optional. After mobilization of the appendix, the mesoappendix is divided. The appendiceal stump is ligated with endo loops or an endoscopic stapler, and the appendix is excised and removed, either in an endoscopic bag or, if the appendix is thin, directly through a 10 mm port. Suction with or without saline irrigation is carried out as per open surgery. Evacuate all carbon dioxide to minimize referred shoulder tip pain. Closure of the fascia should certainly take place in all 10 mm ports, with many surgeons also electing to close the fascia in 5 mm ports in order to reduce the risk of port-site hernia. Skin closure can be with subcuticular sutures or adhesive skin glue. Infiltration of port site wounds with local anesthetic for postoperative analgesia is simple and efficacious (Fig. 7). Single-port laparoscopic appendectomy is evolving as an alternative to the traditional threeport procedure. Broadly speaking, two approaches have been described – an extracorporeal approach and an intracorporeal approach (Ponsky and Krpata 2011). In the former a single umbilical port is used to exteriorize the appendix for appendectomy. There have been concerns that this may be associated with an increased risk of wound infection. In an intracorporeal approach, a multi-trochar port, or three separate trochars, are placed in the umbilicus, and the appendix is retracted using a transcutaneous stitch allowing dissection to take place (Ponsky and Krpata 2011). When compared to conventional laparoscopic surgery, single-port appendectomy is associated with longer operating time and increased perioperative narcotic usage (Li et al. 2013). It remains to be seen if the cosmetic advantages of this approach will lead to its use becoming more widespread with time.

176

A. E. Mortell and D. Coyle

Fig. 7 Typical appearance of uncomplicated acute appendicitis seen at laparoscopy. It appears hypervascular, and there is fibrin peel seen following mobilization of the appendix from omentum

Laparoscopic Versus Open Appendectomy The role of laparoscopic surgery in the management of appendicitis in children has become more defined in recent times due to increasing numbers of large studies and meta-analyses addressing this topic. In the main, laparoscopic appendectomy appears to be associated with less postoperative ileus, lower analgesic requirements, faster return to diet and normal activity, and shorter hospital stay than open surgery (Aziz et al. 2006; Sauerland et al. 2010). Operating times appear to be similar for uncomplicated appendicitis but longer with laparoscopy for complicated appendicitis. Although the incidence of wound infection appears to be lower with laparoscopic appendectomy, there is concern that it is associated with an increased risk of postoperative abscess formation (Sauerland et al. 2010). Laparoscopic surgery appears to be particularly advantageous in obese patients (Kutasy et al. 2011). Conversion from laparoscopic to open appendectomy occurs in approximately 0–25.9% but in general is less than 10% (Aziz et al. 2006). Where appropriately trained surgical staff and equipment are available, laparoscopic appendectomy has several advantages over open appendectomy indicating its preferential use (Sauerland et al. 2010).

Complicated Appendicitis Perforated Appendicitis The reported incidence of perforated appendicitis in children varies greatly depending on age, but

recent large studies have reported the incidence to be approximately 30% (Anderson et al. 2012). The incidence is much higher in preschool children, with over one half of the children in this age group having perforated appendicitis (Mallick 2008). Mortality from perforated appendicitis is vanishingly uncommon, with better evidence advancing the management of postoperative complications in recent times. Antibiotics have a proven role in preventing postoperative wound infection and intra-abdominal abscess in acute appendicitis. There is still some disagreement about the duration of antibiotic therapy and which drugs to use. In those who have undergone appendectomy, the duration of intravenous antibiotic treatment should be determined by clinical criteria. A minimum course of 3 days may be effective, but 5 days of treatment is probably a more common regimen, with completion of a 7day course using oral antibiotics being recommended. This approach is both efficacious and economical. As previously stated, even in cases of complicated appendicitis, the placement of a peritoneal drain is not recommended (Tander et al. 2003). Laparoscopic appendectomy for perforated appendicitis compares well with open surgery, albeit with longer operating times and potentially higher rates of postoperative abscess (Aziz et al. 2006). Intraoperative irrigation of the peritoneal cavity, with or without antibiotics, was previously routinely practiced in children with perforated appendicitis. However, whether this adds any benefit regarding postoperative infection has yet

12

Appendicitis

177

Fig. 8 Transverse computed tomography imaging demonstrating a complex pelvic abscess in a girl with a 10-day history of abdominal pain and a diagnosis of appendicitis. Collections of this extent are ideal for percutaneous or transrectal radiologically guided drainage. (Image courtesy of Children’s University Hospital, Dublin 1, Ireland)

to be demonstrated in high-quality studies. The placement of a peritoneal drain following perforated appendicitis has not been shown to improve outcome, with no reduction in the duration of hospitalization or nasogastric drainage time, and is therefore not advocated (Tander et al. 2003). One area of continuing contention is the role of delayed operative management for perforated appendicitis. Compared with those in whom appendicitis has been complicated by phlegmon formation, successful initial non-operative management may be less likely in perforated appendicitis, with concern regarding the high risk of representation with recurrent appendicitis prior to planned interval surgery, with approximately one third having surgery earlier than originally planned. While some feel that an initial non-operative approach to care may have some merit in those with a long (>5 days) history of symptoms prior to presentation, a review of the literature on this topic has concluded that, despite lower complication rates, there is no evidence to support non-operative management of perforated appendicitis in children (Svensson et al. 2012). However, where perforated appendicitis is associated with abscess formation, there may be a role for initial percutaneous drainage as source control, followed by interval appendectomy, as it shortens operating time compared to immediate appendectomy (Fig. 8).

Appendix Mass Appendicitis that is localized by edematous, adherent omentum and loops of small bowel

results in an appendix mass. While appendiceal abscess formation can occur at any time in the course of appendicitis, it may also complicate an appendiceal mass. Clinically, it is not possible in most cases to distinguish with certainty between the two conditions. The incidence is higher during the first 3 years of life, when one third of the patients with appendicitis have been reported to present with an appendiceal mass (Puri et al. 1981). Abdominal examination under anesthesia prior to appendectomy is vital as many appendix masses are only discovered at this point. The management of an appendiceal mass in children is controversial, with evidence in support of both early appendectomy and non-operative management with antibiotics followed by interval appendectomy available in equal measure. The controversy over conservative management of appendiceal masses has arisen mainly from the belief that children, and particularly infants, have a poor ability to localize intraperitoneal inflammatory processes, and so children with an appendiceal mass should be managed operatively. Nonetheless the aforementioned high rate of mass formation in infants is evidence that the ability to localize appendiceal inflammation is present even in toddlers. A suggested regimen for conservative management includes close clinical observation for deterioration, broad-spectrum parenteral antibiotic coverage with 2–3 agents, oral fluids, and diet as tolerated, with planned interval appendectomy, usually laparoscopic, in 4–6 weeks from hospital discharge. Progression to oral antibiotics depends

178

on improvement of clinical parameters, and successful management is determined by the resolution of abdominal pain and the presence of normal heart rate and temperature for 48 h (Gillick et al. 2001). Failure rates of non-operative management are generally reported to be in the order of 10–15% (Puri et al. 1981; Gillick et al. 2001). The increased technical difficulty and operating time with early appendectomy in this population, especially when performed laparoscopically, is widely acknowledged. While this approach is gaining favor in adult surgery, supporting evidence in the pediatric population is slow to accumulate. Most surgeons continue to practice initial non-operative management and interval appendectomy for the pediatric population, finding it to be associated with a low complication rate, faster return to diet postoperatively, and surgical advantages regarding ease of dissection and adhesiolysis, although does require two hospital admissions (Puri et al. 1981; Gillick et al. 2001). Some would argue that surgery is not required at all after successful non-operative treatment of an appendix mass given the low incidence of recurrent appendicitis in this setting and that an approach of “watchful waiting” can be encouraged. This approach may not be appropriate in cases where an appendicolith has been identified, and many would also argue that appendectomy also eliminates the possibility of missed pathology such as neoplasm and inflammatory bowel disease.

Complications and Outcomes Advances in perioperative care and antibiotics have resulted in mortality rates that approach zero and low morbidity in children with appendicitis. The long-term outcome of the vast majority of patients who undergo appendectomy in childhood is very good. A small number of patients may develop early complications due to surgical site infection or stump appendicitis, or late complications, the most common of which is adhesive intestinal obstruction. More controversial putative outcomes such as adulthood infertility in girls who have previously had perforated appendicitis,

A. E. Mortell and D. Coyle

inguinal hernia, and chronic pain are worthy of attention.

Postoperative Intra-abdominal Abscess Intra-abdominal abscess formation after appendectomy prolongs hospital stay and duration of antibiotic therapy and healthcare costs. The incidence of postoperative intra-abdominal abscess is approximately 3.4% following open appendectomy and 3.8% following laparoscopic appendectomy (Aziz et al. 2006). Complicated appendicitis is generally considered to be associated with a higher risk of abscess formation. Occasionally retained fecaliths may form a nidus for abscess formation. Typical findings in those with intra-abdominal abscess include undulating pyrexia, increasing abdominal or pelvic pain, diarrhea or irritative voiding symptoms, and persistent raised inflammatory markers, all of which may be resistant to antibiotic therapy. Imaging with ultrasound and with or without cross-sectional imaging using computed tomography (CT) is invaluable, not just as a means of confirming diagnosis but also in helping to plan management. Nonetheless, routine postoperative imaging of asymptomatic patients with complicated appendicitis is unlikely to provide any clinically detectable benefit. Conservative treatment with broad-spectrum antibiotics alone is frequently all that is required depending on size, location, and the degree of sepsis. Radiologically guided percutaneous drain insertion, with ultrasound or CT, carried out transabdominally or transrectally, can provide excellent source control in those who have failed medical management, except where a retained appendicolith is forming the focus for infection. Surgical management is rarely indicated for postappendectomy abscess and generally only takes place in situations where medical management has failed and a collection is present that is not amenable to percutaneous drainage. Laparoscopic abscess drainage is safe and effective and allows excellent access to the whole peritoneum. Thus, it may be preferable to open drainage.

12

Appendicitis

Intestinal Obstruction Intestinal obstruction requiring surgery has been reported in approximately 0.7% of patients following appendectomy and is more common in those who have perforated appendicitis and in those who undergo open appendectomy (Tsao et al. 2007). The cause of increased adhesions after perforated appendicitis is evident as peritonitis induces adhesions although adhesive intestinal obstruction can occur even after removing a normal appendix. Most cases of intestinal obstruction occur in the early period after appendectomy, although late presentations are not uncommon. Laparoscopic appendectomy appears to be associated with a lower incidence of adhesive small bowel obstruction compared to open appendectomy (Tsao et al. 2007). Band adhesions are frequently the cause of mechanical obstruction after appendectomy. This is often associated with a higher rate of failure of non-operative management.

Stump Appendicitis Complications related to the appendix stump after appendectomy are thankfully rare. Stump appendicitis, also frequently referred to as recurrent appendicitis, has a similar pathogenesis and clinical course as traditional appendicitis. It has been reported after both laparoscopic and open appendectomies, and can occur up to 50 years after the initial surgery (Kanona et al. 2012). One of the key factors predisposing patients to this complication is an excessively long appendix stump left behind at appendectomy, often greater than 3 cm in length, although this problem has been described in a stump of 0.8 cm in length (Kanona et al. 2012). Excision of excess residual stump with or without pursestring invagination of the remaining stump appears to be an effective operative management. Of note the appendix stump can also become a lead point for intussusception or a site of malignancy or mucocele formation in later life.

179

Nerve Entrapment After Appendectomy Neuralgia, usually as a result of entrapment of the ilioinguinal nerve, and less commonly the iliohypogastric nerve, is a rarely reported complication of appendectomy (Rauchwerger et al. 2008). These patients have the classic triad of the entrapment syndrome – pain accurately localized near the incision; objective sensory impairment in the appropriate area of the skin; and temporary relief by injection of local anesthetic agents. The symptoms may arise immediately after operation or several years later, implying that the nerve may be involved either directly by a suture or indirectly by pressure from mature scar tissue. Non-operative management with neuromodulators and nerve blocks is commonly employed, with a proportion of these patients going on to have neural stimulators or surgical management with neurectomy (Rauchwerger et al. 2008).

Appendectomy and Subsequent Development of Right Inguinal Hernia Historically there has been a suggestion that appendectomy was associated with a higher incidence of subsequent right inguinal hernia. The cause of the right-sided inguinal hernia is thought to be damage to the nerve supply of the inguinal muscles during appendectomy. Malazgirt et al. (1992) investigated the effect of appendectomy on the subsequent development of right inguinal hernia in 583 patients. They found that the incidence of right inguinal hernia was no greater in patients who had previously undergone appendectomy compared with those who had not had their appendices removed (Malazgirt et al. 1992).

Perforated Appendicitis and Subsequent Fertility in Girls The view that perforated appendicitis in girls is associated with an increased risk of tubal infertility is long-held and has been the basis for a more

180

liberal attitude to surgical intervention in young females with suspected appendicitis. However, there is no convincing evidence base for this practice. Most early studies that examined the frequency of infertility in women who had undergone appendectomy for perforated appendix in adult life were based on a small number of cases, lacked detailed investigations of infertility, or had flawed methodology. It is possible that in women who have borne children, there may have been damage to the right fallopian tube owing to its proximity to the appendix. However, the left tube in such cases may function normally – a situation that arises in cases of ectopic pregnancy in which salpingectomy has previously been carried out – and the other tube retains its normal physiological function. These data indicate that perforated appendicitis before puberty has little, if any role in the etiology of tubal infertility. Several authors have compared fertility rates of those who have undergone appendectomy in childhood versus those who did not. None have demonstrated an association between subsequent tubal infertility and uncomplicated or perforated appendicitis (Puri et al. 1989). Those women who underwent appendectomy for perforated appendicitis and who subsequently had difficulty conceiving in these studies predominantly had alternative causes documented for subfertility, such as pelvic inflammatory disease, endocrine disorders, or partner subfertility. Thus, there is no quality or convincing evidence base for an association between perforated appendicitis and infertility in later life.

Inflammatory Bowel Disease The etiology and pathogenesis of ulcerative colitis (UC) and Crohn’s disease (CD) are not known. Recent studies have suggested a link between appendectomy and the subsequent risk of developing an inflammatory bowel disease (Andersson et al. 2001). In a large cohort study of 212,963 patients who underwent appendectomy before the age of 50 years, Andersson et

A. E. Mortell and D. Coyle

al. (2001) found that patients who had an appendectomy for an inflammatory condition (appendicitis or lymphadenitis) had a lower risk of subsequent UC (Andersson et al. 2001). This inverse relation was limited to patients who had surgery before the age of 20 years. In contrast to this, an increased risk of CD was found in patients who had an appendectomy at the age of 20 years and over (Andersson et al. 2003). Crohn’s disease patients with a history of perforated appendicitis generally had a worse prognosis. Recent evidence suggests that the increased risk of CD after appendectomy is transient and probably due to diagnostic bias (Kaplan et al. 2007). Further studies of the associations of inflammatory bowel disease and appendicitis are therefore warranted because such studies may give clues to the etiology and pathogenesis of both disease processes.

Medicolegal Aspects Missed Appendicitis Missed appendicitis remains a high-risk area in professional liability. The failure to diagnose appendicitis is routinely listed among important reasons for a malpractice suit to be brought to the accident and emergency physician. Diagnosing appendicitis accurately and early is therefore very important. One recurring feature of malpractice cases is the failure of the physician to reexamine patients within a reasonable timeframe, thus leading to delayed diagnosis. Although classic symptoms are present in the majority of patients with appendicitis, atypical symptoms are not uncommon, especially in preschool children with appendicitis as previously alluded to. In one study 44% of children had six or more atypical features of appendicitis (Becker et al. 2007). In view of the atypical presentation and increased incidence of advanced appendicitis and morbidity, a high index of suspicion is necessary in preschool children presenting with acute abdominal pain.

12

Appendicitis

Other Causes of Litigation Related to Appendicitis Despite the evidence presented above, putative damage to fertility continues to be a leading cause of successful litigation due to delayed diagnosis or treatment. Delayed re-intervention for complications such as postoperative abscess and iatrogenic injuries such as vascular injury secondary to port-site puncture are also quoted as factors in litigation.

Conclusion and Future Directions Early recognition of the symptoms and signs of acute appendicitis can lead to expeditious treatment and lower rates of perforation and lower morbidity. Only about half of children with appendicitis present with the classic collection of symptoms and signs. Knowledge of the various atypical features that can manifest in children with appendicitis should allow the clinician to maintain an appropriately high index of suspicion for appendicitis when evaluating a child with abdominal pain. While recently evaluated biomarkers for appendicitis such as pro-calcitonin and interleukin-6 have been shown to be predictive of complicated appendicitis, there are, as of yet, no markers of early appendicitis that are sufficiently sensitive or specific to be of clinical use. In cases where the diagnosis is in doubt on clinical grounds, ultrasound appears to be a low-radiation, accurate diagnostic modality, with computed tomography being preserved for selected cases, such as the very obese. As experience with laparoscopic appendectomy becomes more widespread, it is becoming the operative treatment of choice, although open appendectomy still has a role, especially in the treatment of complicated appendicitis. It remains to be seen if the cosmetic benefits of single-port laparoscopic appendectomy will sufficiently outweigh its shortcomings to lead to its widespread adoption. Similarly, highquality studies are required to determine if there is a role for non-operative treatment in the management of uncomplicated appendicitis in children.

181

Cross-References ▶ Crohn’s Disease

References Anderson JE, Bickler SW, Chang DC, Talamini MA. Examining a common disease with unknown etiology: trends in epidemiology and surgical management of appendicitis in California, 1995–2009. World J Surg. 2012;36:2787–94. Andersson R, Hugander A, Thulin A, Nystrom PO, Olaison G. Clusters of acute appendicitis: further evidence for an infectious aetiology. Int J Epidemiol. 1995;24:829–33. Andersson RE, Olaison G, Tysk C, Ekbom A. Appendectomy and protection against ulcerative colitis. N Engl J Med. 2001;344:808–14. Andersson RE, Olaison G, Tysk C, Ekbom A. Appendectomy is followed by increased risk of Crohn’s disease. Gastroenterology. 2003;124:40–6. Aziz O, Athanasiou T, Tekkis PP, Purkayastha S, Haddow J, Malinovski V, et al. Laparoscopic versus open appendectomy in children: a meta-analysis. Ann Surg. 2006;243:17–27. Bansal S, Banever GT, Karrer FM, Partrick DA. Appendicitis in children less than 5 years old: influence of age on presentation and outcome. Am J Surg. 2012;204:1031–5; discussion 5. Becker T, Kharbanda A, Bachur R. Atypical clinical features of pediatric appendicitis. Acad Emerg Med. 2007;14:124–9. Bundy DG, Byerley JS, Liles EA, Perrin EM, Katznelson J, Rice HE. Does this child have appendicitis? JAMA. 2007;298:438–51. Cavusoglu YH, Erdogan D, Karaman A, Aslan MK, Karaman I, Tutun OC. Do not rush into operating and just observe actively if you are not sure about the diagnosis of appendicitis. Pediatr Surg Int. 2009;25:277–82. D’Souza N. Appendicitis. BMJ Clin Evid (Online). 2011;2011:0408. Di Sebastiano P, Fink T, di Mola FF, Weihe E, Innocenti P, Friess H, et al. Neuroimmune appendicitis. Lancet. 1999;354:461–6. Doria AS. Optimizing the role of imaging in appendicitis. Pediatr Radiol. 2009;39(Suppl 2):S144–8. Doria AS, Moineddin R, Kellenberger CJ, Epelman M, Beyene J, Schuh S, et al. US or CT for diagnosis of appendicitis in children and adults? A meta-analysis. Radiology. 2006;241:83–94. Environment ECD-Gft. UK royal college of radiologists. Radiation protection 118: referral guidelines for imaging. 2000. Retrieved from http://www.zvd.si/media/ medialibrary/2010/11/rp-118.pdf on 11th January 2020.

182 Feldman M, Friedman L, Brandt L. Sleisenger and Fordtran’s gastrointestinal and liver disease, vol. 1. 9th ed. Philadelphia: Saunders; 2010. p. 2059–71. Friday JH. Update on appendicitis: diagnosis and presurgical management. Curr Opin Pediatr. 2006;18: 234–8. Gauderer MW, Crane MM, Green JA, DeCou JM, Abrams RS. Acute appendicitis in children: the importance of family history. J Pediatr Surg. 2001;36:1214–7. Gillick J, Velayudham M, Puri P. Conservative management of appendix mass in children. Br J Surg. 2001;88: 1539–42. Goldin AB, Khanna P, Thapa M, McBroom JA, Garrison MM, Parisi MT. Revised ultrasound criteria for appendicitis in children improve diagnostic accuracy. Pediatr Radiol. 2011;41:993–9. Hall NJ, Eaton S, Abbo O et al. Appendectomy versus nonoperative treatment for acute uncomplicated appendicitis in children: study protocol for a multicentre, open-label, noninferiority, randomised controlled trial. BMJ Paediatrics Open. 2017;11:bmjpo-2017-000028. https://doi.org/10.1136/bmjpo-2017-000028 Henry MC, Moss RL. Primary versus delayed wound closure in complicated appendicitis: an international systematic review and meta-analysis. Pediatr Surg Int. 2005;21:625–30. Hutchings N, Wood W, Reading I, et al. CONTRACT study – CONservative TReatment of Appendicitis in Children (feasibility): study protocol for a randomised controlled Trial. Trials. 2018;19(1):153. Kanona H, Al Samaraee A, Nice C, Bhattacharya V. Stump appendicitis: a review. Int J Surg. 2012;10:425–8. Kaplan GG, Pedersen BV, Andersson RE, Sands BE, Korzenik J, Frisch M. The risk of developing Crohn’s disease after an appendectomy: a population-based cohort study in Sweden and Denmark. Gut. 2007;56:1387–92. Karaman A, Cavusoglu YH, Karaman I, Cakmak O. Seven cases of neonatal appendicitis with a review of the English language literature of the last century. Pediatr Surg Int. 2003;19:707–9. Karim OM, Boothroyd AE, Wyllie JH. McBurney’s point–fact or fiction? Ann R Coll Surg Engl. 1990;72:304–8. Knaapen M, van der Lee JH, Heij HA, et al. Clinical recovery in children with uncomplicated appendicitis undergoing non-operative treatment: secondary analysis of a prospective cohort study. Eur J Pediatr. 2019;178(2):235–42. Kulik DM, Uleryk EM, Maguire JL. Does this child have appendicitis? A systematic review of clinical prediction rules for children with acute abdominal pain. J Clin Epidemiol. 2013;66:95–104. Kutasy B, Hunziker M, Laxamanadass G, Puri P. Laparoscopic appendectomy is associated with lower morbidity in extremely obese children. Pediatr Surg Int. 2011;27:533–6. Li P, Chen ZH, Li QG, Qiao T, Tian YY, Wang DR. Safety and efficacy of single-incision laparoscopic surgery for appendectomies: a meta-analysis. World J Gastroenterol. 2013;19:4072–82.

A. E. Mortell and D. Coyle Livingston EH, Woodward WA, Sarosi GA, Haley RW. Disconnect between incidence of nonperforated and perforated appendicitis: implications for pathophysiology and management. Ann Surg. 2007;245:886–92. Malazgirt Z, Ozen N, Ozkan K. Effect of appendicectomy on development of right inguinal hernia. Eur J Surg. 1992;158:43–4. Mallick MS. Appendicitis in pre-school children: a continuing clinical challenge. A retrospective study. Int J Surg. 2008;6:371–3. McCarty AC. History of appendicitis vermiformis: its diseases and treatment. Presented to the innominate society, vol. 2013. 1927. Naiditch JA, Lautz TB, Daley S, Pierce MC, Reynolds M. The implications of missed opportunities to diagnose appendicitis in children. Acad Emerg Med. 2013;20:592–6. Nemeth L, Reen DJ, O’Briain DS, McDermott M, Puri P. Evidence of an inflammatory pathologic condition in "normal" appendices following emergency appendectomy. Arch Pathol Lab Med. 2001;125:759–64. Park JS, Jeong JH, Lee JI, Lee JH, Park JK, Moon HJ. Accuracies of diagnostic methods for acute appendicitis. Am Surg. 2013;79:101–6. Ponsky TA, Krpata DM. Single-port laparoscopy: considerations in children. J Minim Access Surg. 2011;7:96–8. Puri P, O’Donnell B. Appendicitis in infancy. J Pediatr Surg. 1978;13:173–4. Puri P, Boyd E, Guiney EJ, O’Donnell B. Appendix mass in the very young child. J Pediatr Surg. 1981;16:55–7. Puri P, McGuinness EP, Guiney EJ. Fertility following perforated appendicitis in girls. J Pediatr Surg. 1989;24:547–9. Rao PM, Rhea JT, Rao JA, Conn AK. Plain abdominal radiography in clinically suspected appendicitis: diagnostic yield, resource use, and comparison with CT. Am J Emerg Med. 1999;17:325–8. Rauchwerger JJ, Giordano J, Rozen D, Kent JL, Greenspan J, Closson CW. On the therapeutic viability of peripheral nerve stimulation for ilioinguinal neuralgia: putative mechanisms and possible utility. Pain Pract. 2008;8:138–43. Rothrock SG, Pagane J. Acute appendicitis in children: emergency department diagnosis and management. Ann Emerg Med. 2000;36:39–51. Sack U, Biereder B, Elouahidi T, Bauer K, Keller T, Trobs RB. Diagnostic value of blood inflammatory markers for detection of acute appendicitis in children. BMC Surg. 2006;6:15. Sauerland S, Jaschinski T, Neugebauer EA. Laparoscopic versus open surgery for suspected appendicitis. Cochrane Database Syst Rev. 2010;(11):CD001546. Singh JP, Mariadason JG. Role of the faecolith in modernday appendicitis. Ann R Coll Surg Engl. 2013;95: 48–51. Surana R, O’Donnell B, Puri P. Appendicitis diagnosed following active observation does not increase morbidity in children. Pediatr Surg Int. 1995;10:76–8. Svensson JF, Hall NJ, Eaton S, Pierro A, Wester T. A review of conservative treatment of acute appendicitis. Eur J Pediatr Surg. 2012;22:185–94.

12

Appendicitis

Tander B, Pektas O, Bulut M. The utility of peritoneal drains in children with uncomplicated perforated appendicitis. Pediatr Surg Int. 2003;19:548–50. Toorenvliet BR, Wiersma F, Bakker RF, Merkus JW, Breslau PJ, Hamming JF. Routine ultrasound and limited computed tomography for the diagnosis of acute appendicitis. World J Surg. 2010;34:2278–85. Trout AT, Sanchez R, Ladino-Torres MF. Reevaluating the sonographic criteria for acute appendicitis in children: a review of the literature and a retrospective analysis of 246 cases. Acad Radiol. 2012;19:1382–94. Tsao KJ, St Peter SD, Valusek PA, Keckler SJ, Sharp S, Holcomb GW 3rd, et al. Adhesive small bowel obstruction after appendectomy in children: comparison

183 between the laparoscopic and open approach. J Pediatr Surg. 2007;42:939–42; discussion 42. Tsuji M, Puri P, Reen DJ. Characterisation of the local inflammatory response in appendicitis. J Pediatr Gastroenterol Nutr. 1993;16:43–8. Weissleder R, Wittenberg S, Harisinghani MG, Chen JW. Primer of diagnostic imaging. 4th ed. Philadelphia: Mosby Elsevier; 2007. Yu CW, Juan LI, Wu MH, Shen CJ, Wu JY, Lee CC. Systematic review and meta-analysis of the diagnostic accuracy of procalcitonin, C-reactive protein and white blood cell count for suspected acute appendicitis. Br J Surg. 2013;100:322–9.

Intussusception

13

Shabnam Parkar and Amulya K. Saxena

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 Primary Intussusception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 Secondary Intussusception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ultrasonography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Computed Tomography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contrast Enema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

188 188 189 189 189

Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-operative . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hydrostatic Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pneumatic Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

190 190 190 191

Operative Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 Recurrent Intussusception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 Small Bowel Intussusception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 Ileocoloic Intussusception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

S. Parkar (*) Paediatric Surgery, St George’s Hospital NHS Foundation Trust, London, UK e-mail: [email protected] A. K. Saxena Department of Paediatric Surgery, Chelsea Children’s Hospital, Imperial College London, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK e-mail: [email protected] © Springer-Verlag GmbH Germany, part of Springer Nature 2021 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43559-5_104

185

186

S. Parkar and A. K. Saxena Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

Abstract

Intussusception is one of the most common causes of acute bowel obstruction in children and occurs in 1–4 in 2000 children worldwide. This condition was initially associated with high morbidity and mortality; however, with the advent of better imaging with ultrasound and knowledge in diagnosis, the clinical management has dramatically improved clinical outcomes. Due to the essential knowledge of allowing adequate aggressive fluid resuscitation at presentation, earlier diagnosis, and prompt attempt at reduction, this common condition is being treated more successfully. Non-operative interventions, including ultrasound-guided pneumatic reduction and hydrostatic reduction, have become the mainstay of treatment and have dramatically reduced the need for surgical intervention. In cases where surgery is indicated, laparoscopy provides a useful less invasive technique to treat as well as aid in diagnosis. This once fatal phenomenon is now becoming more easily and successfully managed in pediatric surgical centers around the world. Keywords

Intussusception · Ileocolic · Ileoileal · Lead point · Ultrasound · Pneumatic reduction · Hydrostatic · Peyer’s patches · Laparoscopic reduction

Introduction Intussusception is the telescoping of one portion of bowel into another. The word intussusception is derived from the Latin words intus (within) and suscipere (to receive) (Hamby et al. 1996). It was first identified as a disease in the 1600s by Barbette in Amsterdam (Barbette 1674), but it

was not until 1793 that Hunter described the condition of intussusception in detail (Hunter 1793). Management of intussusception was initially considered to be surgical, with Jonathan Hutchinson (1873) in 1873 describing the first successful operation for intussusception in a 2-year-old child. The possibility of conservative management was confirmed 3 years later by Harald Hirschsprung (1876), who employed hydrostatic reduction in the treatment for intussusception. Early historical records, however, have also indicated toward the use of pneumatic reduction via hand bellows through the anus, first tried at the time of Hippocrates (McAlister 1998). However, the first documented description of pneumatic reduction in the literature was only found in the 1800s (McDermott 1994). With the advent of fluoroscopic-based techniques in medicine, the use of barium enemas to reduce intussusceptions was also introduced, with Ravitch popularizing the use of this method in the United States (Ravitch 1959). In 1864, the Scottish surgeon Greig (Hirschsprung 1876; McAlister 1998) was the first to lay down strict criteria for the clinical diagnosis of intussusception. He claimed that he successfully reduced four out of five actual pediatric intussusceptions with hand bellows: “Contrary to our expectations the air passed readily into the bowel and seemed to give the child great relief” (Greig 1864).

Epidemiology Intussusception occurs in 1–4 in 1000 live births in the United Kingdom (Sinha and Davenport 2010) with a worldwide incidence of 1–4 in 2000 among infants and children. It occurs mainly between the ages of 3 months and 3 years; however, idiopathic intussusception can occur at any age. In 75% of cases, intussusceptions occur

13

Intussusception

within the first 2 years of life, whereas 90% occur within the first 3 years of age. Over 40% of cases of intussusception are encountered within 3–9 months of life (Ein and Stephens 1971). As well as occurring in term infants and toddlers, intussusception has been described in premature infants and in utero and may lead to small bowel atresia, namely, ileal atresia (Pueyo et al. 2009). The implication of intussusception resulting in small bowel atresia has also been reported in term newborns (Saxena and Van Tuil 2008). Perinatal intussusception (0.3%), on the other hand, is more likely caused by a pathological lead point such as that found in older patients (Avansino et al. 2003). The male to female ratio is approximately 3:2 and there is no racial variation. The incidence of intussusception peaks during epidemics of respiratory infections and gastroenteritis. The rotavirus vaccine (RotaShield™) has been postulated to cause intussusception (Bines 2005). The risk was reported to be between 1 in 10, 000 and 1 in 32, 000, with the highest risk being within the first 3 to 14 days after the first dose of RotaShield™, especially in children older than 3 months of age. Intussusception is one of the most frequent causes of acute bowel obstruction in toddlers and infants (Ashcraft et al. 2005), and clinical deterioration can be quick. Therefore, it highlights the importance of expedited recognition and hence treatment of this condition. A combined effort between the pediatrician, pediatric surgeon, and pediatric radiologist is of utmost importance in recognizing the condition and managing it under the hospital protocols.

Pathogenesis Intussusception involves plugging of bowel segment into the adjacent segment. The invaginated proximal bowel (the inner and middle walls) is termed the “intussusceptum,” and the distal portion of the bowel (the outer walls) is termed the “intussuscipiens.” With regard to the localization of intussusception within the gastrointestinal tract, it has been observed that more than 80% of intussusceptions are of the “ileocolic” type,

187

although other forms such as ileoileal types (~10%) or caecocolic-, colocolic- (~10%), jejunojejunal types can also occur. An intussusception can occur due to an identifiable lesion which acts like a “pathological lead point” and causes the proximal bowel to invaginate into the distal bowel during normal peristalsis.

Primary Intussusception The cause of intussusception may be primary or secondary. Primary or idiopathic etiology for intussusception is more common as it involves an array of factors that could result in inflammation of gut lymphatic tissues (such as inflamed Peyer’s patches) that could trigger the process of invagination. These include upper respiratory tract infections (e.g., adenovirus, rotavirus) and gastroenteritis infections which cause hypertrophy of Peyer’s patches in the intestine. These protrude into the lumen and act as the lead point causing the initial invagination. In fact, during surgery of intussusception in the selective cases requiring operative management, careful examination of the pathology demonstrates marked hypertrophy of the lymphoid tissue of the intestinal wall at the leading edge of the intussusceptum (Stringer et al. 1992). Whereas the primary causes of intussusception are correlated to viral infections, secondary causes (~5%) of intussusception are deemed to be a result of specific anatomical lead points. The incidence of secondary intussusception is reported to range between 2% and 12% in the literature (Meier et al. 1996). For some unknown reason, the incidence of anatomical lead points has been found to increase with age (Blakelock and Beasley 1998). The pathological lead points that are the secondary causes of intussusception include: – Meckel’s diverticulum (most common) – Polyps (Peutz-Jeghers syndrome rarely, familial adenomatous polyposis) – Duplication cysts – Appendix – Lymphoma – Carcinoid tumors

188

– Intramural hematoma (Henoch-Schonlein purpura, blunt abdominal trauma) – Foreign bodies – Ectopic pancreas or gastric mucosa – Gastrojejunal tubes Irrespective of the primary or secondary “triggering factor,” as the proximal bowel invaginates into the distal bowel, the mesentery of the bowel is compressed, leading to venous obstruction and edema of the bowel wall. If the process is not reversed in a reasonable amount of time, arterial insufficiency and then bowel wall necrosis will ultimately ensure. Although spontaneous reduction can occur as observed in small bowel intussusceptions, the natural history of this condition is to progress; and if the condition is not recognized and treated early, the progression of necrosis can lead to sepsis and even fatality. The morbidity and mortality of this condition have dramatically decreased over the last few decades due to a better understanding of the condition, optimal investigation techniques for detection of the pathology, and the success of non-operative interventions (Kaiser et al. 2007).

Secondary Intussusception This is seen in children of age 9–12 years with cystic fibrosis. It is due to inspissated secretions and thick fecal matter in the intestinal lumen that acts as a lead point to produce intussusception. These can occur repeatedly, and reductions may be required on multiple occasions (Stringer et al. 1992).

S. Parkar and A. K. Saxena

quickly as they had started. Presentation may also be associated with breath holding, writhing around, and vomiting as well. The vomiting may initially be undigested food, which may become bilious after further bouts. In between attacks, the child may be well or lethargic. The constrained bowel may become ischemic, leading to mucus production from venous and lymphatic production to eventual sloughing off of the mucosa from ischemia causing the classic “red-currant jelly” stool in these children. During episodes of cramping, the right lower quadrant may appear flat or empty, and the right upper quadrant may have a sausage-shaped mass palpable (Dance’s sign) (Jean Baptiste Dance 1832). This is due to the progression of the cecum and ileocecal portion of the intussusception into the right or transverse colon. The mass may be palpable anywhere in the abdomen. Occult blood per rectum, as aforementioned, is a late sign. There may be signs of dehydration or septicemia, causing tachycardia and fever. Sometimes the children may present with septic shock, so it is important to consider this as a differential diagnosis in children presenting to emergency rooms with shock. Progression of the disease or a delay in diagnosis may lead to the intussuscepting mass to progress along the GI tract. It can cause prolapse of the intussusceptum through the anus. This indicates severe compromise of the blood supply and ischemia of the gut. It can be mistaken for a rectal prolapse; however, rectal prolapse is not associated with vomiting or sepsis. One can examine with a gloved finger which can pass between the prolapsing bowel and the anus, whereas this is not possible in a true rectal prolapse (Torres and McCafferty 2010).

Clinical Features Children with intussusception present with intermittent colicky abdominal cramps associated with pulling up of the legs. These occur in children who may have previously been absolutely free of symptoms and comfortable, and commonly following an episode of viral infection. At the time of presentation, most of these children may look lethargic. The abdominal cramp may occur in a periodic fashion with episodes often stopping as

Investigations Radiography A plain abdominal X-ray may show signs of intussusception such as an abdominal mass, air/ fluid levels in dilated bowel loops due to bowel obstruction, or abnormal distribution of fecal and gas pattern (Smith et al. 1992) (Fig. 1).

13

Intussusception

189

Fig. 2 Ultrasound showing the target sign which represents the transverse section of intussusception Fig. 1 Plain abdominal X-ray showing prominent bowel loops and a crescent sign in the epigastrium showing the site of the intussusception

Ultrasonography The ultrasound findings of intussusception were first described in 1977 (Burke and Clarke 1977). Ultrasound is now the gold standard in the diagnosis of intussusception (Henrikson et al. 2003). The diagnostic features seen on ultrasound are a “target lesion” consisting of a transverse section showing two rings of low echogenicity separated by a hyperechoic ring (see Figs. 2 and 3). Another sign is the “pseudokidney” sign seen on the longitudinal view showing the superimposed hypoechoic and hyperechoic layers of the intussuscepting bowel loops. This is thought to represent the edematous walls of the intussusception (Fig. 4). Screening ultrasound in experienced hands is highly accurate and decreases the number of unnecessary contrast enema reduction and hence also decreases the exposure to ionizing radiation (Edwards et al. 2017). Ultrasound can differentiate between small bowel intussusception and ileocolic intussusception. It may show evidence of free intra-abdominal fluid, and if used

with color Doppler, it can comment on bowel vascularity in terms of wall edema (from ischemic compromise) and peristalsis and hence indicate if surgery is more appropriate rather than imageguided reduction if there is compromised bowel involved (Saxena and Hollwarth 2007).

Computed Tomography Computed tomography (CT) investigations can be done in older children where there are irregular features or the diagnosis is not clear. There may be associated pathology (such as lymphoma) which needs to be investigated. This decision to perform a CT should be in keeping with the clinical features and condition of the child. The CT may show an intraluminal mass with a characteristic layered appearance within the mass or even evidence of intramural hematomas.

Contrast Enema This can be diagnostic as well as therapeutic and will be discussed in more detail in the management section.

190

S. Parkar and A. K. Saxena

Fig. 3 Ultrasound showing the target lesion and the use of color Doppler illustrating bowel viability

Fig. 4 Longitudinal representation of the intussusception on ultrasound along with the use of color Doppler providing information on bowel viability

Management Non-operative Good intravenous access, adequate fluid resuscitation, the insertion of a nasogastric tube, and broad-spectrum antibiotics are the first-line management in all cases. In the absence of peritonitis or perforation, the gold-standard method of treatment is radiological-guided reduction either pneumatic or hydrostatic (Ko et al. 2007; Tareen et al. 2011). The older the child, the longer the history, and certain features such as the presence of blood per rectum make enema reduction less successful, and operative approach may be needed instead (Daneman and Navarro 2004).

Hydrostatic Reduction Hydrostatic reduction of intussusception was first described in 1926 (Hipsley 1926). These reductions were performed under anesthesia and using saline solution. The fundamental implications of this technique however were incorporated into the modern methods of hydrostatic and pneumatic reduction. In the present form of hydrostatic reduction, which was the main treatment up until the mid1980s (Kaiser et al. 2007), a lubricated straight or Foley catheter is inserted into the rectum and held in place by firmly holding the buttocks together to create a tight seal. The catheter balloon is not normally inflated here. The contrast material is

13

Intussusception

191

Fig. 5 The image on the left shows the abdominal X-ray revealing the intussusception in the right upper quadrant. The image in the middle is the initial fluoroscopy screen demonstrating the intussusception in the right upper

quadrant corresponding to that in the abdominal X-ray. The last image on the right demonstrates successful pneumatic reduction with free flow of bowel gas through the small bowel. No free air

then run into the rectum from a height of 3 ft above the patient. Constant hydrostatic pressure is continued as long as reduction is occurring. Filling of the bowel is observed fluoroscopically. If there is no progress, the contrast is drained, and the procedure can be repeated up to two further times. Usually, reduction is seen up until the ileocecal valve, which is followed then by a delay at that point until a free flow of contrast is seen into the distal small bowel. A successful reduction depends on observation of the free flow of contrast into the distal small bowel. The advantages of this technique compared to surgical intervention are decreased morbidity, cost, and length of hospital stay. However, if this method is the preferred option of treatment, owing to the risk of bowel perforation, a water-soluble isotonic contrast is a better alternative to barium.

fluoroscopic guidance. The maximum safe air pressure is 80 mmHg in young infants and up to 110–120 mmHg for older infants. The British Society of Paediatric Radiologists (BSPR) published guidelines for suggested safe practice in 2003 (British Society of Paediatric Radiologists 2007). They recommend a maximum pressure of 120 mmHg with an initial attempt at pressures of 60–80 mmHg. It is recommended that a maximum of three attempts are performed with each sustained attempt lasting up to 3 min as long as the child remains stable. Accurate pressure measurements are possible, and reduction rates have been reported to be higher than hydrostatic reduction (Ondhia et al. 2019). The method has been reported to be quicker, safer, and with decreased exposure to radiation (Fig. 5). However, there is a risk of perforation leading to a pneumoperitoneum. The use of a needle puncture to decompress can help stabilize the patient when proceeding to theatre for laparotomy. Perforation occurs usually in ischemic bowel. The success rates are variable 50–90%, but most units should aim to achieve a success rate of 65–70% (Guo et al. 1986; Ondhia et al. 2019); this is documented by seeing free flow of air in the distal small bowel. However, there can be false-positive results if there is poor

Pneumatic Reduction Pneumatic reduction of intussusception was first described in 1897 by Holt (1897). Its use became the mainstay of treatment after the international reports of large series of higher rates of successful reduction (Guo et al. 1986). In this technique, air is insufflated into the rectum via a catheter, under

192

visualization of the lead points or of the reduction itself (Maoate and Beasley 1998). The process can be repeated again after 3 h if reduction is incomplete, but only if the child is stable. If there is no progress, then the child should proceed to theatre for surgical reduction. Non-operative reduction is not useful in ileoileal intussusceptions and is relatively contraindicated in older atypical presentations with a secondary pathology, in which surgical intervention is required. It is worth considering that the incidence of a lead point increases with age (Bines 2005). After successful reduction, the child should be observed for 24 h and initially kept nil by mouth and on IV fluids. There is a possibility of recurrence of 5–10% in the first 72 h, and hence the family should be informed about this (Niramis et al. 2010).

Operative Treatment A surgical approach is indicated in children who have had a perforation or incomplete hydrostatic or pneumatic reduction, or in children with signs of shock and peritonitis at initial examination. It is also considered in children who present atypically or with features of secondary causes. Again the child should have fluid resuscitation, broad-spectrum antibiotics, and nasogastric decompression prior to theatre. A right lower quadrant muscle-splitting incision is made as this is the most common site of intussusception at the ileocecal valve and the caecum is mobile; the bowel can be easily mobilized from there even if the intussusception has progressed further to the rectosigmoid area. The bowel should be gently manipulated with pushing rather than pulling the bowel involved in intussusception. However, care should be taken if reduction is difficult as too much handling may cause serosal tears or perforation. Resection of affected bowel may become necessary if bowel viability is impaired; there is lack of peristalsis or the presence of perforation. The rest of the bowel should be examined to look for a pathological lead point and should be suspected in older children presenting with intussusception or atypical features. An appendicectomy is usually done so as

S. Parkar and A. K. Saxena

Fig. 6 Intraoperative findings of bowel intussusception

to avoid confusion in the future as the patient will have a right lower quadrant scar (Fig. 6). Laparoscopy is a growing alternative in many centers and can also be quite advantageous as a diagnostic tool if there is doubt over the adequacy of reduction after enema. The bowel handling may not be easy, and “pulling” rather than “pushing” of the bowel has been advocated here.

Recurrent Intussusception Recurrence has been described from 2% to 20% with about 1/3 occurring in the first 24 h and the majority within the first 6 months (Daneman et al. 1998). Guo et al. studied risk factors for recurrent intussusception in 191 children and found that in children older than 1 year of age, symptom duration (12 h), the absence of vomiting, location of mass in the right abdomen, and pathological lead points were significantly predictive of recurrent intussusception (Guo et al. 2017). Patients tend to have fewer symptoms with recurrent intussusception and may only present with discomfort and irritability, so it should be highly suspected in these patients. Recurrences are usually less likely to occur after surgical reduction or resection.

Outcomes Small Bowel Intussusception Ileocolic intussusceptions remain the most common form of intussusception, but small bowel intussusceptions have been reported to range

13

Intussusception

from 1.68% to 17% (Kornecki et al. 2000) with predominance for ileoileal intussusception (80%) followed by the jejunojejunal type (20%) (Saxena et al. 2007). As aforementioned, the symptoms of intussusception are similar regardless of the site of pathology and may cause diagnostic confusion. Symptoms of small bowel intussusception may mimic that of acute gastroenteritis. Abdominal ultrasound is extremely useful in differentiating between ileocolic and ileoileal intussusception. It can also comment on the proximity of the intussusception, in relation to the ileocecal valve, as well as vascularity of the bowel and any lead points. This therefore determines the ongoing management and clinical course of the condition (Guo et al. 2017). Most small bowel intussusceptions can reduce spontaneously and do not need any active intervention or management (Kornecki et al. 2000). It has been postulated to be due to the increased motility of the small bowel, thereby causing spontaneous reduction (Saxena and Hollwarth 2007). Successful conservative treatment has been associated with early presentation and diagnosis. Pneumatic reduction was largely regarded as unsuccessful in small bowel intussusception due to the impedance caused by the ileocecal valve as the limiting factor (Koh et al. 2006); however, it has been reported that pneumatic reduction can be successful in small bowel intussusception if the intussusception is ileoileal and close to the ileocecal valve (Saxena et al. 2007). In patients where the small bowel intussusception has not reduced spontaneously, ultrasound with color Doppler is useful to localize the site and evaluate the bowel. If the site of small bowel intussusception is close to the ileocecal area and there is good bowel viability, then a pneumatic reduction can be successful. However, if the site of small bowel intussusception is high, or there is compromised bowel, then a surgical approach is recommended.

Ileocoloic Intussusception One of the most important criteria for the management of intussusception is the timing of presentation. This depends on availability and access

193

to quality healthcare, increased awareness, and knowledge in referring hospitals of the salient features and initial management of intussusception. Patients with ileocolic intussusception may present earlier as their symptoms may be more pronounced or they present more unwell. Symptoms of small bowel intussusception may mimic acute gastroenteritis and hence delay diagnosis. In fact, delayed presentation is directly associated with an increase in surgical intervention and bowel resections (Shapkina et al. 2006). Ileocolic intussusception is less likely to reduce spontaneously as the pathology most commonly starts at the ileocecal region, with edema at the ileocecal valve being the limiting factor. Successful pneumatic reduction in ileocolic intussusception has been reported to be as high as 91% in some centers (Saxena and Hollwarth 2007), provided the presentation is not delayed and the ultrasound confirms viable bowel. Most studies in literature include both small bowel and ileocolic intussusception in their data and do not differentiate features or outcomes between them. A study by Saxena et al. in 2007 (Saxena and Hollwarth 2007) compared the difference between patients with small bowel and ileocolic intussusception. Spontaneous reduction occurred in 13.3% of ileocolic and 64.3% of small bowel intussusception. Pneumatic reduction was successful in 91% of ileocolic compared with 85.7% of small bowel intussusception. Primary surgical intervention was required in 6% of patients with ileocolic intussusception in whom 2.4% required bowel resection and in 10.7% of patients with small bowel intussusception, all of whom necessitated bowel resection.

Conclusion and Future Directions In conclusion, the efficacy of intussusception treatment in terms of closed reduction, surgery, and outcomes depends on a combination of factors: the timing of presentation, the type of intussusception (ileocolic versus small bowel), the presence of pathological lead points, ultrasound/ Doppler findings, and expertise in reduction techniques to avoid complications.

194

Cross-References ▶ Gastrointestinal Bleeding ▶ Genetics of Pediatric Tumors

References Ashcraft KW, Holcomb GW, Murphy JP. Pediatric surgery. Philadelphia: Elsevier Saunders; 2005. Avansino JR, Bjerke S, Hendrickson M, et al. Clinical features and treatment outcome of intussusception in premature neonates. J Pediatr Surg. 2003;38:1818. Barbette P. Oeuvres Chirurgiques et Anatomiques. Geneva: François Miege; 1674. Bines JE. Rotavirus vaccines and intussusception risk. Curr Opin Gastroenterol. 2005;21(1):20–5. Blakelock RT, Beasley SW. The clinical implications of non-idiopathic intussusception. Padiatr Surg Int. 1998;14:163–7. British Society of Paediatric Radiologists. Draft guidelines for the reduction of intussusception. http://www.BSPR. org.uk. Accessed 7 Nov 2007. Burke LF, Clarke E. Ileocolic intussusception: a case report. J Clin Ultrasound. 1977;5:346–7. Daneman A, Navarro O. Intussusception. Part 2: an update on the evolution of management. Pediatr Radiol. 2004;34(2):97–108. Epub 2003 Nov 21. Daneman A, Alton DJ, Lobo E, et al. Patterns of recurrence of intussusception in children: a 17 year review. Pediatr Radiol. 1998;28:913–9. Edwards EA, Pigg H, Courtier J, et al. Intussusception: past, present and future. Pediatr Radiol. 2017;47:1101–8. Ein SH, Stephens CA. Intussusception: 354 cases in 10 years. J Pediatr Surg. 1971;6:16. Greig D. On insufflation as a remedy in intussusception. Edinb Med J. 1864;10:306. Guo J, Ma X, Zhou Q. Results of air pressure enema reduction of intussusception: 6396 cases in 13 years. J Pediatr Surg. 1986;21:1201–3. Guo WL, Hu ZC, Tan YL, et al. Risk factors for recurrent intussusception in children: a retrospective cohort study. BMJ Open. 2017;7(11):e018604. Hamby LS, Fowler CL, Pokorny WJ. Intussusception. In: Donnellan WL, editor. Abdominal surgery of infancy and childhood. Australia: Harwood; 1996. p. 1. Henrikson S, Blane CE, Koujok K. The effect of screening sonography on the positive rate of enemas for intussusception. Pediatr Radiol. 2003;33:190–3. Hipsley P. Intussusception and its treatment by hydrostatic pressure: based on an analysis of 100 consecutive cases so treated. Med J Aust. 1926;2:201–6. Hirschsprung H. Et Tilfaelde af suakut Tarminvagination. Hospitals-Tidende. 1876;3:321–7.

S. Parkar and A. K. Saxena Holt LE. The diseases of infancy and childhood: for the use of students and practitioners in of medicine. New York: Appleton; 1897. p. 378–88. Hunter J. On introsusception. Trans Soc Improv Med Surg Knowl. 1793;1:103. Hutchinson J. A successful case of abdominal section for intussusception. Proc R Med Chir Soc. 1873;7:195–8. Jean Baptiste Dance (1797–1832) – French pathologist and physician. Kaiser AD, Applegate KE, Ladd AP. Current success in the treatment of intussusception in children. Surgery. 2007;142(4):469–75; Discussion 475–7. Ko HS, Schenk JP, Troger J, Rohrschneider WK. Current radiological management of intussusception in children. Eur Radiol. 2007;17(9):2411–21. Epub 2007 Feb 17. Koh EPK, Chua JHY, Chui CH, Jacobsen AS. A report of 6 children with small bowel intussusception that required surgical intervention. J Pediatr Surg. 2006;41:817–20. Kornecki A, Daneman A, Navarro O, Connolly B, Manson D, Alton DJ. Spontaneous reduction of intussusception: clinical spectrum, management and outcome. Pediatr Radiol. 2000;30:58–63. Maoate K, Beasley SW. Perforation during gas reduction of intussusception. Pediatr Surg Int. 1998;14:168–70. McAlister WH. Intussusception: even Hippocrates did not standardize his technique of enema reduction. Radiology. 1998;206:595. McDermott VG. Childhood intussusception and approaches to treatment: a historical review. Pediatr Radiol. 1994;24:153. Meier DE, Coln CE, Rescoria FJ, et al. Intussusception in children: international perspective. World J Surg. 1996;20:1035–40. Niramis R, et al. Management of recurrent intussusception: non-operative or operative reduction? J Pediatr Surg. 2010;45(11):2175–80. Ondhia MN, Al-Mutawa Y, Harave S, et al. Intussusception: a 14-year experience at a UK tertiary referral centre. J Pediatr Surg. 2019. Pueyo C, Maldonado J, Royo Y, et al. Intrauterine intussusception: a rare cause of intestinal atresia. J Pediatr Surg. 2009;44:2028. Ravitch MM. Intussusception in infants and children. Springfield: Charles C Thomas; 1959. Saxena AK, Hollwarth ME. Factors influencing management and comparison of outcomes in paediatric intussusceptions. Acta Pediatr. 2007;96:1199–202. Saxena AK, Van Tuil C. Intrauterine intussusception in aeitiology of jejunal atresia. Dig Surg. 2008;25(3):187. Saxena AK, Seebacher U, Bernhadt C, Hollwarth ME. Small bowel intussusceptions: issues and controversies related to pneumatic reduction and surgical approach. Acta Paediatr. 2007;96(11):1651–4. Epub2007 Sep 19. Shapkina AN, Shapin VV, Nelubov IV, Pyanishena LT. Intussusception in children: an 11 year experience in Valdivostok. Pediatr Surg Int. 2006;22:901–4.

13

Intussusception

Sinha C, Davenport M. Handbook of paediatric surgery. London: Springer; 2010. Smith DS, Bonadio WA, Losek JD, et al. The role of abdominal x-rays in the diagnosis and management of intussusception. Pediatr Emerg Care. 1992;8: 325–7. Stringer MD, Pablot SM, Brereton RJ. Paediatric Intussusception. Br J Surg. 1992;79:867–76.

195 Tareen F, Ryan S, Avanzini S, Pena V, McLaughlin D, Puri P. Does the length of history influence the outcome of pneumatic reduction of intussusception in children? Pediatr Surg Int. 2011;27(6):587–9. https://doi.org/ 10.1007/s00383-010-2836-6. Torres ML, McCafferty MH. Rectosigmoid intussusception through the anus mimicking rectal prolapse. Am Surg. 2010;76(7):718–20.

Primary Peritonitis

14

Robert Baird and Jean Martin Laberge

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 Predisposing Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hepatic Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nephrotic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Systemic Lupus Erythematosus (SLE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Familial Mediterranean Fever (FMF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Peritoneal Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ventriculoperitoneal Shunts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Predisposing Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

199 199 200 200 200 201 202 203

Primary Peritonitis in Healthy Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 Conclusion and Future Direction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

Abstract

Primary peritonitis is a clinical entity rarely encountered by practicing pediatric surgeons

R. Baird Department of Pediatric Surgery, BC Children’s Hospital, Vancouver, BC, Canada e-mail: [email protected] J. M. Laberge (*) Department of Pediatric Surgery, Montreal Children’s Hospital, McGill University Health Center, Montreal, QC, Canada e-mail: [email protected]; [email protected]

today, although intervention for the diagnosis and treatment is occasionally required. Typically, it develops in the context of a recognized predisposing factor, including underlying hepatic or renal dysfunction or the presence of an indwelling catheter. Occasionally, primary peritonitis may be encountered in the context of a patient without an overt predisposition. An astute clinician must recognize the possibility of an index presentation of familial Mediterranean fever (FMF) or systemic lupus erythematosus (SLE), when clinical presentation is inconsistent with a cause of more

© Springer-Verlag GmbH Germany, part of Springer Nature 2021 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43559-5_111

197

198

conventional secondary peritonitis; failure to do so can result in unnecessary interventions and morbidity. Keywords

Primary peritonitis · Children · Peritoneal dialysis · Spontaneous bacterial peritonitis · Ascites · Nephrotic syndrome · Ventriculoperitoneal shunting · Systemic lupus erythematosus · Familial Mediterranean fever

Introduction Primary peritonitis (PP) refers to an intra-abdominal inflammatory process not originating from an intra-abdominal organ and is most commonly encountered in the context of nephrotic syndrome or hepatic dysfunction – both of which result in ascites (El-Hakim Allam et al. 2018). In the era before antibiotics, up to 10% of abdominal operations in children fell into the category of PP and carried an associated mortality of up to 50% (Ein 1986). Conn described the etiology of PP in 1964, linking the presence of intra-abdominal ascites with bacterial translocation of intestinal flora as the necessary constituents of primary peritonitis (Conn 1964). Today, PP is a rare cause of peritonitis in children and represents less than 1% of all pediatric laparotomies, because the diagnosis and treatment typically no longer require operative intervention (Fowler 1971). This chapter reviews the definition, symptomatology, and predisposing conditions commonly associated with the development of PP.

Definition Primary peritonitis (PP) is now more commonly encountered by pediatric nephrologists and hepatologists than pediatric surgeons, as the diagnosis and management rarely require intervention. It is distinguished from more familiar forms of peritonitis in that the source of infection originates outside the abdomen (Ein 1986). Routes of infection include hematogenous, lymphatic, transmural,

R. Baird and J. M. Laberge

or retrograde extension from the vagina via the fallopian tubes. Spontaneous bacterial peritonitis is another expression used for PP, in the context of liver failure or nephrotic syndrome. Secondary peritonitis arises within the abdominal cavity through extension from or rupture of an intraabdominal hollow viscus or a primary abscess within an intra-abdominal solid organ – appendicitis remains the most common example. Tertiary peritonitis refers to recurrent diffuse or localized peritoneal inflammation and is associated with poorer outcomes than secondary peritonitis. Sterile peritonitis may be chemical or mechanical and refers to peritoneal inflammation in the absence of a causative organism. While meconium peritonitis in utero and pancreatitis meet this strict definition, they originate from within the abdominal cavity; more traditional examples of sterile PP include familial Mediterranean fever (FMF) and systemic lupus erythematosus (SLE).

Clinical Presentation PP should be suspected in any child with acute abdominal pain associated with a febrile illness and an underlying predisposition to primary peritonitis – see Table 1. These include medical conditions that result in chronic ascites such as nephrotic syndrome and hepatic dysfunction, the presence of indwelling catheters like peritoneal dialysis catheters or ventriculoperitoneal Table 1 Conditions associated with primary peritonitis in children Conditions associated with ascites Hepatic dysfunction Nephrotic syndrome Inflammatory conditions Systemic lupus erythematosus Familial Mediterranean fever Conditions associated with immunosuppression Dermatomyositis Postsplenectomy Chronic steroid use Devices Peritoneal dialysis Ventriculoperitoneal shunt

14

Primary Peritonitis

(VP) shunts, or inflammatory conditions like SLE and FMF. The time course may be more protracted than that for secondary peritonitis, and diffuse rebound tenderness is often present. The absence of localized pain may result from irritation of visceral surfaces. Diagnostic paracentesis is frequently helpful in the presence of ascites, as is sampling of the dialysate in children with renal failure on ambulatory peritoneal dialysis programs, and tapping of the shunt reservoir in patients with VP shunts. PP is traditionally associated with the identification of a single organism – if more than one organism is present on Gram stain, a perforated viscus should be suspected. Sending a minimum of 10 mL of fluid for Gram stain and culture analysis will increase the number of positive isolates, yet cultures may be negative in as many as 60% of reported cases (Runyon et al. 1987). The isolation and sensitivity pattern of specific bacteria decreases the spectrum of antibiotics required and potentially eliminates the need for nephrotoxic drugs in patients with compromised renal function. The diagnosis of PP is confirmed when the leukocyte count in peritoneal fluid is higher than 500/mm3 and granulocytes predominate (lymphocytes are usually present in higher numbers in normal peritoneal fluid). Typical peritoneal fluid in patients with bacterial PP also has a pH of less than 7.35 and an elevated lactate level (Garcia-Tsao et al. 1985). Samples of blood and urine should be sent for culture, and radiographs of the chest and abdomen should be obtained to eliminate an intra-abdominal source of peritoneal contamination. Routine electrolytes and total protein levels should be investigated, as low serum protein levels and resultant paucity of opsonins may contribute to the development of PP. Ultrasound studies and computed tomography (CT) of the abdomen may be required to differentiate primary from secondary peritonitis (caused by common pediatric processes such as appendicitis), depending on the clinical context. Doublecontrast (oral and intravenous) CT scan findings in PP include the presence of diffusely distributed peritoneal fluid and secondary enhancement of the bowel wall (Dann et al. 2005). In addition, the absence of appendicitis or another intra-

199

abdominal source is a sine qua non of the diagnosis of PP. Ultimately, the investigation of patients with peritonitis depends greatly on the presence or absence of underlying medical conditions; in many instances, radiation-emitting imaging modalities can be obviated. In all instances of peritonitis without an overt source of infection, failure to improve with intravenous antibiotics is an indication for laparoscopy or laparotomy. An appendectomy can be done safely, even in the presence of cloudy exudate, and the bowel surface should be inspected for an alternative cause of secondary infection. After the surgical intervention, antibiotics should be continued until the leukocytosis normalizes and the ileus resolves (Ein 1986).

Predisposing Conditions Hepatic Dysfunction The liver with its rich reticuloendothelial tissue normally filters the bacteria found in the portal circulation. As cirrhosis develops, or in patients with extrahepatic portal vein obstruction (“cavernomatous transformation”), portal venous flow is partially shunted away from the liver, thereby decreasing the clearance of bacteria and fungi from both the blood and lymphatic systems. This decreased clearance likely allows for the persistence of bacteria in ascitic fluid. Liver disease in the pediatric population can be due to a number of different congenital or acquired conditions, including biliary atresia, Alagille syndrome, cholestasis secondary to parenteral nutrition, and many more. In adults with end-stage liver disease and PP, gram-negative enteric bacteria are the most frequent organisms, but in pediatric patients, Streptococcus pneumoniae and other gram-positive cocci predominate in some series (Leonis and Balistreri 2008). The treatment of choice for PP, in this context, is a third-generation cephalosporin in most pediatric patients, with treatment initiated once the diagnosis is suspected and not delayed for confirmatory cultures. Because of a high recurrence rate, pneumococcal vaccination and antibiotic prophylaxis with trimethoprim-

200

sulfamethoxazole should be used in children with cirrhosis and ascites after a first episode of PP (Leonis and Balistreri 2008).

Nephrotic Syndrome PP has been reported in 3–17% of children with nephrotic syndrome (Warady et al. 2007). Before the availability of antibiotic therapy, PP was the leading cause of death in this patient population. An increased susceptibility to infection in these patients may be related to impaired cellular immunity and chemotaxis, decreased opsonization, and reduced levels of circulating immunoglobulins. Complement proteins I and B are reduced in the serum but increased in the urine of patients with peritonitis and NS (Matsell and Wyatt 1993). The episodes of peritonitis are recurrent in 15–26% of cases and have been associated with decreased levels of circulating IgG (Warady et al. 2007). Multivalent pneumococcal vaccination has been recommended in this group of patients, although peritonitis has occurred despite protective immunization (Milner et al. 1987). In the context of the developing world, one report advocates immunization only for the small number of children who have steroid-dependent or steroid-resistant nephrotic syndrome (Uncu et al. 2010), while a more recent one from India recommends pneumococcal vaccination early in the course for all patients (Kumar et al. 2019). Large reported series in children indicate that gram-negative organisms are isolated in 6–30% of patients with primary peritonitis and nephrotic syndrome (Alwadhi et al. 2004). Even when the peritoneal fluid shows no bacterial isolates, children have been shown to respond to the systemic administration of intravenous penicillin, although the development of resistant organisms remains a concern (Milner et al. 1987). In almost 80% of children with nephrotic syndrome in whom PP developed, steroids were used as treatment of the condition (Alwadhi et al. 2004). Initial treatment of PP in patients with nephrotic syndrome should include the administration of antibiotics to cover both gram-positive and gram-negative bacteria. In cases in which

R. Baird and J. M. Laberge

clinical improvement does not occur within 24 h after the initiation of therapy, further diagnostic studies such as abdominal CT or diagnostic laparoscopy should be employed to eliminate other causes of peritonitis. However, abdominal CT scans may not always successfully differentiate primary from secondary peritonitis. Laparoscopy and abdominal irrigation have been successfully used with medical management when the clinical course shows no improvement.

Systemic Lupus Erythematosus (SLE) Lupus is a chronic autoimmune condition characterized by the formation of autoantibodies directed at self-antigens. The pathophysiology is multifactorial, and the presentation can vary greatly between patients. Serositis is a frequent manifestation of the disease, and primary peritonitis has been described as the index presentation for SLE (Fathalla et al. 2010). Peritoneal inflammation is not a consequence of bacterial contamination but rather a reaction to antibody-antigen interaction, yielding a sterile peritonitis. A review of pediatric-onset SLE demonstrated a 19% rate of abdominal involvement, most commonly due to pancreatitis or new-onset ascites; three children in the series (8%) underwent laparotomies for peritonitis prior to the diagnosis of SLE, one of whom was found to have acalculous cholecystitis (Richer et al. 2007). For patients with known SLE, high-dose steroids are usually effective as first-line therapy for acute abdominal pain once other surgical pathologies have been ruled out. This can sometimes prove difficult in immunodeficient children, in whom clinical signs of intraabdominal perforation or ischemia may be masked; clinical vigilence is required, and extensive investigations are frequently necessary to rule out appendicitis or other more common causes of peritonitis.

Familial Mediterranean Fever (FMF) Familial Mediterranean fever (also known as recurrent polyserositis) is a hereditary

14

Primary Peritonitis

201

inflammatory condition characterized by transient episodes of fever, abdominal pain, pleuritis, arthritis, and skin rash and primarily affects individuals originating from the Mediterranean area. Its inheritance is generally recessive, although varying penetrance has been reported depending on the specific genetic mutation. Nonsense or missense mutations in the MEFV (Mediterranean fever) gene on chromosome 16 appear to cause the disease in most cases. MEFV produces a protein called pyrin (derived from the association with predominant fever) or marenostrin (derived from the phrase “our sea,” because of the Mediterranean heritage of most patients). There are frequent episodes of inflammation of the peritoneum (85%), joints (50%), and pleura (33%) associated with high fever and abdominal tenderness. A recent review has demonstrated that 31% of patients manifest symptoms by 2 years of age, and these patients had a longer delay until diagnosis (Padeh et al. 2010). In FMF, the abdominal symptoms typically begin to relent within 12 h of onset, with resolution within 24–48 h. If surgical intervention is undertaken, the bowel is characteristically seen to be coated with a sterile exudate containing fibrin. As in SLE, ascitic fluid is characteristically sterile in FMF; as opposed to other examples of primary peritonitis, antibiotics do not play a role in the acute setting or as prophylaxis. The use of colchicine may decrease the severity of painful episodes and reduce the incidence of longterm adhesive small bowel obstruction (Granat et al. 1983). Five to 10% of patients have been found to be non-responders to colchicine;

Fig. 1 Data from 144 episodes of peritonitis in 66 children with nephrotic syndrome (Furth et al. 2000)

anakinra (an interleukin-1 receptor antagonist) has been found to control the acuity of febrile attacks in adolescents (Calligaris et al. 2008). Once the diagnosis of FMF has been considered, a complete family history should be obtained and genetic testing promptly offered. Long-term complications include the development of adhesive small bowel obstruction and/or strangulation in up to 3% of pediatric cases, which represent a diagnostic challenge when a known FMF patient presents with abdominal pain (d’Annunzio et al. 2011).

Peritoneal Dialysis In children maintained on chronic peritoneal dialysis (PD), peritonitis is the primary complication compromising technique survival. The problem has prompted formation of the International Pediatric Peritonitis Registry (IPPR), an Internetbased prospective registry of 47 pediatric centers across 14 countries (Warady et al. 2007). Peritonitis (either bacterial or fungal) occurs at a rate of one episode per 11.1–13.2 patient-months in separate multi-institutional studies (Furth et al. 2000). Gram-positive organisms were isolated in 44–49% of cases, gram-negative bacteria in 21–25%, and fungi in 1.8%, and 21–31% of the symptomatic patients did not have positive cultures (Furth et al. 2000); see Fig. 1. Risk factors for the development of peritonitis in this group of children include contamination of the connectors during dialysate fluid exchange, exit site or tunnel

Causative organism of peritonitis in children on peritoneal dialysis

13.9

Staphylococcus aureus Staphylococcus epidermidis 38.9

13.9

Group A streptococci Pseudomonas species Other bacteria or fungi No organisms found on culture

9 9.7

13.2

202

infections, local trauma to the tunnel site, and nasal colonization with staphylococcal organisms (Furth et al. 2000). Additional risk factors for the development of PD-related peritonitis include the duration of PD (longer than a year), chronologic age younger than 2 years, and decreased serum IgG levels (Kuizon et al. 1995). A recent study involving a large cohort of pediatric peritoneal dialysis patients reported that 8.4% of PD catheters were associated with the development of peritonitis (Keswani et al. 2019). The authors found that the occurrence of peritonitis was significantly higher in those children in whom PD catheters were used for dialysis earlier than the current International Society for Peritoneal Dialysis wait time of 14 days following insertion of the catheter. A consensus guideline has articulated many of the key principles in preventing and treating peritonitis in children undergoing peritoneal dialysis (Warady et al. 2012). Evidence-based preventive steps include the involvement of dedicated pediatric dialysis nursing with updated training, the use of a double-cuffed Tenckhoff catheter with a downward or lateral subcutaneous tunnel configuration placed with appropriate antibiotic prophylaxis, and appropriate dressing changes and catheter immobilization (Furth et al. 2000; Warady et al. 2012). Additional maneuvers include routine cleaning of the exit site as well as application of topical antibiotics, suitable connectology – particularly for continuous ambulatory peritoneal dialysis, antibiotic prophylaxis for high-risk procedures (dental, GI, or GU procedures), and exit sites remote from ostomies (Warady et al. 2012). Clinical findings of peritonitis include abdominal pain, fever, and an elevated neutrophil count in the cloudy dialysate. Once suspected, the fluid should be cultured, and both intravenous and intraperitoneal antibiotics should be instituted, with close monitoring of antibiotic levels. Because in vitro evaluation revealed 69% sensitivity of grampositive organisms to a first-generation cephalosporin and 80% sensitivity of gram-negative organisms to a third-generation cephalosporin worldwide, current treatment guidelines for empiric therapy include intraperitoneal cefepime as first-line therapy, with first-generation

R. Baird and J. M. Laberge

cephalosporin combined with ceftazidime or an aminoglycoside if cefepime is not available (Warady et al. 2007). Antibiotic therapy should be tailored once culture and sensitivity results become available. Symptoms should begin to improve within 24–36 h after initiation of therapy. Long-term multi-institutional longitudinal studies suggest that the peritoneal dialysis catheter must be removed to eradicate the infection when Pseudomonas, Candida, or atypical mycobacterial species are isolated (Kuizon et al. 1995; Furth et al. 2000). There is also a risk of peritoneal membrane failure when these organisms are involved, thus precluding the continued use of peritoneal dialysis. In addition, PD catheters should be removed for refractory peritonitis. Relapsing, repeat and recurrent peritonitis remain a common clinical problem for these patients (Bakkaloglu and Warrady 2015). Defined as recurrence of peritonitis with the same organism within 4 weeks after termination of antibiotic treatment, relapsing peritonitis was found to occur in 11% of PD patients experiencing an episode of peritonitis; it significantly decreased the rate of full functional recovery and increased the rate of necessitating permanent PD discontinuation (Lane et al. 2010).

Ventriculoperitoneal Shunts Spontaneous bacterial peritonitis has been described in children with indwelling ventriculoperitoneal (VP) shunts without evidence of cerebrospinal fluid infection (Gaskill and Marlin 1997). Cultures from these patients have resulted in a variety of gram-positive organisms, and improvement in peritoneal irritation occurs with exteriorization of the shunt tubing. VP shunt infection from a readily identifiable source remains a common complication; however, shunt infection may present as an acute abdomen for which laparoscopy/laparotomy is unnecessary; a complete diagnostic work-up is required including a shunt series, tapping of the shunt reservoir for culture and sensitivity, a head CT scan, as well as abdominal imaging depending on the presenting complaints. Multiple cases of shunt migration into the

14

Primary Peritonitis

colon have been reported, but the majority of patients have not developed peritonitis (Glatstein et al. 2011). When shunt fluid appears sterile, Gram stain and culture of peritoneal fluid may help to differentiate primary peritonitis or shunt infection from an intra-abdominal source (Vinchon and Dhellemmes 2005). Common intra-abdominal infectious processes like appendicitis must be treated promptly and shunt exteriorization strongly considered (Ein et al. 2006).

Other Predisposing Factors Several case reports exist in the literature describing alternative conditions that may predispose to the development of PP. Given the rarity of these reports, as well as the possibility of inaccurate diagnostics given the standards of today, it is impossible to determine whether a true association exists. Fowler et al. described a single patient that presented with PP and was being treated with systemic steroids for adrenogenital syndrome (Fowler 1971). Chung et al. described one patient with juvenile dermatomyositis treated with steroids that expired from primary peritonitis (Chung et al. 1994). Both of these reports highlight the possible role of immunosuppression in the pathophysiology of PP, which may accelerate bacterial translocation and also mask the presenting symptoms. Doershuk and Stern describe two patients with cystic fibrosis that developed PP, both of whom had a splenectomy without additional portosystemic shunting for cirrhosis (Doershuk and Stern 1994). It is likely that the underlying predisposition in this case is not the cystic fibrosis but rather the cirrhosis combined with the relative immunosuppresion associated with asplenism. Furthermore, additional cases of PP after splenectomy have been reported (Wong et al. 2013).

Primary Peritonitis in Healthy Children Gross reported 58 cases of PP in a group of previously healthy infants and toddlers (mean age, 2 years) who had a pre-existing upper

203

respiratory infection. A later series, from the same facility, recorded 33 patients with a mean age of 5 years who were treated for PP over the next 30 years (Harken and Shochat 1973). The decrease in the number of affected children was considered the result of increased availability and use of oral antibiotics. Although multiple potential sources of infection have been implicated, including hematogenous (dental procedures, bacteremia), lymphatic, gut translocation, and ascending gynecologic processes, the etiology remains unclear in most cases. In 1985, two previously healthy children with dehydration, abdominal distention, and Group A streptococcal peritonitis were reported. At the time of laparotomy, no source of infection was identified, although one of the children had a concomitant right-sided diaphragmatic hernia (Serlo et al. 1985). The literature has since identified a group of healthy children with idiopathic peritonitis and simultaneously positive cultures for Group A streptococci from the trachea, pharynx, or tonsils (Gillespie et al. 2002. In prepubertal girls with gonococcal vaginitis, 6% may have evidence of peritonitis. Treatment with parenteral cephalosporins is indicated, and the presence of other associated simultaneous sexually transmitted bacteria should be investigated. In earlier reported series of PP, most of the patients were girls, and the vagina was often implicated as the source of the infections. However, vaginitis was uncommon, and the ultimate source of the infection remained obscure (Harken and Shochat 1973). The prepubertal cervix lacks the endocervical glands that may harbor bacteria, so ascending infections in this age group would more likely be associated with some traumatic force that pushes the bacteria up through the vagina, as in sexual abuse cases or by jumping feet first into swimming pool or lake water. In a more recent series, the incidence of PP in children without any underlying predisposing factor is equally distributed between boys and girls (Moskovitz et al. 2000). In some cases, the same bacteria causing the peritoneal infection have also been cultured from the respiratory and urinary tract, as well as from the oral cavity (Clark 1984).

204

Conclusion and Future Direction Primary peritonitis remains a diagnosis of exclusion, whose recognition and management vary depending on the clinical presentation. For patients at increased risk of developing PP, vigilant preventative measures, appropriate antibiotic prophylaxis, and prompt treatment for suspected infection remain the cornerstones of care. Occasionally, patients fail to respond to maximal medical therapy. In these instances, an exploratory laparoscopy/laparotomy is indicated, and a thorough inspection of all potential occult sources of infection should be performed. This is a rare clinical scenario, however. Continued improvement in the diagnosis and care of patients with PP – as well as initial preventive strategies – will fortunately continue to render PP an uncommon condition encountered by practicing pediatric surgeons.

Cross-References ▶ Complications of Immunosuppression in Pediatric Surgery ▶ Portal Hypertension

References Alwadhi RK, Mathew JL, Roth B. Clinical profile of children with nephrotic syndrome not on glucocorticoid therapy but presenting with infection. J Pediatr Child Health. 2004;40:28–32. Bakkaloglu SA, Warady BA. Difficult peritonitis cases in children undergoing chronic peritoneal dialysis: relapsing, repeat, recurrent and zoonotic episodes. Pediatric Nephrology. 2015 Sep 1;30(9):1397–406. Calligaris L, Marchetti F, Tommasini A, et al. The efficacy of anakinra in an adolescent with colchicine-resistant familial Mediterranean fever. Eur J Pediatr. 2008;167:695–6. Clark JH, Fitzgerald JF, Kleiman MB. Spontaneous bacterial peritonitis. J Pediatr 1984;104 (4):495–500. Chung HT, Haung JL, Wang HS, et al. Dermatomyositis and polymyositis in childhood. Zhomghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1994;35(5):407–14. Conn HO. Spontaneous peritonitis and bacteremia in Laennec’s cirrhosis caused by enteric organisms. Ann Int Med. 1964;60:568–80.

R. Baird and J. M. Laberge d’Annunzio E, Chafai N, Tiret E. Piège de la fièvre méditerranéenne familiale: occlusion intestinale aiguë sur adhérence péritonéale primaire. J Visc Surg. 2011;148(3):248–50. Dann PH, Amodio JB, Rivera R, et al. Primary bacterial peritonitis in otherwise healthy children: imaging findings. Pediatr Radiol. 2005;35:198–201. Doershuk CF, Stern RC. Spontaneous bacterial peritonitis in cystic fibrosis. Gut. 1994;35:709–11. Ein SH. Primary peritonitis. In: Welch KJ, Randolph JG, editors. Pediatric surgery. 4th ed. Chicago: Year Book; 1986. p. 976. Ein SH, Miller S, Rutka JT. Appendicitis in the child with a ventriculo-peritoneal shunt: a 30-year review. J Pediatr Surg. 2006;41:1255–8. El-Hakim Allam AA, Eltaras SM, Hussin MH, et al. Diagnosis of spontaneous bacterial peritonitis in children using leukocyte esterase reagent strips and granulocyte elastase immunoassay. Clin Exp Hepatol. 2018;4(4):247–52. Fathalla B, Shah R, Goldsmith D. Peritonitis as the primary manifestation at onset of childhood systemic lupus erythematosus. J Clin Rheumatol. 2010;16:43–4. Fowler R. Primary peritonitis: changing aspects 19561970. Aust Pediatr J. 1971;7:73–83. Furth SL, Donaldson LA, Sullivan EK, et al. Peritoneal dialysis catheter infections and peritonitis in children: a report of the North American pediatric renal transplant cooperative study. Pediatr Nephrol. 2000;15:179–82. Garcia-Tsao G, Conn HO, Lerner E. The diagnosis of bacterial peritonitis: comparison of pH lactate concentration and leukocyte count. Hepatology. 1985;5:91–6. Gaskill SJ, Marlin AE. Spontaneous bacterial peritonitis in patients with ventriculoperitoneal shunts. Pediatr Neurosurg. 1997;36:115–9. Gillespie RS, Hauger SB, Holt RM. Primary group A streptococcal peritonitis in a previously healthy child. Scand J Infect Dis. 2002;34:847–8. Glatstein M, Constantini S, Scolnik D, et al. Ventriculoperitoneal shunt catheter protrusion through the anus: case report of an uncommon complication and literature review. Childs Nerv Syst. 2011;27(11):2011–4. Granat M, Tur-Kaspa I, Zylber-Katz E, Schenker JG. Reduction of peritoneal adhesion formation by colchicine: a comparative study in the rat. Fertil Steril. 1983;40:369–372. Harken AH, Shochat SJ. Gram-positive peritonitis in children. Am J Surg. 1973;125:769–72. Keswani M, Redpath Mahon AC, Richardson T, et al. Risk factors for early onset peritonitis: the SCOPE collaborative. Pediatr Nephrol. 2019;34(8):1387–94. Kuizon B, Melocoton TL, Holloway M, et al. Infections and catheter related complications in pediatric patients treated with peritoneal dialysis at a single institution. Pediatr Nephrol. 1995;9(Suppl):S12–7. Kumar M, Ghunawat J, Saikia D et al. Incidence and risk factors for major infections in hospitalized children with nephrotic syndrome. J Bras Nefrol. 2019;41(4): 526–533. pii: S0101-28002019005028101. Lane JC, Warady BA, Feneberg R, et al. Relapsing peritonitis in children who undergo chronic peritoneal

14

Primary Peritonitis

dialysis: a prospective study of the international pediatric peritonitis registry. Clin J Am Soc Nephrol. 2010;5:1041–6. Leonis MA, Balistreri WF. Evaluation and management of end-stage liver disease in children. Gastroenterology. 2008;134:1741–51. Matsell DG, Wyatt RJ. The role of I and B in peritonitis associated with the nephrotic syndrome of childhood. Pediatr Res 1993;34:84–8. Milner LS, Berkowitz FE, Ngwenya E, et al. Penicillin resistant pneumococcal peritonitis in nephrotic syndrome. Arch Dis Child. 1987;62:964–5. Moskovitz M, Ehrenberg E, Grieco R, et al. Primary peritonitis due to group A streptococcus. J Clin Gastroenterol. 2000;30:332–5. Padeh S, Livneh A, Pras E, et al. Familial Mediterranean fever in the first two years of life: a unique phenotype of disease in evolution. J Pediatr. 2010;156: 985–9. Richer O, Ulinski T, Lemelle I, et al. Abdominal manifestations in childhood-onset systemic lupus erythematosus. Ann Rheum Dis. 2007;66:174–8. Runyon BA, Umland ET, Merlin T. Inoculation of blood culture bottles with ascitic fluid: improved detection of

205 spontaneous bacterial peritonitis. Arch Intern Med. 1987;147:73–5. Serlo W, Heikkinen E, Kouvalainen K. Group A streptococcal peritonitis in infancy. Ann Chir Gynaecol. 1985;74:183–4. Uncu N, Bülbül M, Yıldız N, et al. Primary peritonitis in children with nephrotic syndrome: results of a 5-year multicenter study. Eur J Pediatr. 2010;169:73–6. Vinchon M, Dhellemmes P. Abdominal complications of peritoneal shunts. In: Pediatric hydrocephalus. Milan: Springer; 2005. p. 315–27. Warady BA, Feneberg R, Verrina E, et al. Peritonitis in children who receive long-term peritoneal dialysis: a prospective evaluation of therapeutic guidelines. J Am Soc Nephrol. 2007;18:2172–9. Warady BA, Bakkaloglu S, Newland J, et al. Consensus guidelines for the prevention and treatment of catheterrelated infections and peritonitis in pediatric patients receiving peritoneal dialysis: 2012 update. Perit Dial Int. 2012;32(Suppl 2):S32–86. Wong GK, Goldacker S, Winterhalter C, et al. Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients. Clin Exp Immunol. 2013;172(1):63–72.

Gastrointestinal Bleeding

15

Pamela Choi, Josh Sommovilla, and Brad Warner

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 Resuscitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 General Diagnostic Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 Upper Gastrointestinal Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Swallowed Maternal Blood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hemorrhagic Disease of the Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stress Gastritis Ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Gastritis and Peptic Ulcer Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Esophageal Varices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

210 210 210 211 211 211

Lower Gastrointestinal Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anal Fissures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Allergic Colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Necrotizing Enterocolitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Malrotation with Midgut Volvulus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Meckel’s Diverticulum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Enteric Duplication Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hirschsprung’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intussusception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Polyps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henoch-Schonlein Purpura . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

212 212 212 213 213 213 214 214 214 215 215 215

Infectious Causes of Gastrointestinal Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 Vascular Malformations as Causes of Gastrointestinal Bleeding . . . . . . . . . . . . . . . . . . 216

Pamela Choi and Josh Sommovilla contributed equally with all other contributors. P. Choi (*) · J. Sommovilla · B. Warner Washington University, St Louis, MO, USA e-mail: [email protected] © Springer-Verlag GmbH Germany, part of Springer Nature 2021 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43559-5_108

207

208

P. Choi et al. Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

Abstract

Gastrointestinal bleeding is a commonly encountered problem in pediatric practice. While many causes of gastrointestinal bleeding exist, age and presenting symptoms aid in narrowing the differential diagnosis and in selecting initial diagnostic studies. Management strategies vary depending upon the diagnosis and source of bleeding and may include medical, radiographic, endoscopic, or surgical interventions. Keywords

Gastrointestinal bleeding · Endoscopy · Upper gastrointestinal bleeding · Lower gastrointestinal bleeding · Colonoscopy

Introduction Children who present with gastrointestinal (GI) bleeding must first be assessed for hemodynamic stability. Bleeding may be sudden and life-threatening or subtle without visible evidence of blood loss but presenting with non-specific symptoms of fatigue or pallor. The majority of cases are benign and self-limiting, but patients who show signs of hemodynamic instability require immediate resuscitation with subsequent investigation as to the cause of bleeding. The diagnostic approach for gastrointestinal bleeding in children includes definition of etiology, localization of the bleeding site, and determination of the severity of the bleeding; timely and accurate diagnosis is necessary to reduce morbidity and mortality (Romano et al. 2017). A differential diagnosis can initially be based upon patient presentation and age (Table 1). The gastrointestinal bleed is generally defined anatomically, by location of suspected blood loss relative to the ligament of Treitz. A careful

history and physical examination is essential in identifying the likely source of bleeding and guiding the use of appropriate diagnostic tools (Table 2).

Resuscitation Most patients with gastrointestinal bleeding are hemodynamically stable. All children, however, should first be assessed for the status of airway, breathing, and circulation. Stabilization should take precedence over diagnosis. Signs of circulatory compromise include tachycardia, hypotension, pallor, altered mental status, lethargy, or decreased urine output. An ill-appearing child should have two large bore IVs placed and be given 10–20 mL/kg boluses of crystalloid. Rapid blood loss may need to be replaced with packed red blood cells and appropriate clotting factors, particularly if the patient continues to be tachycardic and hypotensive despite boluses of crystalloid.

General Diagnostic Principles In hemodynamically unstable patients, initial attention must be directed toward patient resuscitation. While resuscitation is underway, a basic diagnostic work-up and plan can also be initiated concurrently. In cases when the source of bleeding is unclear, placement and irrigation of a nasogastric tube can provide useful information. Return of frank blood or coffee-ground aspirant suggests a source proximal to the ligament of Treitz. Clear returns favor a more distal source, but this maneuver is insufficiently sensitive to rule out an upper GI bleed since pylorospasm may obscure duodenal bleeding. Risk factors obtained in the history, along with consideration of patient age, can help create a differential

15

Gastrointestinal Bleeding

209

Table 1 Differential diagnosis of gastrointestinal bleeding based on age and location Age Newborn (3.4–5.1 Spherocytes

Severe 10% >5.1 Microspherocytes and poikilocytosis

254

resulting in an abnormal sickle-shaped red blood cell. The sickled red blood cells are sequestered and/or prematurely destroyed as they attempt to pass through the red pulp of the spleen, resulting in anemia, vascular congestion, and microvascular occlusion. Children with SCD require chronic transfusion therapy to prevent or treat the end-organ complications of the disease, including stroke, acute chest syndrome, severe pain syndrome, and acute splenic sequestration. The majority of patients with SCD ultimately become functionally asplenic secondary to continued microvascular occlusion, ischemia, infarction, and subsequent fibrosis of the spleen (Brousse et al. 2012). However, in a subset of patients with recurrent acute splenic sequestration episodes and/or severe hemolysis from hypersplenism, a splenectomy may be indicated. Acute splenic sequestration is diagnosed when a child presents with severe worsening of anemia, reticulocytosis, and a tender and enlarging spleen (Topley et al. 1981). Splenic sequestration can be life-threatening, secondary to hypovolemia and end-organ ischemia (Airede 1992). Unfortunately, splenic sequestration is not typically a single event, recurring in up to 67% of patients (Brousse et al. 2012; Airede 1992; Haricharan et al. 2008). In the majority of children, splenectomy is recommended after the child recovers from an acute episode of splenic sequestration (Brousse et al. 2012). Hypersplenism (severe anemia, thrombocytopenia, and splenomegaly) is also a relative indication for splenectomy in SCD, particularly in children receiving frequent red cell transfusions. The preoperative preparation and postoperative care of a patient with SCD require special mention. Children with SCD are chronically anemic and remain at lifelong risk of recurrent vaso-occlusive crises. Current recommendations are that SCD patients should be transfused to a hemoglobin level of 10 g/dL and then aggressively hydrated prior to induction of anesthesia (Howard et al. 2013). Simple blood transfusion has been shown to be as effective as exchange transfusions in decreasing postoperative complications related to sickle cell disease (Vichinsky et al. 1995). A type and cross for compatible blood should be done at

K. A. Barsness

least 1 day prior to the planned operation, as alloimmunization is common and can lead to difficulty in finding compatible blood that can be used in case of intraoperative misadventure or postoperative complications (Rosse et al. 1990; Vichinsky et al. 1990). Intraoperatively, hypoxemia and hypothermia should be avoided, as these conditions can lead to increased sickling of red blood cells. Postoperatively, acute chest syndrome is one of the most frequently identified complications after splenectomy, occurring in up to 20% of all SCD patients undergoing abdominal surgery (Kokoska et al. 2004; Hyder et al. 2013). Acute chest syndrome is characterized by the development of a new pulmonary infiltrate, chest pain, temperature greater than 38  C, and tachypnea, wheezing, or a cough. Treatment is mainly supportive with appropriate hydration, transfusion and antibiotics as indicated, and pain control. Other postoperative complications include stroke and vaso-occlusive pain crises (Hyder et al. 2013). The surgical approach for SCD has traditionally been a total splenectomy. Since SCD patients are all considered functionally asplenic by their second decade of life, preservation of a portion of the spleen has typically not been considered a viable alternative to a total splenectomy. However, as partial or near-total splenectomy has gained in popularity for hereditary spherocytosis, some authors have begun to advocate for the same in young SCD patients (Mouttalib et al. 2012). No matter the surgical approach to the spleen, all children with SCD should be preoperatively screened for cholelithiasis and gallbladder sludge. More than 65% of pediatric patients with SCD have abnormalities on biliary imaging (McCarville et al. 2012). If biliary disease is found on preoperative screening, the patient should undergo a simultaneous cholecystectomy and splenectomy. Patients with SCD are currently living longer due to improvements in diagnosis and comprehensive care. Due to these advances, long-term chronic complications pose a greater challenge in the management of patients with SCD, particularly sickle cell neuropathy which is associated with significant morbidity and mortality (Olaniran et al. 2019). The earliest manifestation is an increase in the glomerular filtration rate.

18

Splenic Disorders

Significant albuminuria is observed early and is the most common presentation in childhood. Regarding the therapeutic approach, the reninangiotensin system inhibitors and angiotensin receptor blockers seem to be effective in adults with SCD, although new studies are needed in children (Belisário et al. 2019).

Beta Thalassemia Beta thalassemia is a hereditary hemoglobinopathy characterized by reduced or absent beta globin synthesis. The resultant relative excess of unbound alpha globin chain causes membrane damage to peripheral erythrocytes, leading to removal of these erythrocytes as they pass through the red pulp of the spleen. The most common surgical indications for splenectomy in these patients include an annual transfusion requirement greater than 180–200 mL/Kg, hypersplenism, leukopenia, thrombocytopenia, and increasing iron overload (Galanello and Origa 2010). Similar to other hemoglobinopathies, biliary imaging should be completed preoperatively given the increased risk of cholelithiasis and sludge. While total splenectomy remains the favored approach, partial splenectomy is gaining increased attention in the treatment of complications of this disease as well.

255

better understanding of patterns of remission, splenectomy may ultimately be reserved for those patients with severe bleeding complications (British Committee for Standards in Haematology General Haematology Task, F. 2003). The surgical procedure of choice is total splenectomy, with the goal of removing an important site of antiplatelet antibody formation and the primary site of platelet destruction. Biliary disease is not a feature of ITP; therefore preoperative evaluation of the gallbladder is not typically indicated.

Splenectomy Preoperative Immunizations All children who undergo partial or total splenectomy should receive appropriate immunizations at least 2 weeks prior to the planned splenectomy. In the event of an emergent splenectomy, patients should receive postoperative vaccinations as soon as possible. Current recommendations for children greater than 2 years of age include pneumococcal polysaccharide vaccine-23, Haemophilus influenzae type b conjugate vaccine, and meningococcal vaccine (Rubin et al. 2013). In addition, all asplenic children should receive annual flu vaccinations to decrease the risk of a secondary bacterial infection associated with flu.

Immune Thrombocytopenia

Laparoscopic Splenectomy

Immune thrombocytopenia (ITP) is an autoimmune disease against platelets, resulting in isolated thrombocytopenia and risk for bleeding complications. More than 75% of children that present with ITP will have disease remission within 6 months of diagnosis (Neunert et al. 2013). Children also appear to be at low risk for severe thrombocytopenia and serious bleeding events. First-line therapy for ITP is corticosteroids. Second-line therapy has traditionally been a splenectomy, as it can be safely performed with few complications, and has the highest remission rate of any second-line therapy. However, with recent advances in alternative therapies and a

Laparoscopic splenectomy can be completed in supine, semi-lateral, and lateral positions. For purposes of this chapter, the supine position will be described, as a significant percentage of patients will require a combined splenectomy and cholecystectomy. Once fully anesthetized, the patient is positioned in a supine position with a rolled towel bump under the left costal margin. The entire abdomen and left flank are then prepped and draped with appropriately. The umbilicus is accessed with a 12 mm trocar using a direct transumbilical fascial incision. Once gas insufflation has been satisfactorily obtained, a 5 mm working port is placed in a midepigastric position in the

256

midline of the abdomen. A 5 mm retracting port is then placed at the left costal margin, near the anterior axillary line. In patients with marked splenomegaly, the spleen may need to be retracted superiorly in order to safely place the trocar without injury to the splenic parenchyma. The retracting port should not migrate lower than the costal margin, as the anterior iliac crest will then begin to interfere with retraction. The second 5 mm working port is then placed in the left lower abdomen, approximately 1–2 cm below the umbilicus at the lateral edge of the rectus sheath. While this port may be placed more medially through the rectus sheath, care must be taken to ensure that the inferior epigastric artery is not injured during port placement. Initial release of the phrenicocolic ligament will allow the colon to fall away from the operative field and begin to expose the lower pole of the spleen. Release of the splenorenal ligament will further expose the lower pole of the spleen and begin to expose the inferior border of the tail of the pancreas. Subsequent release of the gastrosplenic ligament, with division of the short gastric vessels medial to the spleen, will allow entry into the lesser sac. Careful dissection around the hilar vessels can then begin. Once a window has been obtained around the splenic vessels, an endomechanical stapling device can be deployed across the splenic vein and artery as a single fire load. Occasionally, the tail of the spleen prevents a safe transection angle of the hilum when the stapling device is deployed from the umbilical port. In these events, the left lower abdominal 5 mm port may be upsized to a 10 mm port for a more direct approach to the hilar transection. If the tail of the pancreas is still not free of the transection plane, additional hilar dissection is indicated, including individual distal ligation of vascular branches in select cases. Once the spleen has been devascularized, the splenophrenic ligament can be released. At this point, a careful evaluation of the perisplenic tissue should be performed for identification of accessory splenules. The spleen and any identified splenules are then placed inside a 12 cm endomechanical specimen retrieval bag placed through the umbilical port. A 15 cm port and

K. A. Barsness

endomechanical specimen bag may be needed for patients with marked splenomegaly. Once all splenic tissue is completely within the specimen bag, the deployment device is withdrawn with the access port, bringing the most proximal portion of the cinched specimen bag through the abdominal incision. The edges of the specimen bag are then everted; ring forceps are used to morcellate and remove the spleen. Care must be taken during splenic morcellation, as a tear in the specimen bag can be associated with iatrogenic intestinal or vascular injury and increases the risk of secondary splenosis and recurrent anemia.

Partial Splenectomy A partial splenectomy is an alternative to a complete splenectomy in the treatment of hereditary spherocytosis and beta thalassemia. The goals of the operation are to remove the majority of the splenic tissue yet preserved enough of the spleen to maintain effective humoral immunity. The range of preserved splenic tissue is anywhere from as little as 5% and up to 25% of the native splenic volume. The remnant can be based off of the short gastric arteries or the splenic artery to the upper or lower pole of the spleen. The operative setup for a partial splenectomy is similar to that for a complete splenectomy. However, greater care is taken during the dissection of the splenic hilum and short gastric vessels. If the short gastric vessels are the chosen blood supply for the remnant, the hilum is dissected and transected in similar fashion as a total splenectomy. Once the main splenic artery and vein are transected, demarcation of the blood supply to the spleen should quickly become visible. The spleen is then divided along the line of demarcation, using one or more endosealing, electrocautery, or argon beam devices for adequate hemostasis of the remnant’s cut edge. The phrenosplenic ligament is ideally left intact at the upper margin of the remnant, to decrease its risk of subsequent torsion. For upper or lower pole artery-based remnants, a meticulous dissection of the hilar blood vessels is necessary to prevent injury, while preserving

18

Splenic Disorders

flow. A test clamp of the endomechanical stapler is required to confirm preservation of flow through the preserved vessel. Lower pole remnants are at highest risk of subsequent torsion. Therefore, fixation of the remnant to the lateral peritoneal surface or the greater curvature of the stomach may be necessary. The devascularized segment of spleen and any accessory splenules are then removed using the same techniques as described above.

Open Splenectomy An open splenectomy is traditionally performed through a left subcostal incision but may also be performed through a midline vertical incision. The relevant operative steps are the same as the laparoscopic approach discussed above. However, once the spleen has been devascularized and the phrenosplenic ligaments are released, the spleen and any associated splenules are removed as intact specimens.

Postoperative Antibiotic Prophylaxis All children undergoing partial, near-complete, and near-total splenectomy should start oral penicillin on postoperative day 1 and continue to take it once daily for the remainder of their life. In children who are unable to take oral medication, intravenous administration of a first-generation cephalosporin may be used until the child is able to take oral medication.

Intraoperative and Postoperative Complications A number of intraoperative and postoperative complications have been described during and after splenectomy, including bleeding, colonic perforation, diaphragmatic perforation and/or hernia, missed accessory spleen with recurrent symptoms, acute chest syndrome (SCD), pneumonia, portal vein thrombosis, priapism, hemolytic

257

uremic syndrome, and trocar hernias (Cadili and de Gara 2008; Rescorla et al. 2007). However, outside of patients with sickle cell disease, the overall risk of any one of these events is extremely low. A few select complications that have not been discussed elsewhere in this chapter deserve special mention.

Overwhelming Postsplenectomy Sepsis Overwhelming postsplenectomy sepsis (OPSS) is a fulminant sepsis, meningitis, or pneumonia that occurs at a much higher frequency in functionally or anatomically asplenic patients, compared to normal children. Children less than 5 years of age are at particularly high risk for OPSS and also have a higher mortality rate compared to older children. The risk of death with OPSS can be greater than 50% if it is not recognized within the first several hours of the infection beginning to manifest the clinical signs or symptoms. Mortality rates are closer to 10% when immediate care is provided at the onset of symptoms. The most common bacterial pathogens are encapsulated bacteria, including Streptococcus pneumococcus, Haemophilus influenzae, and Meningococcus. However, other gram-positive and gram-negative bacteria have also been described in the literature as causative agents and are increasingly identified among patients previously vaccinated against encapsulated bacteria. Clinical signs and symptoms include a brief prodrome of fever, myalgia, vomiting, diarrhea, and headache. Septic shock then quickly develops, often within a few hours of onset of prodromal symptoms. All patients at risk and with any signs or symptoms of OPSS should receive immediate, broad-spectrum parenteral antibiotics that cover the typical causative organisms, with close observation for signs of clinical deterioration (Di Sabatino et al. 2011). The most effective means of preventing OPSS include preoperative immunizations prior to removal of the spleen, continued postoperative prophylaxis with penicillin, annual flu vaccination, and frequent reeducation of patients and parents about the signs, symptoms, and risks associated with OPSS.

258

Thromboembolic Disease Splenic vein thrombosis, with or without extension in the superior mesenteric and portal veins, is a particular concern in adult patients immediately after splenectomy. However, this complication occurs less frequently in children. Therefore, routine antiplatelet therapy (acetylsalicylic acid) is not indicated in children, even those children with marked thrombocytosis after splenectomy. However, risk factors for thromboembolic events include marked splenomegaly and lymphoproliferative or myeloproliferative disorders as the underlying disease process necessitating splenectomy (Rodeghiero and Ruggeri 2012).

Cardiac Complications Postsplenectomy Ischemic heart disease and pulmonary hypertension occur with increased frequency in patients who are asplenic (Rodeghiero and Ruggeri 2012). The majority of patients who develop cardiac complications are decades out from the original splenectomy. Interestingly, patient with spherocytosis who are able to retain their spleen have a lower risk of ischemic heart disease later in life, while asplenic patients tend to have the same risk as non-spherocytosis patients. This represents a relative increased risk, but the risk does not exceed baseline population risks for ischemic heart disease. For asplenic patients without spherocytosis, data support a 1.5–2 times increased risk of ischemic heart disease, compared to population controls. Pulmonary hypertension is less well characterized or understood, but the risk appears to be highest in patients with disorders associated with ongoing hemolysis.

Conclusions and Future Directions The spleen has a combined function of immune defense and quality control of senescent or altered blood cells. Many pediatric disorders of splenic functions may require partial or complete splenectomy as the definitive treatment of the disorder. It

K. A. Barsness

is well acknowledged that the splenectomized child is at increased risk of infection, overwhelmingly postsplenectomy infection. Overwhelming postsplenectomy sepsis can be prevented by vaccination, chemoprophylaxis, and education.

References Airede AI. Acute splenic sequestration in a five-week-old infant with sickle cell disease. J Pediatr. 1992;120 (1):160. Belisário AR, da Silva AA, Silva CV, et al. Sickle cell disease nephropathy: an update on risk factors and potential biomarkers in pediatric patients. Biomark Med. 2019;13(11):967–87. Bolton-Maggs PH, et al. Guidelines for the diagnosis and management of hereditary spherocytosis. Br J Haematol. 2004;126(4):455–74. Bolton-Maggs PH, et al. Guidelines for the diagnosis and management of hereditary spherocytosis – 2011 update. Br J Haematol. 2012;156(1):37–49. British Committee for Standards in Haematology General Haematology Task, F. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol. 2003;120(4):574–96. Brousse V, et al. Acute splenic sequestration crisis in sickle cell disease: cohort study of 190 paediatric patients. Br J Haematol. 2012;156(5):643–8. Cadili A, de Gara C. Complications of splenectomy. Am J Med. 2008;121(5):371–5. Davenport M, et al. The biliary atresia splenic malformation syndrome: a 28-year single-center retrospective study. J Pediatr. 2006;149(3):393–400. Delforge X, Chaussy Y, Borrego P, et al. Management of nonparasitic splenic cysts in children: a French multicenter review of 100 cases. J Pediatr Surg. 2017;52 (9):1465–70. Di Sabatino A, Carsetti R, Corazza GR. Post-splenectomy and hyposplenic states. Lancet. 2011;378(9785):86–97. Eber SW, Armbrust R, Schroter W. Variable clinical severity of hereditary spherocytosis: relation to erythrocytic spectrin concentration, osmotic fragility, and autohemolysis. J Pediatr. 1990;117(3):409–16. Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis. 2010;5:11. Gupta NA, et al. Pediatric hepatopulmonary syndrome is seen with polysplenia/interrupted inferior vena cava and without cirrhosis. Liver Transpl. 2007;13 (5):680–6. Haricharan RN, et al. Splenectomy reduces packed red cell transfusion requirement in children with sickle cell disease. J Pediatr Surg. 2008;43(6):1052–6. Hassoun J, Ortega G, Burkhalter LS, et al. Management of nonparasitic splenic cysts in children. J Surg Res. 2018;223:142–8.

18

Splenic Disorders

Howard J, et al. The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: a randomised, controlled, multicentre clinical trial. Lancet. 2013;381(9870):930–8. Hyder O, et al. Surgical procedures and outcomes among children with sickle cell disease. Anesth Analg. 2013;117(5):1192–6. Ikeda H, et al. Portosystemic shunt with polysplenia and hypoplastic left heart syndrome. Pediatr Cardiol. 2005;26(4):446–8. Kim T, et al. Hepatic nodular lesions associated with abnormal development of the portal vein. AJR Am J Roentgenol. 2004;183(5):1333–8. Kokoska ER, et al. Risk factors for acute chest syndrome in children with sickle cell disease undergoing abdominal surgery. J Pediatr Surg. 2004;39(6):848–50. Lauffer JM, et al. Intrapancreatic accessory spleen. A rare cause of a pancreatic mass. Int J Pancreatol. 1999;25 (1):65–8. Lazzareschi I, Curatola A, Pedicelli C, et al. A previously unrecognized Ankyrin-1 mutation associated with hereditary spherocytosis in an Italian family. Eur J Haematol. 2019;103(5):523–6. McCarville MB, et al. Effects of chronic transfusions on abdominal sonographic abnormalities in children with sickle cell anemia. J Pediatr. 2012;160(2):281–285 e1. McElhinney DB, Marx GR, Newburger JW. Congenital portosystemic venous connections and other abdominal venous abnormalities in patients with polysplenia and functionally univentricular heart disease: a case series and literature review. Congenit Heart Dis. 2011;6 (1):28–40. Morinis J, et al. Laparoscopic partial vs total splenectomy in children with hereditary spherocytosis. J Pediatr Surg. 2008;43(9):1649–52. Mouttalib S, et al. Evaluation of partial and total splenectomy in children with sickle cell disease using an internet-based registry. Pediatr Blood Cancer. 2012;59 (1):100–4. Neunert CE, et al. Bleeding manifestations and management of children with persistent and chronic immune thrombocytopenia: data from the Intercontinental Cooperative ITP Study Group (ICIS). Blood. 2013;121(22):4457–62. Olaniran KO, Eneanya ND, Nigwekar SU, et al. Sickle cell nephropathy in the pediatric population. Blood Purif. 2019;47(1–3):205–13. Peitgen K, Majetschak M, Walz MK. Laparoscopic splenopexy by peritoneal and omental pouch construction for intermittent splenic torsion (“wandering spleen”). Surg Endosc. 2001;15(4):413. Perrotta S, Gallagher PG, Mohandas N. Hereditary spherocytosis. Lancet. 2008;372(9647):1411–26. Prendiville TW, et al. Heterotaxy syndrome: defining contemporary disease trends. Pediatr Cardiol. 2010;31 (7):1052–8.

259 Rescorla FJ, et al. Laparoscopic splenic procedures in children: experience in 231 children. Ann Surg. 2007;246(4):683–7.. discussion 687-8 Rodeghiero F, Ruggeri M. Short- and long-term risks of splenectomy for benign haematological disorders: should we revisit the indications? Br J Haematol. 2012;158(1):16–29. Rosse WF, et al. Transfusion and alloimmunization in sickle cell disease. The cooperative study of sickle cell disease. Blood. 1990;76(7):1431–7. Roy SM, Buchanan GR, Crary SE. Splenectomy in children with “mild” hereditary spherocytosis. J Pediatr Hematol Oncol. 2013;35(6):430–3. Rubin LG, et al. IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis, 2014. 2013;58(3):309–18. Rutkow IM. Twenty years of splenectomy for hereditary spherocytosis. Arch Surg. 1981;116(3):306–8. Schaarschmidt K, et al. The technique of laparoscopic retroperitoneal splenopexy for symptomatic wandering spleen in childhood. J Pediatr Surg. 2005;40(3):575–7. Slater BJ, et al. Institutional experience with laparoscopic partial splenectomy for hereditary spherocytosis. J Pediatr Surg. 2010;45(8):1682–6. Steinberg R, et al. Clinical presentation of wandering spleen. J Pediatr Surg. 2002;37(10):E30. Topley JM, et al. Acute splenic sequestration and hypersplenism in the first five years in homozygous sickle cell disease. Arch Dis Child. 1981;56(10):765–9. Tsakayannis DE, et al. Splenic preservation in the management of splenic epidermoid cysts in children. J Pediatr Surg. 1995;30(10):1468–70. Uchiyama S, et al. Intrapancreatic accessory spleen mimicking endocrine tumor of the pancreas: case report and review of the literature. J Gastrointest Surg. 2008;12(8):1471–3. Varga I, et al. Congenital anomalies of the spleen from an embryological point of view. Med Sci Monit. 2009;15 (12):RA269–76. Vasilescu C, et al. Laparoscopic subtotal splenectomy in hereditary spherocytosis: to preserve the upper or the lower pole of the spleen? Surg Endosc. 2006;20 (5):748–52. Vichinsky EP, et al. Alloimmunization in sickle cell anemia and transfusion of racially unmatched blood. N Engl J Med. 1990;322(23):1617–21. Vichinsky EP, et al. A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. The preoperative transfusion in sickle cell disease study group. N Engl J Med. 1995;333(4):206–13. Wu HM, Kortbeek JB. Management of splenic pseudocysts following trauma: a retrospective case series. Am J Surg. 2006;191(5):631–4. Yildiz AE, Ariyurek MO, Karcaaltincaba M. Splenic anomalies of shape, size, and location: pictorial essay. ScientificWorldJournal. 2013;2013:321810.

Ulcerative Colitis

19

Risto J. Rintala, Mikko P. Pakarinen, and Antti Koivusalo

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 Extraintestinal Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laboratory Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pediatric UC Activity Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

264 264 265 265 265

Medical Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266 Surgical Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267 Principles and Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267 Preoperative Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268 Operative Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Selection of Surgical Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Restorative Proctocolectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Proctocolectomy with Permanent Ileostomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laparoscopic-Assisted Proctocolectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

268 268 269 270 270

Postoperative Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 Surgical Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271

R. J. Rintala (*) · M. P. Pakarinen · A. Koivusalo Department of Pediatric Surgery, Children’s Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland e-mail: risto.rintala@hus.fi; risto.rintala@saunalahti.fi; mikko.pakarinen@hus.fi; antti.koivusalo@hus.fi © Springer-Verlag GmbH Germany, part of Springer Nature 2021 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43559-5_106

261

262

R. J. Rintala et al. Outcomes of Ileoanal Pull-Through . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stooling Frequency and Fecal Continence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pouchitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fertility and Sexual Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

272 272 272 273 273

Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274

Abstract

Keywords

Pediatric ulcerative colitis (UC) is a disease of the developed world. In some parts of the Western World, its incidence is stable, but in Northern Europe it is still increasing. UC presentation and symptoms are similar to adultonset disease, but the rate of extensive disease is much higher in children. Typical symptoms include bloody diarrhea and abdominal tenesmus. General symptoms and significant growth retardation may occur but are less common than in Crohn’s disease (CD). Extraintestinal symptoms in various organ systems occur in a significant percentage of patients. Prompt diagnostic workup is required in a symptomatic patient to establish correct diagnosis and to avoid medical problems associated with delayed diagnosis. The initial treatment is medical, and the aim is to achieve remission of symptoms. Although treatment may be started with 5-ASA preparations, most pediatric patients require high dose steroids to achieve remission. Corticosteroids will prove unsuccessful in approximately 30–40% of children who will require second-line medical therapy with infliximab, tacrolimus or cyclosporines, or colectomy. A colectomy is indicated in toxic megacolon or severe bleeding or in cases refractory to optimal medical therapy. In principle, removal of the diseased colon and rectum cures ulcerative colon. Today, restorative proctocolectomy is the surgical treatment of choice. The outcomes of surgery in recalcitrant UC are generally satisfactory, and the quality of life of the operated patients is similar to healthy peers. This is despite a high incidence of early and late surgical complications and pouchitis.

Ulcerative Colitis · Children · Pediatric · Ileonal anastomosis · Pouchitis

Introduction Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) of unknown etiology confined to the rectum and colon. Males and females are equally affected. UC is suspected in patients who have diarrhea that is often bloody, abdominal pain, and rectal tenesmus. In severe cases, the disease is associated with weight loss, fatigue, and a general feeling of illness. The incidence of UC ranges between 1 and 4/100,000 per year in Northern America and Europe (Benchimol et al. 2011). The incidence is highest in the Nordic countries and in the British Isles. About 5% of all cases of UC have their onset before the age of 10 years and about 20% before the age of 20 years. The incidence of pediatric cases has remained unchanged since the 1980s in some parts of the Western World but is still increasing in Northern countries, especially in Finland (Lehtinen et al. 2011). At diagnosis, pediatric UC is extensive in 60–80% of cases, much more than in adults (Van Limbergen et al. 2008). Widespread disease is associated with a more severe disease course. Thus, the risk of colectomy in pediatric onset UC within the following 10 years is reported to be higher than in adults, 30–40% of patients require colectomy compared to about a 20% colectomy rate in adults (Van Limbergen et al. 2008; GowerRousseau et al. 2009). Lower colectomy rates have, however, been reported by some other pediatric studies (Jakobsen et al. 2011).

19

Ulcerative Colitis

Pediatric UC has unique features when compared to adult-onset disease. The disease may affect the development of growth and puberty in preadolescent patients. Moreover, the disease onset is commonly at a psychosocially vulnerable age, namely, prepuberty or puberty.

Etiology The etiology of UC is unknown and most likely multifactorial. Various potential contributing factors have been studied including environmental factors, infections, psychosocial factors, immunological factors, and genetic factors. A positive family history remains the strongest recognizable risk factor for the development of IBD and is reported in around 8–12% of IBD patients. The risk of developing IBD in first-degree relatives of an affected proband is increased to 4–8-fold (Santos et al. 2018). The risk in twins and children born to couples who both have IBD is also substantially higher; a cumulative effect of the number of family members affected has been described, with the highest incidence being reported for families with three or more affected members (Santos et al. 2018). There is a clear inherited predilection for UC with up to a 20% chance of UC in identical twins (Orholm et al. 2000). Also, a genetic basis for the disease has long been implied by the high prevalence of disease within families. No specific gene locus has been identified. It has been postulated that some inherited defect(s) in immunoregulation may lead to clinical manifestation of the disease in certain environmental conditions, including infective agents. Most believe intestinal bacterial flora is vital for the persistence of the inflammatory process (Sartor 2005). Numerous environmental factors have been implicated; these include cigarette smoke (protective), appendectomy (protective), breastfeeding (protective), diet (high fat/sugar), perinatal or early childhood infections, wild-type measles infections, Mycobacterium paratuberculosis, and oral contraceptives (Loftus 2004).

263

Pathology UC is a chronic inflammatory disease of the rectum and colon affecting mucosa and submucosa of the bowel wall. The rectum is affected in more than 95% of the cases, and the inflammation extends contiguously to the more proximal large bowel. Ileal involvement strongly suggests Crohn’s disease (CD), although low-grade unspecific inflammation of the ileal mucosa, backwash ileitis, is often seen in patients with UC. The characteristic histological appearance of UC consists of diffuse superficial unspecific inflammation, neutrophilic epithelial invasion, crypt abscesses, and crypt deformity. Progression of inflammation leads to mucosal ulceration and epithelial regeneration with pseudopolyp formation. Long-standing disease is associated with atrophic and dysplastic mucosa. The risk of colon cancer associated with UC is of special concern in pediatric patients. The risk of colorectal cancer in early onset UC ( distal) gradient of inflammation) or with 2–3 of the following features (severe scalloping of stomach and duodenum or duodenitis not explained by celiac disease or H. pylori, focal active colitis on histology in more than one biopsy of macroscopically inflamed site, non-bloody diarrhea and aphthous ulcerations of colon or upper gastrointestinal tract, should be diagnosed as IBD-U (Levine et al. 2014; Turner et al. 2012). Involvement of the small bowel in the presence of a normal cecum is not typical of UC, and any positive finding in endoscopy or radiologic imaging should raise suspicions of CD. Small bowel wall thickening in MRE is sensitive but not pathognomonic for CD. In WCE, the absence of small bowel lesions is supportive of UC, but frequently false-positive lesions complicate the interpretation of the study, and a few small erosions in WCE do not preclude the diagnosis of UC (Feakins 2014; Levine et al. 2014; Turner et al. 2012). Despite careful assessment, however, as many as 13% of children who undergo a colectomy and an ileoanal J-pouch for UC end up with the ultimate diagnosis of CD (Mortellaro et al. 2011).

Medical Management The main goals of UC treatment are to alleviate symptoms, to provide normal growth and development, and to avoid disease-related long-term complications. Children often present with widespread disease and pancolitis necessitating aggressive medical treatment. If patients are significantly malnourished or if there is growth retardation, then intensive nutritional support is provided. In recent years, treatment strategies for

19

Ulcerative Colitis

UC have evolved with an early step up approach, the availability of biologicals, and therapeutic drug monitoring (Bolia et al. 2019). A reduction in the 2-year colectomy rates has been observed in patients with pediatric UC since biologics have been available for treatment (Bolia et al. 2019). Oral treatment with 5-ASA preparations, preferably mesalazine and sulfasalazine, are the firstline medications in induction therapy for mild to moderate active UC in children (Ford et al. 2011; Turner et al. 2012). These drugs are useful for maintenance therapy of remission, regardless of initial induction treatment. Oral 5-ASA therapy may be combined with topical medication, i.e., rectal 5-ASA enemas. Oral steroids are commonly needed to control moderate or severe disease, especially if there are systemic symptoms. In addition, cases failing to achieve remission with 5-ASA therapy should be treated with oral steroids, which are effective for inducing remission but not for maintaining it. Remission should be maintained with sulfasalazine and mesalazine. In patients with severe disease, induction therapy with steroids should be started with intravenous infusions (Turner et al. 2012). Up to 80% of children with UC receive steroids to achieve remission within 3 months after the diagnosis (Hyams et al. 2006). In the majority, this is associated with a clinical response. However, steroid dependency, meaning an inability to achieve and maintain steroid-free clinical remission, has been reported in up to 45% of children with UC (Hyams et al. 2006). Steroid dependency should not be tolerated as this is associated with significant complications such as osteoporosis, changes in body image, psychological alterations, and growth disturbances. Steroid dependency may be avoided by optimization of 5-ASA therapy and considering immunomodulating therapy with thiopurines or biological medications such as infliximab. Thiopurines, such as azathioprine and mercaptopurine, can be used to maintain remission in children who have intolerance to 5-ASA or steroid dependence. However, thiopurines are ineffective for remission induction, and the therapeutic effect may take 2–3 months after the onset of treatment.

267

The role of other immunosuppressive medications such as cyclosporine and tacrolimus in severe childhood UC is unsettled, but they may be useful in steroid dependency (Ziring et al. 2007). Oral tacrolimus may also be used for a couple of months as a bridge to thiopurines, due to its rapid onset of action (Yamamoto et al. 2011). Biological drugs, such as infliximab, may be considered for persistently active or steroiddependent UC that cannot be controlled by 5ASA and thiopurines. Infliximab may also be used as a bridging therapy to thiopurines (Hyams et al. 2012).

Surgical Management Principles and Indications UC can be cured by surgical removal of the diseased colon and rectum in patients, who fail to reach or maintain remission with medical therapy. Children with UC are more likely to have an extensive colonic involvement and a progressive clinical course than their adult counterparts. Approximately 25–40% of children will require surgery after a disease duration of 10 years, with one quarter of them operated on for fulminant colitis (Pakarinen et al. 2009). The operation rate has remained stable over the last decades. Operative treatment offers high-quality functional outcomes in the long term, while abolishing the severe side effects of immunosuppressive medication. Thus, surgical therapy should be considered for any patient prior to development of complications secondary to the disease itself or its medical treatment. Optimally, operative treatment should be performed before completion of growth to enable catch up growth and to avoid developmental delays. Surgery is performed electively in most cases. Elective proctocolectomy may be indicated in children with active or steroid-dependent UC, despite maximal treatment with 5-ASA, thiopurines, calcineurin inhibitors, and anti-TNF therapy (Turner et al. 2012). In practice, the most common elective indications to proctocolectomy in children with UC are persisting disease activity

268

associated with activities limiting symptoms and impaired quality of life, despite optimal medical therapy, steroid-dependent disease, or adverse effects of medical therapy. Confirmed findings of colonic dysplasia, although rare during childhood, should prompt operative treatment without delay. An emergency colectomy is required in about 25% of cases, due to fulminant disease refractory to medical therapy, extensive rectal bleeding, or toxic megacolon. If symptoms and clinical signs of toxic megacolon including fever, tachycardia, dehydration, electrolyte disturbances, hypotension, and altered level of consciousness worsen or do not resolve within 72 h of medical treatment, an immediate colectomy should be performed (Turner et al. 2010). An emergency colectomy for UC entails the removal of the colon, closure of the remaining rectum, and construction of an end ileostomy.

R. J. Rintala et al.

also be addressed. Preoperative discussion with a stoma nurse will accommodate the family with postoperative enterostomy care, and evaluation by a nutritionist helps to optimize diet and nutrition before and after the operation. Malnutrition, anemia, and hypoalbuminemia should be corrected before operation. For optimal placement, the site of protecting loop ileostomy in the right lower abdominal quadrant should be marked preoperatively while the patient is sitting. Prophylactic antimicrobial therapy against gram-negative and anaerobic bacteria is started an hour before surgery and continued 24 h postoperatively. Bowel preparation with polyethylene glycol solution may be performed.

Operative Approach Selection of Surgical Approach

Preoperative Assessment In children, CD often presents as colitis without small intestinal involvement, rendering differential diagnosis between CD and UC challenging. Because CD strongly associates with postoperative fistulous pelvic complications, ileoanal pullthrough failure, and pouch removal, patients undergo full diagnostic workup including upper and lower gastrointestinal endoscopy, determination of serologic markers, capsule endoscopy, and magnetic resonance imaging enterography, before proceeding to proctocolectomy (Nuutinen et al. 2011; Piekkala et al. 2012). It is very important that all aspects and options of surgical therapy are discussed, preferentially well in advance with the patients and parents. Reliable and honest information on possible postoperative complications, pouchitis, and continence expectations, including stooling frequency and nighttime bowel actions, should be provided. Although corticosteroids and other medical treatment for UC can be stopped after operation, most patients continue medical management to improve stool consistency and frequency or for pouchitis. In female patients, potential consequences on sexual function and fertility should

An ileoanal pull-through procedure is invariably chosen, instead of a proctocolectomy with a permanent end ileostomy, by the patients. At present, the latter procedure is mainly performed in a case of pull-through failure. A colectomy with ileorectal anastomosis is not recommended for operative treatment of UC, due to an exceedingly high failure rate, requiring removal of the remaining rectum because of refractory proctitis, dyplasia, or cancer. Ileorectal anastomosis may be considered in selected girls who are primarily concerned about the reduced fecundity associated with restorative proctocolectomy. The ileoanal pull-through may be performed, with or without an ileal pouch, in one to three stages as an open or laparoscopic-assisted procedure. An emergency colectomy should always be performed in three stages. The three-stage surgery may also be considered for malnourished patients, those treated with high-dose corticosteroids or immunosuppressive medication and if the possibility of a diagnosis of CD is appreciable, especially among the youngest patients (Turner et al. 2010). In these patients, a colectomy allows discontinuation of systemic steroids and improvement of nutritional and general status, as well as detailed histological evaluation of the resected

19

Ulcerative Colitis

specimen before proceeding to an ileoanal pullthrough. Following a colectomy and end ileostomy in the first stage, removal of the remaining rectum (proctectomy) and ileoanal pull-through with a protective loop ileostomy is performed in the second stage. After 3–4 months, the loop ileostomy is taken down in the third stage. The two-stage operation is the most common elective surgical approach for UC in children and is safer than the one-stage operation, which is associated with an increased rate of anastomotic leakage and pelvic infections (Turner et al. 2012). However, a one-stage ileoanal pull-through without a protective ileostomy may be safely performed in selected children without apparent risk factors, such as high-dose corticosteroid or immunosuppressive treatment, malnutrition, or high degree of disease activity, and a smoothly performed operation without a significant anastomotic tension. In general, the J-pouch ileoanal anastomosis is preferred over a straight pullthrough, because it is associated with a lower stooling frequency and better fecal continence (Tilney et al. 2006), although it carries a greater risk of pouchitis (Seetharamaiah et al. 2009). A straight pull-through remains a viable option in those rare cases when limited length of the ileal mesentery prevents an ileoanal pouch reconstruction. Laparoscopic-assisted approaches may also be used with comparable complication rates and better cosmetic results.

Restorative Proctocolectomy The main goals of restorative proctocolectomy are to cure the disease by surgical removal of the entire colon and rectum and to retain as good anorectal function as possible. These goals are best achieved by removing the distal rectal mucosa by mucosectomy. When performed endorectally, it avoids extensive dissection in the deep pelvis and associated potential injury to the nervi erigentes. Mucosectomy is continued distally, about 1 cm above the dentate line, preserving transitional epithelium between the anal canal and the distal rectum. Preservation of the transitional epithelium is crucial for undisturbed fecal

269

continence, because it mediates rectal sensation and the ability to discriminate between gaseous, liquid, and solid bowel contents. In addition to endorectal dissection from the abdominal approach, mucosectomy may be performed transanally combined with transabdominal mobilization of the rectum. The latter approach may be more prone to inadvertent stretching and associated damage of the anal sphincters and pelvic autonomic nerve damage. The purpose of an ileoanal pouch is to replace the reservoir function of the removed rectum. This artificial reservoir allows prolonged retention of bowel contents before defecation, thereby reduced stooling frequency and extended urgency period. The J-pouch is simplest to construct, and with the lowest long-term, complication rate is the most commonly used pouch configuration today. The patient is placed in the lithotomy position, in general anesthesia, with a nasogastric tube and urinary catheter in place. The lower extremities are carefully padded in order to avoid neuromuscular damage. The abdominal colectomy is performed in routine fashion, from a midline incision extending from the pubis to just above the umbilicus. Mobilization of the colon may also be performed using a transverse suprapubic Pfannenstiel incision or laparoscopically. The ileal mesentery is fully mobilized to the root of the superior mesenteric vessels and from the duodenum for the distal ileum to reach the anus, which can be anticipated when the operator is able to pull the apex of the planned J-pouch beyond the pubic symphysis. Multiple transverse peritoneal incisions across the mesentery help to minimize anastomotic tension. Occasionally, when the mesentery is scarred and foreshortened, additional length can be gained by ligation of the secondary arcade vessels. In these cases, the distal vascular arcade should be preserved and viability of the terminal ileum confirmed by initial clamping of the vessel. If a significant length of the ileum will be lost, the surgeon may opt for a straight pull-through, which does not require as much ileal length. The J-pouch is constructed by folding the terminal ileum back on itself for no more than 7–10 centimeters. The ileum is opened at the apex, and the anastomosis between the

270

limbs is created with a stapling device. Endorectal dissection is started after incision of the peritoneal reflection of the rectum. Gaining entry into the correct submucosal plane may be difficult, particularly in severely inflamed bowel. Establishment of the correct tissue plane and hemostasis is facilitated by submucosal injection of adrenalin solution (1:200,000) before starting the dissection. Once the mucosal/submucosal tube is developed, countertraction on the rectal muscular cuff aids the dissection, which is continued down to the dentate line. One of the surgeons moves to the perineal field and everts the mucosal/submucosal tube by inserting a clamp into the rectum. The everted mucosal/submucosal tube is incised anteriorly 1 cm proximal to the dentate line. A clamp is inserted and the J-pouch is pulled down to this incision by grasping previously placed traction sutures marking the anterior and posterior edges of the J-pouch opening to prevent twisting. The hand-sewn ileoanal anastomosis is completed with absorbable monofilament sutures. A protecting loop ileostomy is performed in a preoperatively marked location. Alternatively, the ileoanal pouch anastomosis may be performed with a circular stapler (Geiger et al. 2003). The everted mucosal/submucosal tube is stapled linearly proximal to the dentate line, allowed to retract, and a circular stapler device is inserted through the anus. Working in the abdominal field, the anvil of the stapler is placed into the opening of the J-pouch, secured with a purse-string suture, and guided down for stapled anastomosis between the J-pouch and the anal canal. This procedure is less time-consuming and exerts less traction on the anastomosis than the hand-sewn anastomosis.

Proctocolectomy with Permanent Ileostomy After abdominal colectomy, the peritoneal reflection of the rectum is incised. The rectum is mobilized by dissecting directly on the rectal wall, in order to minimize possibility of the pelvic autonomic nerve injury. The dissection is continued as far distally as possible. Next, an incision is made

R. J. Rintala et al.

around the anus and dissection proceeds upward on the rectal wall until the two planes are united. The muscles and skin are closed in layers, and the peritoneum is closed from the abdomen. The distal ileum is exteriorized from a previously marked site by removing a circle of skin about two centimeters in diameter and incising fascia in a cruciated fashion to allow two fingers comfortably through the opening. The ileum is fixed to the peritoneum with interrupted sutures, and a properly everted (2–3 cm) end-ileostomy is created.

Laparoscopic-Assisted Proctocolectomy Laproscopic colectomy involves four to five ports. The resected colon is exteriorized through a port site incision, the rectal canal, or an additional small lower abdominal incision. Pouch construction is performed extracorporeally using either the right lower quadrant port site incision or an additional transverse suprapubic incision. A diverting ileostomy is brought out through a port site incision. A transverse lower incision may be used for performance of endorectal mucosectomy as described above (Adler et al. 2012). Mucosectomy may be performed transanally, combined with hand-sewn ileoanal anastomosis as in the open approach (Linden et al. 2012). Some centers omit mucosectomy and perform circular stapled anastomosis from below following transection of laparoscopically mobilized everted full thickness rectum (Diamond et al. 2010). Laparoscopic and open techniques provide roughly similar outcomes in terms of length of hospital stay, bowel function, and early surgical complications. The laparoscopic technique is more time-consuming than an open operation but provides a superior cosmetic result.

Postoperative Management Prophylaxis against deep venous thromboembolic complications includes pneumatic compression stockings in electively operated older children, combined with low-molecular-weight

19

Ulcerative Colitis

heparin in those undergoing an emergency colectomy. Most elective patients are discharged 1–2 weeks after the operation. Steroids are gradually tapered and discontinued in few weeks time. The patient is readmitted approximately 3 months after the operation for ileostomy closure after anastomotic leakage, or fistula formation has been ruled out by a water-soluble contrast enema. Before the ileostomy closure, patency of the ileoanal anastomosis is ensured by digital examination and gently dilated when necessary. Patency of the pull-through and mucosal condition may be further addressed by an endoscopic examination during the same general anesthesia. The small amount of rectal mucosa remaining proximal to the dentate line at the ileoanal anastomosis necessitates longterm endoscopic surveillance for development of dysplastic or malignant changes. Frequent small meals of low residue and a lactose-free diet and dietary salt supplementation is advised to decrease intestinal excretion and along with bulking fiber preparations increase stool consistency after ileostomy closure. For optimization of enteric fluid absorption, oral sodium chloride capsules (500 mg four to eight times a day) are given to maintain urinary sodium concentration above 20 mmol/l. Readily absorbable dietary energy supplements may be beneficial to promote weight gain during the early postoperative period. Loperamide (2 mg two to six times a day) is prescribed to decrease frequency of bowel actions. Nutritional status and bowel function requires frequent monitoring and adjustment during the first 6 months after ileostomy closure.

Surgical Complications Operative mortality is exceedingly rare. Overall, surgical complications following a proctocolectomy are common, while over half of patients encounter at least one surgical complication. The incidence of complications increases with extending follow-up time mainly due to the cumulative occurrence of adhesive bowel obstructions reaching 50% (Pakarinen et al.

271

2009). In a study including 52 patients, a total of 48 episodes of adhesive bowel obstructions in 26 patients were recorded by 10 years after open proctocolectomy and ileoanal anastomosis. Of them, 35% required operative intervention. A decreased small bowel obstruction rate has been reported following laparoscopically assisted procedures by some (Linden et al. 2013), but not all authors (Diamond et al. 2010). In a large series of children with open proctocolectomy and J-pouch ileoanal anastomosis, the incidence of wound infection was found to be 5%, pelvic sepsis 2–10%, anastomotic stenosis 14–19%, anastomotic leakage 5–7%, and fistula formation 5%, with postoperative hemorrhagia being a rare complication (Tilney et al. 2006; Koivusalo et al. 2007; Seetharamaiah et al. 2009). Septic complications are associated with worsened functional outcome (Koivusalo et al. 2007). According to a meta-analysis, excluding anastomotic strictures, many of these complications including leaks, fistulas, and bowel obstruction appear to be more frequent after a straight ileoanal pullthrough (Tilney et al. 2006). Preoperative steroid therapy and malnutrition are associated with increased rates of postoperative surgical complications (Turner et al. 2012). Complications related to ileostomy are not uncommon including small intestinal obstruction due to tightening of the fascial opening and stomal prolapse. Most anastomotic stenoses are readily dilatable and rarely require surgical intervention. Around 10% of patients undergo repeat ileostomy or an abdominal salvage procedure mainly for management of fistulas, anastomotic dehiscence, or stricture. Other potential reasons for repeat ileostomy include intractable high stooling frequency or severe pouchitis. Overall incidence of pouch failure is approximately 10%. Approximately one third of pouch removals are attributed to ultimate diagnosis of CD, which may manifest as recalcitrant inflammation of the rectal cuff or pouchitis, perianal abscess, fistula, or stricture. Of all children undergoing proctocolectomy and ileoanal anastomosis, approximately 15% will be reclassified as having CD

272

(Alexander et al. 2003; Pakarinen et al. 2009). Discovery of mucosal dysplasia requires removal of the pouch without delay.

R. J. Rintala et al.

through (Tilney et al. 2006; Seetharamaiah et al. 2009).

Pouchitis

Outcomes of Ileoanal Pull-Through Stooling Frequency and Fecal Continence Characteristics of bowel function and fecal continence are crucial outcome measures after ileoanal pull-through, having a strong effect on patients’ overall quality of life. The families should be educated on the dynamic nature of postoperative fecal continence and stool frequency for realistic expectations and to avoid unnecessary anxiety. Following a J-pouch ileoanal anastomosis, loose and frequent bowel motions ranging from 5 to 15 times per 24 h with notable individual variation characterize the early postoperative period after ileostomy closure. Within the following 3–6 months, stooling frequency typically decreases to 3–8 per 24 h. Nighttime bowel actions show a comparable temporal decrease from 2–3 to 1 (Seetharamaiah et al. 2009). In the long term, an average daytime stooling frequency is 5–6, while most patients experience one bowel motion during nighttime, at least occasionally. Stooling frequency remains stable after a mean follow-up of 10 years (Pakarinen et al. 2009). Although fecal accidents occur only in few percent of patients, nighttime seepage or soiling is relatively common, especially during the first few months (Adler et al. 2012). When addressed with special stringency, occasional smearing or staining of underwear is reported by 22% during daytime and by 54% during nights. Nighttime soiling necessitates use of protective pads in a few patients. A vast majority of the patients are able to withhold defecation to meet social needs, whereas around half of them report some imperfections in distinguishing flatus from stools. Over half of patients continue to use medications, mainly loperamide, for stool control. In general, stool and incontinence rates are higher after a straight versus a J-pouch ileoanal pull-

Pouchitis, which refers to idiopathic inflammation of the ileal reservoir, is the most common complication after restorative ileoanal pull-through for UC (Turner et al. 2012). At least one single episode occurs in between 30% and 75% of patients. Long-term risk for pouchitis is significantly high in pediatric onset UC (Dipasquale et al. 2019). Although most patients experience one or a few episodes often during the first few postoperative years, cumulative incidence of pouchitis increases with extending postoperative follow-up period (Pakarinen et al. 2009). Pouchitis is classified as chronic when symptoms last more than 4 weeks. Pouchitis becomes chronic only in a proportion of patients. Chronic pouchitis may severely impair bowel function and necessitate pouch removal in the most refractory cases (Alexander et al. 2003). Clinical symptoms include looser and frequent stools, with or without blood, cramping abdominal pain, malaise, tenesmus, urgency, and even fever. The etiology of pouchitis remains unclear. Histology of pouchitis includes acute and chronic inflammation with neutrophilic infiltration, crypt abscesses, and ulcerations (Pakarinen et al. 2010; Turner et al. 2012). Inflammation of the rectal cuff and pre-pouch ileitis, which are not necessarily associated with CD, may produce similar symptoms. For this reason, and to rule out bowel strictures, ischemia, and rare infections, such as CMV and Clostridium difficile, an initial episode of pouchitis should be confirmed by endoscopic examination and mucosal biopsies (Turner et al. 2012). Endoscopic findings of pouchitis include erythema, granularity, friability, bleeding, and ulcerations. Fecal calprotectin reflects the degree of pouch inflammation and may be used for follow-up purposes (Pakarinen et al. 2010). Most acute episodes of pouchitis respond rapidly to a short course of oral antibiotics, for example, metronidazole or ciprofloxacin. Combined antibiotic therapy or oral budesonide may be used for chronic pouchitis. Probiotics may have a role in

19

Ulcerative Colitis

maintaining remission in chronic pouchitis. The most refractory cases, especially when associated with CD, may respond to infliximab.

Fertility and Sexual Function The impact of IBD on fertility and sexual function is a major concern for IBD patients (Leenhardt et al. 2019; Park and Kim 2019). According to a large adult series, the risk of female infertility increases after restorative proctocolectomy (Turner et al. 2010). Although one long-term study of 52 children showed no difference in fertility in relation to healthy controls (Pakarinen et al. 2009), the possibility of subfertility and sexual dysfunction should be taken seriously. In this respect, endorectal mucosectomy may be theoretically the safest approach, avoiding any dissection outside the rectal wall with potential injury to the autonomic nerves in the deep pelvis. Following restorative proctocolectomy in childhood, up to 50% of women demonstrate sexual dysfunction when assessed by a validated normative questionnaire (Van Balkom et al. 2012). Sexual dysfunction was related to long-term complications of surgery such as pelvic infection, fistulas, and pouchitis. In contrast, men reported no sexual dysfunction, impotence, or retrograde ejaculation (Koivusalo et al. 2009; Van Balkom et al. 2012). Both women and men have similar sexual function after restorative proctocolectomy when compared to their control peers with medically treated UC. The rate of dyspareunia and dysorgasmia were similar between women who had undergone proctocolectomy and ileoanal anastomosis and those managed with medical treatment for UC (Koivusalo et al. 2009).

Quality of Life Several studies have indicated that overall quality of life in UC patients is comparable to that of a normal population among young adults, who have undergone proctocolectomy and ileoanal anastomosis during childhood (Pakarinen et al. 2009; Zmora et al. 2013). Nyholm et al. recently

273

reported long-term results in 87 patients with UC (Nyholm et al. 2019). The long-term outcomes after proctocolectomy with ileoanal anastomosis were reassuring, with 91% retaining their intestinal continuity and presenting with good functional outcomes after a medium follow-up of 8 years, extending beyond 15 years in a quarter of patients (Nyholm et al. 2019). However, surgical treatment and associated complications will delay education by causing an absence from school and interfere with social activities, at least temporarily in approximately one third of patients. Not unexpectedly, decreased quality of life closely correlates with impairments in bowel function, high stool frequency, and surgical complications underscoring the importance of successful surgery (Pakarinen et al. 2009; Van Balkom et al. 2012; Zmora et al. 2013). Well-preserved quality of life and the fact that the great majority of patients are highly satisfied with the operative outcome may be considered surprising, taking into account that many of them continue to experience recurrent pouchitis episodes, nocturnal bowel motions, occasional soiling, and extraintestinal manifestations of UC such as biliary and joint disorders. This is likely to reflect the remarkably poor quality of life before the ileoanal pull-through (Adler et al. 2012).

Conclusion and Future Directions UC in children is a chronic disease of the large bowel that can be cured by surgically removing the diseased intestine. Today, surgery for UC entails restorative proctocolectomy in most patients. Restorative proctocolectomy is, however, associated with significant early and late complications and a permanent change in bowel habits. Moreover, there is little data available regarding long-term outcomes of restorative proctocolectomy performed during childhood or adolescence. The functional outcome following restorative proctocolectomy is generally good, and the quality of life of operated children and adolescents is equal to that of their healthy peers.

274

It is likely that UC will also increase in developing countries as the standard of living increases, and this will create a large number of new pediatric patients that require treatment for this devastating condition. However, the development of more effective and specific medical treatment for UC is likely in the future. The role of surgery in the management of UC will not be abolished as a permanent cure with medical treatment alone is still unlikely.

References Adler J, Coran AG, Teitelbaum DH. Ulcerative colitis. In: Coran A, Adzick NS, Krummel TM, Laberge JM, Shambereger RC, Caldamone AA, editors. Pediatric surgery. 7th ed. Philadelphia: Elsevier; 2012. Alexander F, Sarigol S, Stallion A, Cotman K, Clark H, Lydzinski B, Fazio V. Fate of the pouch in 151 pediatric patients after ileal pouch anal anastomosis. J Pediatr Surg. 2003;38:78–82. Andersen NN, Jess T. Has the risk of colorectal cancer in inflammatory bowel disease decreased? World J Gastroenterol. 2013;19:7561–8. Benchimol EI, Guttmann A, To T, Rabeneck L, Griffiths AM. Changes to surgical and hospitalization rates of pediatric inflammatory bowel disease in Ontario, Canada (1994–2007). Inflamm Bowel Dis. 2011;17:2153–61. Bergquist A, Said K, Broomé U. Changes over a 20-year period in the clinical presentation of primary sclerosing cholangitis in Sweden. Scand J Gastroenterol. 2007;42:88–93. Bernstein CN, Blanchard JF, Houston DS, Wajda A. The incidence of deep venous thrombosis and pulmonary embolism among patients with inflammatory bowel disease: a population-based cohort study. Thromb Haemost. 2001;85:430–4. Bolia R, Rajanayagam J, Hardikar W, et al. Impact of changing treatment strategies on outcomes in Pediatric ulcerative colitis. Inflamm Bowel Dis. 2019;25 (11):1838–44. pii: izz072. Diamond IR, Gerstle JT, Kim PC, Langer JC. Outcomes after laparoscopic surgery in children with inflammatory bowel disease. Surg Endosc. 2010;24:2796–802. Dipasquale V, Mattioli G, Arrigo S, et al. Pouchitis in pediatric ulcerative colitis: a multicenter study on behalf of Italian society of pediatric gastroenterology, hepatology and nutrition. Dig Liver Dis. 2019;51 (11):1551–6. pii: S1590-8658(19)30681-4. Feakins RM. Ulcerative colitis or Crohn’s disease? Pitfalls and problems. Histopathology. 2014;64:317–35. Ford AC, Achkar JP, Khan KJ, Kane SV, Talley NJ, Marshall JK, Moayyedi P. Efficacy of 5-aminosalicylates in ulcerative colitis: systematic review and meta-analysis. Am J Gastroenterol. 2011;106:601–16.

R. J. Rintala et al. Geiger JD, Teitelbaum DH, Hirschl RB, Coran AG. A new operative technique for restorative proctocolectomy: the endorectal pull-through combined with a double-stapled ileo-anal anastomosis. Surgery. 2003;134:492–5. Gower-Rousseau C, Dauchet L, Vernier-Massouille G, Tilloy E, Brazier F, Merle V, Dupas JL, Savoye G, Baldé M, Marti R, Lerebours E, Cortot A, Salomez JL, Turck D, Colombel JF. The natural history of pediatric ulcerative colitis: a population-based cohort study. Am J Gastroenterol. 2009;104:2080–8. Hyams J, Markowitz J, Lerer T, Griffiths A, Mack D, Bousvaros A, Otley A, Evans J, Pfefferkorn M, Rosh J, Rothbaum R, Kugathasan S, Mezoff A, Wyllie R, Tolia V, delRosario JF, Moyer MS, Oliva-Hemker M, Leleiko N, Pediatric Inflammatory Bowel Disease Collaborative Research Group. The natural history of corticosteroid therapy for ulcerative colitis in children. Clin Gastroenterol Hepatol. 2006;4:1118–23. Hyams J, Damaraju L, Blank M, Johanns J, Guzzo C, Winter HS, Kugathasan S, Cohen S, Markowitz J, Escher JC, Veereman-Wauters G, Crandall W, Baldassano R, Griffiths A, T72 Study Group. Induction and maintenance therapy with infliximab for children with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol. 2012;10:391–9. Jakobsen C, Bartek J Jr, Wewer V, Vind I, Munkholm P, Groen R, Paerregaard A. Differences in phenotype and disease course in adult and pediatric inflammatory bowel disease – a population-based study. Aliment Pharmacol Ther. 2011;34:1217–24. Koivusalo A, Pakarinen MP, Rintala RJ. Surgical complications in relation to functional outcomes after ileoanal anastomosis in pediatric patients with ulcerative colitis. J Pediatr Surg. 2007;42:290–5. Koivusalo A, Pakarinen MP, Natunen J, Ashorn M, Rintala RJ, Sipponen T, Kolho KL. Sexual functions in adulthood after restorative proctocolectomy for pediatric onset ulcerative colitis. Pediatr Surg Int. 2009;25:881–4. Kovacs M, Muller KE, Arato A, Lakatos PL, Kovacs JB, Varkonyi A, Solyom E, Polgar M, Nemes E, Guthy I, Tokodi I, Toth G, Horvath A, Tarnok A, Tomsits E, Csoszánszky N, Balogh M, Vass N, Bodi P, Dezsofi A, Gardos L, Micskey E, Papp M, Szucs D, Cseh A, Molnar K, Szabo D, Veres G, Hungarian IBD Registry Group (HUPIR). Diagnostic yield of upper endoscopy in pediatric patients with Crohn’s disease and ulcerative colitis. Subanalysis of the HUPIR registry. J Crohns Colitis. 2012;6(1):86–94. Larsen S, Bendtzen K, Nielsen OH. Extraintestinal manifestations of inflammatory bowel disease: epidemiology, diagnosis, and management. Ann Med. 2010;42:97–114. Leenhardt R, Rivière P, Papazian P, et al. Sexual health and fertility for individuals with inflammatory bowel disease. World J Gastroenterol. 2019;25(36):5423–33. Lehtinen P, Ashorn M, Iltanen S, Jauhola R, Jauhonen P, Kolho KL, Auvinen A. Incidence trends of pediatric inflammatory bowel disease in Finland, 1987–2003, a nationwide study. Inflamm Bowel Dis. 2011;17:1778–83.

19

Ulcerative Colitis

Levine A, Koletzko S, Turner D, Escher JC, Cucchiara S, de Ridder L, Kolho KL, Veres G, Russell RK, Paerregaard A, Buderus S, Greer ML, Dias JA, Veereman-Wauters G, Lionetti P, Sladek M, Carpi JM, Staiano A, Ruemmele FM, Wilson DC. The ESPGHAN revised Porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents. J Pediatr Gastroenterol Nutr. 2014;58:795–806. Linden BC, Bairdain S, Shamberger RC, Zurakowski D, Lillehei CW. Technique of laparoscopic-assisted total proctocolectomy and ileal pouch anal anastomosis in children and adolescents: a single center’s 8-year experience. J Pediatr Surg. 2012;47:2345–8. Linden BC, Bairdain S, Zurakowski D, Shamberger RC, Lillehei CW. Comparison of laparoscopic-assisted and open total proctocolectomy and ileal pouch anal anastomosis in children and adolescents. J Pediatr Surg. 2013;48:1546–50. Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology. 2004;126:1504–17. Mortellaro VE, Green J, Islam S, Bass JA, Fike FB, St Peter SD. Occurrence of Crohn’s disease in children after total colectomy for ulcerative colitis. J Surg Res. 2011;170(1):38–40. Nuutinen H, Kolho KL, Salminen P, Rintala R, Koskenpato J, Koivusalo A, Sipponen T, Färkkilä M. Capsule endoscopy in pediatric patients: technique and results in our first 100 consecutive children. Scand J Gastroenterol. 2011;46:1138–43. Nyholm I, Hukkinen M, Koivusalo A, et al. Long-term single-centre outcomes after proctocolectomy with ileoanal anastomosis for pediatric ulcerative colitis. J Crohns Colitis. 2019;13(3):302–8. Orholm M, Binder V, Sørensen TI, Rasmussen LP, Kyvik KO. Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scand J Gastroenterol. 2000;35:1075–81. Pakarinen MP, Natunen J, Ashorn M, Koivusalo A, Turunen P, Rintala RJ, Kolho KL. Long-term outcomes of restorative proctocolectomy in children with ulcerative colitis. Pediatrics. 2009;123:1377–82. Pakarinen MP, Koivusalo A, Natunen J, Ashorn M, Karikoski R, Aitola P, Rintala RJ, Kolho KL. Fecal calprotectin mirrors inflammation of the distal ileum and bowel function after restorative proctocolectomy for pediatric-onset ulcerative colitis. Inflamm Bowel Dis. 2010;16:482–6. ark YE, Kim TO. Sexual dysfunction and fertility problems in men with inflammatory bowel disease. World J Mens Health. 2019; https://doi.org/10.5534/wjmh.190007. Piekkala M, Kalajoki-Helmiö T, Martelius L, Pakarinen M, Rintala R, Kolho KL. Magnetic resonance enterography guiding treatment in children with Crohn’s jejunoileitis. Acta Paediatr. 2012;101:631–6. Santos MPC, Gomes C, Torres J. Familial and ethnic risk in inflammatory bowel disease. Ann Gastroenterol. 2018;31(1):14–23. Sartor RB. Role of commensal enteric bacteria in the pathogenesis of immune-mediated intestinal inflammation: lessons from animal models and implications for

275 translational research. J Pediatr Gastroenterol Nutr. 2005;40(Suppl 1):S30–1. Seetharamaiah R, West BT, Ignash SJ, Pakarinen MP, Koivusalo A, Rintala RJ, Liu DC, Spencer AU, Skipton K, Geiger JD, Hirschl RB, Coran AG, Teitelbaum DH. Outcomes in pediatric patients undergoing staright vs J pouch ileoanal anastomosis: a multicenter analysis. J Pediatr Surg. 2009;44:1410–7. Tilney HS, Constantinides V, Ioannides A, Tekkis PP, Darzi AW, Haddad MJ. Pouch-anal anastomosis vs staright ileoanal anastomosis in pediatric patients: a meta-analysis. J Pediatr Surg. 2006;41:1799–808. Turner D, Otley AR, Mack D, Hyams J, de Bruijne J, Uusoue K, Walters TD, Zachos M, Mamula P, Beaton DE, Steinhart AH, Griffiths AM. Development, validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study. Gastroenterology. 2007;133(2):423–32. Turner D, Travis SP, Griffiths AM, Ruemmele FM, Levine A, Benchimol EI, Dubinsky M, Alex G, Baldassano RN, Langer JC, Shamberger R, Hyams JS, Cucchiara S, Bousvaros A, Escher JC, Markowitz J, Wilson DC, van Assche G, Russell RK. Consensus for managing acute severe ulcerative colitis in children: a systematic review and joint statement from ECCO, ESPGHAN, and the Porto IBD working group of ESPGHAN. Am J Gastroenterol. 2010;106:574–88. Turner D, Levine A, Escher JC, Griffiths AM, Russell RK, Dignass A, Dias JA, Bronsky J, Braegger CP, Cucchiara S, de Ridder L, Fagerberg UL, Hussey S, Hugot JP, Kolacek S, Kolho KL, Lionetti P, Paerregaard A, Potapov A, Rintala R, Serban DE, Staiano A, Sweeny B, Veerman G, Veres G, Wilson DC, Ruemmele FM. Management of pediatric ulcerative colitis: joint ECCO and ESPGHAN evidencebased consensus guidelines. J Pediatr Gastroenterol Nutr. 2012;55:340–61. Van Balkom KA, Beld MP, Visschers RG, van Gemert W, Breuknik SO. Long-term results after restorative proctocolectomy with ileal pouch-anal anastomosis at a young age. Dis Colon Rectum. 2012;55:939–47. Van Limbergen J, Russell RK, Drummond HE, Aldhous MC, Round NK, Nimmo ER, Smith L, Gillett PM, McGrogan P, Weaver LT, Bisset WM, Mahdi G, Arnott ID, Satsangi J, Wilson DC. Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology. 2008;135:1114–22. Yamamoto S, Nakase H, Matsuura M, Masuda S, Inui K, Chiba T. Tacrolimus therapy as an alternative to thiopurines for maintaining remission in patients with refractory ulcerative colitis. J Clin Gastroenterol. 2011;45:526–30. Ziring DA, Wu SS, Mow WS, Martín MG, Mehra M, Ament ME. Oral tacrolimus for steroid-dependent and steroid-resistant ulcerative colitis in children. J Pediatr Gastroenterol Nutr. 2007;45:306–11. Zmora O, Natanson M, Dotan I, Vinogard I, Nagar H, Rabau M, Tulchinsky H. Lon-term functional and quality of life outcomes after IPAA in children. Dis Colon Rectum. 2013;56:198–204.

20

Crohn’s Disease Risto J. Rintala, Mikko P. Pakarinen, and Antti Koivusalo

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laboratory Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

280 280 281 281 282 282

Extraintestinal Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 Medical Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 Perianal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 Surgical Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Principles and Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Timing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Preoperative Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Operative Approach and Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fistulating Nonperianal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Postoperative Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

285 285 286 286 286 288 288

Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 Outcomes of Surgery for CD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290

Abstract R. J. Rintala (*) · M. P. Pakarinen · A. Koivusalo Department of Pediatric Surgery, Children’s Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland e-mail: risto.rintala@hus.fi; risto.rintala@saunalahti.fi; mikko.pakarinen@hus.fi; antti.koivusalo@hus.fi

Crohn’s disease (CD) in children has become increasingly common in recent years, especially in the developed world. Despite advances considering knowledge of the

© Springer-Verlag GmbH Germany, part of Springer Nature 2021 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43559-5_107

277

278

pathogenesis of these diseases, the precise etiology is not understood, and there remains no permanent cure. Pain, diarrhea, and weight loss are typical symptoms of pediatric CD. Atypical symptoms and extra-intestinal manifestations may occur. The patient’s growth and nutritional status are often compromised at diagnosis of CD. The location and severity of pediatric CD differ substantially from adultonset disease. The initial presentation is more widespread and severe that in adults. Prompt diagnosis, thereby avoiding the consequences of diagnostic delay, is essential in the work-up of suspected CD. The aim of the management of CD is to achieve rapid remission and there are several options to reach this goal. The initial treatment is medical; surgery is considered in a complicated disease course or in the case of refractory disease. Acute indications for surgery include emergent conditions such as toxic megacolon, intra-abdominal abscesses, and sepsis or severe bleeding. Elective indications for surgery are severe strictures and perianal disease, significant prepubertal growth delay, and complications of or unresponsiveness to medical therapy. CD in children requires multidisciplinary care in the context of a growing child. The management of pediatric CD focuses on controlling gut inflammation and optimizing growth, development, and quality of life. Keywords

Crohn’s disease · Children · Pediatric treatment

Introduction Like Ulcerative Colitis (UC), Crohn’s disease (CD) is a chronic inflammation of the bowel which is caused by an interaction of genetic and environmental factors. The exact etiology is not known, therefore there is no causal therapy available. CD is mainly found in developed countries and there is a clear South-North gradient, especially in Europe (Shivananda et al. 1996). The incidence of CD in

R. J. Rintala et al.

children and adolescents ranges between 1 and 8/ 100,000 and has risen across Europe in the past decades (Hildebrand et al. 2003; Sawczenko et al. 2001; Turunen et al. 2006; Amil-Dias et al. 2017). In 20–25% of all patients, the disease presents before the age of 18 years and may occur even in very young children (age < 2 years) (Auvin et al. 2005; Yu and Rodriguez 2017). In children today, CD is usually reported to be more common than UC. Males and females are equally affected. CD occurs more commonly in a Caucasian population than in other ethnic groups. There are some hereditary risk factors for CD: 5–20% patients with CD have a first degree relative who has inflammatory bowel disease (IBD) and offspring of a CD patient have a 10% chance of developing CD. There are clear differences in onset between adult and pediatric CD, in terms of natural history, the impact of the disease on the patient, and the choice of treatment strategies (Van Limbergen et al. 2008). The phenotype of CD in the young differs from adult-onset disease, with more extensive distribution at presentation and extension of disease during the first 2 years of diagnosis in approximately one third of patients (Vernier-Massouille et al. 2008). Other typical features of pediatric CD include growth failure, which is present at diagnosis in 10–40% of affected children. CD presenting in childhood and adolescence is commonly associated with marked psychological and social morbidity, which may have an impact on education, relationships, sexual development, and adherence to therapy (Mackner and Crandall 2005).

Etiology The etiology of CD is unknown and is most likely multifactorial. In addition to genetic factors, immunological and microbiological factors as well as environmental factors are likely to play significant roles. Family history is a well-known risk factor for developing inflammatory bowel diseases such as CD. A positive family history remains the strongest recognizable risk factor in 8–12% of IBD patients, with CD showing a more frequent familial pattern than UC (Santos et al. 2018). As such, the risk of

20

Crohn’s Disease

developing CD has long been recognized to have a genetic contribution. This concept has advanced considerably over the past decade as genetic studies have identified numerous loci involved in IBD susceptibility. These studies have identified key cellular pathways in IBD and enhanced our understanding of how these pathways might contribute to disease. More than a decade ago, nucleotide oligomerization domain 2 (NOD2) was identified as the first susceptibility gene for CD (Ogura et al. 2001). In the last 5 years, population-based genome-wide association studies have greatly expanded the number of CD-associated loci (Jostins et al. 2012). Genetic studies have confirmed the role of mucosal barrier function, T-cell subsets, and cytokine signaling in the pathogenesis of CD. These studies have uncovered new genes and pathways, including autophagy, interleukin 23 signaling, NOD2/CARD in innate immunity, and innate lymphoid cells. CD-associated genes in host cells indicate that altered responses to gut microbiota may be a primary determinant of disease risk and a likely mechanism for the disease (Knights et al. 2013). The diversity and composition of the gut microbiota are major environmental factors influencing gut homeostasis. A severe imbalance in the composition of the gut microbiome has been associated with IBD (Morgan et al. 2012). Particular dietary nutrients and metabolites likely interact with host genetics to influence host–microbiome interactions and thereby contribute to inflammation. Among specific nutrients involved in the pathogenesis of CD are tryptophan, taurocholic acid, and dietary fiber.

Pathology CD may involve any part of the alimentary tract. The terminal ileum is predominantly involved and, in many cases, the disease may stop at the ileocecal valve. In the colon, it affects mainly the right side and may spare the rectum. Patchy or segmental disease can affect the transverse, descending, and sigmoid colon. In some cases, the rectum also may be diseased. The appendix is frequently involved, and perianal disease is

279

present in up to 60% of patients (see below). When CD involves the upper gastrointestinal tract, it generally occurs in conjunction with ileitis (Kleer and Appelman 2001). The prevalence of gastroduodenal involvement is unknown, but it has been suggested that microscopic foci may be present in as many as 83% of cases (Sandborn and Phillips 1995). CD may also affect the oral cavity, pharynx, and esophagus. CD of the mouth, characterized by aphthous ulcerations on the lips, buccal mucosa, or tongue, may indicate clinically unrecognized intestinal involvement (Kleer and Appelman 2001). However, CD may present in isolated parts of bowel without evidence of active disease elsewhere. CD involves the terminal ileum and colon in 60% of cases, small bowel in only 30%, and colon in only 10% of cases. The involved bowel and also mesentery are thickened and fat often migrates towards the antimesenteric border of the bowel wall (creeping fat, fat wrapping). A variable degree of stricturing is commonly seen in the segment of bowel that is mostly affected. Skip lesions are not uncommon and represent smaller areas or patches of active disease outside the main area of involvement. Skip lesions are typically found in the small bowel proximally to the most commonly affected terminal ileum. Histologically, mucosa is often extensively ulcerated and the inflammation is usually transmural. The inflammation is often interspersed with almost normally appearing mucosal areas. The transmural inflammatory changes may develop into fistulas that erode adjacent structures such as the bowel, bladder, vagina, perineum, and abdominal wall. Histological evidence of granulomas, that are the mainstay of histological diagnosis of CD, occurs in 40% of endoscopic biopsies taken from lesions in small bowel, in more than 60% of biopsies from gastric lesions and only 25% of biopsies from colonic lesions. A classification of the location and behavior of pediatric CD has recently been developed based on the Montreal classification of CD (Levine et al. 2011) (Table 1). This consensus Paris classification gives a reasonably solid basis for comparisons between different patient series. Moreover, the effect of various management modalities is

280

R. J. Rintala et al.

Table 1 Montreal and Partis classifications of Crohn’s disease Age at diagnosis

Montreal A1: below 17 years A2: 17–40 years A3: Above 40 years

Location

L1:terminal ileal  limited cecal disease L2: colonic L3: ileocolonic L4: Isolated upper diseasea

Behavior

B1: nonstricturing nonpenetrating B2: stricturing B3: penetrating p: perianal disease modifier

Growth

n/a

Paris A1a: 0–20 mg for 6 week or more) may increase the complications after ileocolonic anastomoses. Therapeutic concentrations of TNF-α antibodies persist for 8 weeks after infusion. Preoperative weaning from steroids and TNF-α antibodies may be beneficial in reducing surgical complications (Dignass et al. 2010). In patients who are malnourished or cannot be weaned from high doses of steroids, staged procedures with enterostomy should be considered. Preoperative discussion with patients and the parents should include all aspects and options of the surgical therapy. Reliable information should be given on the goals of the planned surgery, postoperative complications, expected high probability of a recurrent disease, and the need of renewed surgery. Consultations with stoma nurse and dietician should be arranged when necessary. In the case of colorectal surgery, preoperative bowel preparation may be performed.

Operative Approach and Technique Duodenum Primarily duodenal CD is rare, but it may cause obstructive symptoms or ulcer-like hemorrhage. Symptoms are initially managed medically with anti-TNF agents and proton pump inhibitors, but eventually the majority of affected patients may need surgical intervention. Mild recurrent obstructive symptoms can be successfully treated with endoscopic balloon dilatation. In more severe symptoms, gastrojejunal bypass with or

20

Crohn’s Disease

without duodenal stricturoplasty is recommended, whereas duodenal resections are associated with a high complication rate. A gastrojejunal bypass can be performed laparoscopically. A vagotomy is unnecessary because of proton pump inhibitors (Shapiro et al. 2008). Fistulas from diseased intestine may target stomach and duodenum. Persistent fistulas are treated by resection of the diseased intestine and suture closure of the fistula opening in the stomach or duodenum (Dolgin 2007).

Small Intestine Surgical approach in jejunal, ileal, or ileocolic resections may be open, or laparoscopic assisted (i.e., laparoscopic mobilization of the intestine with an extracorporeal intestinal anastomosis). In adults, the advantages of laparoscopy – shorter hospital stay, reduced complication rate, better cosmesis, and a reduced rate of intra-abdominal adhesions – have emerged as definite benefits of laparoscopy. In selected patients, laparoscopic assisted re-resections are possible. In patients with previous open surgery, fistulas, and abscess, an open approach is preferred. If long segments of small bowel are affected, it is advisable to only deal with the obstructive segments and leave diseased but nonobstructing lesions and skip lesions behind. Disease activity at the anastomotic margins does not compromise the outcome of the anastomosis. In adults, stapled side-to-side anastomosis carries a somewhat lower complication rate than hand-sewn end-to-end anastomosis, but whether the same is true in children is unclear. A wide anastomosis, irrespective of the anastomotic technique, is always recommended. In terms of disease recurrence at the anastomotic site, the anastomotic technique does not play a role (Dolgin 2007; Dignass et al. 2010). Electrosurgical vessel sealing devices are useful in dealing with the thickened mesenterium. In selected patients, stricturoplasty may be successfully used in short jejunoileal strictures (6 cm) or multiple cysts, especially in the liver. Severe symptoms due to a complicated hydatid cyst in the lung may also require surgical excision to reduce morbidity. In the authors’ experience, renal and splenic hydatid cysts usually require surgical excision as it may be difficult to establish the diagnosis preoperatively as the imaging findings are similar to simple cysts. A word of caution is important here, and the suspicion of a hydatid should be kept in mind while dealing with such lesions especially in endemic regions. Hydatid cysts of the liver have been treated surgically by several techniques including evacuation, marsupialization, and filling the cyst with saline after evacuation of the endocyst. Laparoscopic or thoracoscopic removal of hydatid cysts in the liver or lung has been in vogue recently (Maazoun et al. 2007; Sharma et al. 2009). However, one should be cautious that anaphylactic

Treatment Various chemotherapeutic dosage schedules have been described for treating hydatid cysts with albendazole. The usual prescribed dose is 10–15 mg/kg/day in two divided doses (max 800 mg) for 28 days followed by an interval of 2 weeks. Two to four cycles of treatment can be given. The leucocyte count and liver function should be monitored during treatment. Even if surgery is contemplated, it is a wise decision to give at least one cycle of chemotherapy to make the cyst less infected, to avoid an anaphylactic reaction during surgery. Patients with multiple hydatid cysts and cysts with a diameter of less than 6 cm should be treated medically first, and any residual cysts should be tackled with surgery. Adjuvant medical therapy with albendazole should be given even after surgical removal to avoid recurrence of cysts and seedlings in adjacent tissue. Optimal killing of cyst contents is

23

Surgical Manifestations of Parasitic Disease

reaction may occur on accidental puncture (Khoury et al. 1998). Prophylactic steroids may be given preoperatively just before the cyst is handled. Endoscopic removal can be made safer by advocating prior chemotherapy to make the cyst contents sterile or noninfective. PAIR (punctureaspiration-injection-reaspiration) during surgery has been described to make the cyst more manageable. PAIR involves puncture and needle aspiration of the cyst, injection of a scolicidal solution like hypertonic saline, povidone-iodine or hydrogen peroxide for 20–30 min, and cyst-re-aspiration and irrigation (Elayouty et al. 2012). Treatment outcomes are better when surgery or PAIR is combined with albendazole given pre- and/or postoperation (Velasco-Tirado et al. 2018a). Operative removal of a lung hydatid cyst requires planned intervention. The use of a double-lumen endotracheal tube in older children prevents flooding of the hydatid fluid into the opposite bronchus and aspirations, while the gentle maneuver of bagging is done to deliver the cyst. Advances in treatment include percutaneous thermal ablation of the germinal layer in the cyst by means of a radiofrequency ablation device (Eckert and Deplazes 2004). Complications of cystic echinococcosis disease are one of the most common causes of morbidity and mortality, with size, location, and the number of cysts being the main factors associated with mortality (Velasco-Tirado et al. 2018b).

Prevention To control echinococcosis, health education with improved water sanitation and personal hygiene is important. Many countries endemic to echinococcosis have implemented programs geared at deworming dogs and red foxes and vaccinating dogs against E. granulosus and other livestock like sheep.

Amoebiasis Amoebiasis is the most common parasitic disease caused by the protozoan Entamoeba histolytica (amoeba), class Rhizopoda. The prevalence of

317

amoebic infection is more than 10% of the world population and rises to about 50% in the developing countries of the tropical region where the condition is endemic. Though amoebiasis may affect any age group, being equally common in both sexes, amoebic intestinal disease and liver abscesses are more common among adolescents. Factors responsible for its spread include unhealthy living conditions that are exaggerated due to ignorance, poverty, and malnutrition. However, most amoebic infections remain asymptomatic and a high index of suspicion is required to diagnose complications that may develop anytime.

Causative Agent Entamoeba histolytica, a commensal, occurs in two forms; a motile trophozoite stage and a nonmotile cystic stage. The trophozoite is found in intestinal and extraintestinal lesions and diarrheal stools. The nonmotile cyst is present in nondiarrheal stools of patients with amoebic infection. The trophozoite, an average of 25 μ size, has no definite form; it changes its shape by throwing pseudopodia that help in locomotion; it has a spherical nucleus and a cytoplasm clearly divisible into translucent ectoplasm and granular endoplasm.

Pathophysiology Amoebiasis is commonly transmitted via the fecooral route, either directly by direct contact or indirectly by ingesting fecally contaminated food or water. The primary lesion of amoebiasis occurs in the colon, with predilection for the caecum and rectosigmoid region. The invasive disease begins with the adherence of E. histolytica to colonic mucosa. The trophozoites then invade the colonic epithelium to produce the ulcerative lesions. The proteolytic destruction of tissue typically produces flask-shaped ulcers. Trophozoites ascend the portal veins to produce liver abscesses filled with acellular proteinaceous debris, known as anchovy sauce, due to the color. The trophozoites lyse the hepatocytes and the neutrophils. This

318

explains the paucity of inflammatory cells within the liver abscesses. A mucosal IgA response can produce partial, protective immunity to infection with E. histolytica (Haque et al. 2003).

S. Sharma and D. K. Gupta

Severe amoebic colitis in children is usually rapidly progressive with frequent extraintestinal involvement and higher mortality rates. The symptoms can range from mild diarrhea to dysentery with a large amount of malodorous stools with blood and mucus.

Life Cycle Humans are the only reservoir. There is no intermediate host. Upon ingestion of contaminated food or water, the cysts travel to the small intestine, where trophozoites are released (encystations). In 90% of cases, the trophozoites re-encyst and produce asymptomatic infection that usually resolves spontaneously within a year. Symptomatic amoebiasis occurs in only 10% of infected cases. The incubation period varies from 2 days to 4 months. The liver is infected by spread through the blood stream causing liver abscesses.

Clinical Features The symptoms depend upon the severity of infection and spread to an extraintestinal location. Severe amoebiasis infections usually involve either the intestine causing amoebic dysentery or colitis or infecting the liver causing amoebic liver abscesses. Intestinal infestation may vary from asymptomatic cyst passage to amoebic colitis causing mild diarrhea, amoebic dysentery, fulminant colitis, amoeboma, and peritonitis. Extraintestinal disease may involve other organs, most commonly the liver. Rare extraintestinal manifestations include amoebic brain abscess, pleuropulmonary disease, ulcerative skin, and genitourinary lesions (Singhi and Saini 2019)3. Acute amoebiasis can present with diarrhea or dysentery with frequent, small, and often bloody stools. Chronic amoebiasis can present as gastrointestinal symptoms along with fatigue, weight loss, and occasional fever. Amoebic liver abscess presents with moderate- to high-grade fever and right upper quadrant abdominal pain. The fever is of higher grade if there is added bacterial infection. Younger children usually have severe disease, especially in the presence of malnutrition.

Liver Abscess About 4% of patients with amoebic colitis develop an amoebic liver abscess, the most frequent and serious extraintestinal manifestation (CDC 2013). It is more often seen in adolescents than in younger children. It may occur months to years after exposure and can also occur without previous history of amoebic dysentery. Most children with amoebic liver abscess present with solitary right lobe abscess (Jain et al. 2016). Diffuse liver enlargement has been associated with intestinal amoebiasis. Numerous small abscesses may coalesce to form large abscesses, which expand towards the surface and may rupture, giving rise to amoebic peritonitis. In children, the usual presentation of amoebic liver abscess is high-grade fever often associated with abdominal pain, distension, enlargement, and tenderness of the liver. Empyema Changes at the base of the right lung, such as elevation of the diaphragm and atelectasis or effusion, may also occur. In cases that present late for treatment, the liver abscess may rupture into the right hemothorax and present as empyema. These cases are critical and need immediate chest drainage followed by drainage of the liver abscess.

Diagnosis Blood Tests There may be evidence of mild anemia, raised total leucocyte count, raised erythrocyte sedimentation rate, and deranged liver function tests. Serum antibodies against amoebae are present in 70–90% patients with symptomatic intestinal E. histolytica infection. Antiamoebic antibodies are present in 99% of patients with liver abscess who have been symptomatic for longer than a week. However, serologic tests do not distinguish

23

Surgical Manifestations of Parasitic Disease

new from past infection because the seropositivity persists for years after an acute infection. Several immunologic tests are now commercially available, but rarely used.

Stool Test Asymptomatic infections are usually diagnosed by finding cysts shed in the stool. Fresh stool smears may be positive in up to 10% cases, with amoebiasis with trophozoites containing ingested red blood cells. In symptomatic infections, the motile form (trophozoite) can often be seen in fresh feces. Various floatation or sedimentation procedures have been developed to recover the cysts from fecal matter. However a minimum of three stools should be examined as a negative stool sample does not rule out amoebiasis, as the cysts are not shed constantly. An enzyme immunoassay kit to specifically detect E. histolytica in fresh stool specimens is now commercially available. Chest Skiagram A chest skiagram may reveal an elevated hemi diaphragm due to an enlarged liver and a rightsided pleural effusion in patients with amoebic liver abscess. Ultrasonography Ultrasonography is the best mode for evaluation of amoebic liver abscess due to its low cost, rapidity, and noninvasive nature. It can be repeated whenever required to study the response to the treatment. The most common site of amoebic liver abscess is the posterosuperior aspect of the right lobe of the liver. Multiple abscesses may occur in some patients. Ultrasonography-guided diagnostic and therapeutic aspiration of anchovy color pus may guide further management. Care should be taken to prevent contact with skin and spill into the peritoneal cavity as the contents of the amoebic abscess may generate a reaction.

319

asymptomatic infection should be treated because of its potential to progress to invasive disease with luminal agents like paromomycin. Metronidazole is the mainstay of therapy for invasive amoebiasis. Tinidazole is used for intestinal or extraintestinal amoebiasis. Nitroimidazole therapy is effective in approximately 90% of cases with mild to moderate colitis. As nitroimidazole does not affect intraluminal parasites, it should be followed by treatment with a luminal agent such as paromomycin to prevent a relapse. Chloroquine has also been used for patients with hepatic amoebiasis. Broad-spectrum antibiotics may be added to treat bacterial superinfection in fulminant amoebic colitis and suspected perforation. Bacterial coinfection with amoebic liver abscess has occasionally been observed (both before and as a complication of drainage), and adding antibiotics to the treatment regime is reasonable in the absence of a prompt response to nitroimidazole therapy.

Surgical Treatment Though surgical intervention for acute abdomen due to perforated amoebic colitis, massive GI bleeding, or toxic megacolon has been described historically, the authors have not encountered any case of amoebic perforation in children less than 12 years of age (Vargas and Peña 1976). Amoebic colitis leading to stricture formation is more common. Unlike pyogenic liver abscesses, an amoebic liver abscess generally responds to medical therapy alone, and formal drainage is required only in selected cases. Imaging-guided percutaneous treatment by needle aspiration or catheter drainage has replaced surgical intervention. The indications for drainage of amoebic liver abscesses include a leftlobe abscess (>10 cm in diameter), an impending rupture and a nonresponding abscess that does not respond to medical therapy within 5 days.

Prevention Treatment Medical Treatment Asymptomatic infections in endemic areas do not require treatment. However, in nonendemic areas,

Good sanitation, health education, and appropriate sewage disposal or treatment are necessary for the prevention of endemic E. histolytica infection. E. histolytica cysts are usually resistant to chlorination; thus sedimentation and filtration of water

320

supplies are necessary to reduce infection (CDC 2010).

Ascariasis Ascariasis, commonly referred to as roundworm infestation, affects more than 1000 million people in the world.

S. Sharma and D. K. Gupta

Pathophysiology Ascaris lumbricoides is transmitted by ingestion of water or food contaminated by eggs from human feces and occasionally via inhalation of polluted dust. The eggs reach the small intestine, where the larvae are liberated. In endemic regions, poor hand hygiene may be the sole responsible factor.

Life Cycle Causative Agent Ascaris lumbricoides, a nematode, is the causative agent. Ascariasis is the most commonly identified intestinal infestation as the long worm is visible to the naked eye. It is the most common parasite associated with surgical manifestation requiring a surgical intervention as it tends to present with intestinal obstruction or perforation. In endemic areas, it is not uncommon for children posted for elective surgical procedures to vomit or defecate the adult worm while in the hospital (Fig. 3).

The larvae penetrate the small intestinal wall and migrate through the lymphatic stream and bloodstream to the liver and then to the lungs, where they enter the alveoli (Fig. 4). In the alveoli, they pause for around 2–3 weeks and molt, which may cause allergic bronchopneumonia. Later, they wander up the bronchi and trachea, giving rise to bronchitis with bronchospasm, urticaria, and occasionally larvae in the sputum. Most larvae are swallowed and grow to adulthood in the small intestine. The adult worms give rise to mechanical problems due to their size and the smaller diameter of the lumen of the bowel of children. Antihelminthic drugs make these worms immotile. The worms may form a congregate mass resulting in intestinal obstruction. Worms may also migrate into the bile duct, esophagus, mouth, pancreatic duct, or appendix and occasionally the liver. Adult worms may perforate the gut, leading to peritonitis. Sometimes, the presence and activity of large numbers of worms alone may be associated with vomiting, fever, and abdominal pain.

Clinical Features

Fig. 3 An adult Ascaris worm vomited out by a boy during the postoperative period

The only symptom may be mild abdominal discomfort. Heavy infections can cause intestinal obstruction and impair the growth in children resulting in malnutrition. The chief complaint is usually recurrent colicky central abdominal pain. There should be a high index of suspicion in all cases of intestinal obstruction in children. Vomiting may be frequently associated, either due to the activity of the worms or as a result of intestinal obstruction. The vomitus should be examined for the presence of worms. On rare occasions, an ill-

23

Surgical Manifestations of Parasitic Disease

321

= Infected Stage = Diagnostic Stage

FECES

Fertilized egg

Unfertilizerd egg will not under go biological development

Fig. 4 Life cycle of ascariasis (Modified from the Centers for Disease Control and Prevention (CDC 2010))

Diagnosis

Skiagram The radiolucent worms may be identified in cases with massive infestation. The erect skiagram may show features of intestinal obstruction, such as multiple air-fluid levels, dilated bowel loops, and free gas under the diaphragm in cases with intestinal perforation.

Stool Examination for Ova This may be helpful to confirm the diagnosis in suspected cases. However, the stool may be positive for the ova even in asymptomatic cases in endemic regions. Deworming may be performed in the absence of intestinal obstruction.

Ultrasonography On ultrasonography, the roundworms appear as a thick echogenic strip with a central anechoic tube or multiple long, linear, parallel echogenic strips without acoustic shadowing. Swirling movements of the worms may be observed on prolonged scanning.

defined, mobile abdominal mass may be palpable. The early symptoms may be related to larval migration in the lung. Abdominal distention may be apparent due to the dilated proximal bowel loops.

322

Treatment Children with uncomplicated ascariasis usually present with mild symptoms and can be managed as outpatients. In the case of complicated Ascaris infection with intestinal obstruction, the child needs to be admitted for observation and needful management.

Medical Treatment Cases with partial obstruction can be managed conservatively with bowel rest, bowel decompression, intravenous fluid replacement, and antispasmodics. Antihelminthic drugs should not be given during the obstruction phase. They may be given later, around 2 weeks after the attack has subsided. Surgical Treatment Intestinal obstruction not responding to conservative management may require exploratory laparotomy. The mass of worms may be identified on inspection. • Milking: The bolus of worms is broken up and massaged from the small intestine into the larger diameter caecum and ascending colon. • Enterostomy: The antimesenteric border of the bowel is opened longitudinally, through which the worms are carefully extracted in a kidney tray, avoiding contamination, and the intestine is repaired transversely. • Resection: Occasionally, in delayed cases with impending gangrenous changes due to a mass tightly packed worms, the affected bowel segment may be resected with the contained worms, and an end-to-end anastomosis is performed. This will avoid the release of toxins into the operating field.

Other Helminthic Infections Intestinal infestation with smaller helminths like hookworm, pinworm, and threadworm are very common in children living in unhygienic conditions, but they seldom cause surgical manifestations. These worm infestations cause anemia and occult blood in stool. Routine deworming at

S. Sharma and D. K. Gupta

intervals to take care of these infestations is recommended in endemic areas.

Autoinfection with Helminthic Infection Autoinfection refers to infection of a primary host with a parasite, particularly helminths, such that the complete life cycle of the parasite occurs in a single organism, without the involvement of another host. Thus, the primary host serves at the same time as the secondary host of the parasite, e.g., Strongyloides stercoralis, Enterobius vermicularis, Taenia solium, and Hymenolepis nana. Strongyloidiasis may involve premature transformation of noninfective larvae into infective larvae, which can then penetrate the intestinal mucosa (internal autoinfection) or the skin of the perineal area (external autoinfection) and reinfect the host. Infection can be maintained by repeated migratory cycles within the host.

Guinea Worm Disease or Dracunculiasis Dracunculiasis, commonly known as guinea worm disease, is a waterborne disease that is transmitted uniquely by drinking contaminated water. It has been successfully eradicated from many countries of the world by the World Health Organization (WHO) and is now only restricted to rural areas in few countries located in sub-Saharan Africa. Today, active transmission occurs in four countries: Ethiopia, Ghana, Mali, and Sudan (CDC 2014). Dracunculiasis is expected to become the second disease after smallpox to be eradicated. Dracontiasis rarely occurs in infancy as the infestation has a long period of incubation. The incidence of the disease increases significantly after 5 years and is mostly seen in young patients between 15 and 45 years of age.

Causative Agent Dracontiasis is caused by the adult female Dracunculus medinensis, an arthropod known as copepods. Guinea worm disease is caused by

23

Surgical Manifestations of Parasitic Disease

drinking water contaminated with water fleas that host the Dracunculus larva (WHO 2010; Carter Center 2011). Areas with limited access to clean water may have stagnant water sources that may carry the guinea worm larvae.

Pathophysiology The guinea worm requires a definite host-man and an intermediate host-Cyclops for its full development. The larvae mature in the Cyclops found in stagnant dirty water.

Life Cycle The larvae develop for about 2 weeks inside the copepods. At this stage, the larvae can cause guinea worm disease if the infected copepods are not filtered from drinking water (Carter Center 2011). When this contaminated water is consumed, the infected Cyclops is digested by the gastric hydrochloric acid, liberating the larvae. The larvae, male and female, burrow through the intestine to enter the circulation. These larvae burrow to the body cavity where the female mates with a male guinea worm around 3 months after infection. The males, only 2–3 cm long, die after fertilizing the females. The female then matures in deeper connective tissues or adjacent to long bones or joints of the extremities (Carter Center 2011). At 10–14 months after infection, it emerges from the subcutaneous tissue, mainly of the lower leg or ankle (Carter Center 2011). The blister ruptures within 3 days, exposing one end of the emergent worm. This blister causes a very painful burning sensation as the worm emerges. Infected persons often immerse the affected limb in water to relieve the burning sensation. When in contact with water, the blister ruptures; the worm protrudes and discharges hundreds of thousands of larvae into the water, contaminating the water. The larvae are then ingested by the Cyclops and mature in about 3 weeks, thus completing the life cycle. There is no animal or environmental reservoir of D. medinensis, and thus the parasite must pass through a host each year to survive (Tropical medicine Central Resource 2008). Infected

323

copepods can live in the water for only 2–3 weeks if they are not ingested by a human.

Clinical Features The clinical presentation depends on the severity and frequency of infection and the duration of exposure. The earliest reaction is popular dermatitis at the sites of entry of the cercariae, followed by a pulmonary inflammatory reaction as the cercariae pass through the lungs. In the established infection, there is formation of foreign body granulomata and fibrosis provoked by dead ova, consisting of an ovum surrounded by epithelioid cells, plasma cells, lymphocytes, eosinophils, giant cells, and fibroblasts. Guinea worm disease produces a nodular dermatosis causing symptoms when a live worm reaches the skin at the site of emergence. Generally, two types of lesions are produced by guinea worm infestation in man: vesicles, which ulcerate, and subcutaneous or deep abscesses around dead adult worms. A cutaneous blister prior to eruption may be associated with erythema, urticarial rash, intense pruritus, nausea and vomiting, diarrhea, dyspnea, giddiness, and syncope (WHO 2010). The worm may produce calcification. The calcified worms, which remain asymptomatic, have been discovered by chance on skiagram or during a surgical intervention. The authors have seen several such calcified guinea worms in adolescents and adults in endemic areas. As the disease has been eradicated from many regions, it is rarely seen in children now. However in endemic regions, it may be seen in children playing in ponds infected by the worms. Secondary bacterial infection can lead to complications like septicemia and tetanus. Severe arthritis and ankylosis may occur due to joint involvement, leading to physical deformity and limitation of mobility.

Treatment The treatment is extraction of the worm by cautious winding around a stick and gentle traction applied daily until it is removed. Wet compresses and topical antibiotics are applied to the ulcer until

324

the discharge from the wound ceases. Medicines like niridazole, thiabendazole, or metronidazole can help to reduce the tissue reaction, make extraction easier, and relieve pain. There is no vaccine or medicine to treat or prevent Guinea worm disease. Once a Guinea worm begins emerging, a controlled submersion of the affected area in a bucket of water causes the worm to discharge many of its larva, making it less infectious and results in subjective relief of the burning sensation and makes subsequent extraction of the worm easier. Gently massaging the area around the blister can help loosen the worm up a bit (Tropical medicine Central Resource 2008). However, if the infection occurs before an ulcer forms, the worm can also be surgically removed (CDC 2014). One should avoid breaking the worm when pulling it out as broken worms have a tendency to putrefy, leading to the sloughing of skin.

Prevention Guinea worm disease can be transmitted only by drinking contaminated water and can be completely prevented through simple measures like filtering drinking water, boiling or treating water with larvicides like temephos to kill the cyclops, and educating infected people never to wade into water, which perpetuates the life cycle of the disease.

Cysticercosis Cysticercosis, caused by the larvae of Taenia solium, is endemic to many countries, including China, Southeast Asia, India, sub-Saharan Africa, and Latin America. The parasite is also responsible for neurocysticercosis, the most common parasitic infestation of the central nervous system and a cause of late-onset epilepsy.

S. Sharma and D. K. Gupta

from ingestion of contaminated vegetables, food, and water. T. solium worms may be several meters long. The scolex has four suckers. It attaches to the intestinal mucosa via two rows of prominent hooks. The T. solium eggs are spherical and 30–40 μm in diameter. The cysticercus larva completes development in about 2 months. Although infections with Taenia tapeworm cysts may involve many parts of the body, the most common site of severe symptomatic infection is the CNS.

Pathophysiology Humans are T. solium reservoirs. They are infected by eating undercooked pork that contains viable cysticerci. The cysticercus develops into an adult tape worm in the intestine and produces numerous eggs that pass out in the feces. The adult tape worm in the intestine does not cause any harm. The human is an accidental and dead-end intermediate host. Pigs, the intermediate host, get infected with cysticerci when they ingest human feces. The incubation period ranges from months to over 10 years. The most common route is through infected raw-eaten vegetables grown in fields irrigated with an admixture of sewage water with drinking water in pipelines, houseflies, and cockroaches. After ingestion, the eggs pass through the intestinal lumen into the tissues and migrate preferentially to the brain and muscles. There, they form cysts that can persist for years (Fig. 5). In symptomatic cases, the cysts eventually cause an inflammatory reaction presenting as painful nodules in the muscles and seizures when present in the brain. Cysticercosis is different from teniasis. While cysticercosis is the result of ingestion of eggs, teniasis is the carrier stage of the adult tapeworm in the intestine that occurs through ingestion of cysts in an intermediate host. These represent two different stages of the parasite’s life cycle and have different treatments even if found within the same person (Mandell et al. 2010).

Causative Agent The disease cysticercosis is transmitted by the egg form of Taenia solium (pork tapeworm), through the feco-oral route. Cysticercosis, a tissue infection that involves larval cysts of the cestode Taenia solium (the human pork tapeworm), results

Life Cycle The life cycle of T. solium involves man as a definite host and pig as an intermediate host (Fig. 6). Pigs ingest contaminated food or water

23

Surgical Manifestations of Parasitic Disease

Fig. 5 Subcutaneous cysticercosis presenting as a nodule over the left side of the trunk in an 8-year-old boy

that contains eggs or proglottids from human feces. The eggs develop into cysticerci in pig muscles. Humans become infected when they ingest raw or undercooked pork that contains viable cysticerci. Upon reaching the small intestine, the scolex attaches to the intestinal wall and a proglottid chain grows. T. solium releases 3–6 proglottids/day, bearing thousands of eggs per proglottid into the intestine. Infections with cysticercus occur after consumption of ova from external sources or through autoinfection via the feco-oral route. Here, man acts as an intermediate host. Ova are digested in the stomach and release oncospheres which penetrate the intestinal wall and reach the bloodstream. These oncospheres develop into cysticerci in any organ, but are common in the brain, subcutaneous tissue, and eyes.

325

as fluid-filled nodules resembling sebaceous cysts, firm, mobile nodules, occurring mainly on the trunk and extremities (Fig. 5). Subcutaneous nodules are sometimes painful. Cysticerci can develop in any voluntary muscle in humans (Markell et al. 1999). Generalized myalgia is common. Muscle involvement can cause inflammation of the muscle, infection, and later atrophy and fibrosis. In most cases, it is asymptomatic since the cysticerci die and become calcified. Neurocysticercosis can present with seizures and rarely headaches. While lesions in brain parenchyma are usually 5–20 mm in diameter, they may be as large as 6 cm in the subarachnoid space and fissures. Cysts within the ventricles can obstruct cerebrospinal fluid outflow and present with symptoms of increased intracranial pressure (Suri et al. 2008). Racemose neurocysticercosis refers to cysts in the subarachnoid space. Neurocysticercosis involving the spinal cord may present as back pain and radiculopathy. Cysticerci may also involve the globe, extraocular muscles, and subconjunctiva. Depending on the location, they may cause visual difficulties fluctuating with eye position, retinal edema, hemorrhage, a decreased vision, or even visual loss (Markell et al. 1999).

Diagnosis

Clinical Features

Blood Tests Antibodies to cysticerci can be demonstrated in serum by enzyme-linked immunotransfer blot (EITB) assay and in CSF by ELISA. An immunoblot assay using lentil-lectin (agglutinin from Lens culinaris) is highly sensitive and specific. However, individuals with intracranial lesions and calcifications may be seronegative.

Cysticercosis can infect any age group, though is usually seen in children over 8 years, with the most common age group affected being between 8 and 40 years. The clinical features can be divided into two types, neurocysticercosis or extraneural cysticercosis (intestinal tapeworm infection). Subcutaneous cysts may be palpable

Stool Test Demonstrating tapeworm eggs or proglottids in stool samples diagnoses only teniasis, carriage of the tapeworm stage of the life cycle. Very few patients with cysticercosis will harbor a tapeworm; thus stool tests are ineffective for diagnosis.

326

S. Sharma and D. K. Gupta

Oncosphere hatch, penetrate intestinal walls, and circulate to musculature

Embryonated eggs ingested by human host

Oncosphere hatch, penetrate intestinal walls, and circulate to musculature

Cysticerci may develop in any organ, being more comman in subcutaneous tissues, brain and eyes

Cysticercosis

Humans infected by ingesting raw or uncooked infected meat Oncospheres develop into cysticerci in pig muscle

Ingested by pigs Scolex attaches to intestine

Adult is small intestine = Infected Stage = Diagnostic Stage

Eggs or gravis proglottids passed in feces

Fig. 6 Life cycle of cysticercosis (Modified from the Centers for Disease Control and Prevention (CDC 2010))

Fundoscopy Ophthalmic cysticercosis can be diagnosed by visualizing parasite in eye by fundoscopy.

Imaging The diagnosis of neurocysticercosis is mainly clinical, based on the presentation of symptoms and findings of imaging studies. Neuroimaging

with CT or MRI is the most useful method of diagnosis. CT scan shows both calcified and uncalcified cysts and distinguishes active and inactive cysts. Cystic lesions can show ring enhancement and focal enhancing lesions. However, few cystic lesions in the ventricles and subarachnoid space may not be appreciable on CT scan as the cyst fluid is isodense with CSF. The diagnosis of extraparenchymal cysts usually relies on signs like hydrocephalus or enhanced basilar

23

Surgical Manifestations of Parasitic Disease

meninges. In such cases, CT scan with intraventricular contrast or MRI can be used. MRI is more sensitive in the detection of intraventricular cysts.

CSF Examination CSF findings include pleocytosis, elevated protein levels, and depressed glucose levels; but these may not be always present.

Management Neurocysticercosis Neurocysticercosis may present as hydrocephalus and acute-onset seizures; thus the mainstay of therapy is reduction of intracranial pressure and anticonvulsant medications. Antihelminthic treatment is started after control of seizures. The decision to start antiparasitic therapy is complex and based on the stage and number of cysts present, their location, and the patient’s symptoms. Corticosteroids and anticonvulsants are added with the treatment to reduce inflammation around the cysts and check the risk of seizures. When steroids are given along with praziquantel, they decrease the action of praziquantel by enhancing its first-pass metabolism. In such situations, cimetidine may help. Albendazole has fewer drug interactions. Asymptomatic incidental cysts may never become symptomatic and do not require therapy. Calcified cysts have already died and involuted; thus antiparasitic therapy will not benefit. Surgical intervention is much more likely to be needed in cases of intraventricular, racemose, or spinal neurocysticercosis. Treatments include direct excision of ventricular cysts, shunting, and removal of cysts via endoscopy. Ophthalmic Cysticercosis Surgical removal is necessary for ocular infections as treating intraocular lesions with antihelminthic will elicit an inflammatory reaction causing irreversible damage to the eye. Cysts outside the globe can be treated with antihelminthic and steroids. Subcutaneous cysticercosis may be treated by surgery, praziquantel, and albendazole (Wortman 1991).

327

Subcutaneous Cysticercosis Subcutaneous disease does not need specific therapy. Fine needle aspiration cytology is very beneficial to establish the diagnosis in subcutaneous lesions. Painful or troublesome cysts are commonly seen in children in endemic regions and can be surgically excised. These may sometimes be removed for improved cosmesis. On rare occasions, the authors have seen these cysts disappearing on antihelminthic medications. A careful history should be taken for associated neurocysticercosis, and in the presence of suggestive symptoms, imaging for diagnosis should be done.

Prevention Cysticercosis can potentially be eradicated as there are no animal reservoirs apart from man and pigs. The only source of T. solium infection of pigs is from man, a definite host. The life cycle may be interrupted by intervention strategies at various points in the life cycle. A mass treatment modality with single-dose mebendazole or albendazole for all preschool and school-age children every 3–4 months has been used in some communities. Improving sanitation, protecting food from dirt and soil, and educating people are all beneficial. Cooking of pork or freezing it and inspecting meat are effective means to cease the life cycle. The management of pigs by treating them or vaccinating them is another possibility. The separation of pigs from human feces by confining them in enclosed piggeries is a good method for controlling the disease. The proposed strategy for eradication is by multilateral intervention by treating both human and porcine populations. The treatment of pigs with oxfendazole has been found effective and, once treated, protects them from further infections for 3 months. Tapeworm carriers, man and pigs, tend to spread the disease from endemic to nonendemic areas resulting in periodic outbreaks of cysticercosis or outbreaks in new areas. As pigs are part of the life cycle, vaccination of pigs is another feasible intervention to eliminate cysticercosis. The vaccine constituted by three synthetically produced peptides (S3Pvac) has proven its efficacy in natural conditions of transmission (Mandell et al. 2010).

328

Conclusion and Future Directions Parasitic infestations may lead to surgical complications that are more common in endemic regions. A knowledge about the various parasitic infestations that are common in a particular area help to manage these cases and also develop preventive strategies. With improving public awareness and development of the endemic regions, these diseases are being controlled to some extent. Future development of vaccines may help to overcome some diseases like cysticercosis.

References Carter Center. Guinea Worm Eradication Program. The Carter Center. Retrieved 1 Mar 2011. CDC. Parasites and health: Echinococcosis. 2010. http:// www.cdc.gov/dpdx/ CDC. Amebiasis. 2013. http://www.cdc.gov/parasites/ amebiasis/ CDC. Guinae worm. 2014. http://www.cdc.gov/parasites/ guineaworm/ David JT, Petri WA. Markell and Voge’s medical parasitology. 9th ed. St. Louis: Saunders Elsevier; 2006. p. 224–31. Dennis T, Stich A, Frosch M. Emergence of polycystic neotropical echinococcosis. Emerg Infect Dis. 2008;14:292–7. Eckert J, Deplazes P. Biological, epidemiological, and clinical aspects of echinococcosis, a zoonosis of increasing concern. Clin Microbiol Rev. 2004;17:107–35. Elayouty HD, Baterfy AM, Alkamash SH. Hydrogen peroxide versus povidone iodine as intra-operative scolicidal agents to attack hydatid cysts. Open Cardiovasc Thorac Surg J. 2012;5:27–30. Haque R, Huston CD, Hughes M, Houpt E, Petri WA. Amebiasis. NEJM Engl J Med. 2003;348:1565–157. Howorth MB. Echinococcosis of bone. J Bone Joint Surg. 1945;27:401–11. Jain M, Jain J, Gupta S. Amebic liver abscess in childrenexperience from Central India. Indian J Gastroenterol. 2016;35(3):248–9. Khoury G, Jabbour-Khoury S, Soueidi A, Nabbout G, Baraka A. Anaphylactic shock complicating

S. Sharma and D. K. Gupta laparoscopic treatment of hydatid cysts of the liver. Surg Endosc. 1998;12:452–4. Lozano R. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the global burden of disease study 2010. Lancet. 2010;380:2095–128. Maazoun K, Mekki M, Chioukh FZ, Sahnoun L, Ksia A, Jouini R, et al. Laparoscopic treatment of hydatid cyst of the liver in children. A report on 34 cases. J Pediatr Surg. 2007;42:1683–6. Mandell, Douglas, Bennett. Principles and practice of infectious diseases. 7th ed. Philadelphia: Churchill Livingstone; 2010. Markell EK, John DT, Krotoski WA. Medical parasitology. 8th ed. Pennsylvania: Saunders; 1999. Sanaei Dashti A, Kadivar MR, Alborzi A, et al. Analysis of hospital records of children with hydatid cyst in south of Iran. J Parasit Dis. 2017;41(4):1044–8. Sharma D, Babu R, Borgharia S, Baruah D, Thomas S, Kumar A. Laparoscopy for liver hydatid disease: where do we stand today? Surg Laparosc Endosc Percutan Tech. 2009;19:419–23. Singhi P, Saini AG. Fungal and parasitic CNS infections. Indian J Pediatr. 2019;86(1):83–90. Sréter T, Széll Z, Egyed Z, Varga I. Echinococcus multilocularis: an emerging pathogen in Hungary and Central Eastern Europe. Emerg Infect Dis. 2003;9:384–6. Suri A, Goel RK, Ahmad FU, Vellimana AK, Sharma BS, Mahapatra AK. Transventricular, transaqueductal scope-in-scope endoscopic excision of fourth ventricular neurocysticercosis: a series of 13 cases and a review. Emerg Radiol. 2008;1:35–9. Tropical Medicine Central Resource. Dracunculiasis. Uniformed Services University of the Health Sciences. Retrieved 15 July 2008. Vargas M, Peña A. Toxic amoebic colitis and amoebic colon perforation in children: an improved prognosis. J Pediatr Surg. 1976;11:223–5. Velasco-Tirado V, Alonso-Sardón M, Lopez-Bernus A, et al. Medical treatment of cystic echinococcosis: systematic review and meta-analysis. BMC Infect Dis. 2018a;18(1):306. Velasco-Tirado V, Romero-Alegria A, Pardo-Lledías J, et al. Management of cystic echinococcosis in the last two decades: what have we learned? Trans R Soc Trop Med Hyg. 2018b;112(5):207–15. World Health Organization. Dracunculiasis. Retrieved 12 July 2010. Wortman PD. Subcutaneous cysticercosis. J Am Acad Dermatol. 1991;25(2 Pt 2):409–14.

Part IV Transplantation

Principles of Transplantation

24

Evelyn G. P. Ong and Deirdre A. Kelly

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332 Immunology of Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of Costimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of Innate Immunity in Rejection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of Natural Killer Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immunosuppression Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Graft Tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immune Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

333 334 334 336 336 336 338

Organ Donation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338 Cadaveric Donation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338 Live Donation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343 Assessment of the Pediatric Recipient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344 Current Transplantation Legislation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . United States of America . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Japan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

345 346 348 348

Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349

Abstract E. G. P. Ong (*) The Liver Unit, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK e-mail: [email protected] D. A. Kelly The Liver Unit, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK Pediatric Hepatology, Birmingham Women’s and Children’s Hospital, University of Birmingham, Birmingham, UK e-mail: [email protected]

Pediatric solid-organ transplantation is a maturing specialty that has evolved from the close collaboration between surgical and immunological research. It continues to challenge practitioners, both technically and in understanding the underlying processes that allow the human body to distinguish self from foreign tissues. A multidisciplinary approach to both assessment and management of these

© Springer-Verlag GmbH Germany, part of Springer Nature 2021 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43559-5_117

331

332

complex patients is essential for long-term success. Constant innovation in immune suppression, surgical techniques, and organ procurement has advanced pediatric transplantation survival in a relatively short period of time but is still far from attaining the ultimate goal of graft tolerance. The indications for transplantation are ever increasing, placing demands on organ supply which needs to be managed by appropriate legislation. Different countries have taken different approaches to this legislation and are heavily influenced by both cultural and ethical factors. Keywords

Transplantation · Immune system · Human leukocyte antigen · Immunosuppression · Costimulation · Graft rejection · Graft tolerance · Organ donation · Transplant legislation · Transplant assessment

Introduction Legend holds that the first transplant was performed by the martyred brothers Saint Cosmas and Saint Damian, twin brothers who replaced the cancerous leg of their patient with that of a deceased Ethiopian man (Androutsos et al. 2008). However, the foundations of transplant were truly laid when there was a fundamental shift in the understanding of illness and the human body. In the early nineteenth century, the predominant belief was of the human body acting as a single entity subject to a balancing act with its environment. Any disturbance of this balance would lead to illness. However, toward the end of the nineteenth century, this single entity was slowly

Fig. 1 Transplantation milestones

E. G. P. Ong and D. A. Kelly

coming to be viewed as the symbiotic working of a collection of independently functioning organs. Removing a single diseased organ might therefore be curative. A Swiss surgeon, Theodor Kocher, in particular, treated the symptoms of hyperthyroidism with removal of the thyroid gland successfully (Kopp 2009). What he did not predict was the onset of hypothyroidism and so attempted to treat this by replacing normal thyroid tissue into his patients, effectively performing the first transplant. He went on to win the Nobel Prize in 1909, for discovering the function of the thyroid gland. With further work in animal models, the principle that one could replace an entire diseased organ with a healthy one was born. The next advance came in 1902, with technical improvements in vascular anastamoses pioneered by Alexis Carrel (Fig. 1), a French-American surgeon who was awarded the Nobel Prize in 1912 for his work (Moseley 1980). However, he soon came to realize that the technical aspects of the surgery were not enough; an unseen barrier was at work which allowed organs to be transplanted with the same animal but not between different animals. He observed that the organs must therefore be unique to the individual. The German surgeon Georg Schöne was the first to realize that the immune system had a role to play (Schöne 1912). Various strategies were employed to persuade the recipient to accept the graft: bathing the graft in the prospective recipient’s blood serum; injecting the recipient with donor blood; and feeding the recipient animal meat from the donor animal. Finally, attention turned to suppressing the recipient’s immune response. In 1951, Rupert E Billingham and Peter Brian Medawar of the University of Birmingham published their work on animal free skin grafts indicating the

24

Principles of Transplantation

immunological processes behind homografts and allografts (Billingham and Medawar 1951). In 1954, the first successful renal transplant was performed between twin brothers by Joseph Murray, J Hartwell Harrison, and John P Merrill at Peter Bent Brigham in Boston (Merrill et al. 1995). The recipient survived 8 years after the transplant. Renal transplantation continued to be performed between identical twins, and the first successful renal transplant between twins in the United Kingdom was performed by Sir Michael Woodruff in Edinburgh in 1960 (Woodruff et al. 1961). It was not until immunosuppression was developed that cadaveric transplants could be performed. From 1959 to 1962, seven patients successfully received renal transplants, after undergoing sublethal irradiation (Murray et al. 1960). Further characterization of the nature of the immune system enabled development of a safe and effective immunosuppressant agent. Joseph Murray went on to attempt renal transplantation using azathioprine as an immunosuppressant which was successful in one patient. His success encouraged Thomas Starzl to apply the use of azathioprine in his dog models of transplantation (Starzl 2012). He attempted five human liver transplants in 1963, pretreating his recipients with azathioprine and augmenting the immunosuppression with prednisolone posttransplant. The maximum survival was 23 days and all the patients died from sepsis. A voluntary moratorium on liver transplants ensued until 1967. In the intervening 4 years, further research attempted to address the problems with immunosuppression and coagulopathy. Antilymphocyte globulin isolated from horse serum was added to the immunosuppression regimen, and Starzl performed the first successful liver transplant in July 1967. The first heart transplant was also performed in 1967 by Dr. Christiaan Barnard in South Africa, the patient surviving for 18 days (Cooper 2001). The advent of cyclosporin in 1970, initially developed in renal transplantation, was then successfully applied to liver grafts in combination with prednisolone. It proved to be the great leap forward that made transplantation a viable treatment (Calne and Williams 1968). The United Kingdom heart transplant program was initiated in 1979, followed by the

333

performance of the first heart-lung transplant in 1983. In 1986, the first successful single lung transplant was performed. In 1987 the first “domino” transplant was performed of a heart from a heart-lung transplant recipient. This was also the year that in Cambridge, Sir Roy Calne and Prof John Wallwork carried out the world’s first combined liver, heart, and lung transplant, with the recipient acting as a domino heart donor (Wallwork et al. 1987). She survived for 10 years following her transplant. Pancreatic transplantation, combined with renal transplants in 75% of cases, became an established treatment in 2007 for sufferers of diabetic nephropathy, and 1-year pancreatic graft survivals of 80% were being achieved. Donor islet cell infusions have given 60% of patients 1 year following transplantation insulin independence in data published in 2010 by the Collaborative Islet Transplant Registry from data from 32 transplant centers worldwide (Barton et al. 2012). Further developments followed with optimizing recipient assessment and organ donation. National programs and legislation have led to safeguard for recipients and donors. Development of organ perfusion fluids and organ perfusion systems led to longer viable graft ischemia times. Living donor programs were developed to address the shortage in cadaveric donors. Research into immunology has led to better understanding of successful transplantation, graft tolerance, chimerism, and the immunological complications, e.g., graft versus host disease.

Immunology of Transplantation As noted above, the greatest barrier to solid-organ transplantation was not a surgical technique but the body’s ability to recognize nonself organs and to reject them. Understanding of these mechanisms is key to the further advancement of transplantation. An individual’s cells are identified as “self” by the presence of unique cell surface glycoproteins which are coded for by the major histocompatibility complex (MHC) genes. The MHC is located on the short arm of chromosome 6 and is responsible for mediating most rejection reactions to

334

transplants. A person will inherit a haplotype from each parent making the probability of a sibling who is MHC matched 25%. The products of the MHC are called human leukocyte antigens (HLA). Class I antigens are found on all nucleated cells. Class II antigens are found in antigen-presenting cells including B cells and activated T cells. It is T lymphocyte cell reactions that are responsible for the mediation of transplant rejection. Peripheral blood T cells express either CD4 or CD8 cell surface proteins; CD4 binds to HLA class II complexes and initiates the pathway for antigen recognition and transduces the antigenic signal ultimately leading to T cell activation. T cell activation leads to proliferation and subsequently contraction of the activated T cell population, which eventually segues to the formation of memory T cells to perpetuate the recognition of the antigen stimulus. CD8 binds to HLA class I complexes and acts as cytotoxic T cells. Both CD4 and CD8 T cells secrete the cytokines interleukin 2 and gamma interferon, as well as other promoters of cytotoxicity. Interleukin 2 stimulates further proliferation of T cells. IL2 and gamma interferon also stimulate B cells to produce antibodies directed at the donor antigens (Barton et al. 2012; Suthanthiran 2007).

Role of Costimulation T cell activation takes place following three separate forms of stimulus. The first is the binding of T cell receptors to HLA complexes on antigenpresenting cells (APCs) which initiates a signal through the CD3 complex. The second comes from a number of different interactions with cell surface antigens which is called “costimulation” (Bluestone 1996). The receptors expressed vary depending on whether the T cell is naïve or activated. Subsequent stimulatory pathways can either promote T cell activation or inhibit it, and therefore it becomes a powerful mechanism in fine-tuning the immune system reaction to antigens. The third stimulus is provided by the production of cytokines by APCs which then act on the T cell.

E. G. P. Ong and D. A. Kelly

In the absence of costimulation, T cells no longer respond to the same antigen stimulus, and therefore it is a potential target of antirejection therapy (Kinnear et al. 2013). Blockade of costimulation also has the advantage of specifically targeting T cells undergoing activation. The best characterized costimulatory receptor/ligand pair is the CD28:CD80 pair, which when activated leads to stabilization of IL1 mRNA and production of antiapoptotic mediators and promotes T cell proliferation (Weaver et al. 2008). The immunosuppressant belatacept (human CTLA4Ig fusion protein) was created as an analogue for CD28 (Larsen et al. 2005). Binding of belatacept to CD80 thus prevents cell proliferation and cytokine production and promotes apoptosis. Clinical trials have highlighted acute rejection episodes occurring with a lack of suppression of memory T cells. It is thought to be a result of reduced reliance of memory T cells on costimulation, and further work is needed to target this subpopulation of T cells.

Role of Innate Immunity in Rejection Although cellular immunity mediated by T cells has been implicated in the majority of major rejection reactions, innate immunity is increasingly recognized as playing a role in the initiation of cellular immunity and in perhaps preventing tolerance of the graft (LaRosa et al. 2007). As the name implies, it is a composite of cellular and humoral mechanisms, which is not an antigen target specific, but is designed to provide a rapid and immediate response to pathogens. The complement cascade and Toll-like receptor systems are important components of innate immunity (Liu et al. 2006; Spahn et al. 2014). The protein and glycoprotein components of the complement cascade are produced by hepatocytes, monocytes, macrophages, and epithelial cells of the hollow viscera. The complement cascade is initiated via three pathways: the classical pathway, the alternative pathway, and the lectin pathway (Fig. 2). They converge in the activation of C3 to form C3a and C3b. C3a binds to receptors on leukocytes and parenchymal cells and

24

Principles of Transplantation

335

Fig. 2 The complement cascade

promotes an inflammatory reaction while also stimulating T cell activation. C3b and its metabolites also bind to cell surface receptors to promote inflammation and stimulate B cells. C3b also activates C5 to C5a and C5b forms. C5a behaves in the same way as C3a, and C5b produces perforating enzymes that damage cellular integrity of the stimulating target cell and promote cell death. Complement activation has a strong role in ischemia reperfusion injury (Farrar and Sacks 2014). It is well recognized that the cold ischemia at organ procurement initiates complement activation, and this reaction can be perpetuated by the presence of organisms. This has been demonstrated by using animal models with impaired complement mechanisms. Absence or impairment of the complement cascade in these animals has a protective effect against ischemia reperfusion injury of the transplanted lung, liver, heart, intestinal, or renal tissue mediated largely by

direct and indirect injury by activated C5 components. Graft-derived C3 seems to be essential in this process. The complement cascade is also strongly activated in cellular-mediated immunity. C3a and C5a have also been shown to enhance APC activity by increasing the response to alloantigens. In addition, both complement proteins increase T cell activation by a costimulatory effect and increase their reactivity to APC interaction. Binding of complement to graft parenchymal cells also seems to increase their binding to presensitized T cells thereby increasing potential for graft cell damage. Toll-like receptors (TLRs) are transmembrane proteins that were characterized in 1998. They are potent recognizers of specific patterns of protein that are associated with pathological cellular patterns (pathogen-associated molecular patterns or PAMPs) (Tang et al. 2012), initiating a

336

signalling pathway that affects pro-inflammatory cytokine release and promotes T cell activation by increasing the expression of costimulation ligands. TLRs are also expressed on parenchymal cells and are capable of binding damage-associated molecular ligands (DAMPs). DAMPs include high mobility group box 1 (HMGB1), heat shock proteins, uric acid, and DNA. In themselves, they are not cytokines but are passively released in cell necrosis, and binding with TLRs leads to inflammation. Ischemia reperfusion injury stimulates upregulation of TLRs; the pattern of this upregulation varies between organs. TLR2 and TLR4 receptors are upregulated in renal grafts (Rusai et al. 2010), whereas TLR4 receptors alone are upregulated in hepatic grafts (Testro et al. 2011). Donor cells express high levels of TLRs which, when bound, amplify expression of costimulation ligands thereby interacting with cellular immune mechanisms. In addition to this, the interaction of TLRs with DAMPs in rejection upregulates inflammatory processes (Gao et al. 2010). It has also been observed in pancreatic islet transplantation that the production of regulatory T cells is downregulated in the presence of increased DAMP production and TLR4 upregulation (Zhang et al. 2010; Lal et al. 2011).

Role of Natural Killer Cells Natural killer cells (NKCs) have an innate ability to distinguish self from nonself and initiate cytotoxic effects. Cell surface HLA class 1 would normally inhibit the cytolytic action of NKCs by binding with NKC receptors. Therefore, in the absence of these “self”-HLA complexes, NKCs are activated. As well as recognizing the absence of “self”-antigens, they also recognize pathogenic antigens which then initiate the release of perforins, granzyme, FAS ligand, and TNF-related apoptosis-inducing ligand which injure the offending cell. They are found to proliferate in rejection stimulated by the presence of IL2 and have been found in activated form in both acute and chronic rejections (Kroemer et al. 2008).

E. G. P. Ong and D. A. Kelly

Immunosuppression Agents The above recognition pathways offer several targets to block cellular rejection (Table 1). By minimizing the difference in HLA antigens between donors and recipient by HLA matching, the pathway may not be initiated. The production of monokines by antigen-presenting cells can be blocked using steroids. Steroids can also block the production of T cell cytokines. Drugs can also be used to suppress T cells (e.g., antilymphocyte globulin), block antigen binding (e.g., OKT3 monoclonal antibodies), block cytokine production (e.g., cyclosporin A, calcineurin inhibitors), and block clonal expansion (azathioprine, sirolimus, mycophenolate mofetil).

Graft Tolerance The quest to understand the mechanisms of graft tolerance in transplantation is ongoing. Tolerance can be defined as when the host immune system completely accepts the graft without the ongoing need of medication. The question is how this is achieved? Three possible mechanisms have been proposed (Alpdogan and van den Brink 2012; Green and Hind 2016). The first is clonal deletion. In this process, T cells which react against the graft are selectively destroyed by the thymus. This is also the mechanism by which neonates are thought to eliminate immature selfrecognizing T cells. The second mechanism is that of clonal anergy, where prolonged exposure to a high concentration of antigen in the absence of lymphokines causes the immune system to become hyporesponsive to that antigen. As previously mentioned, full activation of T cells occurs with synergic stimulation of T cell receptor/ CD3 binding and the APC-mediated antigen binding. If stimulation only occurs through TCR/ CD3 binding, then this may cause the T cell to become functionally dormant. Similar monostimulation of B cells can also lead to clonal anergy. Finally, inhibition by regulatory T cells, possibly CD4 CD25 T cells, can suppress the reaction of cytopathic and antigen-specific cells.

24

Principles of Transplantation

337

Table 1 Immunosuppressant agents and their actions Immunosuppressant agent Azathioprine

Cyclosporin

Site of action Purine analogue, prodrug for mercaptopurine. Active metabolite methylthioinosine monophosphate blocks DNA synthesis. Inhibits cell proliferation of rapid turnover cells, e. g., T cells and B cells. Also blocks CD28 costimulation required for T cell activation Binds lymphocyte cytophilin, inhibits IL2 transcription, inhibits lymphokine production and interleukin release

Route of excretion Renal

Biliary

Tacrolimus

Binds with immunophilin FKBP12 and complex inhibits calcineurin. IL2 transcription and T lymphocyte transduction inhibited. Lower rate of acute rejection than cyclosporin

Fecal

Sirolimus (rapamycin)

Binds to FKBP12 and complex binds mTOR complex 1. Inhibits T and B cell activation

Fecal

Mycophenolate mofetil

Prodrug of mycophenolic acid, inhibitor of inosine monophosphate dehydrogenase (IMPDH) in purine biosynthesis. Blocks T cell and B cell proliferation. Inhibits TNF and IL1 production Promotes production of antiinflammatory interleukins (IL1 receptor II, IL10), inhibits proinflammatory interleukins (IL1, IL6, IL8, IL2, tumor necrosis factor, granulocyte-macrophage colonystimulating factor), prostaglandin production, histamine and bradykinin release, and dampen monocyte activity Horse- or rabbit-derived T cell antibodies against CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44 and CD45, HLA-DR, HLA class 1 heavy chains, β2 microglobulin. Promotes T cell lysis, inhibits T cell proliferation Targets CD3 T cell marker. Blocks T cell activation by promoting internalization of CD3 receptors

Renal

Monoclonal antibody to CD52 leading to cell lysis of mature lymphocytes Monoclonal antibody to CD25 of IL2 receptor α chain of activated T cells. Inhibits IL2-mediated lymphocyte activation

Unknown

Prednisolone

Antithymocyte globulin

OKT3 monoclonal antibodies

Alemtuzumab Basiliximab

Urine

Side effects Nausea, vomiting, bone marrow suppression, acute pancreatitis, hypersensitivity reactions including skin rash

Renal impairment, gingival hyperplasia, convulsions, hirsutism, hypertension, tingling of the lips, pruritis, hyperkalemia Cardiopathy, hypertension, blurred vision, nephrotoxic, hyperkalemia, hypomagnesemia, hyperglycemia, diabetes mellitus, itching, posterior reversible encephalopathy syndrome (PRES), seizures, tremors Interstitial pneumonitis, impaired glucose tolerance, impaired wound healing. Lower nephrotoxicity than calcineurin inhibitors Hypercholesterolemia, hyperglycemia, hypomagnesemia, hypocalcemia, bone marrow suppression, enterocolitis, pulmonary fibrosis, progressive multifocal leukoencephalopathy Impaired wound healing, growth suppression, osteoporosis, cataracts, glucose intolerance, hypertension, emotional disturbance, peptic ulcers, hyperlipemia, obesity

Renal

Cytokine release syndrome, PTLD

Unknown

Viral infection, pulmonary edema. Patient may develop antimurine antibodies that can neutralize effects of OKT3 over time Hypotension, rigors, fever, tachypnea, ARDS, cardiac arrhythmias Hypersensitivity, gastrointestinal disorders, hyperkalemia, hypokalemia, hyperglycemia, hypercholesterolemia, (continued)

Unknown

338

E. G. P. Ong and D. A. Kelly

Table 1 (continued) Immunosuppressant agent

Daclizumab

Route of excretion

Site of action

Monoclonal antibody to CD25, similar action to basiliximab

Studies involving pancreatic transplants have posed the question of why donor passenger lymphocytes are better tolerogens than parenchymal cells. It appears that the answer lies in the initiation of systemic donor chimerism (Ishikawa et al. 2010). The donor lymphocytes may have the capacity to increase proliferation of donor antigen-specific regulatory T cells to dampen the immune response to donor cells. However, the presence of donor chimerism in itself is not sufficient to initiate full graft tolerance. Indeed, contradictory findings exist when intestinal graft immunogenicity has been examined, and anecdotal evidence suggests rejection occurs despite the existence of donor chimerism.

Unknown

Side effects hypophosphatemia, hyperuricemia, dyspnea, anemia, leukopenia Tremor, headache, insomnia, hypertension, dyspnea, gastrointestinal disorders, hypersensitivity reactions

not known if all HLA types produce humeral antibodies in sufficient amounts to be assayed. Likewise, it is known that some antibodies are absorbed by organs (demonstrated strongly by renal grafts) thereby reducing the concentration that can be assayed by serum sampling. Posttransplant monitoring of donor-specific antibody clearance may aid identifying those more prone to rejection (Everly 2011). High levels of donor T cell chimerism correlate with improved graft survival and imply T cell anergy to donor antigens. Assays involve PCR amplification of short tandem repeats of donor and recipient genotypes.

Organ Donation Immune Surveillance Immune surveillance of the transplanted patient is being developed as a tool to monitor for early indicators of rejection, to measure response to immunosuppressant agents, and to assess the extent of graft suitability for the recipient. C4d complement is found fixed to the capillary endothelium and is a relatively stable marker of the classical complement pathway. Its presence is demonstrated by immunostaining and diagnostic of antibody-mediated rejection. Serum antibody assays on pretransplant recipient blood of C4d may offer a predictor of rejection (Smith et al. 2007). High levels of antibodies, particularly complement-fixing antibodies, to a potential donor have been shown to correlate with incidence of hyperacute rejection (Dheda et al. 2013). However, the interpretation of low levels or absence of donorspecific antibodies can be difficult to interpret. It is

The act of organ donation is an act of altruism unparalleled. Donors fall into two main categories: living and cadaveric. The proportion of living and cadaveric donors in each country can vary widely depending on local practice.

Cadaveric Donation Cadaveric donors still make up the majority of donors in the United Kingdom. Potential donors are identified and referred for consideration if they are being considered for brain stem testing to establish death, if there is an intention to withdraw treatment or if the patient has suffered a catastrophic brain injury resulting in a Glasgow Coma Score of 3–4 accompanied by the absence of at least one cranial nerve reflex that cannot be attributed to the effects of sedation. Donor information including age, gender, weight,

24

Principles of Transplantation

339

Table 2 Guidelines for donor organ acceptance criteria Donor organ Kidney Liver Heart

Acceptable donor age >1 year old >2 months old 1 week to 65 years old

Heart valves Lungs

17 years old

Tendon Meniscus Cornea

17–55 years old 17–50 years old >3 years old

cause of death, past medical history, viral serology, clinical observations, medication, and social history are all considered prior to acceptance of the donor. Current United Kingdom guidelines state absolute contraindications to donation include being more than 85 years old, the presence of any metastasized tumor, melanoma (unless completely excised grade 1 tumor), choriocarcinoma, active hematological malignancy, and neurodegenerative diseases associated with infective causes, e.g., Creutzfeldt-Jakob disease, active untreated tuberculosis, and HIV disease. Note that donors with HIV infection but not active disease can be used for recipients with HIV infection (NHS Blood and Transplant 2013a). There are different donor acceptance criteria for different grafts which vary between transplanting centers. Table 2 illustrates local guidelines used in our center.

Establishing Death Death can be established by two methods. The first is by observing the cessation of all cardiorespiratory activity (cardiac death) following the

Acceptance criteria No history of chronic renal disease No history of chronic liver disease No history or evidence of cardiac disease Stable and minimal inotrope support Normal ECG Normal arterial blood gases No valve disease No evidence of pulmonary dysfunction or infection Good arterial blood gases Normal appearance on chest X-rays No history of diabetes 34  C. • Sedative agents (midazolam, morphine, etc.) have had adequate time to clear (if uncertainty exists, then levels should be measured). • Mean arterial pressure >60 mmHg. • pH maintained between 7.35 and 7.45. • Pa02 >10 KPa. • Potassium levels >2 mmol/L. • Serum sodium 115–160 mmol/L. • Magnesium or phosphate levels 0.5– 3.0 mmol/L. • Glucose levels >3.0 mmol/L. • No continuing neuromuscular blockade (nerve stimulator can be used to test this). The tests are performed twice with an intervening time interval and documented in the patients notes by both clinicians performing the tests. The nature of testing in the United Kingdom precludes

E. G. P. Ong and D. A. Kelly

declaration of brain stem death in children less than 2 months of age.

Organ Procurement It is important to note that the type of cadaveric donor impacts on potential ischemic injury of the graft. Donors after brain stem death (DBD donors) were previously described as heart-beating donors. Ventilation is supported, and as circulation is preserved, dissection of the organs can be performed with normal organ perfusion until the organs are ready to be explanted, thereby minimizing the period of initial warm ischemia before the organs are placed in hypothermic preservation fluid. If donation is following cardiac death, there is a period of warm ischemia prior to asystole and in the interval from asystole to organ procurement. Organ procurement from these donors is therefore performed by rapidly perfusing the organs with cold preservation fluid and then dissecting the organs out in the cold phase. Different organs have different degrees of resistance to damage by this ischemic period, and if the time period is too long, the organs may not be useable. After procurement, there is also a shorter window of ischemic time to reperfusion of the graft in the recipient before organ function declines. In this respect, brain stem dead donors can provide better functioning grafts. Figure 3 shows the sequence of events in procurement for DBD and DCD donors. Organ Preservation Organs have differing levels of sensitivity to ischemic injury. The following are the estimated maximum cold ischemia times for organ viability following DBD donation. DCD times can be considerably shorter. Heart Lungs Intestinal grafts Liver Pancreas Kidneys

4) • No evidence of irreversible brain damage

Inborn Errors of Metabolism Liver transplantation is indicated for specific inborn errors of metabolism (Francavilla et al.

K. Sharif and D. A. Kelly

2000; Burdelski et al. 1991) which are secondary to hepatic enzyme deficiencies which lead to severe extrahepatic disease such as kernicterus in Crigler–Najjar type I and systemic oxalosis in primary oxaluria. Selection and timing of transplantation depends on the quality of life on medical management and the potential mortality and morbidity of the primary disease compared with the risks, complications, and outcome following liver transplantation (Kelly 1998).

Crigler–Najjar Type I Crigler–Najjar type 1 is an autosomal recessive condition in which there is a deficiency of the enzyme bilirubin uridinediphosphateglucuronosyltransferase (UDPGT). Most children with this condition require transplantation in early childhood. The most appropriate operation is auxiliary liver transplantation (Rela et al. 1999) or hepatocyte transplantation (Lysy et al. 2008). Primary Hyperoxaluria Primary hyperoxaluria is a defect of glyoxylate metabolism characterized by the overproduction of oxalate, which is deposited as calcium oxalate in various organs (Rezvani and Auerbach 2012). Presentation is in early childhood with renal failure. Ideally, liver replacement in this condition should be prior to the development of severe irreversible renal failure. If this is not possible, liver and kidney replacement may be required simultaneously (Strobele et al. 2013). Organic Acidemias Children with propionic acidemia or methylmalonic acidemia are at lifelong risk of recurrent metabolic acidosis and long-term brain damage. Liver replacement is considered palliative treatment for these conditions as the enzyme deficiency affects all body tissue. It should be considered early for children who have a particularly severe phenotype or family history. Very careful preoperative management, including preoperative dialysis and perioperative hemofiltration to control acidosis, is essential to ensure good operative control (Kelly 1998).

26

Pediatric Liver Transplantation

Liver Tumors A liver tumor where complete surgical resection is not possible has also been accepted as an indication for liver transplantation. Of the list of pediatric liver tumors, hepatoblastoma is the most commonly accepted for transplantation provided there is no extrahepatic disease (Stringer 2007; Otte et al. 2004; Molmenti et al. 2002; Molmenti et al. 2001). Of the other tumors, liver transplantation has been performed with acceptable outcome in children with massive hemangioma, hepatocellular carcinoma, hepatic sarcoma, and epithelioid hemangioendothelioma (Stringer 2007).

Contraindications There are few conditions where the liver transplantation is not a suitable treatment option (McDiarmid et al. 1998; Shneider 2002) (Table 2). These include severe extrahepatic disease which is not reversible following liver transplantation, e.g., severe cardiopulmonary disease for which corrective surgery is not possible or severe structural brain damage (1). Until recently, hypoxemia (hepato-pulmonary syndrome) was considered as a relative contraindication for liver transplantation. However it has been shown that liver transplantation can be successfully achieved in severely hypoxemic children and that postoperative correction of the right to left shunt is then obtained (Van Obbergh et al. 1998). HIV/AIDS and other major cardiorespiratory, neurological, or renal disease, which would be incompatible with quality of life and long-term survival, are also considered as contraindications.

Table 2 Contraindications 1. Absolute: Uncontrolled systemic infection Malignancy outside the liver Disease in other organs incompatible with quality survival 2. Relative: Cyanotic pulmonary arteriovenous shunting with pulmonary hypertension Psychosocial factors Inadequate vascular supply

369

Transplantation Process The whole process of liver transplantation can be divided into the following components.

Evaluation Liver transplantation is curative treatment for endstage liver stage with lifelong risk of morbidity and mortality. It is therefore important that a thorough evaluation (pretransplant assessment) of the child and family should consider suitability for this treatment. The established transplant centers have developed protocols for this evaluation with striking similarities. The Liver transplant assessment includes (a) a detailed disease assessment (b) time for detailed discussion of treatment options, to prepare for the transplant procedure and (c) the opportunity to assess the family's commitment to sustain long-term compliance after transplantation (d) to put in place supportive strategies to ensure adherence after transplant. However detailed assessment is not possible in children presenting with fulminant acute liver failure or those with acute deterioration of chronic liver disease. The essential components of assessment include:

Child Assessment In the majority of children with chronic liver failure, the diagnosis is already confirmed. A small proportion of children, however, present with acute or acute-on-chronic liver disease, and these children require initial confirmation of the diagnosis, intensive medical/radiological investigation, and nutritional assessment and rehabilitation to treat the complications of the liver disease, portal hypertension, and nutritional deprivation. Disease assessment also includes identification of contraindications. Family Assessment Transplant candidacy inevitably results in emotional stress for parents while waiting for the appropriate donor. Family life may become disrupted especially for those who live afar. Family compliance is more difficult to predict in children with acute hepatic failure, as time from presentation to decision to transplant is much shorter.

370

It is important to offer and assess family members for living related transplant donation. This requires extensive physical and psychological assessment evaluation of the potential donors. The pretransplant assessment protocol from Birmingham Liver Unit is summarized in Table 3.

Table 3 Pretransplant assessment Anthropometry to assess nutrition: Height and weight Head circumference – under 2 years of age (OFC) Mid-arm circumference (MAC) and triceps skinfold (TSF) Routine bloods: Blood group (two samples taken at two different times) FBC PT, PTT, fibrinogen AST, ALT, αGT, Alk Phos, total protein, albumin Na, K, urea, creatinine, calcium, potassium, magnesium phosphate N.B. additional bloods may be required if metabolic liver disease is suspected Serology: EBV (IgG) CMV (IgG) Measles Varicella Hepatitis A (IgG) Hepatitis B (hepatitis B sAg + hep B core antibody – hepatitis B s antibody if previously vaccinated) Hepatitis C antibody HIV 1 and 2 Microbiology: MRSA VRE–Pseudomonas–B. cepacia screen if chronic patient or CF Blood C&S if indwelling catheter Urine: MC + S Protein/creatinine ratio Tubular reabsorption of phosphate Assessment of severity of liver disease: Upper gastrointestinal endoscopy (if required) Liver biopsy (if indicated; otherwise obtain previous biopsy result) Pediatric hepatology scores (PHS and PELD) Radiology: Chest X-ray (continued)

K. Sharif and D. A. Kelly Table 3 (continued) Bone age for rickets or metabolic bone disease (if required) Abdominal ultrasound and Doppler study to evaluate diameter of portal vein and direction of flow, size of spleen, ascites, vascular anatomy, resistivity index if biliary atresia, or reverse flow in portal vein CT/MRI and/or angiography if vascular anatomy uncertain Cardiology: Blood pressure ECG Echo and cardiology opinion if needed Neurology: EEG (in selected cases) Developmental assessment Renal function: Chromium EDTA Calculated GFR (Schwartz index) Urine tubular reabsorption of phosphate (TRP) Urine protein/creatinine ratio Respiratory: Oxygen saturations (resting and on exercise) For children with cystic fibrosis: Pulmonary function tests Cough swab sputum for MC+S Lung perfusion study only if cyanosed Immunizations: Arrange pretransplant immunization as needed especially in children reaching 6 months of age Suspend from list for 2 weeks if live vaccine given Ensure live vaccines are given if time permits, i.e., VZ and MMR (if over 6 months), plus advice on completing other vaccinations such as Prevenar ®, Pneumovax II ®, hepatitis A and B, influenza

Listing for Transplantation In the majority of liver transplant centers, children are accepted onto the transplant waiting list following multidisciplinary discussion. Most countries have national transplant lists, but in other countries there are regional or center-specific lists

Surgical Aspects of Liver Transplantation The surgical aspects of liver transplantation can be summarized as follows:

26

Pediatric Liver Transplantation

Donor Aspect The single most important factor which limits the availability of the transplantation is availability of liver graft for transplantation. In the USA, 1 in 10 infants and 1 in 20 older children die on the liver transplant waiting list (Pham and Miloh 2018). So far these grafts are obtained from healthy human donors. The success of liver transplantation led to increase in demand and shortage of suitable donors resulting in exploration of various suitable donor options. i) Types of donor for liver transplantation These donors are broadly divided into two main groups: a) Cadaveric donors. There are two types of cadaveric donors: i. Brain-dead donors (DBD) or heartbeating donors ii. Donors with cardiac death (DCD) or non-heart-beating donors b) Living donors. The various types of living donors include: iii. Living related donors (family members) iv. Living unrelated donors 1. Altruistic donors (nonfamily members) 2. Domino

DCD or Non-heart-Beating Donation The demand for liver transplantation (OLT) has led to an increasing discrepancy between the number of potential candidates and organ availability. Following the successful use of kidney grafts from non-heart-beating donors (NHBDs) for transplantation (Abt et al. 2006), NHBD has the potential to become an important new source of solid organs for transplantation because of the current shortage of organs for transplantation and improvements in surgical technique, preservation solutions, and immunosuppression. To date, because of concerns over graft function, these livers have been transplanted with short

371

cold ischemic times as whole grafts. With increasing clinical experience, it is possible to safely identify non-heart-beating donors (NHBDs) that can provide livers with good early graft function and which are suitable for liver reduction or splitting for pediatric transplantation. Living related donation: This technique was developed partly due to donor shortages but also to offer this treatment in countries with cultural or religious reticence to accept brain death in a ventilated heart-beating donor (Settmacher et al. 2004; Heffron 1993; Bahador et al. 2009). Donation of the left lateral segment, first successfully performed by Strong, has become widely accepted as a method of acquiring a liver graft. The potential advantages of the living related liver transplantation (LRLT) include (1) planned operation with minimal cold ischemic time resulting in better grafts; (2) better histocompatibility as a result of tissue type matching based on ABO blood group and human leukocyte antigen (HLA) serologic and HLA–DNA analyses; and (3) superior long-term outcome compared to a cadaveric liver grafts (Ozawa et al. 1992). A recent study showed that the recipients of maternal donor liver transplants have lower rates of rejection and improved allograft survival (Perito et al. 2019). The clinical application of orthotopic liver transplantation (OLT) using living donors (LRT) was slow to be accepted because of ethical considerations (Broelsch et al. 1991) and perceived technical difficulties. There are a number of challenges in the surgical procedures of LRLT related to donor morbidity and potential mortality. Current postoperative morbidity is around 10% (wound sepsis, hernia, bile leak, and adhesive bowel obstruction) with a reported mortality of around 0.2%. It is essential that the donor should undergo thorough clinical and psychological screening without coercion and be given the opportunity to withdraw from the procedure at any time before the transplant (Krenn et al. 2004). It is important to recognize the limitation of living related liver transplantation as the major source of organs for children (Baker et al. 1999). Parents usually approach living related liver transplantation with enthusiasm but should be advised of the high

372

chance of unsuitability, including differences in size match, the finding of significant pathology (Baker et al. 1999), and complications, including death (Trotter et al. 2006). Living unrelated donors (altruistic): This is an acceptable alternative, similar to blood donation, i.e., saving life without any financial/personal gain. The protocol and procedure is the same as living related liver transplantation. Domino liver grafts: Some metabolic conditions are corrected by liver transplantation however; the livers removed from the recipient are structurally normal apart from missing an enzyme. When these patients are transplanted, their livers may be offered to another recipient in whom the chances of receiving a liver graft are minimal. ii) Donor suitability Generally, stable cadaver donors from patients with a short intensive care unit stay (less than 3 days), little requirement for inotropic support, and normal or near normal liver function are preferred for pediatric transplantation, with an expected 5) Daily Chest X-ray if indicated FBC and clotting (PT, PTT) Tacrolimus level Urea, creatinine, calcium, phosphate, magnesium, total proteins, albumin, CRP Full LFTs (bilirubin total and unconjugated, ALP, ALT, AST, GGT) Culture: wound swabs Drain fluid ETT aspirates if indicated (i) Antimicrobials 1. Tazocin 90 mg/kg/dose tds for 48 h or till drain is removed If sensitive to penicillin, ciprofloxacin 5 mg/kg/dose BD 2. Metronidazole 8 mg/kg/dose (maximum 500 mg) tds over 1 hour (can give over 30 minutes) for 48 hours; then review 3. Cotrimoxazole: up to 5 years 240 mgs od orally over 5 years 480 mgs od orally (ii) Antivirals Until the donor status for EBV and CMV is known, all transplanted children are to be started on antiviral prophylaxis. Aciclovir IV 500 mg/m2 If the donor is EBV-positive or CMV-positive or the status is unknown, then aciclovir should be continued for 3 months post-transplant If donor is EBV-positive: All to continue on aciclovir irrespective of recipient EBV/CMV status (iii) Antifungals are recommended for 6 months Nystatin 100,000 units (= 1 ml) orally qds if > 10 kg 50,000 units (= 0.5 ml) orally qds if < 10 kg Ambisome 3 mg/kg for 7–10 days Patients already on fluconazole should be changed to amphotericin when a liver becomes available (iv) Gastric acidity prophylaxis Ranitidine 3 mg/kg/dose (I/V) tds; if pH still 30 ng/ml or 75,000) 3 mg/kg/day OD orally/NGT (maximum dose 75 mg) b) Dipyridamole (if platelets > 50,000) If patient weighs 10 kg 50 mg tds orally (vii) Heparin infusion For vascular anastomosis at risk (complex vascular reconstruction or small-diameter arteries or portal vein) (viii) Analgesia and sedation Analgesia is achieved with morphine in the routine transplant patient with reasonable graft function and is titrated against pain level

ganciclovir 5 mg/kg/dose 12 hourly. Leucocyte-filtered blood products are used to reduce CMV load. This considerably reduces the incidence of both cytomegalovirus disease and post-transplantation lymphoproliferative disorder. iv) Anticoagulation Most of the pediatric programs use anticoagulation protocols with a combination of antiplatelet agents (aspirin and dipyridamole) and low-dose heparin. Warfarin is prescribed in cases where vascular anastomosis is at risk of thrombosis.

Post-transplant Complication Most complications which occur in the early posttransplant period (first 2 weeks) are related to the surgical procedure. The late complications (after 2 weeks) are related to drugs, infection, or rejection. Common post-transplant complications are summarized in Table 4.

Surgical Complications Significant development and refinements in the surgical techniques have improved the outcome of liver transplantation in pediatric population. Some of the surgical complications may be reduced to an absolute minimum with adherence to meticulous technique. These complications may present early and late as summarized in Table 4. Most common surgical complications present in the first few days of the surgery and can be summarized as follows: a) Vascular complications may result either from hepatic artery or portal vein thrombosis and can have devastating consequences on graft function. i) Hepatic artery thrombosis (HAT) represents a significant cause of graft loss and mortality after pediatric orthotropic liver transplantation (OLT) (Tan et al. 1988). The reported incidence of this complication varies between 1 and 20%

26

Pediatric Liver Transplantation

(Ackermann et al. 2012) with median rate of 7.8% (Stringer et al. 2001). The incidence is less with the use of reduced-size liver grafts (Chardot et al. 1995) and microsurgical techniques (Panossian et al. 2009) for anastomosis especially in living donor transplants. Incidence is higher in split and living donor grafts considered to be due to small arterial size (Stevens et al. 1992). Microvascular hepatic artery anastomosis in pediatric patients undergoing living donor liver transplantation is reported to be associated with a low hepatic artery complication rate and excellent long-term liver graft function (Zuo et al. 2018). Most centers recommend routine Doppler ultrasound in the early postoperative period ranging from 3 to 7 days to confirm the patency of these vessels. In Birmingham transplant unit, Doppler ultrasound is performed for the first 5 days or when it is clinically indicated. The consequences of vascular thrombosis are graft necrosis, intrahepatic abscess, biliary necrosis, and bile leakage. A massive rise in enzyme activity, particularly in the first few days after transplant, may be the first sign. Immediate intervention with thrombectomy and reanastomosis may be successful if the diagnosis and treatment is carried out as soon as the complication is diagnosed (Ackermann et al. 2012). If thrombectomy fails, urgent re-transplant is required. Late thrombosis may be asymptomatic and has varied presentation. Although technical factors usually account for most cases, it is advisable to pay meticulous attention to fluid balance and to maintain the hematocrit at around 30 to improve microvascular flow. Most centers use some form of anticoagulation including aspirin and dipyridamole as prophylaxis, for 3 months (Stringer et al. 2001). ii) Portal vein thrombosis usually presents with a degree of liver dysfunction with prolonged clotting. If diagnosed in the early post-transplant, immediate thrombectomy may be successful. Significant

379

risk factors for portal vein thrombosis are young age and weight at the time of LT, hypoplastic portal vein, and emergency LT. Overall risk of portal vein thrombosis (PVT) is 2.2% in teams using aspirin with or without dipyridamole compared with 7.8% when no anti-aggregative agents are given (Chardot et al. 1997). When graft thrombosis is established, a meso-portal (Rex) shunt, with a vein graft taken from the internal jugular vein of the patient or donor veins from vascular bank (if available) and interposed between the superior mesenteric vein and the left branch of the portal vein, may be curative (Ville de Goyet et al. 1996). iii) Hepatic venous outflow obstruction is a rare vascular complication particularly since the triangular technique of caval anastomosis has been practiced. It occurs if there is redundancy of the hepatic vein (when the graft hepatic vein is longer) or twisting of anastomosis. It may be suspected if there is persistent ascites in the early post-transplant period and confirmed either by angiography or by liver histology findings of congestion and red cell extravasations around central veins. In some cases, dilatation and stent insertion are required to overcome this problem. During reconstruction of partial graft, the correction of the redundancy is made by pulling the graft caudally and to the left or right side of the abdominal cavity as determined by Doppler ultrasonography (Lo et al. 2005). iv) Inferior vena cava thrombosis is now very rare as most of pediatric transplants are with split or live related grafts. Thrombosis in the IVC may develop either in the immediate postoperative period presenting with ascites and lower body edema or later on due to regeneration of the graft and twisting of the caval anastomosis. Thrombolytic therapy may be successful in late thromboses but should be avoided in early thromboses as uncontrollable bleeding may occur from raw

380

surfaces particularly if a reduced/split liver was transplanted. b) Biliary complications continue to be a challenge with the reported overall incidence of between 10 and 20%. Common complications include bile leak, anastomotic strictures, and non-anastomostic strictures of the donor bile duct. Incidence is particularly high in living related left lateral segment grafts (Heffron et al. 2003b). Most biliary complications (72%) occur in the first 2 weeks following transplantation (Griffith and John 1996). Ultrasound and MRI are the principal imaging modalities used for detection of these complications. Ultrasound is the main investigation of value in the postoperative surveillance of pediatric liver transplants. MR cholangiography is used for confirmation of strictures (Griffith and John 1996). It is imperative with all suspected biliary complications to ensure that the hepatic artery is still patent using Doppler ultrasound or angiography as hepatic artery thrombosis will cause ischemia and necrosis of the biliary tree. Simple bile leaks are diagnosed in the early postoperative period by the presence of bile in drainage fluid or in percutaneous aspirate of fluid collections around the liver. Early biliary complications are best treated by immediate surgery and reanastomosis if required. Late stricture formation may be satisfactorily dealt with by endoscopic or percutaneous balloon dilatation or stenting. c) Postoperative bleeding occurs in 5%–10% of patients (Vilca-Melendez and Heaton 2004). Commonly reported risk factors include poor graft function, renal failure, hemodialysis, and large intraoperative blood loss. Correction of coagulopathy or low platelet count improves hemostasis. Bleeding from the cut surface of a “cutdown” graft may reflect venous outflow obstruction. In order to control bleeding, exploratory laparotomy is often needed; however, in 50% of cases, no specific bleeding site can be identified. d) Bowel perforation is a well-recognized complication following orthotopic liver transplantation (6.7%) (Vilca Melendez et al. 1998). Contributory factors included previous

K. Sharif and D. A. Kelly

operation, steroid therapy, and viral infection. The incidence is higher in children who underwent transplantation for biliary atresia after a previous Kasai porto-enterostomy (Vilca Melendez et al. 1998). Diagnosis may be difficult as symptoms may be masked due to steroid administration; therefore, a high index of suspicion is required. e) Postoperative fluid collections arising from the cut surface of the liver occur in 39% and 44%, of which nearly 50% required intervention. These collections can be due to biliary anastomosis leaks or bowel perforation; however the overall incidence of fluid collections is not increased by the use of reduced-size liver transplants (Duncan et al. 1995). Late presentations may be less acute and typically present with gram-negative sepsis, liver abscess, or biliary complications. f) Diaphragmatic paresis and hernia are rare complications of liver transplantation. The possible role of several contributing factors includes cross clamping of the IVC at the level of the diaphragmatic hiatus, trauma at operation (dissection and diathermy), and diaphragm thinness related to low weight and malnutrition (McCabe et al. 2005). g) Ascites: In 20–30%, ascites persists after liver transplantation. The exact etiology is not known; however it is a complex interplay between the development of ascites, renal function, and the hyperdynamic circulation. Several theories have been postulated (Shirouzu et al. 2012). First, the overflow theory implicates renal sodium retention leads to expansion of plasma volume which leads to a hyperdynamic circulation. Cirera et al. reported that in liver transplant recipients, ascitic losses of more than 500 mL/day for more than 10 days may be related to surgical complications associated with either the surgical technique of the hepatic vein anastomosis or otherwise impaired hepatic venous outflow. Nevertheless the postoperative ascites seems to be linked to either persisting or newly developing portal hypertension. The authors hypothesize that a functional sinusoidal block is responsible for leakage of lymph and the

26

Pediatric Liver Transplantation

generation of ascites. There are vascular or biliary complications that can lead to the accumulation of ascites and all subsequent problems like pleural effusions or infections. The ascites in this group of patients will be selflimiting when the underlying biliary leak or portal vein thrombosis has resolved. However, there are some patients, 7% in all, in whom there may be an ongoing medical imbalance between renal, cardiovascular, and hepatic function. Perhaps graft-related factors such as a long cold ischemic time may be relevant in certain patients but not in others. It is not clear either what active role the sinusoids in the newly transplanted liver may play in the production of ascites. The sinusoids are central to hepatic function, and the injury during reperfusion may be similar to the damage that occurs in veno-occlusive disease.

Late or Medical Complications Most patients are discharged from the intensive care unit within the first few days after transplantation. Medical complications of transplantation include bacterial, viral, fungal, and opportunistic infections, renal dysfunction, hypertension, and rejection, and particular concern is the post-transplant lymphoproliferative syndrome (Sokal 1995). a) Infections The reported incidence of infection in the liver transplant population is 1.36 infection/ patient (Bouchut et al. 2001); the most common sites of infection are bloodstream (36.5%) and abdomen (30%). i) Bacterial infections Bacterial infections in the early postoperative period after pediatric liver transplantation are associated with high morbidity and mortality (Dohna Schwake et al. 2019). Gram-positive bacteria (78%) predominate over gram-negative bacteria (22%). Detailed analysis of risk factors shows that age 8 days, and PICU stay > 19 days are associated with higher risk of infection (Bouchut et al. 2001). ii) Cytomegalovirus (CMV) infection Cytomegalovirus (CMV) infection (seroconversion or virus isolation) and CMV disease (infection plus clinical signs and symptoms) have a reported incidence of 37% and 11.5%, respectively, with significant morbidity and mortality (Mellon et al. 1993). The high prevalence of CMV infection supports the view that clinical signs alone are inadequate to direct investigations for CMV. Cytomegalovirus (CMV) infection is best monitored with PP65 antigen and polymerase chain reaction (PCR) measurement of the virus. Prophylactic treatment with ganciclovir appears the best strategy to implement in high-risk patients (McGavin and Goa 2001; Couchoud 2000). CMV infection has been reported to be associated with hepatic artery thrombosis (Pastacaldi et al. 2001). A rare association with cytomegalovirus (CMV) reactivation is hemophagocytic syndrome (HPS) which is a rare event but often fatal. These patients are treated with a combination of antiviral agents and immunomodulatory and supportive therapy (Hardikar et al. 2006). iii) Epstein–Barr virus (EBV) and post-transplant lymphoproliferative disease (PTLD). EBV infection is the main cause of PTLD. Since many infants are EBV-seronegative at the time of transplantation, and receive a positive graft, PTLD is a major concern. PTLD presents from the first few weeks after transplant to any time after transplant with a mean time of onset of 10 months (Jain et al. 2002). Prophylactic intravenous ganciclovir given for a prolonged period may be effective in preventing EBV activation which is the promoter of PTLD in most cases. The first manifestation of PTLD is adenoidal and/or tonsillar involvement (Rombaux et al. 2005) with acute membranous tonsillitis and associated cervical lymphadenopathy, which is resistant to antibiotic therapy. It is

382

important to remember that tonsillar enlargement in pediatric liver transplant patients does not necessarily imply a diagnosis of PTLD (Meru et al. 2001). Currently there are no tests to accurately identify pediatric liver transplant patients at risk for post-transplant lymphoproliferative disorder (PTLD) other than their preoperative EBV status. Most units monitor real-time quantitative polymerase chain reaction (qPCR) EBV viral load and reduce immunosuppression if the viral load is rising. Use of cytokine genotyping in conjunction with qPCR for EBV viral load may improve the predictive value of diagnostic tests for identification of patients at high risk for PTLD (Lee et al. 2006). Management strategies include reduction of immunosuppression, which may require complete withdrawal. Rituximab is an anti-CD 20 monoclonal antibody which reduces B cells and should be used with ablated replacement immunoglobulin therapy. If no response, then standard anti-lymphoma chemotherapy is required. Mortality varies from 20 to 70%. b) Rejection Despite the availability of potent immunosuppressive drugs, rejection after organ transplantation in children remains a serious concern and may lead to significant morbidity, graft loss, and death (Debray et al. 2003). 1) Acute rejection The diagnosis of rejection is made on the basis of clinical, biochemical, and histologic changes. It presents in the first few weeks after transplant with fever, malaise, a tender graft, and loose stools. Diagnosis is confirmed by liver biopsies performed using the Menghini technique (Hypafix needle (Braun), diameter 1.4 mm), unless biliary dilatation is observed on ultrasonography. Biopsies are routinely assayed for viral and bacterial infection. The grade of rejection is assessed according to established histological criteria on a scale of 0 to 4 (Demetris et al. 2000; Ormonde et al. 1999). Acute rejection is treated with three doses of intravenous

K. Sharif and D. A. Kelly

methylprednisolone (10 mg/kg) on three successive days with adjusted baseline immunosuppression. If corticosteroid-resistant acute rejection develops, the addition of mycophenolate mofetil or sirolimus (Debray et al. 2003) may be effective. Antithymocyte globulins (ATG) or monoclonal anti-CD3 antibodies, muromonab-CD3 (OKT3), are alternatives but are associated with numerous adverse effects, including over-immunosuppression. Other treatments such as plasmapheresis and high-dose immunoglobulins may be useful in difficult cases. In patients with refractory rejection, over-immunosuppression, including opportunistic infections and malignancies (EBV-related PTLD), is a significant risk and may require retransplantation. 2) Late acute cellular rejection Although acute rejection is mostly encountered during the first 3 months after liver transplant, it may occur at any time (D’Antiga et al. 2002). Late cellular rejection in children is usually due to low levels or decreased immunosuppression. Prompt intervention to correct inadequate immunosuppression and careful follow-up to identify other treatable conditions are essential. 3) Chronic rejection Chronic rejection is usually an irreversible phenomenon which is manifested by disruption of bile duct radicals with development of the vanishing bile duct syndrome. The incidence is less frequent with tacrolimus-based immunosuppressive regimens as opposed to cyclosporin where an incidence of up to 10% has been recorded. Late chronic rejection may also be associated with a vasculopathy affecting larger arteries. Once established, retransplantation is required. c) Chronic graft hepatitis (indeterminate hepatitis) The use of serial protocol liver biopsies after transplantation has demonstrated the presence of graft hepatitis and fibrosis despite normal biochemistry at 5 and 10 years with a 15% progression to cirrhosis (Evans et al. 2006; Scheenstra et al. 2009; Hubscher

26

Pediatric Liver Transplantation

2009), suggesting that this may be a cause for graft failure and re-transplantation. No clear etiology for graft hepatitis has been identified, although it is associated with nonspecific liver-associated autoantibodies. It may reflect early immunosuppression regimes especially as graft hepatitis improved with increased immunosuppression (Hubscher 2009). De novo autoimmune or otherwise unexplained hepatitis occurs in 5%–10% of children after transplantation but has not been reported to require re-transplantation (Gupta et al. 2001). d) Recurrent disease Few children are transplanted for diseases that recur post-transplant except for primary sclerosing cholangitis and autoimmune hepatitis which have a 25% recurrence rate. It is essential that steroids are continued post-transplant to prevent recurrence (Duclos-Vallee and Sebagh 2009). It has recently been noted that recurrence may occur following transplantation for the genetic disease PFIC 2 (Jara et al. 2009; Keitel et al. 2009; Duclos-Vallee and Sebagh 2009; Gupta et al. 2001; Duclos-Vallee and Sebagh 2009) which is related to the development of anti-BSEP antibodies against the BSEP receptor. e) Adverse effects of immunosuppression Two-thirds of late post-transplant mortality is associated with the complications of immunosuppression (IS), infection, or malignancy (Wallot et al. 2002). Some drugs are associated with an increased risk of renal dysfunction, diabetes, hyperlipidemia, hypertension, obesity, and metabolic syndrome (Nobili and Ville de Goyet 2012). a) Renal function A degree of renal impairment is almost inevitable in those patients suffering from chronic liver disease. The combination of nephrotoxic calcineurin inhibitors and antibiotics contributes to both acute and chronic post-transplant renal dysfunction in 24% to 70% of reported series (Bartosh et al. 1997). Renal function falls by about 30% immediately post-transplant, but once

383

immunosuppression is reduced, it remains stable for 1 to 5 years after transplantation (Arora-Gupta et al. 2004). In the Birmingham study of 117 pediatric survivors >15 years, renal dysfunction occurred in 15%, and 5 patients required a renal transplant (Legarda et al. 2012). b) Diabetes mellitus (DM) The incidence of post-transplant diabetes mellitus (PTDM) is much less than observed early immunosuppressive regimes, and only 10% of primary LT recipients develop new onset diabetes after transplantation with cumulative incidences of 5.9%, 8.3%, and 11.2% at 1, 3, and 5 years (Kuo et al. 2012). The risk is higher in children with cystic fibrosis, older age at transplant, and African-American race, although the increase in obesity in the population may affect this incidence in future (Nobili and Ville de Goyet 2012). c) Cardiovascular disease Cardiovascular disease is a significant comorbidity in adults undergoing transplantation and is likely to affect longterm pediatric survivors on CNI inhibitors particularly if they also become obese or develop metabolic syndrome (Nobili and Ville de Goyet 2012). SPLIT data on 461 survivors documented obesity in 12% and hypercholesterolemia in 7% of children at 5 years, while 19% and 23% of 10-year survivors had increased cholesterol and triglycerides (22). In addition, 20% of 5to 10-year survivors had blood pressure > 95th percentile or were taking antihypertensive medications (McLin et al. 2012). d) Long-term outcome and quality of life post-transplant Children who survive the initial 3 months post-transplant without major complications should achieve a normal lifestyle despite the necessity for continuous monitoring of immunosuppressive treatment. Children who underwent transplant for metabolic liver disease have both phenotypic and functional recovery (a1-antitrypsin deficiency,

384

K. Sharif and D. A. Kelly

Wilson’s disease, and tyrosinemia type I). Children with organic acidemias will only have palliation of their defect if the enzyme defect is not restricted to the liver (propionic acidemia or methylmalonic acidemia) (Kelly 1998). e) Nutrition and growth Many studies have demonstrated the beneficial effect of transplantation on improving nutrition and growth. The extent of nutritional recovery depends on the degree of malnutrition preoperatively and the prolonged use of steroids postoperatively. Preoperative weight and height z scores predict catch-up growth as those who have lower weight percentiles have less growth acceleration, while those with lower height percentiles have accelerated growth. The Studies of Pediatric Liver Transplant (SPLIT) registry showed that both catch-up growth and linear growth were impaired if steroid therapy is >18 months (OR 3.02) (Alonso et al. 2009). Up to 50% of children have a final adult height 1.3 standard deviation (SD) lower than genetic potential (Scheenstra et al. 2008). f) Endocrine development Long-term studies have shown that children surviving liver transplantation will enter puberty normally, girls will develop menarche, and both boys and girls will have pubertal growth spurts (Codoner-Franch et al. 1994). Successful pregnancies are possible for females, and males have become fathers (Sucato and Murray 2006). It is important that appropriate advice about fertility, contraception, and immunosuppressive therapy is provided. g) Psychosocial development Long-term pediatric survivors of LT have lower physical and psychosocial function compared to normal children although this is similar to other groups of chronically ill young people (Gilmour et al. 2010). A recent study of 800 recipients found psychosocial function was more

affected than physical function, particularly if there was cognitive impairment or significant school absence (Gilmour et al. 2009), while 16% of adolescents reported symptoms consistent with post-traumatic stress disorder. The role in preoperative counselling in preventing this is unproven. h) Neurocognitive function Liver disease in infancy affects neurodevelopment, possibly because of malnutrition or encephalopathy (Gilmour et al. 2009; Kaller et al. 2012). Studies evaluating neurocognitive function before and after LT have noted that neurocognitive delay persists after physical rehabilitation (Krull et al. 2003). 10%–15% of recipients may have severely impaired intellectual ability, while 30% require special education post-transplant (Gilmour et al. 2010). In contrast longterm data from Birmingham on 117 survivors >15 years demonstrated that 32% had been to a university; 50% had been to college; 18% were still at school; and 35% were employed in full-time work (Legarda et al. 2012). i) Quality of life Increased survival rates and the growing population of LT survivors emphasize the importance of long-term health-related quality of life (HRQoL). Recent studies have suggested that HRQoL in pediatric LT recipients is suboptimal (Alonso et al. 2012) although comparable or better than children with chronic liver disease, chronic heart failure, diabetes, or undergoing cancer treatment (Alonso et al. 2012). Emotional functioning is similar to healthy peers (Sundaram et al. 2007). j) Nonadherence with therapy Lifelong immunosuppression is required for the long-term health and survival of graft. Published evidence suggests that 19–42% of liver transplant recipients are functionally tolerant, i.e., they can be weaned from immunosuppression (SchulzJuergensen et al. 2012; Ohe et al. 2012; Bourdeaux et al. 2012), and the remaining

26

Pediatric Liver Transplantation

great majority require adherence to an immunosuppressive regimen. Nonadherence is the major cause of graft loss or rejection in adolescent transplant recipients, accounting for 17% of liver grafts (Shemesh 2004; Annunziato et al. 2007). It is the main cause of late graft loss in adolescence post-liver transplant. Additional risk factors for nonadherence are the age at which transplantation takes place, social and economic factors, and the process of transition to adult care (Lurie et al. 2000; Berquist et al. 2008). There is good evidence that nonadherence with medication, clinic visits, and medical advice increases following transfer to adult care, indicating the need for an appropriate transition policy (Fredericks et al. 2007). The management of nonadherence is difficult and relies on a nonjudgmental approach and efforts to improve education, social functioning, and behavioral strategies to encourage self-motivation (Berquist et al. 2008). k) Transition to adult care Several studies have identified an increase in nonadherence to medication and hospital visits following transfer to adult clinics leading to graft loss and the need for re-transplantation in transplant survivors (Annunziato et al. 2007; Watson 2005). The causes are complex and include the difficulties young people experience in the psychosocial journey from child to adult, their need to become self-reliant, and the different approach between adult and pediatric care (Viner 1999; Soanes and Timmons 2004). In order to ensure a successful transfer to adult care, it is essential to establish a transition team with key workers and trained personnel to manage the process. One strategy is to begin the process early to encourage self-management and to arrange joint adult and pediatric clinics to ensure that young adults remain compliant with medication and clinic appointments (McDonagh 2005). Support of the adolescent patient is

385

crucial and requires a multidisciplinary approach, including measures to increase independence.

Re-transplantation 10–15% of pediatric patients require re-transplantation due to graft failure (Berlakovich 2012). Early indications may be primary non-function, early hepatic arterial thrombosis, severe drug-resistant acute rejection, and established chronic rejection. Early re-transplantation is technically a much less traumatic procedure than the original transplant, although the patient may be in a poorer condition. Outcome largely depends on the indication for retransplantation and is quite good for technical causes but less satisfactory for rejection and infection. An increasingly poorer outcome can be expected after third and fourth re-transplants, and the efficacy and ethics of these interventions are in question (Mattos et al. 2012).

Challenges Faced by Pediatric Transplantation Despite all the advances and improved outcome, pediatric transplantation is facing several challenges. Some of these include: a) Small-for-size syndrome (SFSS) The shortage of liver donors and the increase in the waiting list have led to the development of innovative surgical procedures to expand the donor pool and increase the number of liver transplantations being performed. Transplantation of partial grafts, either from a living donor (LD) or split from a deceased donor (DD), represents two techniques to expand the donor pool. Although these grafts have increased the number of transplants being performed, they have also resulted in new problems which are unique to these transplantations. One of these is commonly seen in children >40 kg, the small-forsize syndrome (SFSS) (Sakamoto et al. 2012).

386

The exact etiology of SFSS is unclear but is believed to be secondary to portal hyperperfusion in a graft that is functionally small for the recipient (Tanaka and Ogura 2004). This results in a characteristic postoperative course characterized by liver dysfunction with prolonged cholestasis, coagulopathy, and portal hypertension (usually manifesting as ascites or high drain output). Histologic features include cholestasis with bile plugs and areas of regeneration and ischemia with patchy necrosis. The natural course for established SFSS is unclear, but generally continued liver dysfunction predisposes to complications such as sepsis and gastrointestinal bleeding. Spontaneous improvement of liver function may occur over time, but approximately 50% of recipients with SFSS die of sepsis or another complication within 4–6 weeks after transplantation (Fujii et al. 2004). If the clinical course is consistent with SFSS, it is important to rule out hepatic outflow obstruction. Various techniques have been described to prevent SFSS, including splenectomy, splenic artery ligation (SAL), splenic artery embolization, and creation of portocaval shunts (Botha et al. 2012; Hou et al. 2012; Humar et al. 2009), but optimal therapy remains unclear. Most centers recommend conservative/ supportive management, while more active management should be early on postoperative day 1. Both coiling and ligation of splenic artery are well tolerated by the recipient, as long as the ligation is done proximally, close to the origin of the splenic artery, and then the risk of a complications seems to be minimal. b) ABO-incompatible liver transplantation Due to organ shortage and increased demand, alternative sources of liver donation are required for transplantation. ABO-incompatible (ABOi) grafts are one of the options (Cacciarelli et al. 1995). Matching systems for matching cadaveric donors in older children and adults give preference for ABO-compatible (ABOc) donors with proven results and work well on the European level; in these systems only selected patients may require ABOi donors.

K. Sharif and D. A. Kelly

ABO mismatching is possible in young infants because of the immaturity of isohemagglutinin development, and this can be performed in children 1y requires a standardized approach which is not commonly agreed. The most commonly used therapy includes one dose of rituximab 2–3 weeks prior to LTx, high-dose steroids (10 mg methylprednisolone/kg body weight) during LTx, high-dose tacrolimus (to obtain through concentration of 10–15 ng/ml), MMF for 3 months, and tapered steroids. It seems that the first 3 months are critical for graft survival after ABOiLTx, and after that time standard immune suppression – the same as for ABOc donors – can be used. Some centers use other regimens which may include basiliximab (Monteiro et al. 2003; Ikegami et al. 2009; Kawagishi et al. 2005).

Conclusion and Future Directions Advances in immunosuppression, organ preservation, refinements of the operative technique, and effective antimicrobial prophylaxis have resulted in pediatric LT being a routine operation with excellent patient outcomes rather than an experimental procedure. However, a number of challenges are still faced by the transplant community.

26

Pediatric Liver Transplantation

One of the major issues is shortage of sizematched organs. Over the years several strategies have been developed to expand the donor pool, such as split liver transplantation, use of donors with cardiac death, and living donor transplantation. These techniques have led to a reduction in the waiting list mortality, but further initiatives are necessary to help bridge the increasing gap between organ supply and demand, such as ABO-incompatible transplantation. Alternative therapies, such as hepatocyte transplantation, gene therapy, and liver replacement therapy, may be viable alternatives to pediatric solid organ transplantation in the future, but their utility remains to be proven outside the laboratory. In addition, adult and pediatric liver transplant recipients face the challenge of maintaining graft function while minimizing long-term immune and nonimmune complications related to immunosuppressive medications. Children have a longer potential life span following liver transplantation, and, consequently, they have a greater potential to develop significant end organ damage and graft fibrosis (Kelly et al. 2016; Bucuvalas and Alonso 2008). Data reported by the United Network for Organ Sharing (UNOS) confirms that in the current era of pediatric transplantation, whole liver transplant (WLT) recipients have better outcome; by 1 year, the adjusted patient and allograft survival are similar in all types of transplantation, i.e., WLT (92.2%), living donor liver transplant (LDLT; 91.1%), and disease donor segmental liver transplantation (DDSLT; 86.6%) (Oliveros et al. 2005). Most of the centers are achieving >95% 1-year survival, with 10-year survivals of around 80–85%. Patients grafted for acute liver failure have done less well with a higher early death rate usually associated with cerebral complications and multi-organ failure (Ee et al. 2003). Excellent quality of life can be achieved, and most children are fully rehabilitated (Avitzur et al. 2004; Burdelski et al. 1999). It is however increasingly evident that prolonged cholestatic jaundice and malnutrition in infancy may have late effects and despite good physical rehabilitation, evidence of significant cognitive deficits, which present

387

during early schooling as learning difficulties and attention deficit disorder, is common (Talcott et al. 2019). Quality of life may not reach perfection and depends also on the way society accepts these imperfections (Sokal 1995). As with any immunosuppressed patient, the incidence of neoplasia in a lifetime is greatly increased.

Cross-References ▶ Complications of Immunosuppression in Pediatric Surgery ▶ Liver Tumors ▶ Portal Hypertension ▶ Principles of Transplantation

References Abt P, et al. Pediatric liver and kidney transplantation with allografts from DCD donors: a review of UNOS data. Transplantation. 2006;82(12):1708–11. Ackermann O, et al. The long-term outcome of hepatic artery thrombosis after liver transplantation in children: role of urgent revascularization. Am J Transplant. 2012;12(6):1496–503. Adani GL, et al. Which type of incision for liver transplantation? Liver Transpl. 2009;15(4):452. Alonso EM, et al. Linear growth patterns in prepubertal children following liver transplantation. Am J Transplant. 2009;9(6):1389–97. Alonso EM, et al. Cross-sectional analysis of health-related quality of life in pediatric liver transplant recipients. J Pediatr. 2012;156(2):270–6e1. Annunziato RA, et al. Adherence and medical outcomes in pediatric liver transplant recipients who transition to adult services. Pediatr Transplant. 2007;11 (6):608–14. Arora-Gupta N, et al. The effect of long-term calcineurin inhibitor therapy on renal function in children after liver transplantation. Pediatr Transplant. 2004;8(2): 145–50. Attia MS, et al. The reduced left lateral segment in pediatric liver transplantation: an alternative to the monosegment graft. Pediatr Transplant. 2008;12 (6):696–700. Avitzur Y, et al. Health status ten years after pediatric liver transplantation–looking beyond the graft. Transplantation. 2004;78(4):566–73. Badger IL, et al. Hepatic transplantation in children using reduced size allografts. Br J Surg. 1992;79(1):47–9. Bahador A, et al. Pediatric liver transplantation in Iran: a 9-year experience. Transplant Proc. 2009;41(7):2864–7.

388 Baker A, Dhawan A, Heaton N. Who needs a liver transplant? (new disease specific indications). Arch Dis Child. 1998;79(5):460–4. Baker A, et al. Assessment of potential donors for living related liver transplantation. Br J Surg. 1999;86(2): 200–5. Bartosh SM, Alonso EM, Whitington PF. Renal outcomes in pediatric liver transplantation. Clin Transpl. 1997;11(5 Pt 1):354–60. Battula NR, Anbarasan R, Thumma V, et al. Utility of a routine bench cholangiogram for ex situ split liver procedure. Clin Transpl. 2019;33(7):e13614. Berlakovich GA. Utility and futility of early liver re-transplantation. Transpl Int. 2012;27(2):139–40. Berquist RK, et al. Non-adherence to post-transplant care: prevalence, risk factors and outcomes in adolescent liver transplant recipients. Pediatr Transplant. 2008; 12(2):194–200. Botha JF, et al. Left lobe adult-to-adult living donor liver transplantation: small grafts and hemiportocaval shunts in the prevention of small-for-size syndrome. Liver Transpl. 2012;16(5):649–57. Bouchut JC, et al. Postoperative infectious complications in pediatric liver transplantation: a study of 48 transplants. Paediatr Anaesth. 2001;11(1):93–8. Bourdeaux C, et al. Living-related versus deceased donor pediatric liver transplantation: a multivariate analysis of technical and immunological complications in 235 recipients. Am J Transplant. 2007;7(2):440–7. Bourdeaux C, et al. Prope tolerance after pediatric liver transplantation. Pediatr Transplant. 2012;17(1):59–64. Broelsch CE, et al. Liver transplantation in children from living related donors. Surgical techniques and results. Ann Surg. 1991;214(4):428–37.. discussion 437–9 Bucuvalas JC, Alonso E. Long-term outcomes after liver transplantation in children. Curr Opin Organ Transplant. 2008;13(3):247–51. Burdelski M, et al. Treatment of inherited metabolic disorders by liver transplantation. J Inherit Metab Dis. 1991;14(4):604–18. Burdelski M, et al. Liver transplantation in children: longterm outcome and quality of life. Eur J Pediatr. 1999;158(Suppl 2):S34–42. Cacciarelli TV, et al. A reassessment of ABO incompatibility in pediatric liver transplantation. Transplantation. 1995;60(7):757–60. Chai PF, et al. Childhood autoimmune liver disease: indications and outcome of liver transplantation. J Pediatr Gastroenterol Nutr. 2012;50(3):295–302. Chardot C, et al. Biliary complications after pediatric liver transplantation: Birmingham’s experience. Transpl Int. 1995;8(2):133–40. Chardot C, et al. Portal vein complications after liver transplantation for biliary atresia. Liver Transpl Surg. 1997;3(4):351–8. Christophi C, Morgan B, McInnes I. A comparison of standard and rapid infusion methods of liver preservation during multi-organ procurement. Aust N Z J Surg. 1991;61(9):692–4.

K. Sharif and D. A. Kelly Cintorino D, et al. In situ split liver transplantation for adult and pediatric recipients: an answer to organ shortage. Transplant Proc. 2006;38(4):1096–8. Codoner-Franch P, Bernard O, Alvarez F. Long-term follow-up of growth in height after successful liver transplantation. J Pediatr. 1994;124(3):368–73. Couchoud C. Cytomegalovirus prophylaxis with antiviral agents for solid organ transplantation. Cochrane Database Syst Rev. 2000;(2):CD001320. Cox KL, Berquist WE, Castillo RO. Paediatric liver transplantation: indications, timing and medical complications. J Gastroenterol Hepatol. 1999;14(Suppl): S61–6. Cuenca AG, Kim HR, Vakil K. Pediatric liver transplantation. Semin Pediatr Surg. 2017;26(4):217–23. D'Antiga L, et al. Late cellular rejection in paediatric liver transplantation: aetiology and outcome. Transplantation. 2002;73(1):80–4. Debray D, et al. Therapy for acute rejection in pediatric organ transplant recipients. Paediatr Drugs. 2003;5 (2):81–93. Demetris A, et al. Update of the international Banff Schema for liver allograft rejection: working recommendations for the histopathologic staging and reporting of chronic rejection. An international panel. Hepatology. 2000;31(3):792–9. Dhawan A, et al. Wilson’s disease in children: 37-year experience and revised King’s score for liver transplantation. Liver Transpl. 2005;11(4):441–8. Diem HV, et al. Pediatric liver transplantation for biliary atresia: results of primary grafts in 328 recipients. Transplantation. 2003;75(10):1692–7. Dohna Schwake C, Guiddir T, Cuzon G et al. Bacterial infections in children after liver transplantation: a single center surveillance study of 345 consecutive transplantations. Transpl Infect Dis. 2019. https://doi.org/ 10.1111/tid.13208. Dowman JK, et al. Long-term impact of liver transplantation on respiratory function and nutritional status in children and adults with cystic fibrosis. Am J Transplant. 2012;12(4):954–64. Duclos-Vallee J-C, Sebagh M. Recurrence of autoimmune disease, primary sclerosing cholangitis, primary biliary cirrhosis, and autoimmune hepatitis after liver transplantation. Liver Transpl Offic Publ Am Assoc Study Liver Dis Int Liver Transpl Soc. 2009;15(Suppl 2): S25–34. Duncan KA, King SE, Ratcliffe JF. Intraperitoneal fluid collections following liver transplantation in a paediatric population. Clin Radiol. 1995;50(1):40–3. Ee LC, et al. Acute liver failure in children: a regional experience. J Paediatr Child Health. 2003;39(2):107–10. Eiseman B. The puzzle people: memoirs of a transplant surgeon. Arch Surg. 1992;127(9):1009–11. Evans HM, et al. Progressive histological damage in liver allografts following pediatric liver transplantation. Hepatology. 2006;43(5):1109–17. Farci P, et al. Hepatitis C virus-associated fulminant hepatic failure. N Engl J Med. 1996;335:631–4.

26

Pediatric Liver Transplantation

Francavilla R, et al. Prognosis of alpha-1-antitrypsin deficiency-related liver disease in the era of paediatric liver transplantation. J Hepatol. 2000;32(6):986–92. Fredericks EM, et al. Psychological functioning, nonadherence and health outcomes after pediatric liver transplantation. Am J Transplant. 2007;7(8):1974–83. Fujii M, et al. Pathophysiology and strategy for small-forsize graft syndrome after living-donor liver transplantation. Nihon Geka Gakkai Zasshi. 2004;105(10):680–6. Ganschow R, et al. Intensive care management after pediatric liver transplantation: a single-center experience. Pediatr Transplant. 2000;4(4):273–9. Gelas T, et al. ABO-incompatible pediatric liver transplantation in very small recipients: Birmingham’s experience. Pediatr Transplant. 2012;15(7):706–11. Gilmour S, et al. Assessment of psychoeducational outcomes after pediatric liver transplant. Am J Transplant. 2009;9(2):294–300. Gilmour SM, et al. School outcomes in children registered in the studies for pediatric liver transplant (SPLIT) consortium. Liver Transpl. 2010;16(9):1041–8. Griffith JF, John PR. Imaging of biliary complications following paediatric liver transplantation. Pediatr Radiol. 1996;26(6):388–94. Gupta P, et al. De novo hepatitis with autoimmune antibodies and atypical histology: a rare cause of late graft dysfunction after pediatric liver transplantation. Transplantation. 2001;71(5):664–8. Hackl C, Schmidt KM, Süsal C, et al. Split liver transplantation: current developments. World J Gastroenterol. 2018;24(47):5312–21. Hadzic N, Francavilla R, Chambers SM, Castellaneta S, Portmann B, Mieli-Vergani G. Outcome of PiSS and PiSZ alpha-1-antitrypsin deficiency presenting with liver involvement. Eur J Pediatr. 2005;164(4):250–2. Hardikar W, et al. Successful treatment of cytomegalovirus-associated haemophagocytic syndrome following paediatric orthotopic liver transplantation. J Paediatr Child Health. 2006;42(6):389–91. Hassan S, Ng VL, Aqul A. It takes a village: primary care of the pediatric liver transplant recipient. Curr Opin Pediatr. 2019;31(5):636–44. Heffron TG. Living-related pediatric liver transplantation. Semin Pediatr Surg. 1993;2(4):248–53. Heffron TG, et al. Pediatric liver transplantation with daclizumab induction. Transplantation. 2003a;75(12): 2040–3. Heffron TG, et al. Biliary complications after pediatric liver transplantation revisited. Transplant Proc. 2003b; 35(4):1461–2. Heisterkamp J, Kazemier G. A J-shaped subcostal incision reduces the incidence of abdominal wall complications in liver transplantation. Liver Transpl. 2009;15(4):453. Hou P, et al. Extracorporeal continuous portal diversion plus temporal plasmapheresis for “small-for-size” syndrome. World J Gastroenterol. 2012;19(33):5464–72. Hubscher S. What does the long-term liver allograft look like for the pediatric recipient? Liver Transpl. 2009;15(Suppl 2):S19–24.

389 Humar A, et al. Delayed splenic artery occlusion for treatment of established small-for-size syndrome after partial liver transplantation. Liver Transpl. 2009;15(2): 163–8. Ikegami T, et al. Rituximab, IVIG, and plasma exchange without graft local infusion treatment: a new protocol in ABO incompatible living donor liver transplantation. Transplantation. 2009;88(3):303–7. Jain A, et al. Posttransplant lymphoproliferative disorders in liver transplantation: a 20-year experience. Ann Surg. 2002;236(4):429–36.. discussion 436–7 Jamieson NV, et al. Results and problems in pediatric liver transplantation in the Cambridge/kings college hospital series: 1968 to July 1986. Transplant Proc. 1987; 19(1 Pt 3):2447–8. Jara P, et al. Recurrence of bile salt export pump deficiency after liver transplantation. N Engl J Med. 2009; 361(14):1359–67. Kaller T, et al. Cognitive abilities, behaviour and quality of life in children after liver transplantation. Pediatr Transplant. 2012;14(4):496–503. Kawagishi N, et al. New strategy for ABO-incompatible living donor liver transplantation with anti-CD20 antibody (rituximab) and plasma exchange. Transplant Proc. 2005;37(2):1205–6. Keitel V, et al. De novo bile salt transporter antibodies as a possible cause of recurrent graft failure after liver transplantation: a novel mechanism of cholestasis. Hepatology. 2009;50(2):510–7. Kelly DA. Current results and evolving indications for liver transplantation in children. J Pediatr Gastroenterol Nutr. 1998;27(2):214–21. Kelly D, Verkade HJ, Rajanayagam J, McKiernan P, Mazariegos G, Hübscher S. Late graft hepatitis and fibrosis in paediatric liver allograft recipients: current concepts and future developments. Liver Transpl. 2016;1593–1602. Kim MH, Akbari O, Genyk Y, et al. Immunologic benefit of maternal donors in pediatric living donor liver transplantation. Pediatr Transplant. 2019;23(7):e13560. Krenn CG, Faybik P, Hetz H. Living-related liver transplantation: implication for the anaesthetist. Curr Opin Anaesthesiol. 2004;17(3):285–90. Krull K, et al. Neurocognitive outcome in pediatric liver transplant recipients. Pediatr Transplant. 2003;7(2): 111–8. Kuo HT, et al. Pretransplant risk factors for new-onset diabetes mellitus after transplant in pediatric liver transplant recipients. Liver Transpl. 2012;16 (11):1249–56. Le Coultre C, Battaglin C, Bugmann P, Genin B, Bachmann R, McLin V, Mentha G, Belli D. Biliary atresia and orthotopic liver transplantation. 11 years of experience in Geneva. Swiss Surg. 2001;7(5): 199–204. Lee WS, McKiernan P, Kelly DA. Etiology, outcome and prognostic indicators of childhood fulminant hepatic failure in the United Kingdom. J Pediatr Gastroenterol Nutr. 2005;40(5):575–81.

390 Lee TC, et al. Use of cytokine polymorphisms and EpsteinBarr virus viral load to predict development of posttransplant lymphoproliferative disorder in paediatric liver transplant recipients. Clin Transpl. 2006;20(3): 389–93. Legarda M, et al. Vitamin D deficiency and insufficiency after pediatric liver transplantation. Pediatr Transplant. 2012;17(7):631–7. Lo CM, Liu CL, Fan ST. Correction of left hepatic vein redundancy in paediatric liver transplantation. Asian J Surg. 2005;28(1):55–7. Lurie S, et al. Non-adherence in pediatric liver transplant recipients–an assessment of risk factors and natural history. Pediatr Transplant. 2000;4(3):200–6. Lysy PA, et al. Liver cell transplantation for Crigler-Najjar syndrome type I: update and perspectives. World J Gastroenterol. 2008;14(22):3464–70. Mattos RO, et al. Liver re-transplantation: internal validation of a predictive mathematical model of survival. Hepatogastroenterology. 2012;59(116):1230–3. McCabe AJ, et al. Right-sided diaphragmatic hernia in infants after liver transplantation. J Pediatr Surg. 2005;40(7):1181–4. McDiarmid SV, et al. Indications for pediatric liver transplantation. Pediatr Transplant. 1998;2(2):106–16. McDiarmid SV, Anand R, Lindblad AS. Development of a pediatric end-stage liver disease score to predict poor outcome in children awaiting liver transplantation. Transplantation. 2002;74(2):173–81. McDonagh JE. Growing up and moving on: transition from pediatric to adult care. Pediatr Transplant. 2005;9(3): 364–72. McGavin JK, Goa KL. Ganciclovir: an update of its use in the prevention of cytomegalovirus infection and disease in transplant recipients. Drugs. 2001;61(8):1153–83. McLin VA, et al. Blood pressure elevation in long-term survivors of pediatric liver transplantation. Am J Transplant. 2012;12(1):183–90. Mellon A, et al. Cytomegalovirus infection after liver transplantation in children. J Gastroenterol Hepatol. 1993;8(6):540–4. Meru N, et al. Epstein-Barr virus infection in paediatric liver transplant recipients: detection of the virus in posttransplant tonsillectomy specimens. Mol Pathol. 2001;54(4):264–9. Metzelder ML, Bottländer M, Melter M, Petersen C, Ure BM. Laparoscopic partial external biliary diversion procedure in progressive familial intrahepatic cholestasis: a new approach. Surg Endosc. 2005;19(12):1641–3. Miller C, Mazzaferro V, Makowka L, Gorgon RD, Todo S, Bowman J, Morris M, Ligush J, Starzl TE. Rapid flush technique for donor hepatectomt: safety and efficacy of an improved method of liver recovery for transplantation. Transplant Proc. 1988;20(Suppl 1):948–50. Mohan N, McKiernan P, Preece MA, Green A, Buckels J, Mayer AD, Kelly DA. Indications and outcome of liver transplantation in tyrosinaemia type 1. Eur J Pediatr. 1999;158(Suppl 2):S49–54.

K. Sharif and D. A. Kelly Molmenti EP, et al. Liver transplantation for hepatoblastoma in the pediatric population. Transplant Proc. 2001;33(1–2):1749. Molmenti EP, et al. Treatment of unresectable hepatoblastoma with liver transplantation in the pediatric population. Am J Transplant. 2002;2(6):535–8. Monteiro I, et al. Rituximab with plasmapheresis and splenectomy in abo-incompatible liver transplantation. Transplantation. 2003;76(11):1648–9. Murray KF, et al. Drug-related hepatotoxicity and acute liver failure. J Pediatr Gastroenterol Nutr. 2008;47(4): 395–405. Nobili V, Ville de Goyet J. Pediatric post-transplant metabolic syndrome: new clouds on the horizon. Pediatr Transplant. 2012;17(3):216–23. Ohe H, et al. Factors affecting operational tolerance after pediatric living-donor liver transplantation: impact of early post-transplant events and HLA match. Transpl Int. 2012;25(1):97–106. Oliveros FH, et al. Comparative study between living and cadaveric donors in pediatric liver transplantation. Transplant Proc. 2005;37(9):3936–8. Ormonde DG, et al. Banff schema for grading liver allograft rejection: utility in clinical practice. Liver Transpl Surg. 1999;5(4):261–8. Otte JB. History of pediatric liver transplantation. Where are we coming from? Where do we stand? Pediatr Transplant. 2002;6(5):378–87. Otte JB. Paediatric liver transplantation–a review based on 20 years of personal experience. Transpl Int. 2004; 17(10):562–73. Otte JB, et al. Recent developments in pediatric liver transplantation. Transplant Proc. 1987;19(5):4361–4. Otte JB, et al. Organ procurement in children–surgical, anaesthetic and logistic aspects. Intensive Care Med. 1989;15(Suppl 1):S67–70. Otte JB, et al. Pediatric liver transplantation: from the fullsize liver graft to reduced, split, and living related liver transplantation. Pediatr Surg Int. 1998;13(5–6):308–18. Otte JB, et al. Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer. 2004;42(1):74–83. Ozawa K, et al. An appraisal of pediatric liver transplantation from living relatives. Initial clinical experiences in 20pediatric liver transplantations from living relatives as donors. Ann Surg. 1992;216(5):547–53. Panossian A, et al. Hepatic artery microvascular anastomosis in pediatric living donor liver transplantation: a review of 35 consecutive cases by a single microvascular surgeon. J Reconstr Microsurg. 2009;25(7):439–43. Pastacaldi S, et al. Hepatic artery thrombosis after orthotopic liver transplantation: a review of nonsurgical causes. Liver Transpl. 2001;7(2):75–81. Perito ER, Roll G, Dodge JL, et al. Split liver transplantation and pediatric waitlist mortality in the United States: potential for improvement. Transplantation. 2019;103(3):552–7.

26

Pediatric Liver Transplantation

Pham YH, Miloh T. Liver transplantation in children. Clin Liver Dis. 2018;22(4):807–21. Psacharopoulos HT, et al. Fulminant hepatic failure in childhood: an analysis of 31 cases. Arch Dis Child. 1980;55:252–8. Rawal N, Yazigi N. Pediatric liver transplantation. Pediatr Clin N Am. 2017;64(3):677–84. Rawat D, et al. Phenotypic variation and long-term outcome in children with congenital hepatic fibrosis. J Pediatr Gastroenterol Nutr. 2012;57(2):161–6. Reding R, et al. Steroid-free liver transplantation in children. Lancet. 2003;362(9401):2068–70. Rela M, et al. Auxiliary partial orthotopic liver transplantation for Crigler-Najjar syndrome type I. Ann Surg. 1999;229(4):565–9. Rezvani I, Auerbach VH. Primary hyperoxaluria. N Engl J Med. 2012;369(22):2162–3. Rombaux P, et al. Post-transplant lymphoproliferative disorder with supraglottic involvement. B-ENT. 2005;1(1):53–6. Sakamoto S, et al. Hepatic venous outflow obstruction in pediatric living donor liver transplantation using leftsided lobe grafts: Kyoto University experience. Liver Transpl. 2012;16(10):1207–14. Scheenstra R, et al. Growth and final height after liver transplantation during childhood. J Pediatr Gastroenterol Nutr. 2008;47(2):165–71. Scheenstra R, et al. Graft fibrosis after pediatric liver transplantation: ten years of follow-up. Hepatology. 2009; 49(3):880–6. Schulz-Juergensen S, et al. Markers of operational immune tolerance after pediatric liver transplantation in patients under immunosuppression. Pediatr Transplant. 2012; 17(4):348–54. Settmacher U, et al. Living-donor liver transplantation–European experiences. Nephrol Dial Transplant. 2004;19(Suppl 4):iv16–21. Shemesh E. Non-adherence to medications following pediatric liver transplantation. Pediatr Transplant. 2004;8(6):600–5. Shirouzu Y, et al. Massive ascites after living donor liver transplantation with a right lobe graft larger than 0.8% of the recipient’s body weight. Clin Transplant. 2012;24(4):520–7. Shneider BL. Pediatric liver transplantation in metabolic disease: clinical decision making. Pediatr Transplant. 2002;6(1):25–9. Shneider BL, Suchy FJ, Emre S. National and regional analysis of exceptions to the pediatric end-stage liver disease scoring system (2003–2004). Liver Transpl. 2006;12(1):40–5. Soanes C, Timmons S. Improving transition: a qualitative study examining the attitudes of young people with chronic illness transferring to adult care. J Child Health Care. 2004;8(2):102–12. Sokal EM. Quality of life after orthotopic liver transplantation in children. An overview of physical, psychological and social outcome. Eur J Pediatr. 1995;154 (3):171–5.

391 Spearman CW, et al. Liver transplantation at red cross war memorial Children's hospital. S Afr Med J. 2006; 96(9 Pt 2):960–3. Squires RH Jr, et al. Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr. 2006;148(5):652–8. Stevens LH, et al. Hepatic artery thrombosis in infants. A comparison of whole livers, reduced-size grafts, and grafts from living-related donors. Transplantation. 1992;53(2):396–9. Stringer MD. The role of liver transplantation in the management of paediatric liver tumours. Ann R Coll Surg Engl. 2007;89(1):12–21. Stringer MD, et al. Survival and outcome after hepatic artery thrombosis complicating pediatric liver transplantation. J Pediatr Surg. 2001;36(6):888–91. Strobele B, Loveland J, Britz R, Gottlich E, Welthagen A, Botha J. Combined paediatric liver-kidney transplantation: analysis of our experience and literature review. S Afr Med J. 2013;12(103):925–9. Sucato GS, Murray PJ. Developmental and reproductive health issues in adolescent solid organ transplant recipients. Semin Pediatr Surg. 2006;15(3):170–8. Sundaram SS, et al. Adolescent health-related quality of life following liver and kidney transplantation. Am J Transplant. 2007;7(4):982–9. Talcott JB, Beath SV, Patel T, Griffiths G, Kelly DA. Long-term effects of cholestatic liver disease in childhood on neuropsychological outcomes and neurochemistry. J Pediatr Gastroenterol Nutr. 2019;69(2): 145–151. Tan KC, et al. Hepatic artery thrombosis in pediatric liver transplantation. J Pediatr Surg. 1988;23(10): 927–30. Tan KC, et al. Surgical anatomy of donor extended right trisegmentectomy before orthotopic liver transplantation in children. Br J Surg. 1991;78(7):805–8. Tanaka K, Ogura Y. “Small-for-size graft” and “small-forsize syndrome” in living donor liver transplantation. Yonsei Med J. 2004;45(6):1089–94. Trotter JF, Adam R, Lo CM, Kenison J. Documented deaths of hepatic lobe donors for living donor liver tarnsplantation. Liver Transpl. 2006;12:1485. UK, L.A.G. 2012. http://www.uktransplant.org.uk. Van Obbergh LJ, et al. Hepatopulmonary syndrome and liver transplantation: a review of the peroperative management of seven paediatric cases. Paediatr Anaesth. 1998;8(1):59–64. Vilca Melendez H, et al. Bowel perforation after paediatric orthotopic liver transplantation. Transpl Int. 1998;11(4): 301–4. Vilca-Melendez H, Heaton ND. Paediatric liver transplantation: the surgical view. Postgrad Med J. 2004; 80(948):571–6. de Ville de Goyet J. Technical-variant liver grafts in pediatric liver transplantation: back to the future. Transplantation. 1999;68(4):471–2. de Ville de Goyet J, et al. Impact of innovative techniques on the waiting list and results in pediatric liver

392 transplantation. Transplantation. 1993;56(5): 1130–6. de Ville de Goyet J, et al. Standardized quick en bloc technique for procurement of cadaveric liver grafts for pediatric liver transplantation. Transpl Int. 1995;8(4): 280–5. de Ville de Goyet J, et al. Original extrahilar approach for hepatic portal revascularization and relief of extrahepatic portal hypertension related to later portal vein thrombosis after pediatric liver transplantation. Long term results. Transplantation. 1996;62(1):71–5. Viner R. Transition from paediatric to adult care. Bridging the gaps or passing the buck? Arch Dis Child. 1999;81(3):271–5.

K. Sharif and D. A. Kelly Wallot MA, et al. Long-term survival and late graft loss in pediatric liver transplant recipients–a 15-year singlecenter experience. Liver Transpl. 2002;8(7):615–22. Watson AR. Problems and pitfalls of transition from paediatric to adult renal care. Pediatr Nephrol. 2005; 20(2):113–7. Zuo KJ, Draginov A, Panossian A, et al. Microvascular hepatic artery anastomosis in pediatric living donor liver transplantation: 73 consecutive cases performed by a single surgeon. Plast Reconstr Surg. 2018;142(6): 1609–19.

Intestinal Transplantation

27

Christophe Chardot

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394 Indications for IT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394 Assessment and Preparation for IT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 Transplant Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 Postoperative Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400 Results of IT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401 Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404

Abstract

Intestinal failure (IF) is characterized by the inability of the digestive tract to absorb nutrients in order to cover metabolic needs. The main etiologies in children are short bowel (mainly after intestinal atresia, gastroschisis, necrotizing enterocolitis, and midgut volvulus), intestinal motility disorders (Long segment Hirschsprung’s disease and intestinal pseudo-obstruction), and congenital enterocyte disorders causing intractable diarrhea (tufting enteropathy and microvillus inclusion disease). The first-line treatment of intestinal failure is parenteral nutrition (PN),

C. Chardot (*) Hôpital Necker-Enfants Malades, Service de chirurgie pédiatrique viscérale, Université Paris Descartes, Paris, France e-mail: [email protected]

which provides excellent long-term results (90% patient survival, with close to a normal quality of life on home PN). In short bowel syndromes, intestinal rehabilitation programs, including intestinal lengthening techniques, may help to partially or totally reverse the dependency on PN. Intestinal transplantation is indicated in cases of irreversible intestinal failure and severe complications of PN: loss of venous access due to large vessel thrombosis, lifethreatening line infections, liver disease, and poor quality of life in some patients, due to chronic intestinal obstruction and/or water and electrolyte losses. Other rare indications include retransplantations and (exceptionally) tumors. Intestinal transplantation is classified into four surgical subtypes, according to the organs needed together with the small bowel +/ right colon: isolated intestinal

© Springer-Verlag GmbH Germany, part of Springer Nature 2021 P. Puri (ed.), Pediatric Surgery, https://doi.org/10.1007/978-3-662-43559-5_118

393

394

transplantation, liver and intestinal transplantation, modified multivisceral transplantation (all digestive organs without the liver), and multivisceral transplantation (all digestive organs with the liver). A renal transplantation may be added if needed. Adequate preparation for the procedure is very important, since the short-term results correlate with the general condition of the child at surgery. The intestine is a highly immunogenic organ, requiring a high level of immunosuppression. After intestinal transplantation, the child is exposed to rejection and early to late graft loss and to complications of immunosuppression, including infections, tumors, and drug toxicity (mainly renal function impairment). Current research aims at improving graft survival and reducing the complications of immunosuppression, the transplant Graal being induced tolerance. Keywords

Intestinal failure · Surgery · Intestinal transplantation · Pediatric

Introduction Intestinal failure (IF) is the critical reduction of the gut mass or its function and is characterized by the inability of the intestine to provide sufficient digestion and absorption capacities to cover nutritional requirements for maintenance in adults and growth in children (Goulet et al. 2004, 2019). Parenteral nutrition (PN), including home PN, is the first-line treatment for children with intestinal failure and allows satisfactory growth and acceptable (although not normal) quality of life in most patients (Colomb et al. 2007; Pironi et al. 2012a). In patients with short bowel (“Short Bowel Syndrome”), intestinal adaptation, a spontaneous process which can be enhanced by intestinal rehabilitation techniques (Stanger et al. 2013), including non-transplant surgery (Frongia et al. 2013), may with time allow partial or total weaning from PN. If irreversible and life-threatening complications of PN occur, intestinal

C. Chardot

transplantation (IT), isolated or combined with the liver and/or other organs, provides children with a second chance of survival. Since the early days of IT in the 1980s (under ciclosporin-based immunosuppressive regimens), significant progress has been made in the medical and surgical management of children requiring IT, with shortterm results (1-year patient and graft survival) nowadays approaching those of liver transplantation (Grant et al. 2005) (▶ Chap. 26, “Pediatric Liver Transplantation”). However, the intestine is a highly immunogenic and septic organ, whose transplantation requires a high level of immunosuppression, and may expose the patient to a wide range of medical complications, including late graft loss. Therefore, significant concerns do persist regarding the medium- and long-term results of IT, which, together with the progress in the management of children with intestinal failure, have limited the expansion of IT in the last decade (Intestinal-Transplant-Association 2013; Norsa et al. 2019) (Fig. 1).

Indications for IT The causes of IF in children can be divided in five groups (Grant et al. 2005; Intestinal-TransplantAssociation 2013) (Fig. 2): 1. Short bowel syndrome is the leading cause of IF and is mainly due to gastroschisis, midgut volvulus, necrotizing enterocolitis, and intestinal atresia. 2. Motility disorders: long-segment Hirschsprung’s disease and chronic intestinal pseudoobstruction. 3. Epithelial disorders with intractable diarrhea, like microvillus inclusion disease and tufting enteropathy. 4. Retransplantations. 5. Miscellaneous, including tumors. Parenteral nutrition (PN), including home PN, is the first-line treatment of children with IF. However, severe complications of PN may occur, mainly line sepsis, loss of venous access due to thrombosis, liver disease leading to cirrhosis

27

Intestinal Transplantation

395

Number of Transplants

150

SBT MVT Modified MVT Liver/SBT

100

50

0 1986

1990

1994

1998

2002

2006

2010

2014

Year of Transplant Fig. 1 Intestinal transplantation worldwide: 1985-2017 Data from the international Intestinal Transplant Registry (Raghu et al. 2019)

Fig. 2 Indications for pediatric IT. Data from the Intestine Transplant Registry 2013 update report (Intestinal-TransplantAssociation 2013): 1611 pediatric intestinal transplantations (patients’ age