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Author: Prem Puri

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Newborn Surgery

To Veena, Abir, Anita and Niki for their love and patience

Newborn Surgery Second Edition

Edited by

Prem Puri MS FRCS FRCS (Ed) FACS Newman Clinical Research Professor, University College Dublin Consultant Paediatric Surgeon, Our Lady’s Hospital for Sick Children and National Children’s Hospital, Dublin, Ireland Director of Research, Children’s Research Centre, Our Lady’s Hospital for Sick Children, Dublin, Ireland

A member of the Hodder Headline Group LONDON

First published in Great Britain in 1996 by Butterworth-Heinemann Ltd This edition published in 2003 by Arnold, a member of the Hodder Headline Group, 338 Euston Road, London NW1 3BH http://www.arnoldpublishers.com Distributed in the United States of America by Oxford University Press Inc. 198 Madison Avenue, New York, NY 10016 Oxford is a registered trademark of Oxford University Press © 2003 Arnold All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronically or mechanically, including photocopying, recording or any information storage or retrieval system, without either prior permission in writing from the publisher or a licence permitting restricted copying. In the United Kingdom such licences are issued by the Copyright Licensing Agency: 90 Tottenham Court Road, London W1T 4LP Whilst the advice and information in this book are believed to be true and accurate at the date of going to press, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. In particular (but without limiting the generality of the preceding disclaimer) every effort has been made to check drug dosages; however it is still possible that errors have been missed. Furthermore, dosage schedules are constantly being revised and new side effects recognized. For these reasons the reader is strongly urged to consult the drug companies’ printed instructions before administering any of the drugs recommended in this book. British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN 0 340 76144 X (hb) 2 3 4 5 6 7 8 9 10 Publisher: Joanna Koster Development Editor: Michael Lax Production Editor: James Rabson Production Controller: Bryan Eccleshall Cover Design: Stewart Larking Typeset in Great Britain by Phoenix Photosetting, Chatham, Kent Printed and bound in Great Britain by CPI Bath

Contents

Preface Contributors PART 1

xi xiii

GENERAL

1

1

Embryology of malformations Dietrich Kluth, Wolfgang Lambrecht and Christoph Bührer

3

2

Prenatal diagnosis of surgical diseases Tippi C. MacKenzie and N. Scott Adzick

15

3

Fetal and birth trauma Prem Puri

27

4

Transport of the surgical neonate Prem Puri and Diane De Caluwé

39

5

Preoperative assessment Prem Puri and Diane De Caluwé

45

6

Anesthesia Declan Warde

59

7

Postoperative management Desmond Bohn

71

8

Fluid and electrolyte balance in the newborn Winifred A. Gorman

89

9

Nutrition Agostino Pierro

103

10

Vascular access in the newborn Juda Z. Jona

121

11

Radiology in the newborn Noel S. Blake

131

12

Immune system of the newborn Denis J. Reen

139

13

Hematological problems in the neonate Owen P. Smith

147

14

Genetics in neonatal surgical practice Andrew Green

157

15

Ethical considerations in newborn surgery Jacqueline J. Glover and Donna A. Caniano

173

16

Minimally invasive neonatal surgery Ashley Vernon, Timothy Kane and Keith E. Georgeson

183

vi Contents 17

Fetal surgery Jyoji Yoshizawa, Lourenço Sbragia and Michael R. Harrison

189

PART 2

HEAD AND NECK

199

18

Choanal atresia in the newborn Francesco Cozzi and Denis A. Cozzi

201

19

Pierre Robin sequence Evelyn H. Dykes

207

20

Macroglossia George G. Youngson

215

21

Tracheostomy in infants Thom E. Lobe

219

22

Miscellaneous conditions of the neck and oral cavity Anies Mahomed

227

PART 3

CHEST

237

23

Congenital thoracic deformities Robert C. Shamberger

239

24

Mediastinal masses in the newborn Steven J. Shochat

247

25

Subglottic stenosis Felix Schier

253

26

Tracheomalacia I. Vinograd and R. M. Filler

259

27

Vascular rings Ehud Deviri and Morris J. Levy

267

28

Pulmonary air leaks Prem Puri

277

29

Chylothorax and other pleural effusions in neonates Richard G. Azizkhan

283

30

Congenital malformations of the lung Horace P. Lo and Keith T. Oldham

295

31

Congenital diaphragmatic hernia Tina Granholm, Craig T. Albanese and Michael R. Harrison

309

32

Extracorporeal membrane oxygenation for neonatal respiratory failure Eugene S. Kim and Charles J. H. Stolar

317

33

Bronchoscopy in the newborn John D. Russell

329

PART 4

ESOPHAGUS

335

34

Esophageal atresia and tracheo-esophageal ﬁstula Paul D. Losty and Colin T. Baillie

337

35

Congenital esophageal stenosis Shintaro Amae, Masaki Nio, Yutaka Hayashi and Ryoji Ohi

353

Contents vii 36

Esophageal duplication cysts Leela Kapila, H. W. Holliday

359

37

Esophageal perforation in the newborn Hirikati S. Nagaraj

365

38

Gastro-esophageal reﬂux Victor E. Boston

369

PART 5

GASTROINTESTINAL

381

39

Pyloric atresia and prepyloric antral diaphragm Vincenzo Jasonni

383

40

Hypertrophic pyloric stenosis Prem Puri and Ganapathy Lakshmanadass

389

41

Gastric volvulus Mark D. Stringer

399

42

Gastric perforation Robert K. Minkes

405

43

Gastrostomy Michael W. L. Gauderer

411

44

Duodenal obstruction Yechiel Sweed

423

45

Malrotation Lewis Spitz

435

46

Persistent hyperinsulinemic hypoglycemia of infancy Lewis Spitz

441

47

Jejuno-ileal atresia and stenosis Heinz Rode and A. J. W. Millar

445

48

Colonic and rectal atresias Tomas Wester

457

49

Meconium ileus Edward Kiely

465

50

Meconium peritonitis Jose Boix-Ochoa and J. Lloret

471

51

Duplications of the alimentary tract Prem Puri

479

52

Mesenteric and omental cysts Daniel L. Mollitt

489

53

Neonatal ascites Prem Puri

497

54

Necrotizing enterocolitis Ann M. Kosloske

501

55

Hirschsprung’s disease Prem Puri

513

56

Anorectal anomalies Alberto Peña

535

57

Congenital segmental dilatation of the intestine Hiroo Takehara and Hiroki Ishibashi

553

viii Contents 58

Intussusception Spencer W. Beasley

557

59

Inguinal hernia Juan A. Tovar

561

60

Short bowel syndrome and surgical techniques for the baby with short intestines Michael E. Höllwarth

569

PART 6

LIVER AND BILIARY TRACT

577

61

Biliary atresia Ken Kimura

579

62

Congenital biliary dilatation (choledochal cyst) Takeshi Miyano and Atsuyuki Yamataka

589

63

Hepatic cysts and abscesses David A. Partrick and Frederick M. Karrer

597

PART 7

ANTERIOR ABDOMINAL WALL DEFECTS

603

64

Omphalocele and gastroschisis Steven W. Bruch and Jacob C. Langer

605

65

Omphalomesenteric duct remnants David A. Lloyd

615

66

Bladder exstrophy: considerations and management of the newborn patient Fernando A. Ferrer and John P. Gearhart

619

67

Cloacal exstrophy Jonathan I. Groner and Moritz M. Ziegler

629

68

Prune belly syndrome Prem Puri and Hideshi Miyakita

637

69

Conjoined twins Harry Applebaum

643

PART 8

TUMORS

649

70

Epidemiology and genetic associations of neonatal tumors Sam W. Moore and Jack Plaschkes

651

71

Hemangiomas and vascular malformations Prem Puri and Laszlo Nemeth

663

72

Congenital nevi Bruce S. Bauer and Julia Corcoran

675

73

Lymphatic malformations (cystic hygroma) Jacob C. Langer and Vito Forte

687

74

Cervical teratomas Michael W. L. Gauderer

697

75

Sacrococcygeal teratoma Kevin C. Pringle

703

76

Nasal tumors Alfred Lamesch and Peter Lamesch

715

Contents ix 77

Neuroblastoma Raymond J. Fitzgerald

721

78

Soft-tissue sarcoma David A. Lloyd

733

79

Hepatic tumors Yoshiaki Tsuchida and Norio Suzuki

739

80

Congenital mesoblastic nephroma and Wilms’ tumor Robert Carachi

747

81

Neonatal ovarian tumors Jean Gaudin

751

PART 9

SPINA BIFIDA AND HYDROCHEPHALUS

759

82

Spina biﬁda and encephalocele Prem Puri and Rajendra Surana

761

83

Hydrocephalus Raymond J. Fitzgerald

775

PART 10 GENITOURINARY

785

84

Imaging of the renal tract in the neonate Isky Gordon

787

85

Management of antenatally detected hydronephrosis Jack S. Elder

793

86

Multicystic dysplastic kidney David F. M. Thomas and Azad S. Najmaldin

809

87

Upper urinary tract obstructions Prem Puri and Boris Chertin

817

88

Duplication anomalies Prem Puri and Hideshi Miyakita

831

89

Vesico-ureteric reﬂux Prem Puri

837

90

Ureteroceles in the newborn Peter Frey, Mario Mendoza-Sagaon and Blaise J. Meyrat

845

91

Congenital posterior urethral obstruction Reisuke Imaji, Daniel Moon and Paddy A. Dewan

855

92

Neuropathic bladder Paddy A. Dewan, Paul D. Anderson and Gunnar Aksnes

867

93

Hydrometrocolpos Devendra Gupta

875

94

Intersex Ronald J. Sharp

883

95

Male genital anomalies John M. Hutson

903

96

Neonatal testicular torsion David M. Burge

909

x Contents PART 11 LONG-TERM OUTCOMES IN NEWBORN SURGERY

913

97

Long-term outcomes in newborn surgery Mark D. Stringer

915

Index

925

Preface to the Second Edition

The 2nd edition of Newborn Surgery has been extensively revised. Many new chapters have been added to take account of the recent developments in the care of the newborn with congenital malformations. This edition which comprises 97 chapters by 121 contributors from all ﬁve continents of the world, provides an authoritative, comprehensive and complete account of the various surgical conditions in the newborn. Each chapter is written by the current leading expert(s) in their respective ﬁelds. Newborn Surgery in the 21st century demands of its practitioners detailed knowledge and understanding of the complexities of congenital anomalies as well as the highest standards of operative techniques. In this textbook great emphasis continues to be placed on providing a comprehensive description of operative techniques of each individual congenital condition in the newborn.

The book is intended for trainees in paediatric surgery, established paediatric surgeons, general surgeons with an interest in paediatric surgery as well as neonatologists and paediatricians seeking more detailed information on newborn surgical conditions. I wish to thank most sincerely all the contributors for the outstanding work they have done for the production of this innovative textbook. I also wish to express my gratitude to Mrs Karen Alfred and Ms Ann Brennan for their secretarial help and to the staff of Arnold for their help during the preparation and publication of this book. I am thankful to the Children’s Medical & Research Foundation, Our Lady’s Hospital for Sick Children, Dublin for their support. Prem Puri 2003

Preface to the First Edition

During the last three decades, newborn surgery has developed from an obscure subspeciality to an essential component of every major academic paediatric surgical department throughout both the developed and the developing world. Major advances in perinatal diagnosis, imaging, neonatal resuscitation, intensive care and operative techniques have radically altered the management of newborns with congenital malformations. Embryological studies have provided new valuable insights into the development of malformations, while improvements in prenatal diagnosis are having a signiﬁcant impact on approaches to management. Monitoring techniques for the sick neonate pre- and postoperatively have become more sophisticated and there is now greater emphasis on physiological aspects of the surgical newborn as well as their nutritional and immune status. This book provides a comprehensive compendium of all these aspects as a prelude to an extensive description of surgical conditions in the newborn. Modern-day newborn surgery demands detailed knowledge of the complexities of newborn problems. Research developments, laboratory diagnosis, imaging and innovative

surgical techniques are all part of the challenge facing surgeons dealing with congenital conditions in the newborn. In this book, a comprehensive description of operative techniques of each individual condition is presented. Each contributor was selected to provide an authoritative, comprehensive and complete account of their respective topics. The book, comprising 90 chapters, is intended primarily for trainees in paediatric surgery, established paediatric surgeons, general surgeons with an interest in paediatric surgery and neonatologists. I am most grateful to all contributors for their willingness to contribute chapters at considerable cost of time and effort. I am indebted to Mr Maurice De Cogan for artwork, Mr Dave Cullen for photography and Ms Ann Brennan and Ms Deirdre O’Driscoll for skilful secretarial help. I am thankful to the Children’s Research Centre, Our Lady’s Hospital for Sick Children, for their support. Finally, I wish to thank the editorial staff, particularly Ms Susan Devlin, of Butterworth-Heinemann for their help during the preparation and publication of this book. Prem Puri

Contributors

N. Scott Adzick MD Professor of Surgery Surgeon-in-Chief Department of Surgery The Center for Fetal Diagnosis and Treatment Children’s Hospital of Philadelphia Philadelphia, USA Gunnar Aksnes MD PhD Consultant Paediatric Surgeon Department of Paediatric Surgery Ulleval University Hospital Oslo, Norway Craig T. Albanese MD Professor of Surgery Chief, Division of Pediatric Surgery Stanford University Medical Center Palo Alto California, USA

Colin T. Baillie MBChB DCH ChM FRCS(Paeds) Consultant Paediatric Surgeon Royal Liverpool Children’s Hospital (Alder Hey) Liverpool, UK Bruce S. Bauer MD FACS FAAP Professor & Head Division of Pediatric Plastic Surgery Children’s Memorial Hospital Division of Plastic Surgery McGraw Medical School of Northwestern University Chicago Illinois, USA Spencer W. Beasley MBChB (Otago) MS (Melb) FRACS Professor of Paediatric Surgery Paediatric Surgeon and Urologist Department of Paediatric Surgery Christchurch Hospital Christchurch, New Zealand

Shintaro Amae MD Lecturer Division of Pediatric Surgery Tohoku University School of Medicine Sendai, Japan

Noel S. Blake FRCR FFRRCSI Consultant Radiologist Our Lady’s Hospital for Sick Children Dublin, Ireland

Paul D. Anderson MBBS Urology Research Fellow Urology Unit Royal Children’s Hospital Melbourne, Australia

Desmond Bohn MB FRCPC MRCP(UK) FFARCS Associate Chief Department of Critical Care Medicine The Hospital for Sick Children Toronto, Canada

Harry Applebaum MD Head, Division of Pediatric Surgery Department of Surgery Kaiser Permanente Medical Center Los Angeles California, USA Richard G. Azizkhan MD Surgeon-in-Chief Lester Martin Chair of Pediatric Surgery Cincinnati Children’s Hospital Professor of Surgery and Pediatrics University of Cincinnati School of Medicine Cincinnati Ohio, USA

Jose Boix-Ochoa MD Chairman of Pediatric Surgery Professor of Pediatric Surgery Autonomous University of Barcelona Hospital Materno-Infantil Vall d’Hebron Barcelona, Spain Victor E. Boston MD FRCS(Ed) FRCSI FRCS (Eng) Consultant Paediatric Surgeon Royal Belfast Hospital for Sick Children Honorary Senior Lecturer Department of Surgery Queen’s University Belfast, UK

xiv Contributors LCDR Steven W. Bruch MC USNR Staff Pediatric Surgeon Naval Medical Center Portsmouth, USA Christoph Bührer MD Consultant Paediatrician Department of Neonatology Campus-Virchow-Klinikum Medical Faculty Charite Humboldt University Berlin, Germany

Ehud Deviri MD MSurg Consultant Cardiothoracic Surgeon Department of Cardiothoracic Surgery Hadassah University Hospital Hebrew University Jerusalem, Israel Paddy A. Dewan PhD MD MS MmedSc FRCS FRACS Paediatric Urologist Royal Children’s Hospital Melbourne, Australia

David Burge FRCS FRCPCH Consultant Paediatric Surgeon Wessex Regional Centre for Paediatric Surgery Southampton, UK

Evelyn H. Dykes MBChB FRCS (Paeds) Senior Lecturer in Paediatric Surgery Kings College London, UK

Diane De Caluwé MD Consultant Paediatric Surgeon Department of Paediatric Surgery Chelsea and Westminster Hospital London, UK

Jack S. Elder MD Director Division of Pediatric Urology Rainbow Babies & Children’s Hospital Professor of Urology & Pediatrics Case Western Reserve University School of Medicine Cleveland Ohio, USA

Donna A. Caniano MD Surgeon-in-Chief Department of Pediatric Surgery Children’s Hospital Ohio, USA Robert Carachi MD FRCS Head of Department Department of Surgical Paediatrics Royal Hospital for Sick Children Glasgow, UK Boris Chertin MD Consultant Pediatric Urologist Department of Urology Shane Zedek Medical Center Jerusalem, Israel Julia Corcoran MD FACS FAAP Attending Surgeon Division of Pediatric Plastic Surgery Children’s Memorial Hospital Division of Plastic Surgery McGraw Medical School of Northwestern University Chicago Illinois, USA

Fernando A. Ferrer MD Assistant Professor of Pediatric Urology Connecticut Childrens’ Hospital Hartford Connecticut, USA R. M. Filler MD FRCS(C) Professor and Surgeon-in-Chief Hospital of Sick Children Professor of Pediatrics University of Toronto Ontario, Canada Raymond J. Fitzgerald MA MB FRCSI FRCS FRACS (Paed Surg) FRCS (Ed) Ad. hom

Associate Professor in Paediatric Surgery Trinity College Consultant Paediatric Surgeon Children’s Hospital and Our Lady’s Hospital for Sick Children Dublin, Ireland

Denis A. Cozzi MD Consultant Pediatric Surgeon Department of Pediatric Surgery University of Rome Rome, Italy

Vito Forte MD FRCSC Paediatric Otolaryngologist Hospital for Sick Children Associate Professor of Otolaryngology University of Toronto Toronto, Canada

Francesco Cozzi MD Associate Professor and Head of Pediatric Surgery Department of Pediatric Surgery University of Rome Rome, Italy

Peter Frey MD BSc PD FMH Consultant Pediatric Surgeon Department of Pediatric Surgery Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne, Switzerland

Contributors xv Michael W. L. Gauderer MD FACS, FAAP Professor of Surgery University of South Carolina School of Medicine Chief, Department of Pediatric Surgery Children’s Hospital Greenville Hospital System Greenville South Carolina, USA Jean Gaudin MD Paediatric Surgeon Department of Paediatric Surgery Hôpital St Louis La Rochelle, France John P. Gearhart MD Professor & Director Division of Pediatric Urology James Buchanan Brady Urological Institute Johns Hopkins Hospital Baltimore Maryland, USA Keith E. Georgeson MD Professor and Director Division of Pediatric Surgery Children’s Hospital of Alabama Birmingham Alabama, USA Jacqueline J. Glover PhD Associate Professor Center for Health Ethics and Law West Virginia University College of Medicine and Children’s Hospital Morgantown West Virginia, USA

Andrew Green MB, PhD, FRCPI, FFPath(RCPI) Director National Centre for Medical Genetics Our Lady’s Hospital for Sick Children Dublin, Ireland Jonathan I. Groner MD Assistant Professor Department of Surgery Children’s Hospital Columbus Ohio State University Columbus Ohio, USA Devendra Gupta MS MCH Professor of Paediatric Surgery All India Institute of Medical Sciences New Delhi, India Michael R. Harrison MD Professor of Surgery Pediatrics and Obstetrics Gynecology and Reproductive Sciences Director, Fetal Treatment Center Chief, Division of Pediatric Surgery University of California` San Francisco California, USA Yutaka Hayashi MD Professor Division of Pediatric Oncology Tohoku University School of Medicine Sendai, Japan Howard W. Holliday FRCS Consultant Paediatric Surgeon Derbyshire Children’s Hospital Derbyshire, UK

Isky Gordon FRCR Consultant Radiologist Great Ormond Street Hospital for Children Honorary Senior Lecturer Institute for Child Health London, UK

Michael E. Höllwarth MD Professor & Head Department of Paediatric Surgery University of Graz Medical School Graz, Austria

Winifred A. Gorman BSc FRCPI FAAP Consultant Paediatrician Department of Neonatology National Maternity Hospital Dublin, Ireland

John M. Hutson BS MD(Monash), MD(Melb) FRACS Professor & Director Russell Howard Department of General Surgery Royal Children’s Hospital F Douglas Stephens Surgical Research Laboratory Murdoch Children’s Research Institute Melbourne, Australia

Tina Granholm MD PhD Associate Professor Department of Pediatric Surgery Astrid Lindgren Children’s Hospital Director of Postgraduate Studies Department of Woman and Child Health Karolinska Hospital Karolinska Institute Stockholm, Sweden

Reisuke Imaji MD PhD Clinical Research Fellow Urology Unit Royal Children’s Hospital Department of Paediatrics University of Melbourne Murdoch Children’s Research Institute Melbourne, Australia

xvi Contributors Hiroki Ishibashi MD Pediatric Surgeon Department of Digestive and Pediatric Surgery University of Tokushima Tokushima, Japan Vincenzo Jasonni MD Professor and Director School of Pediatric Surgery Istituto Scientiﬁco ‘G Gaslini’ University of Genoa Genoa, Italy Juda Z. Jona MD FACS FAAP(S) Chief Division of Pediatric Surgery Evanston Northwestern Healthcare Evanston Illinois, USA Timothy Kane MD Chief Clinical Fellow Division of Pediatric Surgery Children’s Hospital of Alabama Birmingham Alabama, USA Leela Kapila OBE FRCS Consultant Paediatric Surgeon Department of Paediatric Surgery Queen’s Medical Centre Nottingham, UK Frederick M. Karrer MD Associate Professor of Surgery & Pediatrics & Head Division of Pediatric Surgery University of Colorado Health Sciences Center Surgical Director Pediatric Liver Transplantation Department of Pediatric Surgery The Children’s Hospital Denver Colorado, USA Edward Kiely FRCSI FRCS FRCPCH Consultant Paediatric Surgeon Hospital for Sick Children Great Ormond Street London, UK Eugene S. Kim MD Chief Resident Division of Pediatric Surgery College of Physicians and Surgeons Columbia University Children’s Hospital of New York New York Presbyterian Hospital New York, USA

Ken Kimura MD Professor of Surgery and Pediatrics Department of Surgery University of Iowa Hospitals & Clinics Iowa City Iowa, USA Dietrich Kluth MD PhD Paediatric Surgeon Department of Paediatric Surgery University Hospital Hamburg Hamburg, Germany Ann M. Kosloske MD MPH Professor of Surgery and Pediatrics Texas Technical University Health Science Center Lubbock Texas, USA Ganapathy Lakshmanadass MS MChFRCS Senior Registrar in Paediatric Surgery Department of Paediatric Surgery National Children’s Hospital Dublin, Ireland Wolfgang Lambrecht MD Surgeon-in-Chief Department of Paediatric Surgery Eppendorf University Hospital Hamburg, Germany Alfred Lamesch MD FACS Emeritus Professor Université Libre de Bruxelles Surgeon-in-Chief Emeritus Department of Paediatric Surgery Luxembourg Hospital Center Honorary Member of the Académie Royale de Médecine Belgium Peter Lamesch MD FACS Professor of Surgery Department of Abdominal, Transplant & Vascular Surgery University of Leipzig Leipzig, Germany Jacob C. Langer MD FRCSC Chief, Paediatric General Surgery Hospital for Sick Children Toronto, Canada Morris J. Levy MD Professor of Surgery Department of Thoracic and Cardiovascular Surgery Sackler School of Medicine Tel Aviv University Tel Aviv, Israel David A. Lloyd MChir FRCS FCS(SA) Professor of Paediatric Surgery Institute of Child Health Royal Liverpool Children’s Hospital (Alder Hey) Liverpool, UK

Contributors xvii J. Lloret MD Pediatric Surgeon Neonatal and Oncological Unit Hospital Materno-Infantil Vall d’Hebron Barcelona, Spain Horace P. Lo MD Senior Resident Department of Surgery Medical College of Wisconsin Milwaukee Wisconsin, USA Thom E. Lobe MD Chairman, Section of Pediatric Surgery University of Tennessee Memphis Tennessee, USA Paul D. Losty MD FRCSI FRCS(Eng) FRCS(Ed) FRCS(Paed) Reader & Honorary Consultant Paediatric Surgeon Department of Paediatric Surgery Royal Liverpool Children’s Hospital (Alder Hey) and The University of Liverpool Liverpool, UK Tippi C. MacKenzie MD Fetal Surgery Research Fellow The Center for Fetal Diagnosis and Treatment Children’s Hospital of Philadelphia Philadelphia, USA Anies Mahomed MBBCH FCS(SA) FRCS(Glas.Ed) FRCS(Paeds) Consultant Paediatric Surgeon Department of Paediatric Surgery Royal Aberdeen Children’s Hospital Aberdeen, UK Mario Mendoza-Sagaon MD Senior Registrar Department of Pediatric Surgery CHUV Lausanne, Switzerland Blaise J. Meyrat MD Consultant Paediatric Urologist and Surgeon Department of Pediatric Surgery CHUV Lausanne, Switzerland A. J. W. Millar FRCS (Eng) (Edin) FRACS DCH Associate Professor Department of Paediatric Surgery University of Cape Town Senior Surgeon Red Cross War Memorial Children’s Hospital Cape Town, South Africa

Robert K. Minkes MD PhD Associate Professor of Surgery Chief, Section of Pediatric Surgery Louisiana State University Heath Sciences Center Children’s Hospital of New Orleans Louisiana, USA Hideshi Miyakita MD Consultant Paediatric Urologist Tokai University School of Medicine Kanagawa, Japan Takeshi Miyano MD, PhD, FAAP(Hon), FACS, FAPSA(Hon) Director of Juntendo University Hospital Professor and Head Department of Pediatric Surgery Juntendo University Scholl of Medicine Tokyo, Japan Daniel L. Mollitt MD Professor and Chief Division of Pediatric Surgery University of Florida Health Scince Center Jacksonville Florida, USA Daniel Moon MB, BS Urology Research Fellow Kids Urology Research Unit Royal Children’s Hospital Melbourne, Australia Sam W. Moore MBChB FRCS MD Professor & Head Department of Paediatric Surgery Faculty of Medicine University of Stellenbosch Tygerberg, South Africa Hirikati S. Nagaraj MD Associate Professor of Surgery Kosair Children’s Hospital University of Louisville Chief, General and Thoracic Surgery Kentucky, USA Azad S. Najmaldin MB ChB MS FRCSEd FRCS Consultant Paediatric Surgeon & Urologist St James’s University Hospital Leeds, UK Laszlo Nemeth MD Consultant Paediatric Surgeon University of Szeged Szeged, Hungary Masaki Nio MD Associate Professor of Pediatric Surgery Senior Lecturer Division of Pediatric Surgery Tohoku University School of Medicine Sendai, Japan

xviii Contributors Ryoji Ohi MD Professor and Chief Division of Pediatric Surgery Tohoku University School of Medicine Sendai, Japan Keith T. Oldham MD Professor and Chief Division of Pediatric Surgery Vice Chairman Department of Surgery Medical College of Wisconsin Milwaukee Wisconsin, USA David A. Partrick MD Assistant Professor in Surgery and Pediatrics University of Colorado Health Sciences Center Director of Surgical Endoscopy The Children’s Hospital Denver Colorado, USA Alberto Peña MD FACS FAAP Professor & Chief Division of Pediatric Surgery Albert Einstein College of Medicine Schneider Children’s Hospital New Hyde Park New York, USA Agostino Pierro MD FRCS FAAP Professor of Paediatric Surgery Institute of Child Health and Great Ormond Street Hospital London, UK Jack Plaschkes MD FRCS Department of Paediatric Surgery Faculty of Medicine University of Stellenbosch Tygerberg, South Africa Kevin C. Pringle MB ChB FRACS Professor of Paediatric Surgery & Head Department of Obstetrics & Gynaecology Wellington School of Medicine and Health Sciences University of Otago Wellington, New Zealand Prem Puri MS FRCS FRCS(Ed) FACS Newman Clinical Research Professor University College, Dublin Consultant Paediatric Surgeon, Our Lady’s Hospital for Sick Children and National Children’s Hospital, Dublin Director of Research, Children’s Research Centre, Dublin, Ireland

Denis Reen MSc PhD Adjunct Professor in Medicine, University College, Dublin Professor, The Children’s Research Centre Our Lady’s Hospital for Sick Children Dublin, Ireland Heinz Rode Mmed(Chir) FCS(SA) FRCSEd Charles F M Saint Professor of Paediatric Surgery Department of Paediatric Surgery Red Cross Children’s Hospital Rondebosch, South Africa John D. Russell FRCSI, FRCS(ORL) Consultant Paediatric Otolaryngologist Our Lady’s Hospital for Sick Children Dublin, Ireland Lourenço Sbragia MD PhD Postdoctoral Research Scholar Fetal Treatment Center Division of Pediatric Surgery University of California San Francisco, USA Robert C. Shamberger MD Professor of Surgery Harvard Medical School Chief of Surgery (Interim) Department of Paediatric Surgery Childrens Hospital Boston Massachusetts, USA Ronald J. Sharp MD Director of Surgery Children’s Mercy Hospital Kansas City Missouri, USA Felix Schier MD Head of Department Department of Paediatric Surgery University Medical Centre Jena, Germany Steven J. Shochat MD Surgeon-in-Chief & Chairman Department of Surgery St Jude Children’s Research Hospital Memphis Tennessee, USA Owen P. Smith MA MB BA Mod (Biochem), FRCPCH FRCPI, FRCPLon, FRCPEdin, FRCPGlasg, FRCPath

Consultant Paediatric Haematologist Our Lady’s Hospital for Sick Children, and St James’s Hospital, Dublin Senior Lecturer in Haematology, Trinity College Dublin, Ireland

Contributors xix Lewis Spitz MB ChB PhD MD(Hon), FRCS(Edin), FRCS(Eng), FAAP(Hon), FRCPCH

Nufﬁeld Professor of Paediatric Surgery Institute of Child Health University College London and Great Ormond Street Hospital London, UK Charles J. H. Stolar MD Professor of Surgery and Pediatrics Division of Pediatric Surgery College of Physicians and Surgeons Columbia University Director of Pediatric Surgery Children’s Hospital of New York New York Presbyterian Hospital New York, USA

Juan A. Tovar MD Professor of Surgery Department of Surgery Hospital Infantil ‘La Paz’ Madrid, Spain Yoshiaki Tsuchida MD PhD FACS Director Department of Surgery Gunma Children’s Medical Center Gunma, Japan Ashley Vernon MD Research Fellow Division of Pediatric Surgery Children’s Hospital of Alabama Birmingham Alabama, USA

Mark D. Stringer BSc MS FRCS FRCS(Paed) FRCP FRCPCH Consultant Paediatric Surgeon Children’s Liver & GI Unit St James’s University Hospital Leeds, UK

I. Vinograd MD Head Department of Pediatric Surgery DANA Children’s Hospital Tel-Aviv, Israel

Rajendra Surana MS FRCS(Paed) Consultant Paediatric Surgeon Welsh Centre for Paediatric Surgery University Hospital of Wales Cardiff, UK

Declan Warde MB BCH FFARCSI Consultant Anaesthetist Department of Anesthesia The Children’s Hospital Dublin, Ireland

Norio Suzuki MD Chief of Surgery Department of Surgery Gunma Children’s Medical Center Gunma, Japan Yechiel Sweed MD Senior Lecturer in Surgery Rappaport School of Medicine The Technion Haifa Head Pediatric Surgery Western Galilee Hospital Nahariya, Israel Hiroo Takehara MD Associate Professor and Chief of Pediatric Surgeons Department of Digestive and Pediatric Surgery University of Tokushima Tokushima, Japan David F.M. Thomas FRCP FRCS Consultant Paediatric Urologist Reader in Paediatric Surgery Leeds Teaching Hospitals University of Leeds Leeds, UK

Tomas Wester MD PhD Consultant Paediatric Surgeon Department of Paediatric Surgery University Children’s Hospital Uppsala, Sweden Atsuyuki Yamataka MD Associate Professor of Pediatric Surgery Department of Pediatric Surgery Juntendo University School of Medicine Tokyo, Japan Jyoji Yoshizawa MD PhD Assistant Professor of Surgery Fetal Treatment Center University of California San Francisco, USA George G. Youngson PhD FRCS Honorary Professor of Paediatric Surgery Department of Paediatric Surgery Royal Aberdeen Children’s Hospital Aberdeen, UK Moritz M. Ziegler MD Robert E Gross Professor of Surgery Harvard Medical School Surgeon-in-Chief Children’s Hospital Boston Maryland, USA

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1 General

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1 Embryology of malformations DIETRICH KLUTH, WOLFGANG LAMBRECHT AND CHRISTOPH BÜHRER

INTRODUCTION

DEFINITION OF THE TERM ‘MALFORMATION’

Approximately 3% of human newborns present with congenital malformations.1 Without surgical intervention, one-third of these infants would die since their malformations are not compatible with sustained life outside the uterus.1,2 In ﬁgures, this means that in a country such as Germany, nearly 6000 children are born every year with a life-threatening malformation. Due to the development of prenatal diagnostic procedures, advanced surgical techniques, and intensive postoperative care, most infants with otherwise fatal malformations can be rescued by an operation in the neonatal period. However, morbidity remains high in some of these children2 with the necessity of repeated operations and hospitalizations despite a successful primary operation. This may also be the fate of many children with non-life-threatening malformations such as hypospadias or cleft palate. Mortality is still high in newborns with certain malformations such as congenital diaphragmatic hernias or severe combined defects. As a consequence, congenital malformations today are the main cause of death in the neonatal period. In the USA, 21% of neonatal mortality can be related to congenital malformations.3 These ﬁgures probably do not reﬂect a real increase of the actual incidence of congenital malformation. The observed mortality shift might rather be due to improved intensive care medicine in today’s western world countries where neonates (even those with birth defects) have a better chance of survival. On the other hand, this statistical shift indicates that knowledge about congenital malformations lags behind the progress clinical research has made in the surrounding ﬁelds. Efforts are needed to close the gap and learn more about baby killer No. 1. Identiﬁcation of teratogens will help to reduce the incidence of malformations when exposure can be avoided, and pathogenetic studies might aid in designing therapeutic measures. Both treatment and prevention critically depend on basic embryological research.

After birth neonates can present with a broad spectrum of deviations from normal morphology. This extends from minor variations of normal morphology without any clinical signiﬁcance to maximal organ defects with extreme functional deﬁcits of the malformed organs or of the whole organism. The degree of functional disorder is decisive when dealing with the question of whether a variation of normal morphology has to be viewed as a dangerous malformation requiring surgical correction. This means that functional disturbance is essential when using the term ‘malformation’. Inborn deviations can be detrimental, neutral, or even beneﬁcial, otherwise evolutionary progress could not take place. An example of a beneﬁcial deviation is the longevity syndrome of people with abnormally low serum cholesterol levels. Abnormalities with little or no functional disturbance might still require surgical correction when patients are in danger of social stigmatization. Coronal or glandular hypospadias might serve as an example for this condition.

ETIOLOGY OF CONGENITAL MALFORMATIONS In most cases, the etiology of congenital malformations remains unclear. Possible etiological factors are listed in Table 1.1. In about 20% of cases genetic factors (gene mutation and chromosomal disorders) can be identiﬁed.1,2,4 In 10% an environmental origin can be demonstrated.1,2 In 70% the factors responsible remain obscure. Table 1.1 Etiology of congenital malformations Genetic disorders Environmental factors Unknown etiology

20% 10% 70%

4 Embryology of malformations

Environmental factors A large number of agents are known which might interfere with the normal development of organ systems during embryogenesis.1,4 The underlying mechanisms of this interference is poorly understood in most cases. Characteristically, during organogenesis, different organs of the embryo show distinct periods of greatest sensitivity to the action of the teratogen. These phases of greatest sensitivity are called the ‘teratogenetic period of determination’.5 The typical patterns of some syndromes can be explained by an overlap of these phases during embryological development. In 1983, Shepard2 published a catalog of suspected teratogenic agents. Over 900 agents are known to produce congenital anomalies in experimental animals. In 30 evidence for teratogenic action in humans could be demonstrated. Teratogenic agents can be divided into four groups (Table 1.2). The teratogenic potential of virus infections,1 especially rubella and herpes, and that of radiation1 has been clearly established. Maternal metabolic defects and lack of essential nutritives can be teratogenic. After a vitamin A-free diet6 and riboﬂavin-free diet7 various congenital malformations were observed in rats and mice. Among these were diaphragmatic hernias, isolated esophageal atresias, and isolated tracheo-esophageal ﬁstulas. Similarly, inappropriate administration of hormones can be associated with intrauterine dysplasias.8 Industrial and pharmaceutical chemicals such as tetrachlor-diphenyl-dioxin (TCDD) or thalidomide have inﬂicted tragedies by their teratogenic action. When thalidomide was prescribed to women in the early 1960s as a ‘safe’ sleeping medication, numerous children were born with dysmelic deformities.4,9,10 In addition, atresias of the esophagus, the duodenum, and the anus were observed in some children.9 The data collected suggest that teratogenic agents do not cause new patterns of malformations but rather mimic sporadic birth defects. This had posed problems in identifying thalidomide as the responsible agent. It appears likely that among those 70% congenital malformations with unclear etiology a considerable percentage might be precipitated by as yet unidentiﬁed environmental factors. In a rat model, the herbicide nitrofen (2.4-dichloro-phenyl-p-nitrophenyl Table 1.2 Teratogenic agents in congenital malformations Physical agents

Radiation, heat, mechanical factors

Infectious agents

Viruses, treponemes, parasites

Chemical, drug, environmental agents

Thalidomide, nitrofen, hormones, vitamin deﬁciencies

Maternal, genetic factors

Chromosomal disorders, multifactorial inheritance

After Nadler.1

ether) has been shown to induce congenital diaphragmatic hernias, cardiac abnormalities and hydronephrosis.11–15 In 1978, Thompson et al. described the teratogenicity of the anti-cancer drug adriamycin in rats and rabbits.16 More recently, Diez-Pardo et al.17 redescribed this model with emphasis to its potentials as a model for foregut anomalies. Today, the adriamycin model is generally described as a model for the VACTERL-association (V=vertebral, A=anorectal, C=cardiac, T=tracheal, E=esophageal, R=renal, L=limb).18,19 Thus, classic malformations such as atresias of the esophagus and the intestinal tract, intestinal duplications and others can be mimicked by teratogens in animal models.

Genetic factors Approximately 20% of congenital malformations are of genetic origin. Most surgically correctable malformations are associated with chromosomal disorders, e.g. trisomy 21,13, or 18, or are of multifactorial inheritance20 with a small risk of recurrence. The assumption of multifactorial inheritance results from the fact that with nearly all major anomalies familiar occurrences had been observed.1 In animals inheritance has also been found for some malformations.21–24

EMBRYOLOGY OF MALFORMATIONS Disturbances of normal embryological processes will result in malformations of organs. This was ﬁrst shown by Spemann25 in 1901 by experimentally producing supernumary organs in the triton embryo after establishing close contact between excised parts of triton eggs and other parts of the same egg. Spemann and Mangold5 coined the term ‘induction’ to describe this observation. They found that certain parts of the embryo obviously were able to control embryonic development of other parts. These controlling parts were called ‘organizers’.5 The process of inﬂuence itself was called ‘induction’. It was believed by many scientists in the ﬁeld that ‘induction’ could serve as the overall principle of hierarchical control of embryonic development. Ensuing investigations, however, made modiﬁcations necessary, which ﬁnally resulted in a very complex model of organizers and inductors. The nature of inductive substances remained obscure and attempts to isolate inductive substances, meanwhile called ‘morphogenes’, were unsuccessful.26 Interestingly, not only live cells could induce development in certain experiments but also dead and denaturated material.5 A process essential for the formation of early embryonic organs is the invagination of epithelial sheets. This invagination is preceded by a thickening of the

Embryology of malformations 5

epithelial sheet,27 a process known as placode formation. The thickening itself is caused by elongation of individual cells of the placode. This process can be studied in detail in epithelial morphogenesis.28 The same sequence of developmental events has been observed in the formation of the neural plate, in the formation of the otic and lens placode and in the development of most epitheliomesenchymal organs including lung, thyroid gland and pancreas. From these observations it can be concluded that most epithelial cells behave uniformly in the early phase of embryonic development. Today it is generally accepted, that early embryonic organs are especially sensitive for alterations. Therefore researchers are more and more interested to understand the formation of early embryonic organs. In 1985 ETTERSOHN.29 stated that most invaginations are the results of mechanical forces that are local in origin. He focussed on three possible mechanisms which might lead to placode formation and subsequent invagination: 1 Change of cell shape by cell adhesion 2 Microﬁlament-mediated change of cell shape 3 Cell growth and division. In the following part, we will discuss some aspects of these mechanisms. A teratological method used to determine the function of cell adhesion molecules in vivo during embryogenesis has been reported recently.30 Mouse hybridoma cells producing monoclonal antibodies against the avian integrin complex were grafted into 2- or 3-day-old chick embryos. Depending on the site of engraftment, local muscle agenesis was observed. This is an example that the immunologic immaturity of the embryo can be exploited to study the contribution of cell attachment molecules to organ development in a functional fashion. A number of monoclonal antibodies directed against cell attachment molecules of various species have become available over the last 8 years, and the structure of the binding molecules has been elucidated biochemically and by cDNA cloning. Functionally, adhesion molecules may be grouped into three families: Cell adhesion molecules (CAMs), which mediate speciﬁc and mostly transient cell recognition of other cells, substrate adhesion molecules (SAMs), necessary for attachment to extracellular matrix proteins, and cell-junctional molecules (CJMs), found in tight and gap junctions. Whereas CJMs apparently play an important role for metabolic signalling within established tissues, CAMs and SAMs are necessary for the formation of histologically distinct structures and directed migration of single cells. Among CAMs and SAMs, at least three families have been identiﬁed biochemically: integrins,31 members of the immunoglobulin superfamiliy, and LEC-CAMS.32 Integrins are heterodimeric molecules consisting of a larger β chain, which is associated with a smaller α chain in a calcium-dependent way. Usually, one given β chain might be found in

association with various chains but promiscuity of α chains has been described recently. Functionally, members of the integrin family present as SAMs (adhesion to vitronectin, collagen, ﬁbronectin, complement components, or other intercellular matrix proteins) or CAMs (direct adhesion to other cells via corresponding cell surface target molecules). For example, cells bearing the integrin LFA-1 on their cell surface bind to cells expressing ICAM-1 or ICAM-2, both of which are members of the immunoglobulin superfamily.33,34 Other members of the immunoglobulin superfamily which are known to be important during morphogenesis include L-CAM35 (liver cell adhesion molecule) and N-CAM36,37 (neural cell adhesion molecule). Both show homophilic aggregation, that is, N-CAM serves as a target structure for N-CAM, and L-CAM serves as a target structure for L-CAM, but there is no cross-reactivity. In developing feather placodes in avian embryos, L-CAM and N-CAM are mutually exclusive expressed on epidermal or mesodermal cells, respectively. When the placodes are incubated with antibodies to L-CAM, primarily only epidermal cell-to-cell contact is disturbed.38 However, the structure of the surrounding mesoderm is altered subsequently, suggesting an inductive signal loop between epidermal and mesodermal cells. A third group of adhesion molecules has been termed LEC-CAMs to indicate that their extracellular part consists of a lectin domain, an epidermal growth factor-like domain, and a complement regulatory protein repeat domain. The lectin domain is presumed to contain the active center; binding mediated by the murine homolog to the leukocyte adhesion molecule 1 (LAM-1)39 can be blocked by mannose-6-phosphate or its polymers.40 Lectindependent organ formation should be accessible experimentally by administration of the respective carbohydrates but few if any data have been reported so far. Cell shape is mainly maintained by microtubules forming the cellular cytoskeleton. In addition, contractile elements exist such as actin, which are essential for cell movement, the so-called microﬁlaments. These structures are thought to be essential for the process of placode formation and invagination.41 Microﬁlamentmediated change of cell shape is based on the idea that actin ﬁlaments could alter the shape of cells by contraction. Most of these ﬁlaments are found at the apex of epithelial cells. Contraction of these ﬁlaments in each individual cell of a cell layer would result in an increasing infolding of the whole cell layer,41,42 ﬁnally resulting in invagination. It is a disadvantage of this model, however, that there is no apparent reason why apical constriction should be proceeded by cell elongation.29 Cell proliferation is probably an essential factor in the morphogenesis of epithelio-mesenchymal organs.22 During morphogenesis of these organs repeated invagination can be observed, which might be dependent upon cell proliferation.43 The way in which epithelial cell growth and proliferation is controlled in the embryo is

6 Embryology of malformations

not clear. However, it is believed that the surrounding mesenchyme might regulate the timing and location of invagination of the epithelial layer. Goldin and Opperman44 proposed that epidermal growth factor (EGF) might be excreted by mesenchymal cells, which would stimulate epithelial cell proliferation and repeated invagination. When agarose pellets impregnated with EGF were cultured alongside 5-day embryonic chick tracheal epithelium, supernumerary buds were induced to form at those sites. EGF and the related peptide transforming growth factor-α (TGFα) have been shown to lead to precocious eyelid opening when injected into newborn mice.45 Thus, complex changes of late-stage organ development can be induced by physiological stimuli in the laboratory. Interestingly, EGF is a mitogen for many epithelial cells in vitro without affecting most mesenchymal cells. A large variety of cells have been demonstrated to display the receptor for EGF/TGF α on their cell surface, which is encoded by the cellular protooncogene c-erbB. Structural alterations of this receptor are known to result in uncontrolled proliferation and ultimately malignant transformation. When secreted locally, EGF might provide physically associated cells with appropriate on- and off-signals required for the formation of complex organs. Other polypeptides, such as platelet-derived growth factor (PDGF) or transforming growth factor-β (TGFβ) appear to function in an antagonistic way in that they stimulate rather the proliferation of mesenchymal cells.46,47 In deﬁned experimental situations, TGFβ has been shown to be a mitogen for osteoblasts while being a potent inhibitor of the proliferation of epithelial and endothelial cells at the same time. Embryonic ﬁbroblasts, however, are also inhibited by TGFβ.48 TGFβ is a powerful chemotactic agent for ﬁbroblasts and enhances the production of both collagen and ﬁbronectin by these cells. There is, however, little data available concerning the involvement of these factors during normal and pathologic development of the embryo. Future investigations using such powerful approaches as in situ hybridization with cloned genes, preparation of transgenic animals, and direct administration of the recombinant proteins to various parts of the embryo might shed some light on signalling pathways mediated by soluble cytokines. The surrounding mesenchyme might limit the epithelial bud to expand49 forcing the epithelial sheet to fold in characteristic patterns. If a growing cell layer is restricted from lateral expansion, ‘mitotic pressure’ by dividing cells will result in elongation of cells and then invagination of the ‘crowded’ cell sheet. This does not necessarily imply that cells divide more rapidly in the region of invagination than in the surrounding areas. The main effect is caused by restriction of lateral expansion.50,51 In the early anlage of the thymus, cell proliferation counts are actually lower in the thymus anlage than in the surrounding epithelium.52 Steding50 and Jacob51 have shown experimentally that restriction

of lateral expansion might be responsible for thickening and subsequent invagination of epithelial sheets. In their experiments, restriction of lateral expansion was caused by a tiny silver ring placed on the epithelium of chick embryos.

EXAMPLES OF PATHOLOGICAL EMBRYOLOGY The focus of our research has been the embryology of foregut, anorectal and diaphragmatic malformations. We studied the normal development of all embryonic organs involved by scanning electron microscopy (SEM).53–59 In addition, we employed two rodent animal models to study malformations of the anorectum and the diaphragm. Pathogenetic concepts concerning these malformations were controversial in the past due to lack of detailed data.

EMBRYOLOGY OF FOREGUT MALFORMATIONS The differentiation of the primitive foregut into the ventral trachea and dorsal esophagus is thought to be the result of a process of septation.60 It is guessed that lateral ridges appear in the lateral walls of the foregut, which fuse in midline in a caudo-cranial direction thus forming the tracheo-esophageal septum. This theory of septation has been described in detail by Rosenthal and Smith.61–62 However, others63–64 were not able to verify the importance of the tracheo-esophageal septum for the differentiation of the foregut. They instead proposed individually that the respiratory tract develops simply by further growth of the lung bud in a caudal direction. Using scanning electron microscopy (SEM), we studied the development of the foregut in chick embryos.53,54 In this study, we were unable to demonstrate the formation of a tracheo-esophageal septum (Fig. 1.1). A sequence of SEM photographs of staged chick embryos suggests that differentiation of the primitive foregut is best explained by a process of ‘reduction of size’ of a foregut region called ‘tracheo-esophageal space’ (Fig. 1.2). This reduction is caused by a system of folds that develops in the primitive foregut. They approach each other but do not fuse (Fig. 1.2). Based on these observations, the development of the malformation can be explained by disorders either of the formation of the folds or of their developmental movements: 1 Atresia of the esophagus with ﬁstula (Fig. 1.3a): • The dorsal fold of the foregut bends too far ventrally. As a result the descent of the larynx is blocked. Therefore the tracheo-esophageal space remains partly undivided and lies in a ventral position. Due to this ventral position it differentiates into trachea.

Development of the diaphragm 7

Figure 1.3 Sketch of formal pathogenesis of typical foregut malformations (see text for details): (a) atresia of esophagus with ﬁstula; (b) atresia of trachea with ﬁstula; (c) laryngotracheo-esophageal cleft. Arrows indicate sites of possible deformation of the developing foregut

Figure 1.1 SEM photograph of the inner layer of foregut epithelium in a chick embryo (approx. 3.5 days old). View from cranial. Between trachea (tr) on bottom and esophagus (es) on top, the tip of the tracheo-esophageal fold (tef) is recognizable. Lateral ridges or signs of fusion are not found 45,46

2 Atresia of the trachea with ﬁstula (Fig. 1.3b): • The foregut is deformed on its ventral side. The developmental movements of the folds are disturbed and the tracheo-esophageal space is dislocated in a dorsal direction. Therefore it differentiates into esophagus. 3 Laryngo-tracheo-esophageal clefts (Fig. 1.3c): • Faulty growth of the folds results in the persistence of the primitive tracheo-esophageal space. Recently it has been shown that esophageal atresias and tracheo-esophageal ﬁstulas can be induced by maternal application of adriamycin into the peritoneal cavity of pregnant rats.16,17 The dosage may vary between 1.5 mg to 2.0 mg/kg depending on the number of days it will be given. In most reports the most promising dosage is 1.75 mg/kg given on days 6–9 of pregnancy. The adriamycin model has been intensively studied over the last couple of years, resulting in more than 30 reports between 1997 and 2001.65 It could be demonstrated that in this model not only foregut malformations but also atypical patterns of malformation can be observed which are usually summarized under the term ‘VATER’ or ‘VACTERL’ association.18,19 Therefore, this model is not only promising for the studies of foregut anomalies but also for anomalies of the hind- and mid-gut.

DEVELOPMENT OF THE DIAPHRAGM Figure 1.2 Summarizing sketch of foregut development. The tracheo-esophageal space (tes) is reduced in size by developmental movements of folds (indicated by arrows) (es, esophagus; la, anlage of larynx; br, bronchus; tr, trachea). Short arrow marks tip of tracheo-esophageal fold (tef) (compare Figure 1.1)

In the past, several theories were proposed to explain the appearance of postero-lateral diaphragmatic defects: 1 Defects caused by improper development of the pleuro-peritoneal membrane66,67

8 Embryology of malformations

2 Failure of muscularization of the lumbocostal trigone and pleuro-peritoneal canal, resulting in a ‘weak’ part of the diaphragm66,68 3 Pushing of intestine through postero-lateral part (foramen of Bochdalek) of the diaphragm69 4 Premature return of the intestines into the abdominal cavity with the canal still open66,68 5 Abnormal persistence of lung in the pleuroperitoneal canal, preventing proper closure of the canal70 6 Abnormal development of the early lung and posthepatic mesenchyme, causing non-closure of pleuro-peritoneal canals.15 Of these theories, failure of the pleuro-peritoneal membrane to meet the transverse septum is the most popular hypothesis to explain diaphragmatic herniation. However, using SEM techniques,55 we could not demonstrate the importance of the pleuro-peritoneal membrane for the closure of the so-called pleuro-peritoneal canals (Fig. 1.4). As stated earlier, most authors assume that delayed or inhibited closure of the diaphragm will result in a diaphragmatic defect that is wide enough to allow herniation of gut into the fetal thoracic cavity. However, this assumption is not the result of appropriate embryological observations but rather the result of interpretations of anatomical/pathological ﬁndings. In a series of normal staged embryos we measured the width of the pleuro-peritoneal openings and the transverse diameter of gut loops.54 On the basis of these measurements we

Figure 1.4 SEM photograph of right pleural sac in a rat embryo (approx. 16.5 days old). View from cranial. The socalled pleuro-peritoneal canal (PPC) is nearly closed. Small arrows point at the margin of PPC. In the depth of the abdomen the right adrenals (ad) are seen. Large arrows point at margins of the so-called pleuro-peritoneal membrane. Its contribution to the closure of the canal is minimal47 (es, esophagus)

estimated that a single embryonic gut loop requires at least an opening of 450 μ size to herniate into the fetal pleural cavity. However, in none of our embryos the observed pleuro-peritoneal openings were of appropriate dimensions. This means that delayed or inhibited closure of the pleuro-peritoneal canal cannot result in a diaphragmatic defect of sufﬁcient size. Herniation of gut through these openings is therefore impossible. Thus the proposed theory about the pathogenetic mechanisms of congenital diaphragmatic hernia (CDH) development lacks any embryological evidence. Furthermore the proposed timing of this process is highly questionable.57 Recently, an animal model for diaphragmatic hernia has been developed11–15 using nitrofen as noxious substance. In these experiments CDHs were produced in a reasonably high percentage of newborns.12,13 Most diaphragmatic hernias were associated with lung hypoplasias. Using electron microscopy, our group56–59 used this model to give a detailed description of the development of the diaphragmatic defect. Our results are as follows:

Timing of diaphragmatic defect appearance Iritani15 was the ﬁrst to notice that nitrofen-induced diaphragmatic hernias in mice are not caused by an improper closure of the pleuro-peritoneal openings but rather the result of a defective development of the socalled post-hepatic mesenchymal plate (PHMP). In our study in rats, clear evidence of disturbed development of the diaphragmatic anlage was seen on day 13 (left side) and day 14 (right side, Fig. 1.5).56,59 In all embryos

Figure 1.5 Cranial view of the pleural sacs in a rat embryo after exposition to nitrofen on day 11 of pregnancy. The embryo is approx. 15 days old. Note the big defect of the right diaphragmatic primordium. Small black arrows point at margins of the defect, which leaves parts of the liver (li) uncoated. On the left, the diaphragmatic anlage is normal. Note the low position of the cranial border of the pleuro-peritoneal opening on this side (white arrows). (ad, adrenals; di, anlage of diaphragm)

Development of the cloaca 9

affected, the PHMP was too short. This age group is equivalent to 4–5-week-old human embryos.56

Location of diaphragmatic defect In our SEM study, the observed defects were localized in the PHMP (Fig. 1.5). We identiﬁed two distinct types of defects: (1) large ‘dorsal’ defects and (2) small ‘central’ defects.56 Large defects extended into the region of the pleuro-peritoneal openings. In these cases, the closure of the pleuro-peritoneal openings was usually impaired by the massive ingrowth of liver (Figs 1.6 & 1.7). If the defects were small, they were consistently isolated from the pleuro-peritoneal openings closing normally at the 16th or 17th day of gestation. Thus, in our embryos with CDH, the region of the diaphragmatic defect was a distinct entity and was separated from that part of the diaphragm where the pleuro-peritoneal ‘canals’ are localized. We conclude therefore that the pleuro-peritoneal openings are not the precursors of the diaphragmatic defect.

Why lungs are hypoplastic Soon after the onset of the defect in the 14-day-old embryo, liver grows through the diaphragmatic defect into the thoracic cavity (Fig. 1.6). This indicates that from this time on the available thoracic space is reduced for the lung and further lung growth hampered. In the following stages, up to two-thirds of the thoracic cavity can be occupied by liver (Fig. 1.7). Herniated gut was found in our embryos and fetuses only in late stages of development (21 days and newborns). In all of these, the lungs were already hypoplastic, when the bowel entered the thoracic cavity.53

Figure 1.6 Liver (li) protrudes through diaphragmatic defect. Arrows point to the margin of the defect (di, diaphragmatic anlage). Rat embryo (approx. 16 days old), nitrofen exposition on day 11 of pregnancy

Figure 1.7 SEM photograph of a right pleural sac in a rat embryo after nitrofen exposure on day 11 of pregnancy. The embryo is approximately 15.5 days old. Note the big defect of the right dorsal diaphragm (large arrows). The closure of the pleuro-peritoneal canal (PPC) is impaired by the ingrowths of liver (small arrows). Li1 = liver growing through PPC. Li1 + Li2 = liver growing through the defect of the diaphragm

Based on these observations, we conclude that the early ingrowth of the liver through the diaphragmatic defect is the crucial step in the pathogenesis of lung hypoplasia in CDH. This indicates that growth impairment is not the result of lung compression in the fetus but rather the result of growth competition in the embryo: the liver that grows faster than the lung reduces the aviable thoracic space. If the remaining space is too small, pulmonary hypoplasia will result.

DEVELOPMENT OF THE CLOACA In the literature several theories have been put forward to explain the differentiation of the cloaca into the dorsal anorectum and the ventral sinus urogenitalis. To many authors this differentiation is caused by a septum which develops cranially then caudally and thus divides the cloaca in a frontal plane. Disorders in this process of differentiation are thought to be the cause of cloacal anomalies such as persistent cloaca and anorectal malformations. However, there is no agreement on the mechanisms of the septational process. While some authors71,72 believe that the descent of a single fold separates the urogenital part from the rectal part by ingrowth of mesenchyme from cranial, others73 think that lateral ridges appear in the lumen of the cloaca, which progressively fuse along the midline and thus form the septum. In a recent paper74 the process of septation had been questioned altogether. Using SEM techniques, our group studied cloacal development in rat and sd-mice embryos. The sd-mouse

10 Embryology of malformations

is a spontaneous mutation of the house mouse characterized by having a short tail (Fig. 1.8). Homozygous or heterozygous offspring of these mice show skeletal, urogenital and anorectal malformations.18 Therefore these animals are ideal in the study of the development of anorectal malformations.

Figure 1.8 Characteristic short tail (arrow) of sd-mouse embryo (approx. 13 days old) (ll, left lower limb; ge, genital tuberculum, abnormal)

Figure 1.9 Malformed cloaca of sd-mouse embryo (approx. 11 days old). The surrounding mesenchyme is removed by microdissection. View on the basal layer of the cloacal entoderm. The cloaca has lost its contact to the ectoderm of the genitals (white arrow). The dorsal part of the cloaca is missing (black arrow). Tailgut (tg) and hindgut (hg) are hypoplastic. This malformed cloaca developed because the anlage of the cloacal membrane was too short in early embryogenesis (see text for details) (cc, rest of cloaca; u, urachus, rudimentary)

Normal cloacal embryology (rat) As in the foregut of chick embryos, signs of median fusion of lateral cloacal parts could not be demonstrated during normal cloacal development in the rat. However, in contradiction to vdPUTTE,74 the current authors think that downgrowth of the urorectal fold takes place, although it is probably not responsible for the formation of cloacal malformations.

Abnormal cloacal embryology (sd-mouse) Cloacal malformations are caused by improper development of the early anlage of the cloacal membrane as demonstrated in sd-mice embryos.75,76 Our studies of abnormal cloacal development in sdmice had the following results: 1 The basis of the pathogenesis of anorectal malformations is too short a cloacal membrane 2 The anlage of the cloacal membrane is too short and results in a maldeveloped anlage of the cloaca, which is undeveloped in its dorsal part (Fig. 1.9) 3 The caudal movement of the urorectal fold is impaired by the malformed cloaca. Thus the hindgut remains in abnormal contact with the cloaca. This opening is true ectopic and will develop into the recto-urogenital ﬁstula (Fig. 1.10).

Figure 1.10 Malformed cloaca of sd-mouse, embryo (approx. 13 days old). Urachus (u) and rectum (re) nearly normal (cl, ventral part of cloaca with short cloacal membrane). The dorsal part of the cloaca is missing (long white arrows). Short white arrow points to the region of the future ﬁstula

HYPOSPADIAS Many investigators77–80 believe that the urethra develops by fusion of the paired urethral folds following the disintegration of the urogenital membrane. Impairment of this process is thought to result in the different forms

References 11

of hypospadia80 However, in our study of normal cloacal development,81 we were puzzled by the fact that disintegration of the urogenital part of the cloacal membrane could not be observed in rat embryos (Fig. 1.11). This ﬁnding caused us to call in question the generally assumed concepts of hypospadia formation. Instead we found that: 1 The urethra is always present as a hollow organ during embryogenesis of rats and that it is always in contact with the tip of the genitals, and that 2 An initially double urethral anlage exists. The differentiation in female and male urethra starts in rats of 18.5 days old. On the other hand, we found no evidence for: • The disintegration of the urogenital cloacal membrane, and • A fusion of lateral portions within the perineum. In our opinion, more than one embryological mechanism is at play in the formation of the hypospadias complex. The moderate degrees, such as the penile and glandular forms, represent a developmental arrest of the genitalia (Fig. 1.12). They take their origin from a situation comparable to the 20-day-old embryo. Consequently the penis, not the urethra is the primary organ of the malformation. Perineal and scrotal hypospadias are different from the type discussed previously. Pronounced signs of feminization in these forms suggest that we are dealing with a female-type urethra. Origin of this malformation complex is an undifferentiated stage as may be seen in the 18.5-day-old rat embryo.

Figure 1.12 Genitals of a normal male rat embryo (approx. 20 days old) (gl, glans; pf, preputial fold; sc, scrotum). Arrow points to the raphe up to this stage; disintegration of the urogenital part of the cloacal membrane was not seen. Note similarity with clinical picture of hypospadia!

CONCLUSION Despite the long history of experimental embryology, we know very little about etiology and pathogenesis of congenital malformations. For decades, hypotheses were abundant while few data existed to support them. The tremendous progress of neighboring biological sciences is now providing powerful tools for researchers in the ﬁeld, such as recombinant DNA and hybridoma technology. Future investigations will monitor closely how genes are switched on and off during embryogenesis and determine the relation of spatial and temporal disturbances to ensuing malformations. Target structures of chemical or viral teratogens within the embryonic cells await identiﬁcation. Finally, improved understanding of growth coordination in utero will extend to related areas such as wound healing and proliferation of cancer cells.

REFERENCES

Figure 1.11 Genitals of a normal female rat embryo (approx. 18.5 days old) (gl, glans). Arrow points to future opening of the female urethra. No signs of disintegration of the cloacal membrane

1. Nadler HL. Teratology. In: Welch KJ, Randolph JG, Ravitch MM, O’Neill JA, Rowe MJ. Pediatric Surgery. 4th edn (eds), Year Book Medical Publishers: Chicago: Year Book Medical Publishers 1986: 11–13. 2. Shepard TH. Catalogue of Teratogenic Agents. 4th edn. Baltimore: Johns Hopkins Press, 1983. 3. United States National Center for Health Statistics. Monthly Vital Statistics Report, Vol. 31. No. 5. Birth, marriages, divorces, and deaths for May 1982. Hyattsville, MD: Public Health Service, 1982:1–10. 4. McCredie J, Loewenthal J. Pathogenesis of congenital malformations. Am J Surg 1978; 135:293–7. 5. Spemann, Mangold, cited by Starck D. Stuttgart: Embryologie, Thieme, 1975: 135–63.

12 Embryology of malformations 6. Warkany J, Roth CB, Wilson JG. Multiple congenital malformations: a consideration of etiological factors. Pediatrics 1948; 1:462–71. 7. Kalter H. Congenital malformations induced by riboﬂavin deﬁciency in strains of inbred mice. Pediatrics 1959; 23:222–30. 8. Kalter H. The inheritance of susceptibility to the teratogenic action of cortisone in mice. Genetics 1954; 39:185. 9. Lenz W. Fragen aus der Praxis. Wochenschr.:Dtsch Med, 1961; 86:25–55. 10. Ministry of Health Reports on Public Health and Medical Subjects No. 112. Deformities caused by thalidomide. London: HMSO, 1964. 11. Ambrose AM, Larson PS, Borcelleca JF et al. Toxicological studies on 2,4-dichlorophenyl-P-nitrophenyl ether. Toxicol Appl Pharmacol 1971; 19:263–75. 12. Tenbrinck R, Tibboel D, Gaillard JLJ et al. Experimentally induced congenital diaphragmatic hernia in rats. J Pediatr Surg 1990; 25:426–9. 13. Kluth D, Kangha R, Reich P et al. Nitrofen-induced diaphragmatic hernia in rats – an animal model. J Pediatr Surg 1990; 25:850–4. 14. Costlow RD, Manson JM. The heart and diaphragm: target organs in the neonatal death induced by nitrofen (2,4dichloro-phenyl-P-nitrophenyl ether). Toxicology 1981; 20:209–27. 15. Iritani L. Experimental study on embryogenesis of congenital diaphragmatic hernia. Anat Embryol 1984; 169:133–9. 16. Thompson DJ, Molello JA, Strebing RJ, Dyke IL. Teratogenicy of adriamycin and daunomycin in the rat and rabbit. Teratology 1978; 17:151–8. 17. Diez-Pardo JA, Baoquan Q, Navarro C, Tovar JA. A new rodent experimental model of esophageal atresia and tracheoesophageal ﬁstula: preliminary report. J Pediatr Surg 1996; 31:498–502. 18. Beasley SW, Diez-Pardo J, Qi BQ, Tovar JA, Xia HM. The contribution of the adriamycin-induced rat model of the VATER association to our understanding of congenital abnormalities and their embryogenesis. Pediatr Surg Int 2000; 16:465–72. 19. Orford JE, Cass DT. Dose response relationship between adriamycin and birth defects in a rat model of VATER association. J Pediatr Surg 1999; 34:392–8. 20. Rosenbaum KN. Genetics and dysmorphology. In: Welch KJ, Randolph MM, Ravitch MM, O’Neill JA, Rowe MJ, editors. Pediatric Surgery, 4th edn. Chicago: Year Book Medical Publishers, 1986: 3–11. 21. van der Putte SCJ, Neeteson FA. The pathogenesis of hereditary congenital malformations in the pig. Acta Morphol Neerl Scand 1984; 22:17–40. 22. Kluth D, Lambrecht W, Reich P et al. SD mice – an animal model for complex anorectal malformations. Eur J Pediatr Surg 1991; 1:183–8. 23. Lambrecht W, Lierse W. The internal sphincter in anorectal malformations: morphologic investigations in neonatal pigs. J Pediatr Surg 1987; 22:1160–8.

24. Dunn LC, Gluecksohn-Schoenheimer S, Bryson V. A new mutation in the mouse affecting spinal column and urogenital system. J Hered 1940; 31:343–8. 25. Spemann H. Entwicklungsphysiologische Studien am Tritonei. ROIIX Arch Entw Mech 1901; 12:224–64. 26. Murray JD, Maini PK. A new approach to the generation of pattern and form in embryology. Sri Progr Oxf 1986; 70:539–53. 27. Gudernatsch JF. Concerning the mechanisms and direction of embryonic folding. Anat Rec 1913; 7:411–31. 28. Oster G, Alberich P. Evolution and bifurcation of developmental programmes. Evolution 1982; 36:444–59. 29. Ettersohn CA. Mechanisms of epithelial invagination. Q Rev Biol 1985; 60:289–307. 30. Jaffredo T, Horwitz AF, Buck CA et al. Myoblast migration speciﬁcally inhibited in the chick embryo by grafted CSAT hybridoma cells secreting an anti-integrin antibody. Development 1988; 103:431–46. 31. Ruoslahti E, Pierschbacher MD. 7 New perspectives in cell adhesions: RDG and integrins. Science 198; 238:491–7. 32. Stoolman LM. Adhesion molecules controlling lymphocyte migration. Cell 1989; 56:907–10. 33. Simmons D, Makgoba MW, Seed B. ICAM, an adhesion ligand for LFA-1, is homologous to the neural cell adhesion molecule NCAM. Nature 1988; 331:624–7. 34. Staunton DE, Dustin L, Springer TA. Functional cloning of ICAM-2, a cell adhesion ligand for LFA-1 homologous to ICAM-1. Nature 1989; 339:61–4. 35. Gallin WJ, Sorkin C, Edelman GM et al. Structure of the gene for the liver cell adhesion molecule, L-CAM. Proc Natl Acad Sci USA 1987; 84:2808–12. 36. Edelman GM. Morphoregulatory molecules. Biochemistry 1988; 27:3533–43. 37. Rutishauser U, Acheson A, Hall AK et al. The neural cell adhesion molecule (NCAM) as a regulator of cell-cell interactions. Science 1988; 240:53–7. 38. Edelman GM. Topobiology. Sci Amer 1989; May: 44–52. 39. Tedder TF, Isaacs CM, Ernst TJ et al. Isolation and chromosomal localisation of cDNAs encoding a novel human lymphocyte cell surface molecule, LAM-1. J Exp Med 1989; 170:123–33. 40. Yednock TA, Rosen D. Lymphocyte homing. Adv Immunol 1989; 44:313–78. 41. Spooner BS. Microﬁlaments, microtubules, and extracellular materials in morphogenesis. BioScience 1975; 25:440–51. 42. Baker PC, Schroeder TE. Cytoplasmatic ﬁlaments and morphogenetic movement in the amphibian neural tube. Devl Biol 1967; 15:432–50. 43. Alescio T, DiMichele M. Relationship of epithelial growth to mitotic rate in mouse embryonic lung developing in vitro. Embryol Exp Morphol 1968; 19:227–37. 44. Goldin GV, Opperman LA. Induction of super-numerary tracheal buds and the stimulation of DNA synthesis in the embryonic chick lung and trachea by epidermal growth factor. J Embryol Exp Morphol 1980; 60:235–43.

References 13 45. Smith JM, Sporn MB, Roberts AB et al. Human transforming growth factor-alpha causes precocious eyelid opening in newborn mice. Nature 1985; 315:515–16. 46. Sporn MB, Roberts AB, Wakeﬁeld LM et al. Transforming growth factor-beta: biological function and chemical structure. Science 1986; 233:532–34. 47. Sporn MB, Roberts AB, Wakeﬁeld LM et al. Some recent advances in the chemistry and biology of transforming growth factor-beta. J Cell Biol 1987; 105:1039–45. 48. Anzano MA, Roberts AB, Sporn MB. Anchor-ageindependent growth of primary rat embryo cells is induced by platelet-derived growth factor and inhibited by type-beta transforming growth factor. J Cell Physiol 1986; 126:312–18. 49. Nogawa H. Determination of the curvature of epithelial cell mass by mesenchyme in branching morphogenesis of mouse salivary gland. J Embryol Exp Morphol 1983; 73:221–32. 50. Steding G. Ursachen der embryonalen Epithelverdickung. Acta Anat 1967; 68:37–67. 51. Jacob HJ. Experimente zur Entstehung entodermaler Organanlagen. Untersuchungen an explantierten Hühnerembryonen. Anat Anzeiger 1971; 128:271–8. 52. Smuts MS, Hilfer SR, Searls RL. Patterns of cellular proliferation during thyroid organogenesis. J Embryol Exp Morphol 1978; 48:269–86. 53. Kluth D, Steding G, Seidl W. The embryology of foregut malformations. J Pediatr Surg 1987; 22:389–93. 54. Kluth D, Habenicht R. The embryology of usual and unusual types of oesophageal atresia. Pediatr Surg Int 1987; 1:223–7. 55. Kluth D, Petersen C, Zimmermann HJ et al. The embryology of congenital diaphragmatic hernia. In: Puri P, editor. Congenital Diaphragmatic Hernia: Modern Problems in Pediatrics, Vol. 24, Basel: Karger, 1989: 7–21. 56. Kluth D, Tenbrinck R, v. Ekesparre M et al. The natural history of congenital diaphragmatic hernia in pulmonary hypoplasia in the embryo. J Pediatr Surg 1993; 28:456–63. 57. Kluth D, Tander B, v. Ekesparre M et al. Congenital diaphragmatic hernia: the impact of embryological studies. Pediatr Surg Int 1995; 10:16–22. 58. Kluth D, Losty PD, Schnitzer JJ, Lambrecht W, Donahoe PK. Toward understanding the developmental anatomy of congenital diaphragmatic hernia. Clin Perinatol 1996; 23:655–69. 59. Kluth D, Keijzer R, Hertl M, Tibboel D. Embryology of congenital diaphragmatic hernia. Semin Pediatr Surg 1996; 5:224–33. 60. His W. Zur Bildungsgeschichte der Lungen beim menschlichen Embryo. Arch Anat Entwickl Gesch 1887; 89–106. 61. Rosenthal AH. Congenital atresia of the esophagus with tracheo esophageal ﬁstula: report of eight cases. Arch Pathol 1931; 12:756–72.

62. Smith EL. The early development of the trachea and the esophagus in relation to atresia of the esophagus and tracheo-oesophageal ﬁstula. Contrib Embyol Carneg Inst 1957; 36:41–57. 63. Zaw Tun HA. The tracheo-esophageal septum – fact or fantasy? Acta Anat 1982; 114:1–21. 64. O’Rahilly R, Muller F. Chevalier Jackson Lecture. Respiratory and alimentary relations in staged human embryos. New embyrological data and congenital anomalies. Ann Otol Rhinol Laryngol 1984; 93:421–9. 65. Medline recherché: http://www.ncbi.nlm.nih.gov/PubMed/. 66. Gray SW, Skandalakis JE. Embryology for Surgeons. Philadelphia: Saunders, 1972: 359–85. 67. Grosser 0, Ortmann R. Grundriß der Entwicklungsgeschichte des Menschen. 7th edn. Berlin: Springer, 1970: 124–7. 68. Holder RM, Ashcraft KW. Congenital diaphragmatic hernia. In: Ravitch MM, Welch KJ, Benson CD, Aberdeen E, Randolph JG, editors. Pediatric Surgery. 3rd edn. Vol. 1. (eds), Chicago: Year Book Medical Publishers, 1979: 432–45. 69. Bremer JL. The diaphragm and diaphragmatic hernia. Arch Pathol 1943; 36:539–49. 70. Gattone VH II, Morse DE. A scanning electron microscopic study on the pathogenesis of the posterolateral diaphragmatic hernia. J Submicrosc Cytol 1982; 14:483–90. 71. Tourneux F. Sur le premiers developpements du cloaque du tubercle genitale et de l’anus chez l’embryon moutons, avec quelques remarques concernant le developpement des glandes prostatiques. J Anat Physiol 1888; 24:503–17. 72. DeVries P, Friedland GW. The staged sequential development of the anus and rectum in human embryos and fetuses. J Pediatr Surg 1974; 9:755–69. 73. Retterer E. Sur l’origin et de l’evolution de la region anogénitale des mammiferes. J Anat Physiol 1890; 26:126–216. 74. vd Putte SCJ. Normal and abnormal development of the anorectum. J Pediatr Surg 1986; 21:434–40. 75. Kluth D, Hillen M, Lambrecht W. The principles of normal and abnormal hindgut development. J Pediatr Surg 1995; 30:1143–7. 76. Kluth D, Lambrecht W. Current concepts in the embryology of anorectal malformations. Semin Pediatr Surg 1997; 6:180–6. 77. Felix W. Die Entwicklung der Harn-und Geschlechtsorgane. In: Keibel F, Mall FP, editors. Handbuch der Entwicklungsgeschichte des Menschen. Vol. 2. Leipzig: Hirzel, 1911: 92–5. 78. Spaulding MH. The development of the external genitalia in the human embryo. Contrib Embryol Carneg 1921; 13:67–88. 79. Glenister TW. A correlation of the normal and abnormal development of the penile urethra and of the intraabdominal wall. J Urol 1958; 30:117–26.

14 Embryology of malformations 80. Gray SW, Skandalakis JE. Embryology for Surgeons. Philadelphia: Saunders, 1972: 595–631.

81. Kluth D, Lambrecht W, Reich P. Pathogenesis hypospadias – more questions than answers. J Pediatr Surg 1988; 23:1095–1101.

2 Prenatal diagnosis of surgical diseases TIPPI C. MACKENZIE AND N. SCOTT ADZICK

Box 2.2 Defects that may require cesarian delivery

INTRODUCTION Prenatal diagnosis has undergone an explosion of growth in the past decade. The primary impetus for this rapid expansion has come from the widespread use of prenatal ultrasonography. Most correctable malformations that can be diagnosed in utero are best managed by appropriate medical and surgical therapy after maternal transport and planned delivery at term. Prenatal diagnosis may inﬂuence the timing (Box 2.1) or mode (Box 2.2) of delivery, and in some cases may lead to elective termination of the pregnancy. In rare cases, various forms of in utero therapy may be possible (Table 2.1). Prenatal diagnosis has deﬁned a ‘hidden mortality’ for some lesions such as congenital diaphragmatic hernia, bilateral hydronephrosis, sacrococcygeal teratoma, and cystic hygroma. These lesions, when ﬁrst evaluated and treated postnatally demonstrate a favorable selection bias. The most severely affected fetuses often die in utero or immediately after birth, before an accurate diagnosis has been made. Consequently, such a condition detected

Myelomeningocele Gastroschisis Large sacrococcygeal teratoma Giant neck masses (EXIT procedure)

prenatally may have a worse prognosis than the same condition diagnosed after delivery.1 The perinatal management of the patients involves many different medical disciplines, including obstetricians, sonographers, neonatologists, geneticists, pediatric surgeons, and pediatricians. It is essential that the affected family be managed using a team approach, and that information and experience be exchanged freely. In this chapter we will discuss the prenatal diagnosis of neonatal surgical lesions. First, a brief summary of the diagnostic methods currently available will be given. Then a review of prenatal diagnosis by organ system will be presented.

DIAGNOSTIC METHODS Box 2.1 Defects that may lead to induced preterm delivery Obstructive hydronephrosis Gastroschisis or ruptured omphalocele Intestinal ischemia and necrosis secondary to volvulus, meconium ileus, etc. Sacrococcygeal teratoma with hydrops

Ultrasound Ultrasound testing has become a routine part of the prenatal evaluation of almost all pregnancies. It is especially important to perform ultrasound for pregnancies with maternal risk factors (e.g. age over 35 years, diabetes,

Table 2.1 Diseases amenable to fetal surgical intervention in selected cases Malformation

Effect on development

In utero treatment

Congenital diaphragmatic hernia CCAM or BPS

Pulmonary hypoplasia, respiratory failure Pulmonary hypoplasia, hydrops

Sacrococcygeal teratoma Urethral obstruction Myelomeningocele

Massive arteriovenous shunting, placentomegaly, hydrops Hydronephrosis, lung hypoplasia Damage to spinal cord, paralysis

Tracheal occlusion Thoracoamniotic shunting, lobectomy Excision Vesicoamniotic shunting Closure of defect

16 Prenatal diagnosis of surgical diseases

previous child with anatomic or chromosomal abnormality) and if there is an elevation in maternal serum alphafetoprotein (MSAFP). Most defects can be reliably diagnosed in the late ﬁrst or early second trimester by a skilled sonographer. More recently, nuchal translucency measurements have emerged as an independent marker of chromosomal abnormalities, with a sensitivity of about 60%.2 This abnormality may be detected on transvaginal ultrasound at 10–15 weeks’ gestation, thus providing an early test for high-risk pregnancies. Nuchal cord thickening may also be a marker for congenital heart disease3 and may be a valuable initial screen to detect high-risk fetuses for referral for fetal echocardiography. It is important to remember that sonography is operator dependent; the scope and reliability of the information obtained is directly proportional to the skill and experience of the sonographer.

Magnetic resonance imaging Until recently, the long acquisition times required for magnetic resonance imaging (MRI) were not conducive to fetal imaging because fetal movements resulted in poor quality images. Obtaining adequate images with the traditional spin-echo techniques required fetal sedation or paralysis.4 With the development of ultrafast scanning techniques, the artifacts caused by fetal motion have almost been eliminated.5 This technique is now an important part of prenatal evaluation of fetuses referred to our institution and has greatly enhanced our ability to diagnose and treat fetal malformations.

Amniocentesis The ﬁrst report of the culture and karyotyping of fetal cells from amniocentesis was by Steele and Berg in 1966.6 Since then, it has become the gold standard for detecting fetal chromosomal abnormalities by karyotyping. It is usually performed at 15–16 weeks’ gestation and involves a very low risk of fetal injury or loss. Attempts at early amniocentesis (at 11–12 weeks’ gestation) have been complicated by a higher pregnancy loss, increased risk of iatrogenic fetal deformities and increased postamniocentesis leakage rate.7 For this reason, the most reliable method for ﬁrst trimester diagnosis remains chorionic villus sampling.

Chorionic villus sampling Chorionic villus sampling (CVS) may be performed at 10–14 weeks’ gestation and involves the biopsy of the chorion frondosum, the precursor for the placenta. Either a transcervical or transabdominal approach may be used, both under ultrasound guidance. The cells obtained may be subjected to a variety of tests including

karyotype, genetic probes, or enzyme analysis. Due to the high mitotic rate of the chorionic villus cells, results for karyotyping may be obtained in less than 24 hours. Disadvantages include diagnostic errors due to maternal decidual contamination or genetic mosaicism of the trophoblastic layer of the placenta. When preformed by experienced operators, the pregnancy loss rate is equivalent to that of second trimester amniocentesis.8

BIOCHEMICAL MARKERS Maternal blood and amniotic ﬂuid can be screened for the presence of various biochemical markers that indicate fetal disease. About two-thirds of women in the USA currently undergo screening for Down syndrome and other chromosomal abnormalities with the ‘triple test,’ which includes measuring serum alphafetoprotein with human chorionic gonadotropin and unconjugated estriol.9 This screening is performed in the early second trimester, and the detection rate for Down syndrome is 69%, with a 5% false-positive test.10 A positive result on the serum screening test indicates a need for chromosome analysis by amniocentesis.

Percutaneous umbilical blood sampling Obtaining umbilical venous blood can also be used to determine the karyotype and diagnose various metabolic and hematological disorders. The percutaneous umbilical blood sampling (PUBS) procedure is performed at around 18 weeks’ gestation under ultrasound guidance. Karyotype results may be obtained within 24–48 hours. In various large series, the mortality from the procedure has been reported to be 1–2%, with increasing mortality rates with long procedure times and multiple punctures.11–13

Fetal cells in the maternal circulation Since the advent of ﬂuorescence-activated cell sorting (FACS), there has been growing interest and progress in detecting circulating fetal cells in maternal blood for diagnostic purposes.14 The cell type most successfully used in this endeavor is the fetal nucleated red blood cell, since these are abundant in the ﬁrst trimester fetal circulation. These cells may be separated from maternal nucleated red blood cells by staining for CD71 or fetal and embryonic hemoglobins.15 Genetic analysis may then be performed using polymerase chain reaction (PCR) or ﬂuorescence in situ hybridization (FISH) for chromosome-speciﬁc probes. Although the test currently has a low sensitivity (40–50%),15 the falsepositive rate is negligible, which is an advantage over the 5% false-positive rate of the conventional triple screen.

Prenatal diagnosis of speciﬁc surgical lesions 17

PRENATAL DIAGNOSIS OF SPECIFIC SURGICAL LESIONS Neck masses Fetal airway obstruction could be a result of extrinsic compression of the airway by lesions such as cervical teratoma or cystic hygroma, or intrinsic defects in the airway such as congenital high airway obstruction syndrome. Although large congenital neck masses causing airway obstruction previously carried an enormous perinatal mortality16 the advent of the ex utero intrapartum treatment (EXIT) procedure17,18 has improved their outcome by providing a means of controlling the airway during delivery and converting an airway emergency into an elective procedure (Fig. 2.1). Cystic hygroma diagnosed in utero is a severe diffuse lymphatic abnormality which is frequently associated with hydrops, polyhydramnios, and other abnormalities.19 Chromosomal abnormalities are very common (62% overall), the most common being Turner’s syndrome.20 There are two groups of prenatally diagnosed cervical lymphangiomas: those diagnosed in the second trimester (usually in the posterior triangle of the neck, have a high incidence of associated abnormalities, and carry a very poor prognosis),21 and those diagnosed later in gestation (most often isolated lesions and generally do not lead to hydrops). Hydrops is an ominous ﬁnding in fetuses with cystic hygroma,16 as is the presence of aneuploidy and septations in the mass.22 However, fetuses with normal karyotype, non-septated masses, and no evidence of hydrops may have a good prognosis.23 Therefore, it is important to monitor the fetus for development of hydrops by serial evaluations.

Teratomas are asymmetrical lesions which are frequently unilateral, with well-deﬁned margins. They may also be multiloculated, irregular masses with solid and cystic components. Most teratomas contain calciﬁcations. MRI is a very useful adjunct to ultrasound in evaluating giant neck masses. We have used it successfully for showing the relationship of the mass to the airway in preparation for an EXIT procedure.24 T1-weighted images may help differentiate teratomas from lymphangiomas.25 The EXIT procedure, originally designed for removal of tracheal clips,17 has proven to be life-saving for many fetuses with giant neck masses.18 This procedure involves performing a maternal hysterotomy and obtaining control of the fetal airway while the fetus remains on placental support. In order to prevent uterine contractions during the procedure, the mother is given inhalational anesthetic and tocolytics, warm saline is infused through a level I device, and only the head and shoulders of the fetus are delivered. After attaching a pulse oximeter to the fetal hand to monitor heart rate and oxygen saturation, direct laryngoscopy and, if possible, endotracheal intubation is performed. If the airway cannot be secured in this way, a rigid bronchoscope is inserted to determine the anatomy. If secure airway establishment is still unsuccessful, a tracheostomy can be performed. After securing the airway, surfactant is administered for premature fetuses, the cord is clamped, and the infant is taken to an adjacent operating room for resuscitation and possible immediate resection of the mass. In our review of the EXIT procedure,19 ten fetuses underwent the procedure and eight survived. In six patients, endotracheal intubation was accomplished, three patients needed a tracheostomy, and one patient expired due to parental refusal for a tracheostomy. One patient expired in the postnatal period due to pulmonary hypoplasia.

Sacrococcygeal teratoma Sacrococcygeal teratoma (SCT) is the most common newborn tumor, occurring in one out of 35 000 to 40 000 births.26 The American Academy of Pediatrics, Surgical Section classiﬁcation27 deﬁnes four types of SCT with differing prognoses: 1 Type 1 tumors are external, with at most a small presacral component, and carry the best prognosis. 2 Type 2 tumors are predominantly external with a large intrapelvic portion. 3 Type 3 lesions are predominantly intrapelvic with abdominal extension with only a minor external component. 4 Type 4 lesions are entirely intrapelvic and abdominal. Figure 2.1 EXIT procedure for giant neck mass

The latter have the worst prognosis since they are difﬁcult to diagnose, sometimes less amenable to surgical

18 Prenatal diagnosis of surgical diseases

We reported the ﬁrst successful case of SCT resection in a fetus of 26 weeks’ gestation with a large SCT and accompanying polyhydramnios, mild placentomegaly, and maternal tachycardia and proteinuria.35 Fetal resection of the mass reversed the pathophysiology and prevented the development of hydrops. The algorithm we currently recommend is to follow the fetus by serial ultrasounds for the development of signs of high output cardiac failure.36 If placentomegaly and hydrops are seen after pulmonary maturation, the fetus should be delivered by emergency cesarian section. If the fetus is too young for immediate delivery after development of hydrops, open fetal surgery may be considered. The role of radiofrequency ablation for minimally invasive fetal treatment is currently being tested in the laboratory.37

Congenital chest lesions CONGENITAL CYSTIC ADENOMATOID MALFORMATION AND BRONCHOPULMONARY SEQUESTRATION

Figure 2.2 MRI of large sacrococcygeal teratoma

resection, and frequently malignant at the time of diagnosis because of the delay in diagnosis. Overall, prenatally diagnosed SCT has a worse prognosis than those tumors diagnosed at time of birth. On prenatal ultrasound, SCT appears as a mixed solid and cystic lesion arising from the sacral lesion. The tumor frequently contains calciﬁcations. Since there is acoustic shadowing by the fetal pelvic bones, it is not always possible to determine the most cephalad portion of the tumor by ultrasound. Ultrafast fetal MRI is superior,28 since it can determine the intrapelvic dimensions of the tumor as well as the presence of hemorrhage (Fig. 2.2). Those fetuses with mainly solid and highly vascular SCT have a higher risk of developing hydrops.29,30 We have demonstrated by Doppler ultrasound that in severe cases, the tumor behaves as a large arteriovenous ﬁstula with markedly increased distal aortic blood ﬂow and shunting of blood away from the placenta to the tumor. High output cardiac failure may occur as a result of the hemodynamic effects of the large blood ﬂow to the tumor31,32 and anemia from hemorrhage into the tumor may compound this problem. In severe cases, the mother with placentomegaly develops ‘mirror syndrome,’ a severe pre-eclamptic state with vomiting, hypertension, proteinuria, and edema. This phenomenon may be mediated by the release of vasoactive compounds from the edematous placenta. The development of hydrops is a grave sign, with almost 100% mortality without fetal intervention.33,34

Congenital cystic adenomatoid malformation (CCAM) represents a spectrum of disease characterized by cystic lesions of the lung.38 Macrocystic lesions are larger than 5 mm in diameter and may be solitary cysts that grow to several centimeters in size (Fig. 2.3). Microcystic disease has multiple cystic lesions less than 5 mm in diameter. Prenatal ultrasound can generally distinguish individual cysts in macrocystic disease while microcystic lesions usually have the appearance of an echogenic, solid lung mass.39 Bronchopulmonary sequestration (BPS) is an aberrant lung mass which is non-functional and usually has a systemic blood supply. It may be difﬁcult to distinguish microcystic CCAM from BPS on ultrasound. Indeed, there is growing evidence that the two lesions may be related embryologically, with several reported cases of hybrid lesions which have CCAM-like architecture and a systemic blood supply.40,41 Some of these

Figure 2.3 Ultrasound image of large CCAM following the placement of a thoracoamniotic shunt. L = lung

Prenatal diagnosis of speciﬁc surgical lesions 19

lesions may decrease in size or disappear altogether during fetal life42 but postnatal evaluation is still warranted to detect residual disease for resection.43 MRI is useful in delineating normal lung from abnormal.44 In CCAM, the number and size of cysts contribute to the signal intensity on T2 weighted images.5 MRI can also deﬁne BPS from surrounding lung due to its high signal intensity and homogeneous appearance.44 To date, ultrasound has been more accurate in demonstrating systemic feeding vessels. MRI may also be helpful in making the correct diagnosis in cases where ultrasound is ambiguous. In a recent series of 18 lung lesions which were viewed with both ultrasound and MRI, multiple chest abnormalities were misdiagnosed as CCAM on ultrasound, including congenital diaphragmatic hernia (CDH), tracheal atresia, pulmonary agenesis, neurenteric cyst, bronchial stenosis, and BPS.44 MRI helped form the correct diagnosis in these cases and was thus crucial for perinatal management. Polyhydramnios is a frequent accompanying ﬁnding in fetuses with large chest masses. This is likely due to esophageal compression caused by the large thoracic mass, decreasing the fetal ability to swallow amniotic ﬂuid.45 The most important prognostic indicator in fetuses with CCAM is the development of hydrops. Hydrops is secondary to obstruction of the vena cava or cardiac compression from extreme mediastinal shift.46 In our recent series,45 all 25 fetuses with managed hydrops died expectantly. The volume of the CCAM compared to the head circumference (CCAM volume ratio, (CVR)) may also have prognostic indications: fetuses with a CVR greater than1.2 are more likely to develop hydrops.47 In utero surgical decompression may reverse hydrops and allow sufﬁcient lung growth to permit survival in severe cases. We recently reviewed the outcome in 175 prenatally diagnosed lung lesions.45 In the CCAM category (134 fetuses) 13 fetuses with hydrops underwent fetal lobectomy, with resolution of hydrops and survival to birth in eight out of 13 (62%) cases. There were ﬁve intraoperative or postoperative deaths. In addition, six fetuses with large cystic masses underwent thoracoamniotic shunting and ﬁve survived. Overall, in our experience, 17 out of 25 fetuses with hydrops who underwent fetal therapy (open surgery or shunting) survived, indicating that this is a feasible option in highly selected cases. In the BPS group, there were 41 total lesions of which 28 regressed or disappeared completely. Three fetuses developed hydrops secondary to tension hydrothorax from ﬂuid or lymph secretion by the mass. These fetuses underwent fetal thoracentesis or thoracoamniotic shunt placement and survived to delivery, after which the masses were resected. One fetus with hydrops who was managed expectantly died after birth despite postnatal resection and extracorporeal membrane oxygenation (ECMO). We have learned from these and other cases that fetuses with large chest masses without hydrops can be managed expectantly with planned

delivery and postnatal resection, whereas those earlier than 32 weeks’ gestation with the development of hydrops may beneﬁt from prenatal intervention.

Congenital diaphragmatic hernia Herniation of abdominal viscera into the chest in utero occurs most commonly due to failure of the pleuroperitoneal folds to fuse normally. The left side is affected ﬁve times more commonly than the right. The ultrasonographic diagnostic criteria include herniated abdominal viscera, abnormal upper abdominal anatomy, mediastinal shift away from the side of herniation and polyhydramnios. The extent of pulmonary hypoplasia is proportional to the timing of herniation, the size of the diaphragmatic defect, and the amount of viscera herniated. Despite earlier impressions that CDH was infrequently associated with other serious congenital lung lesions, recent reports state that other major anomalies occur in 10–50% of cases, including a high proportion of chromosomal abnormalities and cardiac anomalies. Distinguishing CDH from other congenital chest conditions and gastrointestinal lesions can be difﬁcult. The presence of abdominal contents intrathoracically on a transverse sonographic scan at the level of a fourchamber view of the heart is required for diagnosis. In the case of a right-sided defect, the presence of liver and especially gall bladder in the chest makes the diagnosis more clear cut. MRI is superior in deﬁning the position of the liver in CDH (above or below the diaphragm), which carries important prognostic signiﬁcance (Fig. 2.4).48,49 MRI is also better at determining the exact diagnosis, when ultrasound may mistake CDH for congenital lung masses. The best predictor of outcome in CDH has been the right lung to head circumference ratio (LHR), deﬁned as right lung area (measured at the level of the transverse four-chamber cardiac view) divided by head circumference. (Fig. 2.5)50 In a recent prospective study, fetuses with LHR <1 did not survive; those with LHR >1.4 all survived, and those with LHR 1–1.4 had a 38% survival rate.51 The position of the liver is also important, with lower survival rates and more need for ECMO in patients with liver herniation.52 The current strategy for in utero treatment of CDH involves tracheal occlusion with a tracheal clip or a balloon. The basis for this approach is the recognition that fetal tracheal occlusion leads to compensatory lung growth due to a decrease in lung liquid egress, as conﬁrmed in lamb models of CDH.53 The fetal clip may be applied via open fetal surgery or fetoscopically.54 Given the embryology of lung growth, occlusion earlier in gestation, prior to the pseudoglandular stage of lung development, may lead to more reliable lung growth. The outcome in fetuses after tracheal occlusion has been

20 Prenatal diagnosis of surgical diseases

Gastrointestinal lesions ESOPHAGEAL AND BOWEL ATRESIAS

Figure 2.4 MRI of a CDH showing liver (L) and stomach (S) in the chest

Esophageal atresia is typically diagnosed on prenatal ultrasound by the presence of a small or absent stomach bubble and polyhydramnios, but no ultrasound ﬁnding is absolutely predictive. Stringer et al.58 found in a recent series examining the accuracy of these two factors in diagnosing esophageal atresia, that there were many fetuses with these ﬁndings who were born normal (positive predictive value 56%), and many cases in which the diagnosis was missed by antenatal ultrasound (sensitivity 42%). Esophageal atresia is associated with anatomic and chromosomal abnormalities in 63% of cases,59 most notably trisomy 18 and vertebral anomalies, anal atresia, cardiac anomalies, tracheoesophageal ﬁstula, renal agenesis, and limb defects (VACTERL). Duodenal atresia has a characteristic ‘double bubble’ appearance on prenatal ultrasound, resulting from dilatation of the stomach and proximal duodenum. Although the incidence of associated malformations is high (classically with Down syndrome and endocardial cushion defects), prenatally diagnosed duodenal atresia does not select for a group with a worse prognosis, as is the case with esophageal atresia. Survival rates of 94–100% have been reported.60 There are many bowel abnormalities which may be noted on prenatal ultrasound (dilated bowel, ascites, cystic masses, hyperperistalsis, and polyhydramnios); however, none is absolutely predictive of postnatal outcome. Patients with obstruction frequently have ﬁndings of increased bowel diameter (especially in the third trimester), hyperperistalsis, or polyhydramnios, but ultrasound is much less sensitive in diagnosing large bowel anomalies than those in small bowel.61 Since the large bowel is mostly a reservoir, with no physiologic function in utero, defects in this region such as anal atresia or Hirschsprung’s disease are very difﬁcult to detect, although a low MSAFP level may be a marker for anal atresia.62 Bowel dilatations may be associated with cystic ﬁbrosis, therefore all such fetuses should undergo postnatal evaluation for this disease.61

Abdominal wall defects Figure 2.5 Ultrasound of CDH at the level of the transverse four-chamber view of the heart (H) showing measurements used for LHR calculation on the right lung (L)

favorable in both the lamb model55 and in the patients after in utero clip procedures.56,57 Our current algorithm for in utero treatment of CDH is for fetuses with isolated CDH, diagnosed before 26 weeks’ gestation, who have liver herniation with LHR <0.9.

Omphalocele is thought to be secondary to failure of the abdominal viscera to return to the abdomen in the 10th week of gestation.63 It characteristically has a viable sac composed of amnion and peritoneum containing herniated abdominal contents. The defect is in the midline, usually near the insertion point of the umbilical cord. Ultrasound may demonstrate the internal viscera and sometimes the liver within the sac. Ascites may also be present. Since chromosomal and structural abnormalities are very common in omphalocele (cardiac and renal anomalies, chromosomal anomalies including

Prenatal diagnosis of renal anomalies 21

Beckwith–Wiedemann syndromes and Pentology of Cantrell), fetuses with this defect should be screened by karyotype in addition to detailed sonographic review and echocardiogram.64 Gastroschisis is more often an isolated lesion with a right para-umbilical defect.64 There is no membrane covering the exposed bowel. On ultrasound, the bowel appears to be free-ﬂoating and the loops may appear to be thickened due to peel formation from exposure to amniotic ﬂuid (Fig. 2.6). Dilated loops of bowel may be seen from obstruction secondary to protrusion from a small defect. Gastroschisis is sometimes complicated by intestinal atresias or obstruction, leading to polyhydramnios and preterm labor. The pathophysiology of bowel damage is due to amniotic ﬂuid exposure and bowel constriction, the latter leading to ischemia and venous obstruction.65,66 Predicting outcome in fetuses with gastroschisis based on prenatal ultrasound ﬁndings remains a challenge. There is some evidence that maximum small bowel diameter may be predictive,67,68 consistent with the observation that patients who have a poorer outcome frequently have bowel atresias.68 Although bowel ischemia may be a contributing factor in the prenatal damage, Doppler velocimetry measurements of superior mesenteric artery are not predictive of outcome.69 The perinatal management and mode of delivery are also controversial: although there are conﬂicting views as to vaginal vs cesarian section delivery, a recent series failed to detect a difference in outcome based on mode of delivery, site of delivery, diagnostic methods, or prenatal Maternal Fetal Medicine (MFM) consult.70 Currently, we advocate serial ultrasound measurements to monitor for development of bowel obstruction and offer an immediate repair strategy after planned cesarian section.

PRENATAL DIAGNOSIS OF RENAL ANOMALIES Of all fetal abnormalities diagnosed on prenatal ultrasound, 20% involve the genitourinary tract.71 The ultrasound ﬁndings of hydronephrosis (HN) include a dilated renal pelvis and calyces, with or without dilatation of the bladder and ureter, depending on the cause of hydronephrosis (Fig. 2.7). The differential diagnosis of prenatal hydronephrosis includes ureteropelvic junction (UPJ) obstruction, multicystic kidney, primary obstructive megaureter, ureterocele, ectopic ureter, and posterior urethral valves.71 Severe, bilateral hydronephrosis leads to oligohydramnios with a fetus small for gestational age. Because of the lack of amniotic ﬂuid, ultrasound diagnosis may be difﬁcult and MRI may help to deﬁne the cause of hydronephrosis.5

Figure 2.7 Ultrasound of hydronephrosis showing enlarged bladder (BL), compressed renal parenchyma (K), and dilated renal pelvices (P)

Upper urinary tract obstruction

Figure 2.6 Ultrasound of fetus with gastroschisis with crossmarks showing the abdominal wall defect and arrow indicating extra-abdominal bowel

The most common cause of prenatal HN is UPJ obstruction. The prognosis of prenatally diagnosed HN is excellent, if there is unilateral disease72 and if the renal pelvic diameter is < 10 mm.73 In a recent series by Kitagawa et al., 80% were normal at 3 years and 17% were normal at birth, suggesting spontaneous resolution of the problem.74 Only 17% needed surgical intervention. Prenatally diagnosed HN requires follow up with ultrasound at birth and at 1 month. If there is any evidence of abnormality, a voiding cystourethrogram, and diuretic renal scintigram should be performed.75

22 Prenatal diagnosis of surgical diseases

Lower urinary tract obstruction The most common cause of lower urinary tract obstruction (LUTO) is posterior urethral valves. This occurs in male fetuses (in female fetuses, it is usually part of a cloacal anomaly). The most important factor in the morbidity and mortality from fetal urethral obstruction is pulmonary hypoplasia secondary to oligohydramnios.76 For patients with posterior urethral valves, prenatal diagnosis deﬁnes a subgroup of patients with very poor prognosis, with 64% incidence of renal failure and transient pulmonary failure, compared to 33% in the postnatally diagnosed group.77 Serial fetal urine analysis may provide prognostic information in this group of fetuses. Drainage of the bladder three times at 48–72hour intervals with measurement of sodium, chloride, osmolality, calcium, β-2 microglobulin, and total protein should be performed to determine renal function. A decrease in the electrolytes, proteins, and tonicity correlate with a favorable outcome.78 The rationale for prenatal intervention originates from sheep models of the disease, in which bladder outlet obstruction in fetal lambs reproduced the pulmonary hypoplasia and renal dysplasia seen in patients with bilateral obstructive uropathy.79 Correction of the obstruction led to normal lung growth.80 Fetal intervention in prenatal obstructive uropathy is only warranted in male fetuses with oligohydramnios, bladder distention, and bilateral hydronephrosis (with no other abnormalities), who have improving urine proﬁles with serial bladder drainage.81 These fetuses may be considered for vesicoamniotic shunting or fetal cystoscopy with cystoscopic ablation of posterior urethral valves.82 Although shunting has been fraught with technical problems, the beneﬁt in survival following prenatal shunting in carefully selected populations of fetuses has been reported, with 43% of patients having reached normal renal function 2 years after birth.83 Short-term outcomes are variable in different reports,72 underlining the need for careful patient selection.

Arnold–Chiari malformation, characterized by the caudal displacement of the vermis and cerebellum with midbrain herniation through the foramen magnum. Ultrasound conﬁrmation can be made as early as 18 weeks, which allows localization of the defect as well as assessment of limb function, the presence of clubbing or of the Arnold–Chiari malformation (Fig. 2.8). Analysis of the potential beneﬁts of fetal repair of MMC has been accomplished in a sheep model of the defect.87 This model replicates the deﬁcits seen in children with spina biﬁda such as ﬂaccid paraplegia, incontinence, and absent hindlimb somatosensory potentials, indicating that prolonged exposure to amniotic ﬂuid and the intrauterine environment may contribute to the damage seen in MMC. Early experiments showed that in utero repair of the defect using a latissimus dorsi ﬂap prevented the neurological damage in sheep,88 thus providing a compelling reason for in utero repair, the ﬁrst non-lethal disease to be considered for this treatment. Although experimental evidence dictates that the defect be repaired as soon as possible to allow time for neuronal regeneration, preterm labor remains a ratelimiting step in the progress of fetal surgery. The goals of fetal repair are to prevent the chemical and mechanical trauma to the exposed spinal cord, to resolve the hindbrain herniation frequently seen with this defect, to decrease the need for postnatal ventriculoperitoneal shunt, and to allow time for possible neural regeneration after repair. We reported the ﬁrst open repair of fetal MMC which led to improved neurological outcome.89 A 23-week-old fetus with a T11–S1 defect repaired at 23 weeks and delivered at 30 weeks (secondary to preterm labor) showed that the neurological function was intact to the L4 level on the right and L5 level on the left, with resolution of the Arnold–Chiari malformation. We and

Myelomeningocele Myelomeningocele (MMC) is a neural tube defect characterized by the protrusion of the spinal cord and meninges through open vertebral arches. It is the most common form of spina biﬁda, which affects one in 2000 births per year. Maternal serum testing identiﬁes 75–80% of pregnancies with MMC by 16 weeks’ gestation.84 If an increase in serum AFP is noted, amniocentesis is performed to assess amniotic ﬂuid AFP and acetylcholinesterase to conﬁrm the diagnosis.85 The ultrasound characteristics include the ‘lemon’ and ‘banana’ signs, which are a scalloping of the frontal bone and abnormal anterior curvature of the cerebellar hemispheres, respectively.86 Most fetuses have an associated

Figure 2.8 Ultrasound of fetus with MMC showing the sac (cross-marks) over the spinal defect (arrow)

References 23

others have since conﬁrmed the resolution of the hindbrain herniation in nine subsequent fetuses with MMC following open repair.90,91 Since some of the morbidity and mortality of an MMC occurs as a result of the associated Arnold–Chiari malformation, this ﬁnding is signiﬁcant. Our current algorithm for considering fetuses for repair is an age of less than 25 weeks, presence of Arnold–Chiari malformation (Fig. 2.9), good leg movement, absence of clubbed feet, and absence of other anomalies. If fetal repair is not performed, fetuses with MMC should be delivered by planned cesarian section to avoid trauma to the cord during the birth process.92,93

Figure 2.9 MRI of fetus with MMC showing hindbrain herniation (arrow)

CONCLUSION Prenatal ultrasound has led to a rapid increase in the number of pediatric surgical conditions diagnosed in utero. Prenatal detection and serial sonographic study of fetuses with anatomic lesions now makes it possible to deﬁne the natural history of these abnormalities, determine the pathophysiologic causes that affect outcome, and formulate management based on prognosis. Since many congenital anomalies are associated with others, it is important to perform a careful ultrasound evaluation and karyotype analysis when one abnormality is discovered. Careful evaluation of patients followed pre- and postnatally, as well as studies of congenital defects in animal models, has deﬁned select populations of fetuses who may beneﬁt from prenatal intervention. In most cases, these are fetuses who would not be expected to survive the prenatal period given the natural history of their disease. Further progress in prenatal diagnosis and

monitoring as well as continued re-evaluation of outcomes will doubtless tune our current algorithms regarding the management of these congenital anomalies. Pediatric surgeons have a unique opportunity to continue to shape this exciting ﬁeld in this new millennium.

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88.

89.

90.

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92.

93.

myelomeningocele in utero: a model of functional damage from spinal cord exposure in fetal sheep (see comments). J Pediatr Surg 1995; 30:1028-32; discussion 1032–3. Meuli M, Meuli-Simmen C, Hutchins GM et al. In utero surgery rescues neurological function at birth in sheep with spina biﬁda. Nat Med 1995; 1:342–7. Adzick NS, Sutton LN, Crombleholme TM, Flake AW. Successful fetal surgery for spina biﬁda (letter) (see comments). Lancet 1998; 352:1675–6. Sutton LN, Adzick NS, Bilaniuk LT, Johnson MP, Crombleholme TM, Flake AW. Improvement in hindbrain herniation demonstrated by serial fetal magnetic resonance imaging following fetal surgery for myelomeningocele (see comments). Jama 1999; 282:1826–31. Bruner JP, Tulipan N, Paschall RL et al. Fetal surgery for myelomeningocele and the incidence of shuntdependent hydrocephalus (see comments). Jama 1999; 282:1819–25. Luthy DA. Maternal markers and complications of pregnancy (editorial; comment). N Engl J Med 1999; 341:2085–7. Scheller JM, Nelson KB. Does cesarean delivery prevent cerebral palsy or other neurologic problems of childhood? (see comments). Obstet Gynecol 1994; 83:624–30.

3 Fetal and birth trauma PREM PURI

FETAL TRAUMA About 40 years ago,1,2 it was estimated that 6–8% of pregnant women were affected by accidental injury. This number is likely to be greater now because there are more women in the workforce. When a pregnant woman presents with a major trauma, two lives are at risk. The survival of the fetus depends primarily on maternal survival,3 but occasionally the extent of maternal injury does not correlate with the degree of fetal injury.4 Treatment priorities for traumatic pregnant women remain the same as in patients who are not pregnant, although resuscitation and stabilization should be modiﬁed to account for the anatomical and physiological changes of the pregnancy.5,6 The ﬁrst consideration in the management of maternal trauma in an accident is to ensure the survival of the mother, as is recommended by the Advanced Trauma Life Support Program.6 Assessment of the fetus forms part of the secondary survey of the mother, and should be performed in conjunction with an obstetrician, because beyond 26–28 weeks’ gestational age the fetus is potentially viable if urgent delivery is required.6 Assessment of the fetus includes: the date of the last menstrual period, measuring the fundal height, examination for uterine contractions and tenderness, fetal movements and fetal heart rate. An important part is the vaginal examination for amniotic ﬂuid or blood. Fetal distress can occur at any time and without warning. The fetus should be continually monitored to ensure early recognition of fetal distress by using the ultrasonic Doppler cardioscope. Signs of fetal distress include: bradycardia (< 110 b.p.m.), inadequate accelerations in fetal heart rate in response to uterine contraction, and late decelerations in fetal heart rate in response to uterine relaxation. In blunt maternal–fetal trauma, placental injury is the leading cause of death with maternal survival.7,8 Occasionally, minor maternal trauma may disrupt the

placenta ‘lifeline’ by shearing the relatively rigid placenta from the more elastic uterine wall, thereby leading to fetal distress and subsequent fetal death.4 The clinical signs of placental abruption include: vaginal bleeding, uterine irritability, abdominal tenderness, increasing fundal height, maternal hypovolemic shock and fetal distress. Although the common classical presentation of placental abruption involves vaginal bleeding and abdominal pain, some cases of traumatic abruption occur without these symptoms and fetal distress may not develop for several hours. The fetus should be considered salvageable in the face of severe or even mortal maternal injury, and more than 150 cases of successful post-mortem cesarian section delivery and numerous deliveries of normal neonates just before maternal death have been described.7,9 Fetal injuries after trauma may be treatable, but only if they are recognized. Penetrating trauma by gunshot or stab wounds, although rare,4 are usually obvious, and thus appropriate surgical intervention has to be undertaken (Fig. 3.1a,b). Although most cases of penetrating fetal trauma are fatal to the fetus, some cases of fetal salvage have been reported.10,11 In contrast, surgically treatable fetal injury may go unrecognized after blunt maternal trauma, while these injuries are much more frequent. Thus, one can recognize that after 28 weeks’ gestation, cesarian section for fetal salvage is indicated in the presence of placental abruption with fetal distress, treatable life-threatening fetal injury, or if there is obvious impending or recent maternal death. A pediatric surgeon should participate in the evaluation and management of both the pregnant patient and the neonate delivered after maternal trauma, together with the obstetrician and neonatologist. Pregnant women should be hospitalized after trauma for appropriate evaluation and fetal monitoring, in the hope of decreasing traumarelated fetal deaths. In recent years, it is expected that every pediatric surgeon must be familiar with the treatment of pediatric trauma. The treatment of the traumatic pregnant woman and the fetus must be part of this skill, especially if the fetus is to be considered a patient.

28 Fetal and birth trauma

fetal organs or masses. Nevertheless, birth injuries still occur and represent an important problem for the clinician; the incidence of birth trauma is reported to be two to eight per 1000 live births.14,15 Birth injury is usually associated with unusual compressive or traction forces in association with abnormal presentation of the fetus. Factors that predispose birth injury include primiparity, cephalopelvic disproportion, dystocia, prematurity, prolonged labor, macrosomia, abnormal presentation, forceps application, version and extraction.12,14,15 The newborn at greatest risk for birth injury is the one in breech presentation.

Types of birth trauma HEAD INJURIES

(a)

(b) Figure 3.1 (a) X-ray of a neonate born to a mother who sustained accidental gunshot wounds to her abdomen. Note metallic pellet in the right thigh. (b) Clinical photograph of the same infant showing entry wound in the right thigh

Caput succedaneum Caput succedaneum is a diffuse edematous, occasionally hemorrhagic swelling of the scalp, superﬁcial to the periosteum occurring secondary to compression of the presenting part during prolonged labor. Usually, caput succedaneum requires no treatment and the swelling disappears spontaneously in a week or so. Rarely, hemorrhage into soft tissue may cause anemia that requires blood transfusion or may lead to hyperbilirubinemia or both.16 Cephalhematoma Cephalhematoma is a subperiosteal collection of blood most often found in the parietal region and sharply delineated by the surrounding suture lines (Fig. 3.2). In 10–25% of cephalhematomas there is an underlying skull fracture which is usually of linear type and clinically unimportant.17 The precise mechanism of production of cephalhematoma is not well established. Repeated buffeting of the fetal skull against the maternal pelvis during a prolonged labor and mechanical trauma caused by the use of forceps and vacuum extractor in

BIRTH TRAUMA Birth injuries are deﬁned as injuries associated with mechanical forces producing hemorrhage, edema, tissue disruption, or alteration of organ function occurring during the intrapartum period.12 With the improvement in obstetric techniques, increased frequency of cesarian section in potentially difﬁcult deliveries, decreased use of difﬁcult forceps and utilization of fetal heart rate and determination of acid–base status to monitor the fetus during labor, the incidence of birth injuries has decreased in recent years.13 Furthermore, recent advances in the use of prenatal ultrasonography have allowed early identiﬁcation of the risk factors for possible birth trauma, including fetal size and position and enlarged

Figure 3.2 Large cephalhematoma

Birth trauma 29

delivery have been implicated as important factors. Cephalhematomas have been reported to originate in utero, antipartum. Petrikovsky et al. found seven cases of cephalhematomas identiﬁed prenatally on 16 292 fetuses during comprehensive ultrasound examinations. Premature rupture of the membranes was seen and was suggested as an associated factor.18 Most cephalhematomas resolve spontaneously within a few weeks. Aspiration of the hematoma is contraindicated because of the risk of introducing infection. Only in the rare case of superinfection of the cephalhematoma is aspiration, drainage and antibiotic therapy indicated.15 Occasionally, serious complications such as anemia, jaundice, abscess, septicemia, meningitis, osteomyelitis, disseminated intravascular coagulation, shock with acute hemorrhage and depressed skull fractures have been reported in association with cephalhematomas.19–22 Management involves careful observation for these complications. Skull fractures Most of the skull fractures are linear, occurring in association with cephalhematomas and usually involving the parietal bones (Fig. 3.3a). No speciﬁc treatment is required for linear fractures, but skull X-rays should be repeated when the infant reaches 2–4 months of age to rule out ‘growing fracture of the skull’ associated with a leptomeningeal cyst (Fig. 3.3b). A leptomeningeal cyst can occur rarely if the trauma causing the linear fracture tears the underlying dura, thereby permitting herniation of the meninges and brain. This requires surgical intervention to avoid progressive brain damage.20,23 Depressed skull fractures are most often caused by pressure of the fetal head against the maternal pelvis or in association with forceps delivery in all cases of depressed fractures (Fig. 3.4). Several non-surgical techniques for elevation of depressed skull fracture in the newborn have been described, including suction with a breast pump or vacuum extractor,24–26 and by digital manipulation. Indications for surgical elevation of depressed skull fracture include:27 1 Radiographic evidence of bone fragments within the brain 2 Neurological deﬁcit 3 Signs of increased intracranial pressure 4 Failure to elevate the fracture by closed manipulation. Intracranial hemorrhage Intracranial hemorrhage following birth trauma may occur in the subarachnoid space, the subdural space or within the brain. Subarachnoid hemorrhage is the most common form of birth-related traumatic intracranial hemorrhage in the newborn.17 Blood in the subarachnoid space can be documented by lumbar puncture and the diagnosis conﬁrmed by computerized tomography (CT) scan.28 In

(a)

(b) Figure 3.3 (a) Linear fracture of left parietal bone at birth. (b) Three years later the patient presented with a pulsatile swelling in the left parietal region. X-ray shows an extensive bone defect due to leptomeningeal cyst

the vast majority of cases, traumatic subarachnoid hemorrhage is benign and does not require any treatment. Occasionally it may result in a communicating hydrocephalus. Subdural hemorrhage is caused by rupture of the cerebral veins bridging the subdural space, occurring as a result of excessive moulding of the baby’s head during labor or delivery. Most subdural hematomas are infratentorial and bilateral, but occasionally they have been described in the posterior fossa. Principal factors that predispose to the occurrence of subdural hematoma include large-size infants,17 breech delivery29 and forceps extraction in primiparous women.30 Clinical features of neonatal subdural hemorrhage may include pallor, vomiting, irritability, seizures, unequal pupils, drowsi-

30 Fetal and birth trauma

fontanelle. In most cases, subdural collections can be treated successfully with repeated taps. Rarely, membrane stripping or subdural space shunting may be required to deal with persistent subdural collections. Intracerebral hemorrhage Traumatic intracerebral hemorrhage is the least common of intracranial hemorrhage in the newborn.17 The clinical features are those of increased intracranial pressure. The diagnosis can be made with cerebral ultrasonography, CT scan or MRI, and regression or complications can be monitored with serial studies.32

SPINAL CORD INJURIES

Figure 3.4 Depressed fracture or right parietal bone following forceps delivery

ness, hypotonia, high-pitched cry, tense fontanelle and retinal hemorrhages. The diagnosis is conﬁrmed by a subdural tap, CT scan (Fig. 3.5) or magnetic resonance imaging (MRI).32 Ultrasonography is unlikely to be as accurate as a CT scan in diagnosing peripheral lesions in subarachnoid or subdural space.33 The treatment consists of repeated tapping of the subdural space using a 20gauge needle at the lateral margin of the anterior

Figure 3.5 CT brain scan without intravenous contrast medium in a newborn, showing blood in the subarachnoid space (large white arrow) and blood in the ﬂoor of 4th ventricle (small white arrow)

The incidence of birth injury to the spinal cord is difﬁcult to determine because most neonatal postmortem examinations do not include complete examination of the spinal cord.34 The leading cause of neonatal spinal cord injury is delivery of the fetus with marked hyperextension of the neck in a breech presentation. Approximately 75% of reported spinal cord injuries occurred in infants delivered vaginally in breech presentation.35 Other predisposing factors are prematurity, shoulder dystocia, intrauterine hypoxia and precipitous delivery.36 The application of compressive forceps to the fetal spine during fundal pressure to relieve shoulder dystocia has been reported to result in lower thoracic spinal cord injury in the newborn.37 The site of spinal cord injury following breech delivery is usually in the lower cervical and upper thoracic region, while injury following vertex presentation is usually located in the upper or midcervical level.17 The injury is usually caused by stretching of the cord and not by compression. The most common mechanism responsible for spinal cord injury is the use of excessive longitudinal traction on the trunk while the head is still engaged in the pelvis.26 The spinal cord is relatively inelastic compared with the vertebral fracture or dislocation, or both, and cord transection. The clinical manifestations of spinal cord injury may ﬁt into one of the following four recognized groups, depending on the severity of the damage incurred:19,38 1 Babies who are stillborn or die immediately after birth due to a high cervical or brainstem lesion 2 Neonates who die shortly after birth due to respiratory depression and complications and who generally have upper and midcervical lesions 3 Long-term survivors who have ﬂaccid paralysis in the neonatal period and proceed to develop spasticity and hyper-reﬂexia in the ensuing months 4 Those with minimal neurological signs or spasticity who are often classiﬁed as having cerebral palsy.39 The symptoms in these patients result from partial spinal cord injury or cerebral hypoxia. When spinal cord injury is suspected, deﬁnition of the underlying pathology can be difﬁcult using standard diagnostic

Birth trauma 31

procedures, including plain X-ray and CT, with or without myelography MRI, with its excellent deﬁnition and low risk of complication, is the best diagnostic tool available to evaluate clinically suspected spinal cord pathology.40,41 Spinal ultrasound is a good imaging method for guiding diagnosis of traumatic spinal cord lesions.42 Treatment of spinal cord injuries is supportive and includes physiotherapy, braces, and urological, orthopaedic and psychological care. Surgery has little to offer to patients with these types of injuries. Great emphasis should be placed on prevention of spinal cord injury in the newborn.

PERIPHERAL NERVE INJURIES Injury to the peripheral nerves in the newborn is usually caused by excessive traction or direct compression of nerves during delivery. The nerves most commonly involved are the brachial plexus, facial nerve and phrenic nerve. Brachial plexus injury With the improvement in obstetric techniques the incidence of birth-related brachial plexus injuries has decreased considerably in recent years. The incidence varies from 0.15–2.6 per 1000 live births.14,17,43–45 The injury is usually caused by traction and stretching of the plexus. All lesions occur in the plexus above the level of the clavicle and range from simple neuropraxia, classiﬁed by Sunderland46 as grade I, to full neurotemesis when associated with root avulsion, classiﬁed as grade V. Risk factors for brachial plexus injury include a prolonged and difﬁcult labor, breech presentation, large-size baby, and hypotonic, forceps delivery, vacuum extraction, shoulder dystocia and/or asphyxiated infant.47,48 Brachial plexus injury has been divided into three main types depending on the site of the injury: 1 Erb’s palsy, which results from injury of the ﬁfth and sixth cervical nerve roots, is by far the most common type of injury. The affected arm hangs limply adducted and internally rotated at the shoulder, and extended and pronated at the elbow with ﬂexed wrist in the typical ‘waiter’s tip’ posture (Fig. 3.6). The Moro, biceps and redial reﬂexes are absent on the affected side. The grasp reﬂex is intact. These clinical ﬁndings are the result of paralysis of the deltoid, supraspinatus, infraspinatus, brachioradialis and supinator brevis muscles. 2 Klumpke’s paralysis results from injury of the eighth cervical and ﬁrst thoracic nerve roots and is extremely rare as an isolated entity. The intrinsic muscles of the hand and ﬂexors of the wrist and ﬁngers are affected. The grasp reﬂex is absent Injury involving the cervical sympathetic ﬁbres of the ﬁrst thoracic root may result in ipsilateral Horner syndrome.

Figure 3.6 Erb’s palsy. Characteristic deformity of right arm

3 Injury to the entire brachial plexus results in a ﬂaccid arm with absence of sweating, sensation and deep tendon reﬂexes. The differential diagnosis includes: fracture of the clavicle or humerus, traumatic epiphysiolysis of the proximal epiphysis of the humerus, and shoulder dislocation.48 These injuries can of course occur in addition to the plexus paralysis.49 Another associated injury is a phrenic nerve palsy.44 A radiograph of the shoulder, upper arm and clavicle should be taken. A chest X-ray should be obtained because of the possibility of an associated phrenic nerve palsy. Electromyography, although of limited value, may be useful in determining the extent and site of injury and evaluating the prognosis.48, 50 Most neonates with brachial plexus injury make a complete or partial recovery on conservative treatment.17,44 The main principle of management is to maintain the range of ‘motion’ in the affected joints. Treatment should be delayed for a period of 3–4 weeks after the trauma, in which immobilization of the hand and stretched nerve ﬁbers will allow a spontaneous cure. During the ﬁrst 4 weeks, the arm has to be adducted to the thorax. Abduction and external rotation position of the shoulder must be prevented due to considerable tension on the brachial plexus in that position. In the other joints, careful passive physiotherapy should be carried out. Thereafter, a gentle range of motion exercises to shoulder, elbow, wrist and small joints of the hand may have to be started. The prognosis of brachial plexus paralysis is better in the Erb’s patient than in the patient with the Klumpke variety and in both of these groups is better than in total paralysis. In the majority of Erb’s palsy cases, a partial or

32 Fetal and birth trauma

complete recovery can be achieved.51 Surgical exploration and repair of brachial plexus birth injuries are recommended only when there is no recovery of the biceps by 3 months of age. An electromyography and myelogram with CT scanning are performed preoperatively.48 Advances in microsurgical techniques and reconstruction of the injured plexus by grafting from the dural nerve can signiﬁcantly improve the functional result.48,52,53 Facial nerve injury Facial palsy secondary to birth trauma is usually unilateral and most commonly follows compression of the peripheral portion of the nerve, either near its emergence from the stylomastoid foramen or where the nerve transverses the ramus of the mandible. The mechanism of injury is usually either direct trauma from forceps or compression of the side of the face and nerve against the sacral promontory. The affected infant has absent or decreased forehead wrinkling, a persistently open eye, a decreased nasolabial fold and ﬂattening of the corner of the mouth on the affected side (Fig. 3.7). Treatment is conservative, since spontaneous recovery occurs within 1 month in most cases of birth-related facial palsy.15,47 Initial treatment should be directed at protecting the corneal epithelium from drying with the use of methylcellulose drops instilled every 4 hours. Rarely, there is need for surgical intervention and neurolysis or a nerve cable transplant for the injured or degenerative facial nerve, after conﬁrming the diagnosis by electromyographic and electroneurographic tests.54

Phrenic nerve injury Diaphragmatic paralysis in the neonate results from stretching or avulsion of the fourth and ﬁfth cervical roots, which form the phrenic nerve. The most common cause of phrenic nerve injury is a difﬁcult breech delivery. The majority of injuries are unilateral. Bilateral diaphragmatic paralysis is rare.55 Approximately 75% of cases of birth-related phrenic nerve injury have an associated brachial plexus injury.56,57 The clinical features of diaphragmatic paralysis are non-speciﬁc and include respiratory distress with tachypnea, cyanosis and recurrent atelectasis or pneumonia. Chest X-ray demonstrates an elevated hemidiaphragm about two intercostal spaces higher than the adjacent diaphragm (Fig. 3.8a). Diagnosis is conﬁrmed on ﬂuoroscopy, which shows an immobile diaphragm or an abnormal elevation of the diaphragm during inspiration constituting paradoxical movement.58 Real-time ultrasonography can also be employed to diagnose phrenic nerve paralysis and can be performed in the intensive care unit in very young babies (Fig. 3.8b). Most infants with diaphragmatic paralysis make a complete recovery after treatment with oxygen, chest physiotherapy and antibiotics (Fig. 3.8c). A few patients who have severe or increasing respiratory distress may be managed by continuous positive airway pressure (CPAP). Surgery may be required if there is persistent paralysis after 2 weeks of mechanical ventilation or 3 months of medical treatment. The procedures employed include plication of the diaphragm17 or incision and replacement of the diaphragm.59

INTRA-ABDOMINAL INJURIES Birth trauma involving intra-abdominal organs is relatively uncommon. The organs most commonly involved are the liver, spleen, adrenal and kidney.

Figure 3.7 Left facial nerve palsy following difﬁcult forceps. Note obliteration of left nasolabial fold with typical deformity of mouth and wide-open left eye

Liver The liver is the most commonly injured abdominal organ during the birth process. Factors that predispose to liver trauma include breech presentation, infants with hepatomegaly, large infants, prematurity and coagulation disorders.15 The mechanism of birth-related liver injury is thought to be either: (1) thoracic compression and pulling of the hepatic ligaments with consequent tearing of the liver parenchyma, or (2) direct pressure on the liver leading to subcapsular hemorrhage or rupture.15 Hepatic trauma more commonly results in subcapsular hemorrhage than actual rupture of the liver. The infant with subcapsular hemorrhage usually appears to be normal for the ﬁrst 3 days of life, when the capsule ruptures and there is extravasation of blood into the peritoneal cavity. This is followed by sudden circulatory collapse, abdominal distension and a rapid drop in the hematocrit value. If the processus vaginalis is patent, blood may be seen in the scrotum, suggesting hemoperitoneum. In

Birth trauma 33

(a)

(c) Figure 3.8 Phrenic nerve paralysis. (a) Chest radiography shows elevated right diaphragm. (b) Transverse real-time sonogram showing blurring in the region of left diaphragm due to respiratory movement. Right diaphragm did not move and is sharply outlined along the liver. (c) Chest X-ray 3 months later shows normal right diaphragm after conservative treatment

immediate laparotomy, with evacuation of the hematoma and repair of any laceration by sutures or by ﬁbrin glue.60

(b)

patients with primary rupture of the liver, major intraperitoneal bleeding occurs immediately, resulting in severe shock and abdominal distension. Abdominal radiographs are not usually very helpful, but may show uniform opacity of the abdomen, indicating free intraperitoneal ﬂuid. Abdominal ultrasonography may conﬁrm the diagnosis and is also useful in differentiating a solid liver tumor from an unruptured subcapsular hemorrhage. A CT scan is recommended, only if the patient is hemodynamically stable (Fig. 3.9a–d). Abdominal paracentesis is the procedure of choice for rapid diagnosis of hemoperitoneum. Immediate management consists of blood transfusion to restore the blood volume and recognition and correction of any coagulation disorder. This is followed by an

Spleen Rupture of the spleen in the newborn occurs much less often than does rupture of the liver. The predisposing factors and mechanism of injury are quite similar to those of rupture of the liver. Although splenomegaly increases the risk, the vast majority of splenic injuries occur in spleen of normal size.20 The presenting features are cardiovascular collapse and abdominal distension. Abdominal radiographs may indicate free ﬂuid in the peritoneal cavity. Abdominal paracentesis will conﬁrm hemoperitoneum. Management consists of adequate blood transfusion followed by exploratory laparotomy. In the past, management of splenic rupture has been splenectomy. In recent years, repair of the spleen has been advocated because of the risk of subsequent serious infections following splenectomy.61 Since there is a critical mass of spleen which prevents overwhelming post-splenectomy infection (OPSI),62,63 every surgeon should do the utmost to preserve as much of the injured spleen as possible. Fibrin glue, splenorrhaphy or partial splenectomy are the

34 Fetal and birth trauma

(a)

(b)

(c)

(d)

Figure 3.9 Newborn who developed a distended abdomen post-delivery. (a,b) Sonographic scan at 36 h shows echo-poor material due to fresh hemorrhage (white arrow) between the anterior aspect of the right kidney (K) and the inferior aspect of the right lobe of liver (L). (c) Scan through left lobe of liver demonstrating an area of increased echogenicity in keeping with hemorrhage at site of laceration (curved arrows). (d) Laceration in left lobe conﬁrmed on CT scan (black arrow)

preferred surgical procedures.15,64–66 This conservative surgical approach is advocated not only because of the OPSI, but also because of the absence of regeneration of the injured spleen after partial splenectomy, which has been proven in animals.67

Adrenal Neonatal adrenal hemorrhage occurs most commonly following a prolonged and difﬁcult labor, culminating

in a traumatic delivery. Other contributing factors include asphyxia, prematurity, placental hemorrhage, hemorrhagic disease of the newborn, septicemia, renal vein thrombosis, increased vascularity, and congenital syphilis.68–73 The right adrenal is involved in over 70% of cases, with bilateral involvement in 5–10%.74,75 The presenting features vary with the degree of bleeding. The classical adrenal hemorrhage usually presents between birth and the fourth day of life as an abdominal mass with fever and jaundice or anemia.73 The differential

Birth trauma 35

diagnosis may include adrenal cyst, neuroblastoma and Wilms tumour. Diagnosis of neonatal adrenal hemorrhage may be conﬁrmed with a combination of ultrasound and i.v. pyelogram. Sonography would reveal a suprarenal mass that initially is echogenic, and subsequent changes to a cyst-like structure probably indicating fragmentation of the clot (Fig. 3.10a,b). An i.v. pyelogram should demonstrate downward displacement of the kidney on the affected side. An early total body opaciﬁcation ﬁlm may show a lucent region above the kidney. A ‘rim’ suprarenal calciﬁcation may be seen on abdominal radiographs 2–4 weeks after hemorrhage.68,76 In patients with retroperitoneal hemorrhage, treatment consists of blood transfusion, close observation and follow-up ultrasound studies. In infants with massive intra-peritoneal hemorrhage, surgical intervention con-

sists of abdominal paracentesis, laparotomy, evacuation of hematoma, ligation of bleeders or adrenalectomy if indicated. It must be remembered that the underlying pathology may be a neuroblastoma,77,78 and a biopsy should always be taken. Infrequently, a suspicion of an adrenal abscess ensues. In such a situation, a drainage procedure must be performed either percutaneously with ultrasound guidance or by operative exploration. Kidney Birth-related trauma is rare. Rupture of the kidney in the newborn is usually associated with an underlying congenital anomaly.79 The presenting signs are hematuria and renal mass. An i.v. pyelogram may show absence of excretion or leakage of contrast through the renal parenchyma into the perirenal space. Renal ultrasonography may demonstrate renal rupture (Fig. 3.11) or ascites. Treatment consists of conservative management if possible. Only in cases of severe bleeding or a total rupture of parenchyma or pelvis is a laparotomy indicated, with the correction of underlying congenital anomaly whenever it is necessary.

(a) (a)

(b)

(b)

Figure 3.10 (a) Right suprarenal echo-poor mass representing a right adrenal hemorrhage (between cursors) in an infant who suffered birth asphyxia. (b) Scan performed 1 month later, showing that hemorrhage has almost cleared. Small residual echo-poor area persists (white arrow)

Figure 3.11 (a) Longitudinal sonogram showing an echolucent area in upper pole of right kidney consistent with an intracapsular rupture. Both ureters were hydronephrotic with dilated bladder on sonography. (b) Voiding cystogram in the same patient conﬁrmed posterior urethral valves

36 Fetal and birth trauma

BONY INJURIES Fractures due to birth trauma almost always involve the clavicle, humerus or femur. Epiphyseal separations usually involve upper an lower humeral and upper femoral epiphyses. Dislocations caused by birth trauma are rare. Fracture of the clavicle Fracture of the clavicle is the most common fracture in the newborn, usually occurring during a difﬁcult delivery associated with large infants, breech presentation and shoulder dystocia.80 Most fractures are of the greenstick type, occurring in the middle third of the clavicle, but occasionally the fracture is complete (Fig. 3.12). Undisplaced fractures require no treatment. Fractures with marked displacement should be immobilized with a ﬁgure-of-eight bandage. Recovery is usually excellent.

Epiphyseal separations The epiphyseal separation or fracture occurs through the hypertrophied layer of cartilage cells in the epiphysis. The most common cause is a difﬁcult breech delivery.81 A fracture through the proximal epiphyseal plate of the humerus is the most common epiphyseal cartilage injury. Fractures entirely conﬁned to the epiphyseal cartilage cannot be demonstrated radiologically. However, in many cases the fracture extends through a part of the metaphysis, separating a tiny bony fragment. This fragment is attached to the epiphysis and if no displacement of the epiphysis has occurred, the fragment may be the only radiographic evidence of fracture. An increased distance of the metaphysis from the joint compared with the opposite side can also indicate fracture through the epiphyseal plate. After 1–2 weeks, callus becomes visible, conﬁrming the nature of the injury. Diagnosis at the initial stage has to be made primarily on clinical ﬁndings of pain on passive motion, swelling and impaired movement around the joint. Recent reports suggest that epiphyseal separation can be studied by sonography and without the common use of arthrography.81,82 Treatment of a fracture of the proximal epiphysis of the humerus consists of immobilization of the arm by the side with a sling in 90° ﬂexion. Epiphysiolysis of the proximal femur is sometimes confused with congenital dislocation of the hip and septic arthritis, and can occur not only after normal delivery but also after delivery by cesarian section.83 Treatment for a fracture of the proximal epiphysis of the femur is by traction and spica cast for 2 months.

TRAUMA TO THE GENITALIA Figure 3.12 Fracture of right clavicle. Typical fracture of middle third of clavicle following forceps delivery

Fracture of the humerus Fractures of the humerus usually occur in the middle third of the shaft and are either transverse or spiral. They are usually greenstick fractures, but occasionally complete fracture with overriding of fragments may occur. The most common mechanisms responsible for fracture are believed to be traction on the extended arm in the breech presentations and axillary traction to disengage an impacted shoulder in vertex presentations. Treatment consists of strapping the arm to the chest. Complete healing of the fracture fragments usually occurs by 3 weeks. Fracture of the femur Femoral shaft fractures usually occur in the middle third and are transverse. The injury usually follows a breech delivery. X-ray invariably shows overriding of the fracture fragments. Treatment consists of Bryant’s traction for 3–4 weeks. The prognosis in femoral fractures is usually excellent.

The breech delivery is the common cause of tissue injuries involving the external genitalia. Edema, ecchymoses and hematomas of the scrotum or the labia majora can occur. No treatment is needed. Spontaneous resolution of edema occurs within 24–48 hours and of discoloration within 4–5 days. If the tunica vaginalis is injured and blood ﬁlls its cavity, a hematocele is formed. The differential diagnosis should include neonatal torsion and patent processus vaginalis.84 An iatrogenic injury to the scrotum with resultant castration during breech extraction has been reported.85

REFERENCES 1. Peckman CH, King RW. A study of intercurrent conditions observed during pregnancy. Am J Obstet Gynecol 1963; 87:609–24. 2. Patterson RM. Trauma in pregnancy. Clin Obstet Gynecol 1984; 27:32–8. 3. Hoff WS, ‘Amelio LF, Tinkoff GH et al. Maternal predictors of fetal demise in trauma during pregnancy. Surg Gynecol Obstet 1991; 172:175–80.

Referernces 37 4. Farmer DL, Adzick NS, Crombleholme WR et al. Fetal trauma: relation to maternal injury. J Pediatr Surg 1990; 25:711–14. 5. Nash P. Trauma in pregnancy Br Med J 1990; 301:974–6. 6. Committee on Trauma. Trauma in pregnancy. Advanced Trauma Life Support Program (ATLS), Instructor Manual Committee on Trauma, American College of Surgeons, 1998. 7. Ciuil ID, Talucci RC, Schwab CW. Abdominal trauma. J Trauma 1988; 28:708–10. 8. Kettel LM, Branch DW, Scott JR. Occult placental abruption after maternal trauma. Obstet Gynec 1988; 71:449–53. 9. Arthur RK. Postmortem ceserean section. Am Obstet Gynecol 1978; 132:175–9. 10. Buchsbaum HJ, Staples PP. Self inﬂicted gun shot wound to the pregnant uterus: report of two cases.Obstet Gynecol 1985; 65:32S–35S. 11. Zikovic S, Milosevic V, Stanivukovic V. Prenatal gunshot perforation of the colon. J Pediatr Surg 1976; 11:591–2. 12. Curran JS. Birth associated injury. Clin Perinatol 1981; 111–29. 13. Levine MG, Holroye J, Woods JR et al. Birth trauma: incidence and predisposing factors. Obstet Gynecol 1984; 63:792–5. 14. Berle P. Incidence of birth injuries to newborn infants in relation to birth weight. An analysis of the Hessan Perinatal Study. Geburtsch Frauenheilk 1995; 55:23–7. 15. Schullinger JM. Birth trauma. Pediatr Clin North Am 1993; 40:1351–8. 16. Murphy WJ. Birth trauma. In: Cloherty JP, Stark AR, editors. Manual of Neonatal Care. 2nd edn. Boston: Little, Brown, 1985: 251–5. 17. Painter MJ, Bergmen I. Obstectrical trauma to the neonatal central and peripheral nervous system. Semin Perinat 1982; 6:89–104. 18. Petrikovsky BM, Schneider E, Smith-Levitin M, Gross B. Cephalhematoma and caput succedaneum: do they always occur in labor. Am J Obstet Gynecol 1998; 179:906–8. 19. Zelson C, Lee SJ, Pearl, M. The incidence of skull fractures underlying cephalhaematomas in newborn infants. J Pediatr 1974; 85:371–3. 20. Gresham EL. Birth trauma. Pediatr Clin Am 1975; 22:317–28. 21. Curran JS. Birth associate injury. Clin Perinatol 1981; 8:111–29. 22. Raffensperger JG. Trauma in neonate. In: Swenson’s Pedriatic Surgery. 5th edn. Norwalk, CN: Appleton and Lange, 1990: 339–42. 23. Kingsley D, Till K, Hoare R. Growing fractures of the skull. J Neurol Neurosurg Psychiatry 1978; 41:312–18. 24. Schrager GO. Elevation of depressed skull fractures with a breast pump. J Pedriatr 1970; 77:300–1. 25. Saunders BS, Lazoritz S, McArtor RD et al. Depressed skull fracture in the neonate. J Neurosurg 1979; 50:512–14. 26. Tan KL. Elevation of congenital depressed fracture of the

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skull by the vacuum extractor. Acta Periatr Scand 1974; 63:562–4. Loeser JD, Kilburn HL, Jolley T. Management of depressed fracture in the newborn. J Neurosurg 1976; 44:62–4. Kuban K. Intracranial hemorrhage. In: Cloherty JP, Stark AR, editors. Manual of Neonatal Care. 2nd edn. Boston: Little, Brown, 1985: 303–14. Abroms IF, Bresnan MJ, Zucherman JE et al. Cervical cord injuries secondary to hyperextension of the head in breech presentations. Obstet Gynecol 1973; 41:369–78. O’Driscoll K, Meagher , Macdonald D et al. Traumatic intracranial haemorrhage in ﬁrstborn infants and delivery with obstetric forceps. Br J Obstet Gynec 1981; 88:577–81. Hanigan WC, Morgan AM, Stahlberg LK et al. Tentorial hemorrhage associated with vacuum extraction. Pedriatrics 1990; 85:534–9. Barnes PD. Neuroimaging and the timing of fetal and neonatal brain injury. J Perinatol 2001; 21:44–60. Johnson ML, Rumack CM, Mannes EJ et al. Detection of neonatal intracranial hemorrhage utilising real time and static ultrasound. J Clin Ultrasound 1981; 9:427–33. Bucher HU, Boltshauser E, Friderich J et al. Birth injury to the spinal cord. Helv Paediat Acta 1979; 34:517–27. Byers RK. Spinal cord injuries at birth. Ev Med Chil Neurol 1975; 17:103–10. De Sousa SW, Davis JA. Spinal cord damage in a newborn infant. Arch Dis Child 1974; 49:70–71. Hankins GD. Lower thoracic spinal cord injury – a severe complication of shoulder dystocia. Am J Perinatol 1998; 15:443–4. Koch BM, Eng GM. Neonatal spinal cord injury. Arch Phys Med Rehabil 1979; 60:378–81. Nelson KB, Ellenberg JH. Obstetric complications as risk factors for cerebral palsy or seizure disorders. J Am Med Assoc 1984; 251:1843–8. Lanska MJ, Roessmann U, Wiznitzer M. Magnetic resonance imaging in cervical cor lesions in the newborn infant. Pediatr Radiol 1990; 24:245–7. Mills JF, Dargaville PA, Colerman LT, Rosenfeld JV, Ekert PG. Upper cervical spinal cord injury in neonates: the use of magnetic resonance imaging. J Pediatr 2001; 138:105–8. Filippigh P, Clapuyt P, Debauche C et al. Sonographic evaluation of traumatic spinal cord lesions in the newborn infant. Pedriatr Radiol 1994; 24:245–7. Jahnke AH Jr, Bovill DF, McCaroll HR Jr et al. Persistant brachial plexus birth palsies. J Pediatr Orthorp 1991; 11:533–7. Hardy AE. Birth injuries of the brachial plexus: incidence and prognosis. J Bone Joint Surg 1981; 63B:98–101. Gilbert WM, Nesbitt TS, Danielson B. Associated factors in 1611 cases of brachial plexus injury. Obstet Gynecol 1999; 93:536–40. Sunderland S. Nerves and Nerve Injuries. Edinburgh: Churchill Livingstone, 1978: 133. Eng GM. Neuromuscular diseases. In: Avery GB, editor. Neonatalogy. 2nd edn. Philadelphia: JB Lippincott, 1980: 987–92.

38 Fetal and birth trauma 48. Hunt D. Surgical management of brachial plexus birth injuries. Ev Me Child Neurol 1998; 30:824–8. 49. Gordon M, Rich H, Deutschberger J et al. The immediate and long term outcome of obstetric trauma. Brachial plexus paralysis. Am J Obstet Gynecol 1973; 117:51–6. 50. Kwast O. Electrophysiological assessment of maturation of regenerating motor nerve ﬁbres in infants with brachial plexus palsy. Dev Med Child Neurol 1989; 31:56–65. 51. Donn SM, Faix RG. Long term prognosis for the infant with severe birth trauma. Clin Perinat 1983; 10:507–20. 52. Laurent JP, Lee RT. Birth related upper brachial plexus injuries in infants: operative and nonoperative approaches. J Child Neurol 1944; 9:111–17. 53. Piatt JH Jr. Neurosurgical management of birth injuries of the brachial plexus. Neurosurg Clin N Am 1991; 2:175–85. 54. Kornblut AD. Facial nerve injuries in children. Ear Nose Throat 1977; 56:369–76. 55. Zajkowski EJ, Kravath RE. Bilateral diaphragmatic paralysis in the newborn infant: treatment with nasal continuous positive airway pressure. Chest 1979; 75:392–4. 56. Greene W, L’Heureux P, Hunt CE. Paralysis of the diaphragm. Am J Dis Child 1975; 129:1402–1405. 57. Weisman L, Woodall J, Merenstein, G. Constant negative pressure in the treatment of diaphragmatic paralysis secondary to birth injury. Birth Def 1976; 12:297–302. 58. Rugtveit J, Ek J. Isolated birth injury of the phrenic nerve. Ev Med Child Neurol 1989; 31:119. 59. Bowen TE, Zajtchuk R, Albus RA. Diaphragmatic paralysis managed by diaphramatic replacement. Ann Thoracic Surg 1982; 33:184–8. 60. Blocker SH, Ternberg JL. Traumatic liver laceration in the newborn: repair with ﬁbrin glue. J Pedriatr Surg 1986; 21:369–71. 61. Balfranz JR, Nesbit ME, Jarvis C et al. Overwhelming sepsis following splenectomy for trauma. J Pediatr 1976; 88:458–60. 62. Van Wyck DB, Witte MH, Witte CL et al. Critical splenic mass for survival from experimental pneumococcemia. J Surg Res 1980; 28:14–17. 63. Coil JA Jr, Ickerman JD, Horner SR et al. Pulmonary infection in splenectomized mice: protection by splenic remnant. J Surg Res 1980; 28:18–22. 64. Chryss C, Aaron WS. Successful treatment for rupture of normal spleen in newborn. Am J Dis Child 1980; 134:18–19. 65. Matsuyama S, Suzuki N, Nagamachi Y. Rupture of the spleen in the newborn: treatment without splenectomy. J Ped Surg 1976; 11:115–16. 66. Bickler S, Ramachandran V, Gittes GK, Alonso M, Snyder CL. Nonoperative management of newborn splenic injury: a case report. J Ped Surg 2000; 35:500–1.

67. Bar-Maor JA, Sweed Y, Shoshany G. Does the spleen regenerate after partial splenectomy in the dog? J Pediatr Surg 1988; 23:128–9. 68. Mittelstaedt CA, Volberg FM, Merten DF et al. The sonographic diagnosis of neonatal adrenal hemorrhage. Radiology 1979; 131:453–7. 69. Eklof O, Grotte G, Jorulf H et al. Perinatal haemorrhagic necrosis of the adrenal gland. A clinical and radiological evaluation of 24 consecutive cases. Pediatr Radiol 1975; 4:31–6. 70. Khuri FJ, Alton DJ, Hardy BE et al. Adrenal haemorrhage in neonates: report of 5 cases and review of the literature. J Urol 1980; 124:684–7. 71. Pery M, Kaftori JK, Bar-Maor JA. Sonography for diagnosis and follow-up of neonatal adrenal haemorrhage. J Clin Ultrasound 1981; 9:397–401. 72. Lebowitz JM, Belman AB. Simultaneous idiopathic adrenal haemorrhage and renal vein thrombosis in the newborn. J Urol 1983; 129:574–6. 73. Cheves H, Bledsoe F, Rhea WG et al. Adrenal hemorrhage with incomplete rotation of the colon leading to early duodenal obstruction: case report and review of the literature. J Pediatr Surg 1989; 24:300–2. 74. Gross M, Kottmeier PK, Waterhouse K. Diagnosis and treatment of neonatal adrenal hemorrhage. J Pediatr Surg 1967; 2:308–12. 75. Pond GD, Haber K. Echography: a new approach to diagnosis of adrenal hemorrhage. J Can Ass Radiol 1976; 27:40–4. 76. Brill PW, Krasna IH, Aaron H. An early rim sign in neonatal adrenal hemorrhage. Am J Roentgenol 1976; 127:289–91. 77. Murhty TVM, Irving IM, Lister J. Massive adrenal hemorrhage in neonatal neuroblastoma. J Pediatr Surg 1978; 13:31–4. 78. Croitoru P, Sinsky AB, Laberge JM.Cystic neuroblastoma. J Pediatr Surg 1992; 27:1320–1321. 79. Cromie WJ. Genitourinary injuries in the neonate. Perinatal Care Clin Pediatr 1979; 18:292–5. 80. Hsu TY, Hung FC, Lu YJ et al. Neonatal clavicular fracture: Clinical analysis of incidence, predisposing factors, diagnosis and outcome. Amer J Perinatal 2002; 19:17–21. 81. Zeiger M, Dorr U, Schulz RD. Sonography of slipped humeral epiphysis due to birth injury. Pediatr Radiol 1987; 17:425–6. 82. Broker FH, Burbach T. Ultrasonic diagnosis of separation of the proximal humeral epiphysis in the new-born. J Bone Joint Surg 1990; 72A:187–91. 83. Prevot J, Lascombes P, Blanquart D. Geburtstraumatische epiphysenlosung des proximalen femurs 4 falle. Z Kinerchir 1989; 44:289–92. 84. Finan BF, Redman JF. Neonatal genital trauma. Urology 1985; 25:532–3. 85. Samuel G. Castration at birth. Br Med J 1988; 297:1313–14.

4 Transport of the surgical neonate PREM PURI AND DIANE DE CALUWÉ

INTRODUCTION The successful outcome of an operation performed on a newborn with congenital anomalies depends not only on the skill of the pediatric surgeon, but also on that of a large team consisting of a pediatrician, anesthetist, radiologist, pathologist, biochemist, nurses, and others necessary for dealing satisfactorily with the newborn subjected to surgery. Advances in neonatal intensive care (NIC) dictate that effective and efﬁcient treatment of the sickest neonates can only be available by concentrating resources such as equipment and skilled staff in a few specialist pediatric centers which have responsibilities to a particular region.1,2 Neonates with congenital malformations will therefore have to be transported safely to these centers, sometimes over considerable distances.

PRENATAL TRANSFER It has been stated before that prenatal transport of term fetuses with antenatally diagnosed surgical abnormalities does not improve the outcome if the quality of care before and during transport is good.3 The distance involved does not inﬂuence the outcome. However, several other studies support the in utero transportation of the high-risk fetus, particularly the very-low-birth-weight (VLBW) babies and those with life-threatening neonatal surgical problems.4,5,6,7 Hypothermia remains a main problem in these babies and it adversely affects neonatal outcome.8 Poor post-transfer temperature seems to be an independent predictor of death.8,9 Therefore, whenever possible, threatening preterm delivery before 28 weeks’ gestation should be converted to in utero transport.8

PRE-TRANSFER MANAGEMENT Transferring a newborn without proper stabilization is

associated with increased morbidity and mortality. The golden rule still is that no neonate should be transported unless his or her condition has been sufﬁciently stabilized to survive the expected duration of the journey.7 Careful attention to pre-transfer management will provide a higher margin of safety during the journey, when access to the patient is restricted and it may be difﬁcult to provide adequate treatment should problems arise.3 All babies must be properly resuscitated before the journey is undertaken.7 Thermoregulation requires critical attention. Hypothermia causes an increase in the neonate’s metabolic rate with a subsequent increase in glucose and oxygen use ensuing acidosis and if not reversed development of persistent pulmonary hypertension of the neonate.6 This can all be avoided by warming the baby to a core temperature of at least 35°C and using a pre-warmed transport incubator in a pre-warmed ambulance, with the thermal environment adjusted so to maintain correct rectal temperature.10 It should be ensured that the airway is clear and that the baby is well oxygenated, and that ventilation can be maintained during transport. If any risk for deterioration of spontaneous breathing is present, the child should be intubated before departure.3 Every neonate requiring transport must have an adequately sized functioning nasogastric tube to prevent vomiting and aspiration. It should be taped securely in position and kept on open drainage or attached to a low-pressure suction pump which should be aspirated every 10–20 minutes to prevent occlusion.3 Two reliable and secure routes of venous access should be in place. Many surgical newborns have abnormal losses of water, electrolytes and proteins, which must be replaced to prevent hypovolemia and shock. Intravenous ﬂuids must be initiated immediately and sometimes initiation of inotropic vasopressors such as dopamine or dobutamine may be warranted.3,4,6 Glucose homeostasis must also be maintained and close monitoring of glucose blood levels should be performed regularly and corrected if necessary.6 Furthermore, a number of essential data should be transferred with the infant. A summary of the clinical

40 Transport of the surgical neonate

history and any X-ray ﬁlms taken should accompany the patient. All laboratory reports should be included, and the time noted when tests were carried out. It should be clearly documented whether vitamin K was given. Prophylactic broad-spectrum antibiotics should be started if there is a risk of infection. A sample of maternal blood should be sent to facilitate crossmatching. A parental consent for operation, signed by the mother if the parents are not married, should be sent together with a contactable phone number to be able to explain to the parents the surgical condition of their child and the operative procedure.

TRANSPORT TEAM Local and individual circumstances will determine whether the referring or specialist center will send a transport team. The composition of the team may also vary from institution to institution. The team should ideally consist of a pediatrician and a trained neonatal nurse familiar with and able to anticipate potential problems associated with speciﬁc lesions.6,8 They should be familiar with all equipment and its function and should be experienced in stabilizing an infant in suboptimal conditions. Careful delineation of responsibility is important. Some institutions have formed a nursing transport team trained and experienced in the transfer of sick neonates. They guide the doctors and operate the equipment.9

the alveolar membranes becomes more difﬁcult. To maintain the same level of oxygenation, a higher percentage of oxygen may be required. Moreover, the barometric pressure will also decrease with increasing altitude, the volume of gas will increase and any air trapped in a body cavity will expand. This could have a dramatic effect on pulmonary function.6 It is very important to have well-functioning medical and nursing equipment.8 Monitoring is essential during transfer because clinical assessment can be limited due to suboptimal lighting, noise, vibration and lack of space. Invasive and non-invasive measures of arterial pressure, pulse oxymetry, electrocardiograph (ECG), core temperature measurement and pressure transducers for central venous and intracranial pressure readouts must be present. All monitors and syringe pumps should be battery operated.4 A range of airway and ventilatory equipment including self-inﬂating resuscitation bags, masks, airways, laryngoscope handles and blades, uncuffed neonatal endotracheal tubes of various size, humidiﬁers, portable suction apparatus and oxygen supplies must be available in case airway problems should occur. Additionally, an appropriately stocked box including i.v. supplies including intraosseous needles, chest tubes and umbilical catheter kits with sterile equipment and emergency drugs should be present.6 After each transport, a record documenting equipment used should be ﬁlled in and the equipment unit checked and restocked. The equipment kit should be controlled weekly by the neonatal transport nurse on duty and servicing of the transport incubator and the monitoring equipment should be carried out.8

TRANSPORT VEHICLES TRANSPORT INCUBATORS Selection of a transport vehicle is dependent on the distance travelled, geography, weather conditions, the nature of the infant’s problem and the need for speed.1 A variety of conveyances are in popular use, including ground ambulances, helicopters and ﬁxed-wing aircraft. Ambulance transport is generally preferable to that by helicopter but is rather slow. Air transport has several disadvantages. A major disadvantage is that separate ground transport must be arranged at both ends to move the baby between the airport and the hospital. The noise and vibrations and poor lighting makes in-ﬂight monitoring of the infant difﬁcult in a rotary-wing aircraft (helicopter).6,7,11 This problem is not experienced to such a signiﬁcant degree in a ﬁxed-wing aircraft’. The transport incubator should be securely strapped in case of turbulence of the plane. The infant in the incubator should be well ﬁxed with a lockable piece of cloth. Moreover, the space in a plane is limited and can cause difﬁculties in manipulating the airway.6,7 The negative effects of altitude on the neonate’s body can be detrimental.11 With increasing altitude, the partial pressure of oxygen decreases, therefore diffusion of oxygen across

The currently available portable incubator (Fig. 4.1) is designed and equipped for transporting sick newborns.12

Figure 4.1 A portable incubator

Special considerations 41

It is a central piece of equipment that has to provide warmth, visibility and access. It should be able to run on batteries and be capable of providing heat for an extended period of time in various ambient temperature extremes. It should be equipped with a cardiorespiratory monitor, pulse oxymeter, infusion pump, oxygen analyzer, oxygen and air cylinders, double Plexiglas walls and shock-absorbing wheels.6

TRANSPORT PROCEDURE The perfect transfer does not exist yet. It involves early and effective communication between the referring and specialist center, stabilization of the baby pre-transfer and provision of special needs and care during transport.3 All too often, transport is hastily arranged and conducted in a vacuum of communication, resulting in preventable catastrophes such as vomiting and aspiration, hypothermia, hypovolemia and airway obstruction.5 Ideally, transfer is arranged at as senior a level as possible, i.e. a telephone conversation between a specialist pediatric registrar or consultant pediatrician in the referring center and specialist surgical registrar or consultant pediatric surgeon in the receiving center.13 A standardized transfer-form booklet was introduced by the current authors in their institution. A form is ﬁlled in during the initial conversation with the referring center. It contains all the necessary medical and practical details regarding actual transfer and speciﬁc management of the surgical problem of the newborn. By increasing awareness of potential problems, referring hospitals will be less inclined to neglect precise instructions concerning speciﬁc surgical conditions.

RECEIVING CENTER Continuation of care is essential to improving neonatal outcome. On arrival at the tertiary center, a brief report of prenatal, labor, and delivery history should be given by the transport nurse to the newborn intensive care nurse, together with details of the newborn’s resuscitation and any problems experienced during transfer.6 The accompanying pediatrician should review the baby and all documents together with the accepting surgeon and anesthetist, if necessary. The parents should be introduced to all staff who will be involved in the care of their baby. Every procedure should be explained in a clear and comprehensive language to avoid confusion and parental fear. The consent form should be updated if necessary. Blood tests and radiological examinations can be ordered subsequently.

SPECIAL CONSIDERATIONS Gastroschisis The baby with gastroschisis is at a higher risk for hypothermia, excessive ﬂuid loss and shock, infection, intestinal strangulation, necrosis and obstruction due to the small size of the paraumbilical defect and to the lack of a covering peritoneal/amniotic membrane. Treatment starts immediately after delivery in order to prevent water and heat loss (Table 4.1). Heat loss is a frequent problem and hypothermia can result. Therefore radiant heating should be available in the room and the baby should be kept in a warmed incubator with the incubator’s temperature monitored frequently. Intubation and ventilation is carried out if required. Immediate resuscitation with adequate i.v. ﬂuids (120 ml/kg/24 hours) to overcome substantial water, electrolyte and protein losses is started. Pulse rate and mean arterial pressure is observed and blood is taken and glucose level measured. At the same time, vitamin K is given and broad-spectrum antibiotics (ampicillin, gentamicin and metronidazole) are commenced to reduce contamination of the exposed intestinal loops. A nasogastric tube is passed for intestinal decompression and prevention of pulmonary aspiration. A urinary catheter is passed to decompress the bladder and to monitor urinary output. The bowel is localized in the center of the abdomen, and clingﬁlm is used to encircle the exposed intestine and is wrapped around the infant. A dry sterile gauze dressing is draped around the clingﬁlm to support and protect the highly mobile bowel additionally and to prevent mesenteric injury or venous congestion. Table 4.1 Stabilization of a newborn with anterior abdominal wall defect prior to transfer to a referral center Warm environment Evaluate respiratory status Nasogastric tube Gastroschisis: wrap clingﬁlm around defect Omphalocele: wrap dry gauze around sac I.v. ﬂuids, correct deﬁcits Antibiotics Vitamin K

Omphalocele The initial objectives for the neonatologist are to assess and treat respiratory distress, to protect the sac from rupture and infection, and to minimize heat loss.14,15 A nasogastric tube is passed immediately to decompress the stomach and bowel. The sac should be stabilized in the middle of the abdomen to prevent kinking of the vessels and covered with a sterile, dry, non-adherent dressing to prevent trauma and heat loss. I.v. ﬂuids, broad-spectrum antibiotics and vitamin K should be started.

42 Transport of the surgical neonate

Pierre Robin syndrome Babies with Pierre Robin syndrome carry a high risk of tongue swallowing and asphyxiation. The baby should be nursed prone with an oropharyngeal airway.5

Choanal atresia Neonates with choanal atresia suffer from intermittent hypoxia. The baby should be nursed with an appropriately sized oral airway with the end or teeth cut off to keep the mouth open.3

Myelomeningocele The infant with myelomeningocele should be nursed prone in order to prevent trauma and pressure on the spinal area. A warm sterile, saline-soaked dressing is placed over the lesion and clingﬁlm wrapped around the baby to prevent drying and dehiscence. If the sac is ruptured and cerebrospinal ﬂuid (CSF) is leaking, or if the myelomeningocele is open, it should be covered with Betadine-soaked gauze and broad-spectrum antibiotics started. Care must be taken to prevent fecal contamination in sacral lesions.6 Careful observation and documentation of neurological function is essential before, during and after transport including evaluation of the sensorimotor level and assessment of the degree of hydrocephalus.6,14

Bladder extrophy At birth, the umbilical cord should be ligated close to the abdominal wall and the umbilical clamp removed to prevent mechanical damage to the bladder mucosa and excoriation of the bladder surface.4,16,17 Trauma and damage to the exposed bladder mucosa and plate should be avoided by covering the defect with clingﬁlm wrapped around the baby to prevent the mucosa from sticking to clothing or diapers. This will allow urine to escape while establishing a barrier between the environment and the fragile bladder mucosa. Old urine, mucus and any detritus should be washed from the surface of the bladder with sterile saline warmed to body temperature at each diaper change and a clean layer of clingﬁlm applied, also during transfer.16,17 Prophylactic antibiotics should be started immediately.

Cloacal extrophy The same measurements to protect the omphalocele sac as discussed under omphalocele are applicable.

Esophageal atresia with tracheo-esophageal ﬁstula Once the diagnosis of esophageal atresia is suspected, the baby should be transferred to a tertiary referral center for further investigation and surgery. Some babies will require endotracheal intubation and ventilation. These infants are particularly at risk because mechanical ventilation is relatively ineffective due to the presence of a ﬁstula. Therefore, the tip of the endotracheal tube should be placed proximal to the carina but distal to the ﬁstula. Urgent transfer and ligation of the ﬁstula are essential. Generally, the infant should be handled with care and crying avoided to reduce the risk of aspiration and abdominal distension and thereby, respiratory distress.4 Moreover, the baby should be well oxygenated at all times and kept in a warm environment. Regurgitation of gastric contents through the ﬁstula during transport can be prevented by keeping the head of the baby in a slightly elevated position or nursing the baby prone or in a right lateral position and thereby decreasing the work of breathing and improving oxygenation.4,18 The blind upper esophageal pouch should be kept empty. A Replogue sump catheter should be placed in the pouch and connected to low-intermittent or lowcontinuous suction in order to prevent accumulation of saliva. The perforations along the side of the catheter are located only near the tip and therefore minimize the possibility of suctioning oxygenated air away from the larynx.19 However, these double lumen esophageal tubes have a tendency to become blocked with mucus and therefore should be irrigated at frequent intervals during transport. I.v. ﬂuids should be started to provide maintenance and supplemental ﬂuids and electrolytes to compensate esophageal secretion losses. Infection should be prevented and any existing pneumonitis treated by broad-spectrum antibiotics. Vitamin K should be administered prior to transfer.

Congenital diaphragmatic hernia The initial objective for the neonatologist and anesthetist is to stabilize the critically ill neonate before transport to the referral center (Table 4.2). A nasogastric tube should be passed immediately on diagnosis to decompress the Table 4.2 Stabilization of a neonate with congenital diaphragmatic hernia prior to transport Maintain warm environment Nasogastric tube Intubation and ventilation I.v. ﬂuids Arterial blood gases Antibiotics Vitamin K

References 43

gastrointestinal tract and to prevent further compression of the lung. Endotracheal intubation should be performed promptly in a baby with respiratory difﬁculty or poor gas exchange. Full sedation and paralysis will reduce the risk of barotrauma. Mask ventilation should be avoided because it will distend the stomach and further compromise the respiratory status. Hyperventilation, using low pressures and high oxygen content, correction of acidosis and prevention of thermal and metabolic stress are recommended to prevent pulmonary hypertension.6 I.v. ﬂuids, fresh-frozen plasma (FFP) and dopamine, if necessary, should be started to maintain adequate peripheral perfusion. Prophylactic antibiotics should be started and vitamin K administered. Venous access through the umbilicus is useful for obtaining mixed venous blood gas specimens and monitoring central venous pressures if passed across the liver into the right atrium. Arterial access with an umbilical artery catheter will allow monitoring of systemic blood pressure and blood gas measurements at the postductal level. The baby will also need a right radial arterial line to measure preductal blood gasses. This can be inserted on arrival at the referral center. Acute deterioration of the infant’s condition can occur during transfer due to a pneumothorax. Equipment for intercostal drainage must be available since it can be a life-saving maneuver.84,6,18 There has been tremendous growth in the use of extracorporeal life support for neonatal cardiopulmonary failure in the last decade. Extracorporeal membrane oxygenation (ECMO) has been used as a salvage procedure with an 80% survival rate in high-risk neonates with congenital diaphragmatic hernia who fail to respond to mechanical ventilation and meet entry criteria. The number of centers providing ECMO is still limited, so special services are needed to transport critically ill neonates to these centers. These special transport teams should be familiar with the pathophysiology of cardiac and respiratory failure and be equipped to continue the monitoring and treatment started at the referral center, to maintain that level of care during transport, and to treat complications of the disease or therapy itself.20,21 Now, transportable ECMO systems exist that can effectively stabilize and transport high-risk neonates to an ECMOcompetent center.22

Intestinal obstruction Intestinal obstruction can occur as a result of a number of conditions, e.g. malrotation, duplication of the alimentary tract, intestinal atresias, NEC, Hirschsprung’s disease, meconium ileus and anorectal anomalies. The principles of care are the same irrespective of the level or cause of the obstruction.4 The main objectives are to decompress the bowel and prevent aspiration, accurately estimate and correct ﬂuid losses and minimize heat loss. A nasogastric tube should be passed and suction carried

out every 15–30 minutes and left on free drainage between aspirations prior to and during transport. I.v. ﬂuids should be started to correct acid–base and volume deﬁcits and review and adjust these on a 6–8 hourly basis according to the needs of the infant.3 Broad-spectrum antibiotics should be started prophylactically.

Necrotizing enterocolitis Neonates with NEC usually are transferred only if surgery is required in case of perforation of gangrenous bowel resulting in pneumoperitoneum or progressive clinical deterioration with evidence of peritonitis.3. Usually they are critically ill with sepsis and shock. Preferably the transfer is done while the infant’s condition is as stable as possible. Resuscitation with crystalloids, colloids or blood to correct acidosis is started prior to departure. Ventilation with intermittent positive pressure and inotropic support is often required.4. A sump nasogastric tube on continuous suction is passed and suctioned regularly prior and during transport. Broad-spectrum antibiotics are started.

CONCLUSION The approach to the care of the high-risk newborn has changed dramatically in the past 20 years. The newborn with a serious congenital malformation requires assessment and stabilization by experienced staff prior to and during transport to the regional center. Several studies have demonstrated that stabilization of the high-risk newborn before transport is associated with a reduction in perinatal morbidity and mortality.

REFERENCES 1. Darlow BD, Cull AB, Knight DB. Transportation of very low birth weight infants in 1986. N Z Med J 1989; 102:275–7. 2. Ferrera A, Schwartz M, Page H et al. Effectiveness of neonatal transport in New York City in neonates less than 2500 grams – a population study. J Commun Hlth 1988; 13:3–18. 3. Lloyd DA. Transfer of the surgical newborn infant. Semin Neonatol 1996; 1:241–8. 4. McHugh PJ, Stringer MD. Transport of sick infants and children. In: Atwell JD, editor. Pediatric Surgery. New York: Arnold, 1998: 73–9. 5. Harris BA, Wirtschafter DD, Huddleston JF et al. In Utero Versus Neonatal Transportation of High-Risk Pernates: A Comparison. Obstet Gynecol 1981; 57:496–9. 6. Paxton JM. Transport of the surgical neonate. J Perinatal Nurs 1990; 3:43–9.

44 Transport of the surgical neonate 7. Pieper CH, Smith J, Kirsten GF et al. The transport of neonates to an intensive care unit. SAMJ 1994; 84:801–3. 8. Holt J, Fagerli I. Air transport of the sick newborn infant: audit from a sparsely populated county in Norway. Acta Pediatr 1999; 88:66–71. 9. Leslie AJ, Stephenson TJ. Audit of neonatal intensive car transport – closing the loop. Acta Pediatr 1997; 896:1253–6. 10. Morse TS. Transportation of the sick and injured children. In: Gans SL, editor. Surgical Pediatrics. New York: Grune and Stratton, 1980: 27–41. 11. Miller C. The physiological effects of air transport on the neonate. Neonatal Network 1994; 13:7–10. 12. Donn SM, Faix RG, Gates MR. Neonatal transport. Curr Probl Pediatr 1985; 15:1–65. 13. Driver CP, Robinson C, De Caluwé, et al. The Quality of Inter-Hospital Transfer of the Surgical Neonate. Today’s Emerg 2000; 6:102–5. 14. Chance GW. Thermal environment in transport. In: Sinclair JC, editor. Temperature Regulation and Energy Metabolism in the Newborn. New York: Grune and Stratton, 1978: 227–39. 15. Caplan MS, MacGregor SN. Perinatal management of

16.

17.

18. 19. 20.

21.

22.

congenital diaphragmatic hernia and anterior abdominal wall defects. Clin Perinatol 1989; 16:917–38. Gearhart JP, Ben-Chaim J. Extrophy and Epispadias. In: King LR, editor. Urologic Surgery in Infants and Children. Pennsylvania: WB Saunders Company, 1998: 106–13. Gearhart JP. The Bladder Ectrophy-Epispadias-Cloacal Extrophy Complex. In: Gearhart JP, Rink RC, Mouriquand PDE, editors. Pediatric Urology. Pennsylvania: WB Saunders Company, 2001: 511–46. Spitz L, Wallis M, Graves HF. Transport of the surgical neonate. Arch Dis Child 1984; 59:284–8. O’Neill JA, Rowe MI, Grosfeld JL et al. Pediatric Surgery. Mosby – Year Book, St. Louis, 1998. Day SE, Chapman RA. Transport of the critically ill patients in need of extracorporal life support. Crit Care Clin 1992; 8:581–96. Kinsella JP, Schmidt JM, Abman SH. Inhaled nitric oxide treatment for stabilization and emergency treatment of critically ill newborns and infants. J Pediatr 1995; 95:773–6. Cornish JD, Carter JM, Gerstmann DR et al. Extracorporeal membrane oxygenation as a means of stabilizing and transporting high risk neonates. Asaio Trans 1991; 37:564–8.

5 Preoperative assessment PREM PURI AND DIANE DE CALUWÉ

INTRODUCTION Many congenital defects that are of interest to the pediatric surgeon can now be detected before birth, thus the preoperative assessment of the newborn with congenital anomaly starts in utero. When serious malformations incompatible with postnatal life are diagnosed early enough, the family may have the option of terminating the pregnancy. Therefore it is important for every pediatric surgeon who is familiar with the management of the congenital anomalies after birth to be involved in management decisions and family counselling before birth.1 The main goal of prenatal diagnosis is to improve the prenatal care by maternal transport to an appropriate center and delivering the baby in the timing and mode that are appropriate for the speciﬁc fetal malformation. Although prenatal intervention for certain congenital anomalies has been reported recently,2,3 almost all congenital malformations can be successfully managed after birth. During the past 2 decades there have been signiﬁcant advances in modes and techniques for prenatal diagnosis. These modes include: amniocentesis, amniography, fetoscopy, fetal sampling and ultrasonography. The latter, enabling direct imaging of fetal anatomy, is a non-invasive technique, safe for both the fetus and the mother.4 However, it is important to remember that sonography is operator dependent and the reliability of the information obtained is directly proportional to the skill and experience of the sonographer. For example, it is important to distinguish duodenal from jejunal obstruction in a fetus with polyhydramnios, because duodenal obstruction is associated with Down syndrome and requires further genetic evaluation while jejunal obstruction does not. The real-time sonography may yield important information on fetal malformation, fetal movement and fetal vital functions such as breathing movements and heart rate variability. Serial sonographic evaluations are particularly useful in following the progression or regression of any fetal disease. All this important infor-

mation is an integral part of the preoperative assessment of a newborn with any kind of congenital malformation (Figs 5.1 & 5.2). Neonates born with congenital malformations are usually in urgent need of surgery and, in addition to their surgical problem, may suffer from a multitude of medical problems. Furthermore they are at a period when signiﬁcant physiological and maturational changes of transition from fetal to extrauterine life are occurring. The surgical and anesthetic intervention at this time may affect this transition by interfering with normal homeostatic controls of circulation, ventilation, temperature, ﬂuid, and metabolic balance. To facilitate a smooth preoperative course, close cooperation among the neonatologist, pediatric surgeon and pediatric anesthesiologist is necessary. All neonates undergoing surgery must be carefully assessed preoperatively, giving particular attention to the following:

Figure 5.1 Transvaginal ultrasonogram showing a 15-week-old fetus with omphalocele (arrow). Bowel loops protrude through the abdominal wall defect

46 Preoperative assessment

Figure 5.2 Transvaginal ultrasonogram showing 16-week-old fetus with diaphragmatic hernia. The dilated stomach (arrow) appears in the left hemithorax adjacent to the heart

• • • • • • • • •

History and physical examination Maintenance of body temperature Respiratory function Cardiovascular status Metabolic status Coagulation abnormalities Laboratory investigations Vascular access Fluid and electrolytes, and metabolic responses.

HISTORY AND PHYSICAL EXAMINATION The history of a newborn starts months before delivery, as many of the congenital malformations (e.g. Bochdalek hernia, omphalocele, gastroschisis, sacrococcygeal teratoma and others) nowadays are known to the pediatric surgeon prenatally. Not only are the anatomical and structural anomalies important, but even more so are metabolic abnormalities or chromosomal aberrations, which must be diagnosed prenatally or immediately after birth. Anticipation of a problem in the delivery room is often based on prenatal diagnosis. For example, identiﬁcation of a trisomy 21 in the fetus will increase the neonatologist’s awareness in evaluating the infant for those abnormalities closely associated with this chromosomal defect, e.g. evaluation for duodenal atresia and congenital heart disease. Conversely, prenatal identiﬁcation of speciﬁc fetal anomalies should signal the pediatrician to evaluate the infant for a chromosomal abnormality. The most important recent advance in prenatal detection of anatomical problems has been the develop-

ment of fetal ultrasonography (see Chapter 2), and in experienced hands this mode of imaging can be used to detect a wide range of fetal problems, ranging from relatively minor abnormalities to major structural defects. However, this anatomical prenatal diagnosis is only one of the tools that aid in planning care management. An accurate and well-documented family history may increase the suspicion that an infant is at risk for an anatomical defect linked to an inherited disorder. In other cases, only the evidence of polyhydramnios should signiﬁcantly increase suspicion of congenital anomalies. Most problems are best managed expectantly by natural labor and vaginal delivery at term. Certain malformations, however, such as conjoined twins, giant omphalocele, sacrococcygeal teratoma or large cystic hygroma, often require cesarian section for delivery.5 After birth, the assessment of the degree of prematurity, which is an integral part of the physical examination, and the speciﬁc type of congenital anomaly must be identiﬁed and recorded because of the profound anesthetic and postoperative implications that are involved.6,7 The normal full-term infant has a gestational age of 37 weeks or more, and a body weight greater than 2500 g. Infants born with a birth weight of less than 2500 g are deﬁned as being of low birth weight (LBW). Babies may be of LBW because they have been born too early (preterm – earlier than 37 weeks’ gestational age), or because of intrauterine abnormalities affecting growth (growth retardation). ‘Small-for-gestational-age’ (SGA) infants are those whose birth weight is less then the 10th percentile for their age. Infants may, of course, be both growth retarded and born preterm. The principle features of prematurity are: • • • • • •

A head circumference below the 50th percentile A thin, semi-transparent skin Soft, malleable ears Absence of breast tissue Absence of plantar creases Undescended testicles with ﬂat scrotum and, in females, relatively enlarged labia minora.

The physiological and clinical characteristics of these babies are: • • • • • •

Apneic spells Bradycardia Hypothermia Sepsis Hyaline membrane disease Blindness and lung injury due to use of high levels of oxygen • Patent ductus arteriosus. In the SGA infant, although the body weight is low, the body length and head circumference approach that of an infant of normal weight for age. These babies are older and more mature. Their clinical and physiological characteristics are:

Respiratory function 47

• • • • •

Higher metabolic rate Hypoglycemia Thermal instability Polycythemia Increased risk of meconium aspiration syndrome.

In relation to these differences, three important observations have been reported: 1 LBW infants have a mortality 10 times that of fullsized infants. 2 More than 75% of overall perinatal mortality is related to clinical problems of LBW infants. 3 The rate of anatomical malformation in LBW infants is higher then for infants at term.8

MAINTENANCE OF BODY TEMPERATURE The mean and range of temperature for newborns are lower than previously described and most temperatures ≤ 36.3°C are, in fact, within the normal range.9 Newborn infants, particularly premature infants, have a poor thermal stability because of a higher surface area/weight ratio, a thin layer of insulating subcutaneous fat and a high thermoneutral temperature zone. The newborn readily loses heat by conduction, convection, radiation and evaporation, with the major mechanism being radiation. Shivering thermogenesis is absent in the neonate, and the heat-producing mechanism is limited to non-shivering thermogenesis through the metabolizing of brown fat.10 Cold stress in these neonates leads to an increase in metabolic rate and oxygen consumption, and calories are consumed to maintain body temperature. If prolonged, this leads to depletion of the limited energy reserve and predisposes to hypothermia and increased mortality. Hypothermia can also suggest infection and should trigger diagnostic evaluation and antibiotic treatment if required.9 Illness in the newborn, particularly when associated with prematurity, further compounds the problems in the maintenance of body temperature.11 The classic example for such an illness is the newborn with omphalocele or gastroschisis.12 In their group of 23 neonates with gastroschisis, Muraji et al.12 found that hypothermia (31–35.4°C), which was found in seven patients upon arrival at the hospital, was the most serious preoperative problem. To minimize heat losses, it is desirable that most sick neonates be nursed in incubators within a controlled temperature. These incubators are efﬁcient for maintaining the baby’s temperature, but do not allow adequate access to the sick baby for active resuscitation and observation. Overhead radiant heaters, servocontrolled by a temperature probe on the baby’s skin, are preferred and effective in maintaining the baby’s temperature; they also provide visual and electronic monitoring and access for nursing

and medical procedures. Hyperthermia should be avoided, because it is associated with perinatal respiratory depression.13 The environmental temperature must be maintained near the appropriate thermoneutral zone for each individual patient because the increase in oxygen consumption is proportional to the gradient between the skin and the environmental temperature.14 This is 34–35°C for LBW infants up to 12 days of age and 31–32°C at 6 weeks of age. Infants weighing 2000–3000 g have a thermoneutral zone of 31–34°C at birth and 29–31°C at 12 days. In an incubator, either the ambient temperature of the incubator can be monitored and maintained at thermoneutrality, or a servosystem can be used. The latter regulates the incubator temperature according to the patient’s skin temperature, which is monitored by means of a skin probe on the infant. The normal skin temperature for a full-term infant is 36.2°C, but because of many benign factors such as excessive bundling, ambient temperature may affect body temperature. Diurnal and seasonal variations in body temperature have also been described.9 Thus the control of the thermal environment of the newborn and especially the ill baby with congenital malformations is of the utmost importance to the outcome.

RESPIRATORY FUNCTION Assessment of respiratory function is essential in all neonates undergoing surgery. The main clinical features of respiratory distress are restlessness, tachypnea, grunting, nasal ﬂaring, sternal recession, retractions and cyanosis. These symptoms are occasionally present in the delivery room due to anatomical abnormalities involving the airway and lungs and require the most urgent therapy.15 Table 5.1 lists a few common conditions that may be present with respiratory distress at birth. These conditions include: diaphragmatic hernia (Bochalek), lobar emphysema, pneumothorax, esophageal atresia with or without tracheo-esophageal ﬁstula, congenital airway obstruction, congenital cystic adenomatoid malformation of the lung, meconium aspiration syndrome and aspiration pneumonia. It is important to recognize that more than one condition may be present in the same patient. If there is any clinical suspicion or sign of respiratory insufﬁciency, a chest X-ray should be obtained immediately after the resuscitation to determine the cause of respiratory distress. All babies with respiratory distress should have a radio-opaque nasogastric tube passed and a radiograph taken that includes the chest and abdomen in order to localize the esophagus, stomach, and bowel gas, and to avoid misdiagnosis, for example, a diaphragmatic hernia which can be mistaken for a cystic adenomatoid malformation of the lung.16

Condition

Prenatal and perinatal associations

Clinical features

Chest radiographic ﬁndings*

Initial therapy

Respiratory distress syndrome (RDS)

Prematurity, lung immaturity, asphyxia, maternal diabetes, male sex

Increasing respiratory distress after birth, tachypnea, grunting, rib retractions or nasal ﬂaring

Diffuse reticulogranular pattern, air bronchograms

Oxygen, assisted ventilation

RDS, meconium aspiration, endotracheal Acute onset of sternal recession, resuscitation, diaphragmatic hernia, tachypnea, cyanosis, shift in apex assisted ventilation beat position

Intrapleural air, mediastinal shift; varying degrees of lung collapse which is always symmetrical toward the hilum

Oxygen, needle aspiration, chest drain; additional tubes may be needed when large leaks from the lung tissue are present

Polyhydramnios

Sudden respiratory distress usually soon after birth, dyspnea, cyanosis, scaphoid abdomen, shift in heart sounds, decreased breaths sounds in one hemithorax (usually left)

Bowel pattern in one hemithorax, Nasogastric decompression; mediastinal shift with compression intubation and ventilation of the contralateral lung. Abdominal bowel gas is sparse or absent

Occasionally associated with congenital malformations of the heart and great vessels

Rapidly progressive respiratory distress with dyspnea and cyanosis. Absent or diminished breath sounds over the affected side and displacement of the mediastinum

Hyperinﬂation of the affected side – usually left upper (increased translucency). Mediastinum may be shifted.

Thoracotomy and lobectomy required. During induction of anesthesia, the ventilatory pressures must be kept as low as possible until the chest is open

Congenital cystic adenomatoid malformation (CCAM)

Fetal hydrops, polyhydramnios, Severe respiratory distress as above, pulmonary hypoplasia, mediastinal shift, often within hours of birth type II – associated anomalies including prune belly syndrome and pectus excavatum. 25% of infants are stillborn

Homogeneous mass or multicystic lesion on chest X-ray, mediastinal shift. The normal location of the stomach is of help in differentiating CCAM and diaphragmatic hernia

Thoracotomy and lobectomy

Esophageal atresia with tracheo-esophageal ﬁstula

Polyhydramnios, associated malformations (VACTERL), excessive nasopharyngeal saliva

Mild respiratory distress. Early chest auscultation is normal. The abdomen may show progressive distension. (In the common case of atresia and ﬁstula)

Wide, air-ﬁlled pouch in the neck or upper mediastinum. Aspiration pneumonia may be noted, usually in the right upper lobe. Radio-opaque nasogastric tube will be seen to stop and coiled in the blind pouch. The abdomen frequently shows hyperaeration of the intestines

Position of the infant with head elevated 45° or prone position. Place Replogle tube in the blind proximal pouch and connect it to continuous suction. Antibiotics. Evaluate associated congenital malformations

None

Cyanosis at rest, pink when crying; inability to pass catheter through nares; noisy upper airway

None

Placement of oral airway

Air leak syndromes Pneumothorax

Diaphragmatic hernia (Bochdalek)

Lung abnormalities Lobar emphysema

Airway abnormalities Choanal atresia and supralaryngeal lesions

* Combined chest and abdominal ﬁlm is recommended in every newborn baby presenting with respiratory distress. An opaque nasogastric tube in the stomach has an important role both in diagnosis and treatment.

48 Preoperative assessment

Table 5.1 Approach to respiratory distress post-delivery

Cardiovascular status 49

Blood gas studies are essential in the diagnosis and management of respiratory distress. Arterial PO2 and PCO2 indicate the state of oxygenation and ventilation, respectively. In the newborn, repeated arterial blood samples may be obtained either by catheterization of an umbilical artery or by cannulation of radial, brachial or posterior tibial arteries. An important alternative is noninvasive monitoring techniques with transcutaneous PO2 monitors or pulse oximeters.17 Monitoring of arterial pH is also essential in patients with respiratory distress. Acidosis in the neonate produces pulmonary arterial vasoconstriction and myocardial depression. Respiratory alkalosis causes decreased cardiac output, decreased cerebral blood ﬂow, diminished oxyhemoglobin dissociation and increased airway resistance with diminished pulmonary compliance.18 Respiratory failure is the leading cause of death in the neonate. High-frequency ventilation,19 use of surfactant, use of inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation (ECMO) have been shown to improve survival dramatically in selected neonates.20,21 ECMO provides long-term cardiopulmonary support for patients with reversible pulmonary and/or cardiac insufﬁciency. It is well accepted as a standard of treatment for neonatal respiratory failure refractory to conventional techniques of pulmonary support. 21 Typically, patients considered for ECMO are 34 gestational weeks or older or weigh more than 2000 g, have no major cardiac lesions, intracranial hemorrhages less than grade 2, no signiﬁcant coagulopathies and have had mechanical ventilation for fewer than 10–14 days. It is limited to those infants who have a 20% or less chance of survival if treated with only conventional therapies.21,22 The National ECMO Registry in Ann Arbor, MI, USA collected reports from all 46 ECMO centers, summarizing their collective experience with 1489 newborns with an overall survival rate of 81.8%.23 Of this group of neonates, 139 newborns were born with congenital diaphragmatic hernia and underwent ECMO, two-thirds of whom survived. Failure of ventilatory treatment to reverse hypoxemia, acute clinical deterioration after a ‘honeymoon period’ and an alveolar-arterial oxygen gradient > 600 mmHg for 12 hours were the principle criteria that justiﬁed ECMO in these babies. Premature infants were at highest risk and intracranial bleeding was the most common cause of death in these anticoagulated newborns. It is important to emphasize that emergency surgery for congenital diaphragmatic hernia is not necessary and that repair should be done only when the patient has been stabilized using conventional ventilation, high-frequency ventilation, or ECMO if necessary.22,24 ECMO is an accepted form of therapy in the treatment of neonates with otherwise lethal persistent pulmonary hypertension related to meconium aspiration and sepsis.22,25 This mode of therapy has been tried successfully in neonates with congenital cystic lesions of the lung who developed severe pulmonary hypertension

following lobectomy and other life-threatening respiratory problems.22,26 However, the long-term effects on its survivors are unknown. At present, the reported morbidity still ranges between 13% and 33%. The developmental outcome is normal in most patients. 21,27,28 Severe developmental delay has been found in only 2–8% of neonatal patients who undergo ECMO therapy. Only one randomized trial of conventional therapy vs ECMO in 185 full-term infants has been published recently. Of the infants included in the trial, 68% who were randomized to ECMO therapy survived compared to 41% in the conventionally treated group.22 The Extracorporal Life Support Organisation (ELSO), started in 1989, maintains an international database for all ECMO patients and centers. Due to the institution of new therapies and differing management styles for treatment of respiratory failure, there has been a marked decrease in neonatal patients treated with ECMO over time.21 Surfactant replacement is commonly used in the clinical management of neonates with respiratory distress syndrome (RDS). It may also be effective in other forms of lung disease, such as meconium aspiration syndrome (MAS), neonatal pneumonia, the ‘adult’ form of acute respiratory distress syndrome (ARDS), and congenital diaphragmatic hernia (CDH). It ensues that alveolar stability is promoted, atelectasis is reduced, edema formation is decreased, and the overall work of respiration is minimized.29 iNO is available for treatment of persistent pulmonary hypertension of the neonate (PPHN). It decreases pulmonary vascular resistance leading to diminished extrapulmonary shunt and has a microselective effect which improves ventilation/perfusion matching. Clinical trials indicate that the need for ECMO in term newborns with PPHN is diminished by iNO.30,31 In newborns with severe lung disease, HFOV is frequently used to optimize lung inﬂation and minimize lung injury. The combination of HFOV and iNO is reported to cause the greatest improvement in oxygenation in some newborns with severe PPHN complicated by diffuse parenchymal lung disease and underinﬂation.30 In summary, the type of respiratory care in particular neonates will always depend upon clinical and radiological ﬁndings supported by blood gas estimations.

CARDIOVASCULAR STATUS At birth, the circulation undergoes a rapid transition from fetal to neonatal pattern. The ductus arteriosus normally closes functionally within a few hours after birth, while anatomical closure occurs 2–3 weeks later.32 Prior to birth the pulmonary arterioles are relatively muscular and constricted. With the ﬁrst breath, total

50 Preoperative assessment

pulmonary resistance falls rapidly because of the unkinking of the vessels with expansion of the lungs and also because of the vasodilatory effect of inspired oxygen. However, during the ﬁrst few weeks of life, the muscular pulmonary arterioles retain a signiﬁcant capacity for constriction, and any constricting inﬂuences such as hypoxia may result in rapid return of pulmonary hypertension.33 The management of neonates with congenital malformation is frequently complicated by the presence of congenital heart disease. At this time of life, recognition of heart disease is particularly difﬁcult. There may be no murmur audible on ﬁrst examination, but a loud murmur can be audible a few hours, days or a week later.34 A newborn undergoing surgery should have a full cardiovascular examination and a chest X-ray. The presence of cyanosis, respiratory distress, cardiac murmurs, abnormal peripheral pulses or congestive heart failure should be recorded. If there is suspicion of a cardiac anomaly, the baby should be examined by a pediatric cardiologist. In recent years the use of the noninvasive technique of echocardiography allows accurate anatomical diagnosis of cardiac anomalies, in many cases prenatally.35,36

METABOLIC STATUS Acid–base balance The buffer system, renal function and respiratory function are the three major mechanisms responsible for the maintenance of normal acid–base balance in body ﬂuids. Most newborn infants can adapt competently to the physiological stresses of extrauterine life and have a normal acid–base balance. However clinical conditions such as RDS, sepsis, congenital renal disorders and gastrointestinal disorders may result in gross acid–base disturbances in the newborn. Four basic disturbances of acid–base physiology are metabolic acidosis, metabolic alkalosis, respiratory acidosis, and respiratory alkalosis. In a newborn undergoing surgery, identiﬁcation of the type of disorder, whether metabolic or respiratory, simple or mixed, is of great practical importance to permit the most suitable choice of therapy, and for it to be initiated in a timely fashion.37 The acid–base state should be determined by arterial blood gases and pH estimation, and must be corrected by appropriate metabolic or respiratory measures prior to operation.

Hypoglycemia The mechanisms of glucose homeostasis are not well developed in the early postnatal period; this predisposes the neonate, especially the premature neonate, to the risk of both hypoglycemia and hyperglycemia. Prenatally, the

glucose requirements of the fetus are obtained almost entirely from the mother, with very little derived from fetal gluconeogenesis. Following delivery, the limited liver glycogen stores are rapidly depleted and the blood glucose level then depends on the infant’s capacity for gluconeogenesis, the adequacy of substitute stores and energy requirements.38 Table 5.2 identiﬁes infants who are at risk for developing hypoglycemia according to three mechanisms: (1) those with limited glycogen stores, (2) hyperinsulinism, and (3) diminished glucose production. Infants at high risk of developing hypoglycemia include LBW infants (especially SGA infants), infants of toxemic or diabetic mothers and infants requiring surgery who are unable to take oral nutrition and who have the additional metabolic stresses of their disease and the surgical procedure. Hypoglycemia is usually deﬁned as a serum glucose level < 1.6 mmol/L (30 mg%) in the full-term neonate and < 1.1mmol/L (20 mg%) in the LBW infant during the ﬁrst 3 days of life. After 72 hours, serum glucose concentration should always be above 2.2 mmol/L (40 mg%). Hypoglycemia may be asymptomatic or associated with a number of non-speciﬁc signs such as apathy, apnea, a weak or high-pitched cry, cyanosis, hypotonia, hypothermia, tremors and convulsions.39 The differential diagnosis includes other metabolic disturbances or sepsis. The possibility of hypoglycemia must be anticipated to prevent avoidable brain damage. All neonates undergoing surgery should have an infusion of 10% glucose at a rate of 75–100 mg/kg body weight per 24 hours and blood glucose levels should be monitored every 4–6 hours by Dextrostix estimation and/or by blood sugar determinations. Blood glucose level should be maintained above 2.5 mmol/L (45 mg%) at all times. The symptomatic infant should be treated urgently with 50% dextrose, 1–2 ml/kg intravenously, and maintenance i.v. dextrose 10–15% at 80–100 ml/kg/24 hours.

Table 5.2 Categories of hypoglycemia Limited glycogen stores Prematurity Prenatal stress Glycogen storage disease Hyperinsulinism IDM (infant of diabetic mother) Nesidioblastosis/pancreatic islet adenoma Beckwith–Wiedemann syndrome Erythroblastosis fetalis/exchange transfusion Maternal drugs Diminished glucose production SGA Rare inborn errors From Ogata,38 by permission.

Coagulation abnormalities 51

Hypocalcemia Hypocalcemia is usually deﬁned as a serum calcium value < 1.8 mmol/L. However, occasionally the ionized fraction of the serum calcium may be low, but without a great reduction of the total serum calcium level concomitantly and with the end result of clinical hypocalcemia. This may occur in newborns undergoing exchange transfusion, or in any surgical baby receiving bicarbonate. Hypocalcemia occurs usually during the ﬁrst few days of life, with the lowest levels of serum calcium seen during the ﬁrst 48 hours. The most common causes of neonatal hypocalcemia include decreased calcium stores and decreased renal phosphate excretion. The LBW infants are at greater risk, particularly if they are premature, or associated with a complicated pregnancy or delivery. Hypocalcemia may be asymptomatic or associated with non-speciﬁc signs such as jitteriness, muscle twitching, vomiting, cyanosis and convulsions. Asymptomatic hypocalcemia can be effectively treated by a continuous infusion of 10% calcium gluconate 75 mg/kg/day and can be prevented by adding calcium gluconate to daily maintenance therapy. The symptomatic patients should be treated by slow i.v. administration of 10% calcium gluconate, 6 ml in a LBW infant and 10 ml in a full-term infant, with monitoring of heart rate to prevent too rapid an injection. Serum calcium levels should be maintained within the 2.0–2.63 mmol/L (8–10.5 mg%) range.

Hypomagnesemia Hypomagnesemia may occur in association with hypocalcemia in SGA infants and neonates with increased intestinal losses. If there is no response to correction of calcium deﬁciency, a serum magnesium level should be obtained. The treatment of hypomagnesemia is by i.v. infusion of 50% magnesium sulphate 0.2 ml/kg every 4 hours until the serum magnesium level is normal (0.7–1.0 mmol/L).

Hyperbilirubinemia Jaundice in the newborn is a common physiological problem seen in 25–50% of all normal newborn infants and in a considerably higher percentage of premature and SGA infants.40 It is the result of a combination of shortened red cell survival, with a consequent increase in bilirubin load, and an immature glucuronyl transferase enzyme system with a limited capacity for conjugating bilirubin. This results in transient physiological jaundice which reaches a maximum at the age of 3–4 days, but returns to normal levels at the end of the ﬁrst week and the bilirubin level does not exceed 170 mmol/L.

Hyperbilirubinemia in the newborn may have a pathological basis such as severe sepsis, Rh and ABO incompatibilities and congenital hemolytic amemias. Neonatal hemolytic jaundice usually appears during the ﬁrst 24 hours of life, whereas physiological jaundice, as mentioned before, reaches a peak between 2 and 5 days of life.41 Other causes for prolonged hyperbilirubinemia, including those often associated with surgical conditions are: biliary obstruction, hepatocellular dysfunction and upper intestinal tract obstruction. The diagnosis of extrahepatic biliary obstruction should be done as early as possible, because early operations for biliary atresia are essential to obtain good short-term as well as long-term results.42 The major concern in neonatal hyperbilirubinemia (high levels of unconjugated bilirubin) is the risk of kernicterus that can result in brain damage. Predisposing factors include: hypoalbuminemia (circulating bilirubin is bound to albumin), hypothermia, acidosis, hypoglycemia, hypoxia, caloric deprivation and the use of drugs (e.g. gentamicin, digoxin, furosemide). When the serum bilirubin concentration approaches a level at which kernicterus is likely to occur, hyperbilirubinemia must be treated. In most patients, other than those with severe hemolysis, phototherapy is a safe and effective method of treating hyperbilirubinemia. When the serum indirect bilirubin level rises early and rapidly and exceeds 340 mmol/L, hemolysis is usually the reason, and exchange transfusion is indicated.

COAGULATION ABNORMALITIES Coagulation abnormalities in the neonate should be sought preoperatively and treated. The newborn is deﬁcient in vitamin K and this should be given as 1 mg prior to operation in order to prevent hypoprothrombinemia and hemorrhagic disease of the newborn. Thus, 1 mg vitamin K should be administered by i.m. or i.v. injection to every newborn undergoing surgery. Neonates with severe sepsis, such as those with necrotizing enterocolitis, may develop disseminated intravascular coagulopathy with a secondary platelet deﬁciency. Such patients should be given fresh-frozen plasma, fresh blood or platelet concentrate preoperatively. Bleeding is one of the major risks associated with neonatal ECMO, a risk that has a particularly devastating outcome.43 In their group of 45 patients, Weiss and colleagues reported on 12 (27%) patients who sustained hemorrhagic complications.43 Most of these hemorrhages were intracranial and were the most serious complication. Other less frequent sites of bleeding included the cannulation site, the gastrointestinal tract and chest tube sites. Although the hemorrhage is related to systemic heparinization, no correlation was found between the activate clotting time or the amount of

52 Preoperative assessment

heparin used and the hemorrhagic complications.44 An increased risk of hemorrhage was associated with lower platelet counts, so that aggressive platelet transfusion remains important in preventing hemorrhagic complications using ECMO. Attempts at correcting any coagulopathy should be undertaken before the initiation of ECMO.21 Lately, there is an interest in developing heparin-bonded circuits, which would allow ECMO without systemic heparinization.22 The potential of an increased rate of intraventricular hemorrhage (IVH) has also been reported in term and preterm neonates following iNO therapy. INO leads to a prolonged bleeding time and an inhibition of platelet aggregation.31

LABORATORY INVESTIGATIONS A newborn undergoing surgery should have blood drawn on admission for the various investigations, including full blood count, serum sodium, potassium and chloride, urea, calcium, magnesium, glucose, bilirubin, and group and cross-match. Blood gases and pH estimation should also be obtained to assess acid–base state and the status of gas exchange. The availability of micromethods in the laboratory has minimized the amount of blood required to do the above blood tests. The coagulation status of infants who have been asphyxiated may be abnormal and should be evaluated.45 Neonatal sepsis can result in disseminated intravascular clotting and severe thrombocytopenia. A platelet count < 50 000/mm3 in the neonate is an indication of preoperative platelet transfusion. Blood cultures should be obtained wherever there is any suspicion of sepsis.

Adequacy of the intravascular volume and the function of the heart can be assessed by a central venous catheter (CVC), which can be inserted through the umbilical vein, internal jugular vein, subclavian and femoral vein. Usually, catheters are placed using the Seldinger technique.47 This central line is often mandatory and a basic monitoring for the anesthetist at the time of operation, and sometimes can be performed at the theater immediately before starting the operation. It is a useful instrument for ﬂuid resuscitation, administration of medication and central venous pressure monitoring. However, CVC lines are not free from risks. Infection rates of 2.3–5.3% are reported and duration of catheter placement is a risk factor for line infection.47 Most catheter-related bloodstream infections respond to appropriate antibiotic treatment and/or catheter removal.46 Critically ill neonates will require an arterial line especially at the time of operation, either because of the surgery, when it is expected to result in signiﬁcant ﬂuid shift and hemodynamic instability, or because of a signiﬁcant underlying cardiopulmonary disease of the newborn. This arterial line is for monitoring the hemodynamic and biochemical status, especially throughout the operative procedure. Right radial artery percutaneous catheterization is preferred because it allows sampling of preductal blood for measurement of oxygen tension. If the baby has already had an umbilical artery catheter, it is safer to use it strictly for the purpose of blood pressure monitoring and blood sampling and not for the administration of drugs. A good ﬁxation of all these venous and arterial lines is essential while these newborns have to be transported frequently, and reinsertion of these vascular lines can be very difﬁcult. In an emergency, temporary vascular access can also be obtained by the intraosseous route.46

VASCULAR ACCESS Most newborns with surgical conditions cannot be fed in the operative and early postoperative period. It is essential, therefore, to administer ﬂuids in these patients by the i.v. route. With the availability of 22–24-gauge plastic cannulas, percutaneous cannulation of veins has become possible even in small premature infants. Scalp veins and veins of the dorsum of the hand and palmar surface of the wrist are the most common sites used for starting i.v. infusion. With the improvements of techniques and equipment, it is now rarely necessary to perform a ‘cutdown’ in order to administer i.v. ﬂuids. Longer term venous access can be obtained with ﬁne percutaneous intravascular central catheters inserted at bedside without general anesthesia.46 The development of these silastic catheters of appropriate size has reduced the incidence of thromboembolic complications and made it possible to leave central venous catheters in place for long periods of time.28

FLUID AND ELECTROLYTES, AND METABOLIC RESPONSES Estimation of the parental ﬂuid and electrolyte requirements is an essential part of management of newborn infants with surgical conditions. Inaccurate assessment of ﬂuid requirements, especially in premature babies and LBW infants, may result in a number of serious complications.48 Inadequate ﬂuid intake may lead to dehydration, hypotension, poor perfusion with acidosis, hypernatremia and cardiovascular collapse. Administration of excessive ﬂuid may result in pulmonary edema, congestive heart failure, opening of ductal shunts, bronchopulmonary dysplasia and cerebral intraventricular hemorrhage. In order to plan accurate ﬂuid and electrolyte therapy for the newborn, it is essential to understand the normal body ‘water’ consumption and the routes through which

Renal function, urine volume and concentration in the newborn 53

water and solute are lost from the baby. In fetal life around 16 weeks’ gestation, total body water (TBW) represents approximately 90% of total body weight, and the proportions of extracellular and intracellular water components are 65% and 25%, respectively.49 At term, these two compartments constitute about 45% and 30%, respectively, of total body weight, indicating that (1) a shift from extracellular water to intracellular water occurs during development from fetal to neonatal life, and (2) relative TBW and extracellular ﬂuid volume both decrease with increasing gestational age.49 In very small premature infants water constitutes as much as 85% of total body weight and in the term infant it represents 75% of body weight. The total body water decreases progressively during the ﬁrst few months of life, falling to 65% of body weight at the age of 12 months, after which it remains fairly constant.50 The extracellular and intracellular ﬂuid volumes also change with growth. These changes are shown in Table 5.3. The objectives of parenteral ﬂuid therapy are to provide: • Maintenance ﬂuid requirements needed by the body to maintain vital functions • Replacement of pre-existing deﬁcits and abnormal losses • Basic maintenance requirement of water for growth. Maintenance ﬂuid requirement consists of water and electrolytes that are normally lost through insensible loss, sweat, urine and stools. The amount lost through various sources must be calculated to determine the volume of ﬂuid to be administered. Insensible loss is the loss of water from the pulmonary system and evaporative loss from the skin. Approximately 30% of the insensible water loss occurs through the pulmonary system as moisture in the expired gas; the remainder (about 70%) is lost through the skin.51 Numerous factors are known to inﬂuence the magnitude of insensible water loss. These include the infant’s environment (ambient humidity and ambient temperature52), metabolic rate,53 respiratory rate, gestational maturity, body size, surface area, fever51 and the use of radiant warmers and phototherapy.54 In babies weighing less than 1500 g at birth, insensible loss may be up to three times greater than that estimated for term infants.55 Faranhoff and colleagues found insensible

water loss in infants weighing less than 1250 g to be 60–120 ml/kg/day.56 Chief among the factors that affect insensible water loss are the gestational age of the infant and the relative humidity of the environment.57,58 The respiratory water loss is approximately 5 ml/kg/24 hours and is negligible when infants are intubated and on a ventilator.58 Water loss through sweat is generally negligible in the newborn except in patients with cystic ﬁbrosis, severe congestive heart failure or high environmental temperature. Fecal water losses are 5–20 ml/kg/day.

RENAL FUNCTION, URINE VOLUME AND CONCENTRATION IN THE NEWBORN The kidneys are the ﬁnal pathway regulating ﬂuid and electrolyte balance of the body. The urine volume is dependent on water intake, the quantity of solute for excretion and the maximal concentrating and diluting abilities of the kidney.51 Renal function in the newborn infant varies with gestational age and should be evaluated in this context. Very preterm infants younger than 34 weeks’ gestational age have reduced glomerular ﬁltration rate (GFR) and tubular immaturity in the handling of the ﬁltered solutes when compared to term infants. Premature infants between 34 and 37 weeks’ gestational age undergo rapid maturation of renal function similar to term infants with rapid establishment of glomerulotubular balance early in the postnatal period.59 The full-term newborn infant can dilute urine to osmolarities of 30–50 mmol/L and can concentrate it to 550 mmol/L by approximately 1 month of age. The solute for urinary excretion in infants varies from 10–20 mmol per 100 cal metabolized, which is derived from endogenous tissue catabolism and exogenous protein and electrolyte intake. In this range of renal solute load, a urine volume of 50–80 ml/100 cal would provide a urine concentration of between 125 and 400 mmol/L. If the volume of ﬂuid administered is inadequate, urine volume falls and concentration increases. With excess ﬂuid administration, the opposite occurs. We aim to achieve a urine output of 2 ml/kg/hour, which will maintain a urine osmolarity of 250–290 mmol/kg

Table 5.3 Changes in total body water (TBW) and body compartments during development Age Premature Newborn 3 months 1 year Adolescence Male Female

TBW (% body weight)

Extracellular ﬂuid (% body weight)

Intracellular ﬂuid (% body weight)

75–80 70–75 70 60

– 45 35 27

– 35 35 40–45

60 55

20 18

40–45 40

54 Preoperative assessment

(speciﬁc gravity 1009–1012) in newborn infants. For older infants and children, hydration is adequate if the urine output is 1–2 ml/kg/hour, with an osmolarity between 280 and 300 mmol/kg. Accurate measurements of urine ﬂow and concentration are fundamental to the management of critically ill infants and children, especially those with surgical conditions, and extensive tissue destruction or with infusion of high osmolar solutions. In these situations, it is recommended that urine volume be collected and measured accurately.

SERUM ELECTROLYTES AND METABOLIC RESPONSES IN NEONATAL SURGICAL PATIENTS Electrolyte and metabolic responses to surgical trauma in neonates must be assessed against the background of the normal metabolic responses of an infant to extrauterine life. Table 5.4 represents a reasonable composite of some of the changes occurring in the metabolism of electrolytes, nitrogen, water and calories in healthy newborn infants.60,61 Phase I lasts for 1–3 days after birth. In newborns with minimal oral intake, the salient metabolic features of this phase are the development of negative balances for electrolytes, water, calories, and nitrogen. The nitrogen balance observed during phase I depends on the stress incident to labor and delivery, and on caloric intake. Nitrogen excretion is accompanied by potassium excretion, and the potassium level is negative. During phase II, which is characterized by an increasing oral intake of nutrients, nitrogen and potassium balances become positive. Body weight begins to rise because of transition to positive caloric metabolism. Phase III is characterized by a further increase of body weight because of positive nitrogen, potassium, water and caloric balances.60 Physiological changes in ﬂuids, electrolytes and energy metabolism, during postnatal life, however, can vary with

different feeding regimens, gestational age, and other associated medical and surgical problems.62 Table 5.5 shows ﬂuid and electrolyte disturbances, their mechanisms and treatment of common neonatal surgical conditions.

PREOPERATIVE MANAGEMENT OF VARIOUS SURGICAL NEONATAL CONDITIONS Preoperative management is critical to the success of surgical intervention and the postoperative restoration of normal function. It has been observed that patients who have operations conserve sodium postoperatively.63 In fact, this sodium concentration is usually caused by hypovolemia, which has its genesis in preoperative dehydration, because of various surgical conditions. The remedy is to provide parenteral maintenance ﬂuid preoperatively when oral restriction of ﬂuid is required. Some patients may need ﬂuid resuscitation preoperatively, and their extracellular ﬂuid volume must be restored. Assessment of adequacy of the intravascular space can be done by measurement of pulse, blood pressure, capillary ﬁlling in the skin, core temperature, temperature of the skin, urine output, speciﬁc gravity and urinary sodium level. In addition to vital signs, an accurate weight, and especially changes in weight, electrolyte levels and calcium and blood gas analyses should be obtained. Attempts should be made to correct any abnormalities encountered during this assessment. Newborn surgical patients shift large amounts of protein and water into tissues or into potential spaces such as the peritoneal or pleural cavity. These so-called third-space losses are hard to quantify. Inadequate replacement of these losses can cause hypovolemia and shock. This is commonly seen in peritonitis (e.g. necrotizing enterocolitis, perforated viscus) and other congenital abnormalities such as gastroschisis and omphalocele. Infusion of colloid in the form of fresh-frozen plasma, 5% albumin, packed red cells,

Table 5.4 Metabolic and electrolyte changes of the healthy newborn* Variable

Phase I

Phase II

Phase III

Age Intake Body weight K+ metabolism Na+ metabolism Cl- metabolism H2O metabolism Urine volume N metabolism Caloric metabolism

1–3 days Low consumption of breast milk Decrease Negative balance Negative balance Negative balance Negative balance Small output Negative balance Negative balance

3–6 days Intake of breast milk rose progressively Begin to rise Positive balance† Positive balance Positive balance Negative balance Increased Positive balance Positive§

6–7 days Intake of breast milk stable Increase Positive balance Positive balance Positive balance ±Balance‡ Stable Positive balance Positive balance

From Wilkinson et al.,48 by permission. * This group of 10 male newborn babies include ﬁve who were healthy and ﬁve who suffered degrees of fetal distress. † Potassium probably gives the most sensitive indication of metabolic changes at this time of life. The day on which potassium balance ﬁrst became positive varied a good deal. ‡ Balance may be slightly positive or slightly negative. § Transition to positive balance. In preterm infants all three phases can last longer and have more profound changes.

Preoperative management of various surgical neonatal conditions 55

whole blood or plasma-like product is required to maintain intravascular integrity in the face of protein and ﬂuid losses. Enterocolitis complicating Hirschsprung’s disease or other intestinal obstructive lesions can cause massive losses of ﬂuid and electrolytes and result in hypovolemia, hyponatremia, metabolic acidosis and hypokalemia. In the presence of severe enterocolitis secondary to obstruction, with accompanying large ﬂuid losses into the intestine, adequate preoperative ﬂuid replacement is mandatory to ensure a reasonable outcome. Vomiting of gastric contents as a result of gastric outlet obstruction caused by a duodenal atresia, a

diaphragm or web, pyloric stenosis, intestinal bands, or malrotation, results in a chronic loss of gastric contents and primary hydrogen and chloride ions, in turn resulting in hypochloremic alkalosis. Chronic hypochloremic alkalosis results in hypokalemia. In renal compensation, hydrogen ions are conserved at the expense of potassium loss. Preoperative management of patients with gastric outlet obstruction includes ﬂuid replacement and at least potential correction of the hypochloremic alkalosis by infusion of chloride and potassium chloride (Table 5.5). This preoperative metabolic correction greatly enhances surgical outcome. Table 5.6 represents the

Table 5.5 Fluid and electrolyte disturbances in common neonatal surgical conditions Neonatal condition

Fluid and electrolyte disturbances

Mechanism

Treatment

Tracheo-esophageal ﬁstula

Mild dehydration Hyponatremia Dehydration, hypokalemia, hypochloremia, metabolic alkalosis

External loss of salivary secretions, lack of intake Loss of gastric secretions, hydrogen ions, potassium and chloride

Volume replacement with dextrose–saline Volume replacement with dextrose–saline and potassium chloride

Severe dehydration Hyponatremia Metabolic acidosis, hyperkalemia, high levels of BUN

Shift of ﬂuids into third space, Fast volume replacement loss of sodium in stool or Blood or blood products emesis. Low blood pressure Dextrose–saline with poor peripheral perfusion

Upper intestinal obstruction Duodenal atresia Malrotation (Ladd’s bands) Midgut volvulus

Mild to severe dehydration Hypothermia, hypochloremia, hypocalcemia

Loss of gastric and duodenal ﬂuids: hydrogen ions, chloride and bicarbonate

Low intestinal obstruction Ileal atresia Hirschsprung’s disease Imperforate anus

Dehydration, hyponatremia, metabolic acidosis, hypokalemia

Loss of ﬂuids into the intestine. Fluid replacement by Enterocolitis dextrose–saline, plasma and blood as needed

Abdominal wall defects Omphalocele Gastroschisis

Severe dehydration, metabolic acidosis, hyponatremia

Loss of serum from the intestinal wall in gastroschisis. Aspiration of large volume of bile by nasogastric catheter. Low perfusion

Pyloric stenosis Pyloric atresia Peritonitis Necrotizing enterocolitis Perforated viscous

Volume replacement with dextrose–saline and potassium chloride

Urgent ﬂuid replacement by plasma, albumin, Ringer’s lactate

Table 5.6 Electrolyte content of bodily ﬂuids* Fluid Gastric Pancreatic Bile Small intestine Ileostomy Diarrhea Sweat normal cystic ﬁbrosis

Na+

K+

Cl–

HCO3–

20–80 120–140 130–160 100–140 45–135 10–90

5–30 5–15 5–15 5–25 3–15 10–80

100–140 90–120 80–120 90–135 20–115 10–110

0 110 40 30 13–100 15–50

10–30 50–130

3–10 5–25

10–35 50–110

0 0

From Chesney and Zelikovic,64 by permission.* Values are mEq/L.

56 Preoperative assessment

electrolyte content of bodily ﬂuids, which are lost by various routes, and must be corrected with the appropriate balance to be replaced accurately. Bilateral obstruction uropathy exhibits a number of important and sometimes complex abnormalities of electrolyte metabolism and acid–base regulation. Depending on the severity of a lesion, patients can have dehydration, ﬂuid overload, hypernatremia, hyponatremia, hyperkalemia, renal tubular acidosis and azotemia with variable degrees of renal failure. Patients with water and salt-losing nephropathy need additional salt and water supplements. Patients with defective dilutional capacity and renal failure require ﬂuid restriction. Patients with renal tubular acidosis require bicarbonate supplementation with or without potassium exchange resins.

FLUID MANAGEMENT PROGRAM Based on a consideration of the sources of water loss, an average parenteral ﬂuid design for an infant receiving no oral feeding should provide about 40 ml of water per 100 cal metabolized for insensible loss and 50–80/100 cal for urine, with about 5 ml /100 cal for stool water, resulting in a total volume of 100–125 ml/100 cal for the maintenance ﬂuid losses under baseline conditions per 24 hours. LBW infants will require considerably more ﬂuid because of an increasing insensible loss. Neonates weighing less than 1000 g may need 160 ml/kg/24 hours and those over 1000 g may require 110–130 ml/kg/24 hours. With premature infants, a ﬂuid intake >170 ml/kg/24 hours is associated with an increased risk of congestive cardiac failure, patent ductus arteriosus and necrotizing enterocolitis. Serial measurements of body weight are a useful guide to total body water in infants. Fluctuations over a 24hour period are primarily related to loss or gain of ﬂuid, 1 g body weight being approximately equal to 1 ml water. Errors will occur if changes in clothing, dressings and tubes are not accounted for and if scales are not regularly calibrated. The assessment of hydration status in every newborn surgical patient is essential for the infant’s outcome. This can best be obtained by changes in body weight, measurement of urine ﬂow rate, concentration of urine, hematocrit and total serum protein. Estimation of serum electrolytes, urea, sugar and serum osmolarity gives an excellent indication of the hydration status.

REFERENCES 1. Harrison MR, Golbus MS, Filly RA. The Unborn Patient – Diagnosis and Management of the Foetus with a Congenital Defect. San Diego: Grune and Stratton, 1984.

2. Harrison MR, Scott NS, Flake AW. Correction of congenital diaphragmatic hernia in utero: VI. Hard-earned lessons. J Pediatr Surg 1993; 28:1411–18. 3. Harrison MR, Adzick NS, Jennings RW et al. Antenatal intervention for congenital cystic adenomatoid malformation. Lancet 1990; 336:965–7. 4. Hirata GL, Medearis AL, Platt LD. Foetal abdominal abnormalities associated with genetic syndromes. Clin Perinatol 1990; 17:675–702. 5. Azick NS, Flake AW, Harrison MR. Recent advances in prenatal diagnosis and treatment. Pediatr Clin Am 1985; 32:1103–16. 6. Govaerts MJ. Perioperative considerations in paediatric anaesthesia. Pediatr Anaesth 1990; 3:353–7. 7. Mullins GC. Anaesthesia and intensive care in critically ill neonates. Paediatr Anaesth 1990; 3:361–6. 8. Cook RWI. The low birth weight baby. In: Lister J, Irving IM, editors. Neonatal Surgery. 3rd edn. London: Butterworths, 1990: 77–88. 9. Takayama JI, Teng W, Uyemoto J et al. Body temperature of newborns: what is normal? Clin Pediatr 2000; 39:503–10. 10. Silverman WA, Sinclair JC. Temperature regulation in the newborn infant. N Engl J Med 1966; 274:146–8. 11. Swyer PR. Heat loss after birth. In: Sinclair JC, editor. Temperature Regulation and Energy Metabolism in the Newborn. New York: Grune and Stratton, 1978: 91–128. 12. Muraji T, Tsugawa C, Nishijima E, et al. Gastrochisis: a 17 year experience. J Pediatr Surg 1989; 24:343–5. 13. Niermeyer S, Winkel JK, Van Reempts P et al. International Guidelines for Neonatal Resuscitation: An Excerpt From the Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care: International Consensus on Science. Pediatr 2000; 106:1–16. 14. Hey EN. The relation between environmental temperature and oxygen consumption in the newborn baby. J Physiol 1969; 200:589–603. 15. Ringer SA, Stark AR. Management of neonatal emergencies in the delivery room. Clin Perinatol 1989; 16:23–41. 16. Walker J, Cudmore RE. Respiratory problems and cystic adenomatoid malformation of lung. Arch Dis Child 1990; 65:649–50. 17. Dziedzic K, Vidyasagar D. Pulse oximetry in neonatal intensive care. Clin Perinatol 1989; 16:177–97. 18. Philippart AI, Sarnik AP, Belenky WM. Respiratory support in paediatric surgery. Surg Clin N Am 1980; 60:1519–32. 19. Schmitt M, Prevot J, Lotte E et al. Relevance of highfrequency ventilation in neonatal surgery. Pediatr Surg Int 1986; 1:55–9. 20. Milerad J, Walsh WF. Commentary on neonatal ECMO: a North American and Scandinavian perspective. Acta Paediatr 1995; 84:841–7. 21. Reis-Bahrami K, Sort BL. The Current Status of Neonatal Extracorporal Membrane Oxygenation. Sem Perinatol 2000; 24:406–17.

References 57 22. Anthony ML, Hardee E. Extracorporal Membrane Oxygenation. Saving tiny lives. Crit Care Nurs Clin N Am 2000; 12:211–17. 23. Toomasian JM, Bartlett RH. Neonatal ECMO registry. In: Handbook for the Seventh Annual Spring Workshop on Neonatal ECMO. USA: MI, Ann Arbor: 1988: 236. 24. Langer JC, Filler RM, Bohn DJ et al. Timing of surgery for congenital diaphragmatic hernia. Is emergency operation necessary? J Pediatr Surg 1988; 23:731–4. 25. McCune S, Short BL, Miller MK et al. Extracorporeal membrane oxygenation therapy in neonates with septic shock. J Pediatr Surg 1990; 25:479–82. 26. Atkinson JB, Ford EG, Kitagawa H et al. Persistent pulmonary hypertension complicating cystic adenomatoid malformation in neonates. H Pediatr Surg 1992; 27:54–6. 27. Adolph V, Ekelund C, Smith C et al. Developmental outcome of neonates treated with extracorporeal membrane oxygenation. J Pediatr Surg 1990; 25:43–6. 28. Neubauer AP. Percutaneous central iv access in the neonate: experience with 535 silastic catheters. Acta Paediatr 1995; 84:756–60. 29. McCabe AJ, Wilcox DT, Holm BA et al. Surfactant – A review for pediatric surgeons. Pediatr Surg 2000; 35:1687–1700. 30. Kinsella JP, Abman SH. Inhaled nitric oxide: current and future uses in neonates. Sem Perinatol 2000; 24:387–95. 31. Hoehn T, Krause MF. Response to inhaled nitric oxide in premature and term neonates. Drugs 2001; 61:27–39. 32. Heymann MA, Randolph AM. Control of the ductus arteriosus. Physiol Rev 1975; 55:62–78. 33. Fyler C, Lang P. Neonatal heart disease. In: Avery EB, editor. Neonatology. 2nd edn. Philadelphia: Lippincott, 1981: 443–4. 34. McNamara DG. Value and limitations of auscultation in the management of congenital heart disease. Pediatr Clin N Am 1990; 37:93–113. 35. Fyfe DA, Kline CH. Foetal echocardiographic diagnosis of congenital heart disease. Pediatr Clin N Am 1990; 37:45–67. 36. McEwan AI, Birch M, Bingham R. The preoperative management of the child with a heart murmur. Pediatr Anaes 1995; 5:151–6. 37. Brewer ED. Disorders of acid-base balance. Pediatr Clin N Am 1990; 37:429–47. 38. Cowett RM, Loughead JL. Neonatal glucose metabolism: differential diagnosis, evaluation and treatment of hypoglycemia. Neonatal Netw 2002; 21:9–19. 39. Lynch RE. Ionised calcium: paediatric perspective. Pediatr Clin N Am 1990; 37:373–89. 40. Maisels MJ. Neonatal jaundice. In: Avery GB, editor. Neonatalogy. 2nd edn. Philadelphia: Lippincott, 1981: 482. 41. Weber JL. Liver disease in childhood. Med (International) 1982; 1:748–51. 42. Ohi R, Nio M, Chiba T et al. Long term follow-up after

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surgery for patients with biliary atresia. J Pediatr Surg 1990; 25:442–5. Weiss RG, Ball WS, Warner BW et al. Mediastinal hemorrhage during extracorporeal membrane oxygenation. J Pediatr Surg 1989; 24:1115–17. Sell LL, Cullen ML, Whittlesey GC et al. Haemorrhagic complications uring extracorporeal membrane oxygenation: prevention and treatment. J Pediatr Surg 1986; 21:1087–91. Gregory GA. Anaesthesia for premature infants. In: Paediatric Anaesthesia. New York: Churchill Livingstone, 1983: 879. Wardle SP, Kelsall AWR, Yoxall CW et al. Percutaneous femoral arterial and venous catheterisation during neonatal intensive care. Arch Dis Fetal Neonatal Ed 2001; 85:119–22. Chiang VW, Baskin MN. Uses and complications of central venous catheters inserted in a pediatric emergency department. Pediatr Emerg Care 2000; 16:230–2. El-Dahr SS, Chevalier RL. Special needs of the newborn infant in ﬂuid therapy. Paediatr Clin N Am 1990; 37:323–36. Friis-Hansen B. Water distribution in the foetus and newborn infant. Acta Paediatr Scand (Suppl) 1983; 305:7–11. Shaffer SG, Bradt SK, Hall RT. Postnatal changes in total body water and extracellular volume in the preterm infant with respiratory distress syndrome. J Pediatr 1986; 109:509–14. Boineau FG, Lewy JE. Estimation of parenteral ﬂuid requirements. Pediatr Clin N Am 1990; 37:257–64. Hey EN, Katz G. Evaporative water loss in the newborn baby. J Physiol 1969; 200:605–19. Roy RN, Sinclair JC. Hydration of the low birth weight infant. Clin Perinatol 1975; 2:393–417. Engle WD, Baumgart S, Schwartz JG et al. Insensible water loss in the critically ill neonate. Combined effect of radiant-warmer power and phototherapy. Am J Dis Child 1981; 135:516–20. Bell EF, Gray JC, Weinstein MR et al. The effects of thermal environment on heat balance and insensible water loss in low-birth weight infants. J Pediatr 1980; 96:452–9. Faranhoff AA, Wal M, Gruber HS et al. Insensible water loss in low birth weight in infants. Pediatrics 1972; 50:236–45. Hammarlun K, Sedin G, Stromberg B. Trans-epidermal water loss in newborn infants. Acta Paed Scand 1983; 72:721–8. Albanese CT, Rowe MI. Preoperative and postoperative management of the neonate. In: Spitz L, Coran AG, editors. Operative Surgery. London: Butterworths, 1995: 5–12. Shaffer SE, Norman ME. Renal function and renal failure in the newborn. Clin Perinatol 1989; 16:199–218. Wilkinson AW, Stevens LH, Hughes ZA. Metabolic changes in the newborn. Lancet 1962; 1:983–7.

58 Preoperative assessment 61. John E, Klavdianou M, Vidyasagar D. Electrolyte problems in neonatal surgical patients. Clin Perinatol 1989; 16:219–32. 62. Pierro A, Carnielli V, Filler RM et al. Partition of energy metabolism in the surgical newborn. J Pediatr Surg 1991; 26:581–6.

63. Winters RW. Fluid therapy for paediatric surgical patients. In Winters RW. The Body Fluids in Paediatrics. Boston: Little Brown, 1973: 595–611. 64. Chesney RW, Zelikovic I. Pre- and postoperative ﬂuid management in infancy. Pediatr Rev 1989; 11:153–8.

6 Anesthesia DECLAN WARDE

INTRODUCTION Over the past 60 years or so, provision of anesthesia for the neonate requiring surgery has developed from being a relatively haphazard affair to achieving the status of a recognized subspeciality. The improved survival rates seen following surgery, where even the smallest and sickest infants are concerned, have been due in no small part to advances in anesthetic management. Equally important has been an increased appreciation of the need for an efﬁcient smooth-working team. The success of neonatal surgery depends on maximum cooperation between surgeon, anesthetist, neonatologist, and nursing and paramedical personnel. It is appropriate therefore that everyone involved in the care of neonates, whether working inside or outside the operating theatre, should be familiar with the basic techniques used to maintain a favorable physiologic milieu in the face of surgical intrusion, while at the same time ensuring adequate anesthesia. This chapter will consider the preoperative evaluation and preparation of the surgical neonate, anesthetic equipment, choice of anesthetic agent and technique (with reference to the pharmacology of the newborn), induction of anesthesia and endotracheal intubation, maintenance and reversal of anesthesia, perioperative monitoring and ﬂuid therapy, the anesthetic implications of congenital anomalies and, ﬁnally, speciﬁc considerations for the premature infant undergoing surgery.

PREOPERATIVE PREPARATION AND EVALUATION Much neonatal surgery is performed on an emergency basis. However, operation is rarely so urgent as not to allow for adequate evaluation and stabilization beforehand. The cornerstone of preoperative anesthetic management is a detailed knowledge of the infant’s history combined with a thorough physical examination.

Consideration must also be given to the speciﬁc surgical procedure to be undertaken and its implications in terms of potential blood loss, monitoring requirements and postoperative care.

History Although many neonates requiring surgery are only a few hours old, considerable information that is useful as regards anesthetic management will have been accumulated by the time of the anesthetist’s visit. This information should be obtained from the parent(s) (if available) and medical and nursing colleagues. Of profound importance is an accurate estimation of gestational age, as prematurity has major implications for the anesthetist (see later). Trends in blood pressure and heart rate, body weight, ﬂuid intake and output, laboratory measurements, X-ray appearances and the extent of any respiratory support required will normally be readily available and are very helpful both in planning anesthetic technique and in anticipating problems. A knowledge of recent or current drug therapy is also important.

Physical examination The anesthetist should make a brief appraisal of the infant’s overall condition and follow this with a careful assessment of individual body systems. Overhydration or hypovolemia can be detected by assessment of skin turgor, the anterior fontanelle and liver size. Peripheral vasoconstriction may indicate either hypovolemia or acidosis. Jaundice will normally be self-evident, but anemia and cyanosis can be difﬁcult to detect in the neonate. Pulmonary function is also less easily evaluated than in older children and adults, but any of the following may indicate impending respiratory failure: nasal ﬂaring, tachypnea, chest wall recession, grunting respiration or apneic spells. Airway anatomy should be carefully assessed in order that potential difﬁculties with endo-

60 Anesthesia

tracheal intubation can be anticipated. One should look for other associated congenital anomalies in the surgical neonate. This is particularly so when examining the cardiovascular system (e.g. one-third of infants with esophageal atresia also have some form of congenital heart disease). Accurate preoperative neurological assessment is mandatory in infants presenting for anesthesia for neurosurgery.

Laboratory investigations Minimum laboratory data required includes full blood count, blood urea and serum electrolytes, blood glucose and calcium, coagulation proﬁle and urine speciﬁc gravity. Arterial blood gas analysis for pH, oxygen and carbon dioxide partial pressure (PO2 and PCO2), and bicarbonate levels is also frequently indicated. The preoperative hemoglobin level should be at least 12 g/dL – if lower, consideration should be given to transfusion with packed red blood cells prior to anesthesia and surgery. Any dehydration, hypovolemia, hypoglycemia, hypocalcemia, or hypo- or hyperkalemia should be corrected. pH, PO2, PCO2 and body temperature should be normalized.

transfer to the operating theater, as it is usually easier to maintain an infant’s body temperature in the ICU environment. Overall ﬁtness must be assessed in light of the urgency of surgery. This may require consultation between anesthetist, surgeon and other interested personnel. If transfer to the operating theater is considered to be unacceptably hazardous, for example in the case of some extremely ill and low birth weight (LBW) infants, it may be advantageous to undertake surgery in the ICU itself.1,2

TRANSFER TO OPERATING THEATER The time during which the neonate is transferred to the operating theater is one which is not without hazard. Risks are minimized if he or she is accompanied by experienced medical and nursing personnel and if the theater is close at hand. Transfer should be in either an incubator or an isolette with overhead heater to reduce heat loss. Any treatment in progress (e.g. i.v. ﬂuid or drug infusion, respiratory support) should be continued by the use of battery-operated infusion pumps and portable respiratory equipment. Monitoring should not be interrupted during this critical phase.

Premedication Sedative premedication is not used in neonates. However many pediatric anesthetists consider it advisable to administer an anticholinergic drug either prior to or at induction of anesthesia in order to reduce secretions (which interfere with the airway) and to protect against bradycardia (which may occur with hypoxemia or after halothane, succinylcholine or airway instrumentation). Atropine is the most widely used drug, usually in a dose of 0.02 mg/kg by i.v. injection immediately prior to induction. Prior to transfer to the operating theater, the anesthetist should conﬁrm that: • The infant has been fasting for at least 3 hours (but not for much longer unless an i.v. ﬂuid infusion is in progress) • Blood has been cross-matched (if indicated) • Vitamin K, 0.5–1 mg i.m., has been administered (to allow for possible deﬁciency in vitamin K-dependent clotting factors) • The stomach has been decompressed (especially in cases of intestinal obstruction) • Any premedication ordered has been given. Estimated blood volume, allowable blood loss and maintenance ﬂuid requirements should be calculated. Where it is anticipated that multiple vascular access routes will be required (e.g. for central venous pressure or direct arterial pressure monitoring), it may be advisable to establish these in the intensive care unit (ICU) before

OPERATING THEATER AND ANESTHETIC EQUIPMENT The prime objectives of neonatal anesthesia are the provision of sleep, analgesia, life support, intensive surveillance and appropriate operating conditions for the infant requiring surgery. In order for these to be achieved it is imperative that both operating theater environmental conditions and anesthetic equipment be appropriate. It has been shown that maximum heat loss occurs between the time of arrival of the neonate in theatre and the skin incision. Measures should be taken to minimize the risk and extent of this occurrence. Before the infant arrives, the theater, which should be draught free, should be warmed to a temperature of 24oC or 25oC. Once the baby is removed from the incubator or isolette, he or she should be placed on a water or air mattress which has been heated to 40oC and kept covered as much as possible – plastic drapes and blankets are particularly useful in this regard. The warming mattress used must be electrically safe and accurately monitored, have an easily adjustable thermostat and a fail-safe cutout device in the event of thermostat failure. If an overhead radiant heater is available, it should be set to maintain skin temperature at 36oC. Other measures which assist in maintaining body temperature during this critical period include warming and humidifying inspired anesthetic gases and warming i.v. and skin preparation ﬂuids.

Operating theater and anesthetic equipment 61

Breathing systems An appropriate anesthetic circuit for use in infants needs to be light, have minimal resistance and dead space, allow for warming and humidiﬁcation of inspired gases and be adaptable to spontaneous, assisted or controlled ventilation. The most widely used is the T-piece system designed by Philip Ayre3 and later modiﬁed by Rees4 (Fig. 6.1). Connectors and tubes should also offer minimal ﬂow resistance and dead space. Most endotracheal tubes used during neonatal anesthesia are manufactured of polyvinyl chloride. A knowledge of the probable diameter and length of tube appropriate for any given infant is highly desirable (Table 6.1), but must always be conﬁrmed clinically. The optimal diameter is the largest which will pass easily through the glottis and subglottic region and will produce a slight leak when positive pressure is applied. A convenient guideline for length of orotracheal tube from gum to mid-trachea is 7 cm for an infant weighing 1 kg, with an additional centimeter for each kilogram increase in weight.5 Use of an endotracheal tube of too large a diameter may result in tracheal wall damage, while excess length leads to endobronchial intubation. The presence of a cuff limits the diameter of tube which can be used, with consequent increased resistance to airﬂow. For this reason, uncuffed tubes are invariably used in neonates.

Once satisfactory positioning has been conﬁrmed visually and by auscultation of both lungs, the tube should be taped securely to prevent accidental extubation. Consideration should be given to secondary ﬁxation to the forehead to prevent rotational movement. Face masks are generally used for only brief periods in neonates, but should provide a good ﬁt and have a low dead space. The Rendell–Baker–Soucek mask remains popular (Fig. 6.2). Oral airways are not generally necessary except in cases of choanal atresia, but have the advantage of splinting the endotracheal tube and preventing lateral movement. The incidence of airway complications associated with the laryngeal mask airway (LMA) in infants is high.6 However the device can occasionally prove to be useful, especially when endotracheal intubation is difﬁcult.7–9

Figure 6.2 Rendell–Baker–Soucek masks

Laryngoscopes Because of the anatomical peculiarities of the infant’s airway, most anesthetists prefer to use a laryngoscope with a straight blade, lifting the epiglottis forwards from behind to facilitate intubation. The Miller number 0 and 1 blades are suitable in most cases. A modiﬁed laryngoscope which assists in maintaining oxygenation during laryngoscopy in infants and children has been described.10

Ventilators

Figure 6.1 Ayre’s T-piece with Jackson–Rees modiﬁcation

Table 6.1 Approximate diameter and length of endotracheal tubes for use in neonatal anesthesia Post-conceptual age (weeks)

Internal diameter (mm)

Length (cm) Oral Nasal

< 30 < 30–40 > 40

2.0–2.5 2.5–3.0 3.0–3.5

7–8 8–9 9–10

8–9 9–10 10–11

Most infants and children can be ventilated using standard adult ventilators provided the ventilator is of low internal compliance and equipped with pediatric breathing tubes. The ventilator should be capable of delivering small tidal volumes and rapid respiratory rates, and have an adjustable inspiratory ﬂow rate and inspiratory:expiratory ratio so that peak airway pressure is kept as low as possible.11 Pressure-controlled ventilation is widely used in order to minimize the risk of pulmonary barotrauma. A suitable temperaturecontrolled humidiﬁer should be incorporated in the inspiratory side of the ventilator circuit. The ability to deliver air/oxygen mixtures through ventilator or anesthetic circuit should be available.

62 Anesthesia

Monitoring equipment A complete range of monitoring equipment suitable for infant use is required.

CHOICE OF ANESTHETIC AGENT AND TECHNIQUE Neonates perceive pain, while even babies born at 28 weeks’ gestation mount a substantial and potentially harmful response to surgically induced stress.12,13 Thus, few would argue with the contention that adequate anesthesia should be provided for all infants undergoing surgery. The anesthetic agents employed are similar to those used for older children and adults. However the responses of the neonate to these potent drugs differ in a number of respects from those of older patients. An understanding of these differences is essential for the safe conduct of neonatal anesthesia and also inﬂuences choice of anesthetic agent and technique.

Inhalational agents Inhalation induction of anesthesia with nitrous oxide, oxygen and a volatile agent remains popular. Provided that respiration is not depressed, both induction of and emergence from anesthesia are rapid in infants. The reasons for this are multiple, but include the relatively higher cardiac output, greater alveolar ventilation, smaller functional residual capacity and larger proportion of vessel-rich tissues relative to body mass seen in the newborn infant.14–16 An additional consideration is that the minimal alveolar concentration (MAC) of inhaled agents required to prevent reﬂex responses to surgical stimulation varies with age.

stered (especially during controlled ventilation) and caution is advised. Like most other inhalational agents, halothane increases cerebral blood ﬂow with a consequent rise in intracranial pressure. This effect is minimal at low concentrations if controlled ventilation is employed. Halothane hepatitis has not been reported in newborn infants.

ISOFLURANE Despite its lower blood gas solubility coefﬁcient, inhalation induction with isoﬂurane is generally not as rapid or as smooth as with halothane. Indeed this agent has been shown to be associated with a signiﬁcant incidence of hypoxic episodes during inhalation induction of anesthesia in older children.25 Sedative premedication26 and use of a highly inspired isoﬂurane concentration from the outset27 both reduce the incidence of these adverse occurrences, but are relatively contraindicated in the surgical neonate. The respiratory depressant effects of isoﬂurane are similar to those of halothane. Once again MAC values are lower in the newborn28 and lower still in premature infants.29 Isoﬂurane has been shown to maintain systolic arterial pressure in the normal range even in preterm neonates and, unlike halothane, does not sensitize the myocardium to the effects of circulating catecholamines. It has considerable potentiating effects on non-depolarizing muscle relaxants, so that lower doses of the latter can be used. Metabolic degradation of the agent is minimal and recovery rapid. In summary, isoﬂurane is an excellent agent for maintenance of anesthesia, perhaps the agent of choice in the neonate, but halothane remains superior for inhalation induction.

ENFLURANE This agent is not widely used in neonatal and pediatric anesthesia because its irritant effects render it relatively unsatisfactory for inhalation induction.

HALOTHANE Halothane was for many years the most widely used volatile anesthetic for inhalation induction in infants and young children. This is largely because it is usually associated with a smooth induction without irritant effects on the airway. Like other potent inhalational agents, it leads to a dose-related depression of spontaneous respiration.17 This is particularly important in the neonate, in whom the ventilatory response to hypoxia is one of hypoventilation. Halothane MAC is signiﬁcantly lower in newborn infants than in those between 1 and 6 months of age and appears to be still lower in the fetus.18–21 The agent is considered by many to be a more potent depressor of cardiovascular function in infants and young children than in older patients, but its use does not appear to be associated with increased morbidity.22–24 However, hypotension can occur when high concentrations are admini-

DESFLURANE Airway irritant effects also render desﬂurane unsuitable for inhalation induction in pediatric practice. However recovery times in infants are shorter with this agent than those following use of other volatile anesthetics. The agent has been recommended for maintenance of anesthesia in the ex-premature infant prone to apnea and ventilatory depression.30

SEVOFLURANE Induction time with sevoﬂurane is shorter than with halothane in older children.31 However, this does not appear to be the case where infants are concerned.32 The agent has been reported to cause more respiratory depression than halothane in infants and young children, but perhaps not to a clinically signiﬁcant degree.33

Choice of anesthetic agent and technique 63

NITROUS OXIDE This gas does not provide adequate anesthesia when used alone with oxygen.13 It is most often employed as a carrier, which supplements potent volatile anesthetics, thereby reducing the concentration required and minimizing cardiovascular depressant effects. Animal work indicated that it might induce pulmonary vasoconstriction, with resultant increased right-to-left shunting in the newborn,34 but this does not appear to be so.35 It does cause moderate respiratory and cardiovascular depression. One limitation to the use of nitrous oxide in neonatal anesthesia is the fact that it is many times more soluble in blood than is nitrogen. As a result, the inhalation and subsequent diffusion of the gas causes an increase in the volume of compliant spaces. It follows that the agent should not be used in infants with congenital diaphragmatic hernia, lobar emphysema or necrotizing enterocolitis.

Intravenous agents THIOPENTONE Despite the fact that it was introduced to anesthetic practice over 60 years ago and that many supposedly superior agents have since been developed, this drug remains the preferred agent for i.v. induction in infants. The induction dose (ED50 3.4 mg/kg) is lower in neonates younger than 14 days of age than in older infants.35

after a similar time to that seen in adults (approximately 4 minutes). Because of the number of side effects, including bradycardia, hyperkalemia and triggering of malignant hyperpyrexia reactions associated with this agent, it has been suggested that its use in young infants should be re-evaluated.38 However, it remains pre-eminent in rapidly providing optimum conditions for endotracheal intubation, and is still very widely used.

Non-depolarizing muscle relaxants For many years it was generally agreed that newborn infants exhibited an increased sensitivity to these agents, but recent studies have demonstrated that full relaxation demands doses similar to those used in adults. A lower plasma concentration is required (presumably because of immaturity of the neuromuscular junction), but this is produced in any event by distribution of injected drug throughout the relatively larger extracellular ﬂuid compartment. Alterations in plasma protein binding may also play a role in determining dose requirements, which are much more variable than in adults.39 It follows that careful titration of dose against response is advisable and that these drugs should be administered slowly to neonates. Use of a peripheral nerve stimulator as a guide to degree of relaxation is strongly recommended.

PROPOFOL

ATRACURIUM AND VECURONIUM

Experience with this drug is somewhat limited in neonates. However it has been used successfully in the management of pyloric stenosis.36

These two agents were introduced because their duration of action was intermediate between that of suxamethonium and older non-depolarizing muscle relaxants such as pancuronium and because they offered increased cardiovascular stability. In addition, atracurium is attractive in that its metabolism is independent of hepatic and renal function, although it is dependent on pH and temperature. Recommended initial doses are 0.3–0.5 mg/kg for atracurium and 0.05–0.1 mg/kg for vecuronium. Because of their pharmacokinetic proﬁles, both drugs are suitable for use by continuous i.v. infusion, although atracurium infusion requirements show marked individual variation.40 Nightingale found the duration of effect of atracurium to be longer in infants younger than 3 days of age.41 Other studies have shown the dose–response curves of this agent to be parallel in infants, older children and adults and in fact demonstrate recovery times to be shorter in infants.42,43 Histamine release, an occasional problem with the drug in adults, has not caused problems in the pediatric population.41 Vecuronium, on the other hand, has been found to have a longer recovery time in infants compared to older children and adults and should be regarded as a longacting muscle relaxant in this age group.44

KETAMINE This agent is associated with greater cardiovascular stability than many other anesthetic drugs.37 However, its metabolism is considerably delayed in infants younger than 1 year of age. It has the advantages of having a profound analgesic effect and of being capable of being given by i.m. injection.

Neuromuscular blocking agents SUXAMETHONIUM Relatively higher doses (2 mg/kg) of this drug are required to produce full relaxation in infants than in adults (1 mg/kg). This is because of the neonate’s larger extracellular ﬂuid space, throughout which the drug is distributed. Suxamethonium is metabolized by plasma pseudocholinesterase. Although plasma levels of this enzyme are low in the ﬁrst 6 months of life, activity is adequate to metabolize the drug, and recovery occurs

64 Anesthesia

MIVACURIUM Mivacurium is a short-acting, non-depolarizing neuromuscular agent which is rapidly hydrolyzed by plasma pseudocholinesterase. The time course of block produced by the drug is more rapid in younger pediatric patients.45 Satisfactory intubating conditions are not achieved as quickly as with suxamethonium but serious side effects occur less frequently.

ROCURONIUM This agent causes more neuromuscular depression and has a longer duration of action during halothane anesthesia in infants than in children older than 2 years.46

d-TUBOCURARINE AND PANCURONIUM These drugs were widely used in neonatal anesthetic practice in the past but have largely been replaced by alternatives with a shorter duration of action. The cardiovascular effects of pancuronium are more pronounced than in adults and tachycardia may be a problem.

NARCOTIC ANALGESICS AND THEIR DERIVATIVES The neonate exhibits an exaggerated response to narcotic administration when compared with the older child.47 The reasons for this include immaturity of hepatic enzyme systems leading to impaired conjugation and glucuronide excretion48 and the greater permeability of the infant blood-brain barrier to these drugs.49 Morphine elimination half-life is prolonged in babies younger than 4 days old, while morphine clearance in the newborn in less than one-half that of older infants.50 In addition, neonates are more susceptible than adults to the respiratory depressant effects of morphine and its derivatives.49 It follows that where narcotic analgesics are administered to neonates, dosage regimens should be modiﬁed so that patient safety is not compromised. Recent evidence indicates that neonates do perceive and respond to pain and there is little doubt that the intraoperative administration of opiates to infants undergoing major surgery can be beneﬁcial.13 There can be no justiﬁcation for denying adequate analgesia to infants who are to be mechanically ventilated in the postoperative period. Morphine (0.05–0.1 mg/kg) and fentanyl (0.005–0.02 mg/kg) given intravenously are the two most widely used drugs, with the latter being particularly well tolerated hemodynamically.37,51 Intraoperative infusions of ultra-short-acting opioids such as remifentanil have been used successfully although recovery times were prolonged in some infants younger than 7 days old.52,53

In recent years, continuous infusions of i.v. morphine have been popular for provision of postoperative analgesia in ventilated infants and those nursed in highdependency units. Infusion rates above 0.01 mg/kg/hour are rarely necessary. Respiratory monitoring should be continued for 24 hours after discontinuation of the infusion. The situation with regard to other infants is more difﬁcult. It should be recognized that while failure to treat discomfort or pain effectively may have signiﬁcant long-term effects, overaggressive treatment has its own morbidity.54 The easy option is to avoid intra- or postoperative opioids altogether but one dose of codeine phosphate (1 mg/kg) given by i.m. injection is probably safe.55 Local anesthetic techniques (e.g. lumbar or caudal epidural block, intrathecal block, intercostal block, wound inﬁltration, etc.) can often be used as an alternative method of providing analgesia for these babies and will undoubtedly be more widely adopted in the future.

Regional anesthesia In recent times there has been a signiﬁcant increase in the use of regional anesthetic techniques as an alternative to general anesthesia in neonates. Local anesthetic blocks are safe and efﬁcacious and may be particularly valuable in the high-risk infant. Spinal and epidural routes, or a combination of both, have been used.56–60

Induction of anesthesia and endotracheal intubation Most pediatric anesthetists advocate that infants should have anesthesia induced and a muscle relaxant administered prior to attempts at endotracheal intubation. Awake intubation is less popular than in the past61 because it is considered that the ensuing hypertension62 and rise in anterior fontanelle pressure63 may contribute to the development of intraventricular hemorrhage, especially in premature infants and those with disorders of coagulation. The induction technique depends on the: (1) age, size and physical status of the infants, (2) relative hazard of regurgitation, and (3) personal preferences of the anesthetist. In most instances, i.v. induction followed by administration of a short-acting muscle relaxant is satisfactory. Inhalation induction is an acceptable alternative. In either case, i.v. access should be established beforehand and the induction itself should be preceded by a short period of preoxygenation. Intubation is best accomplished with the infant’s head extended at the atlanto-occipital joint. This position allows the straightest and shortest distance between the lips and larynx.64 The laryngoscope blade is inserted into the right side of the mouth, displacing the tongue to the left. As the blade is advanced the epiglottis comes into view. In the neonate this structure is long and ﬂoppy and it should be displaced anteriorly from behind to aid

Monitoring 65

visualization of the larynx. If difﬁculty is encountered, the little ﬁnger of the left hand can be used to press gently on the larynx to improve visualization. The use of an atraumatic but rigid bougie can also be extremely valuable in these cases. Once intubation has been achieved, one should carefully auscultate both lungs to check for equal air entry, and the endotracheal tube should be securely ﬁxed. While the indications for awake intubation are not as broad as they once were, the technique retains a limited place in neonatal anesthesia. The main advantage is that the baby can still breathe if attempts at intubation fail. If the anesthetist is inexperienced in dealing with neonates or if there is signiﬁcant upper airway obstruction (e.g. cystic hygroma, Pierre Robin syndrome), it may occasionally be safer to intubate prior to inducing anesthesia. Correct holding of the infant is essential if the maneuver is to be successful; an assistant should stabilize the head and shoulders during the intubation process. The endotracheal tube is inserted on inspiration – this facilitates intubation and minimizes laryngeal trauma. If it is considered at the time of induction of anesthesia that postoperative mechanical ventilation will be required, the tube should be inserted by the nasal rather than the oral route. It is difﬁcult to manipulate Magill’s forceps in the mouth of a small infant, but ﬂexing the neck usually facilitates passage of nasotracheal tubes.

Consideration should be given to the use of air/ oxygen mixtures in preterm neonates. I.v. analgesics are rarely indicated unless it is proposed to ventilate the infant in the postoperative period.

REVERSAL AND EXTUBATION If a volatile agent has been used for maintenance of anesthesia, it should be discontinued shortly prior to the end of surgery. Once surgery has been completed, residual muscle relaxation is reversed by either neostigmine (0.06 mg/kg) or edrophonium (1 mg/kg) combined with either atropine (0.02–0.03 mg/kg) or glycopyrrolate (0.01 mg/kg). Controlled ventilation is continued with 100% oxygen or with oxygen in air until spontaneous respiration has returned. Suctioning through the endotracheal tube is carried out if secretions are obviously present. The nostrils should be gently suctioned as routine. The infant should not be extubated until fully awake and breathing adequately. In most cases, reversal of neuromuscular blockade and resumption of spontaneous respiration occurs rapidly.65 If difﬁculty is encountered this may be due to hypothermia, acidosis or hypocalcemia, or the fact that an incremental dose of relaxant has been given too close to the end of surgery.

MONITORING MAINTENANCE OF ANESTHESIA Because of the vulnerability of the infant’s respiratory system, spontaneous respiration is not used for long periods in the anesthetized neonate. Mechanical ventilation helps to ensure adequate gas exchange and also leaves the hands of the anesthetist free to perform other tasks. Suitable ventilators have already been discussed and, depending on the particular machine available, may be set in either pressure- or volume-cycled modes. With the former, suitable settings would include a fresh gas ﬂow of 2–3 L/minute, peak airway pressure of approximately 20 cmH2O of water and a ventilatory rate of 30–40/minute. With the latter, a delivered tidal volume of approximately 10 ml/kg at a rate of 30–40 breaths/ minute is appropriate. Inspired gases should be warmed and humidiﬁed to prevent damage to the mucosal lining of the respiratory tract and to minimize heat loss. Manual ventilation allows rapid detection of airway obstruction or disconnection, and is particularly useful during thoracic surgery. The most widely used agents for maintenance of anesthesia in the neonatal population are isoﬂurane, sevoﬂurane and desﬂurane, usually combined with 50% oxygen in nitrous oxide, along with a small dose of relaxant.

The clinical condition of the anesthetized neonate can deteriorate more rapidly and with less warning than that of patients in any other age group. It follows that careful and continuous monitoring is essential. While no piece of machinery will adequately replace the careful anesthetist, there are a number of devices available which provide helpful information that cannot be gleaned by clinical means alone. The monitoring employed in any particular case depends upon the physical status of the infant and the surgical procedure to be undertaken. The following should be positioned prior to induction (and, indeed, regarded as the minimum equipment required for monitoring anesthetized neonates): • • • • •

ECG leads and electrodes Precordial or esophageal stethoscope Blood pressure cuff Core temperature probe Pulse oximeter probe.

Although its use in pediatric anesthetic practice has declined,66 the stethoscope is particularly valuable, allowing continuous monitoring of heart and breath sounds. In the neonate, the intensity of the heart sounds varies with the stroke volume so that an indication of cardiac

66 Anesthesia

output is provided. Use of a monaural earpiece greatly improves the comfort of the listener. Most neonates undergoing anesthesia and surgery require additional monitoring. The various options available will be discussed in relation to the particular body system being monitored.

Respiration Chest wall movement should be observed continuously if at all possible. When mechanical ventilation is employed, airway pressure and minute volume alarms are mandatory. It should not be forgotten that alarms can fail. Oxygenation and adequacy of gas exchange are monitored continuously by pulse oximetry and capnography. Serial arterial blood gas analysis is mandatory in critically ill infants undergoing major surgery.

Cardiovascular function Observation of peripheral perfusion and palpation of a peripheral pulse are both useful but may be difﬁcult to achieve because of problems of access. Blood pressure monitoring is essential because of the reduced cardiovascular reserve of the neonate and the risk of hypotension if high concentrations of inhaled anesthetics are used. Conventional measurement using an inﬂatable cuff combined with auscultation of the Korotkoff sounds is often difﬁcult. The use of automated oscillotonometry represents an advance, but concern has been expressed about the accuracy of the devices used when blood pressure is low. The cuff should be of an appropriate width (approximately 4 cm). If either the infant’s physical status or the type of surgery to be performed necessitates continuous monitoring of blood pressure, a suitable vessel (usually the right radial artery) should be cannulated, the cannula being connected to a pressure transducer by narrow-bore tubing. Central venous pressure monitoring is useful in infants with congenital heart disease, and also if signiﬁcant blood loss (and replacement) are anticipated. The right internal jugular vein is usually the simplest to cannulate. Monitoring of left atrial pressure and/or pulmonary capillary wedge pressure is rarely indicated in the neonate.

Fluid balance The goal of intraoperative ﬂuid management is to sustain homeostasis by providing the appropriate amount of parenteral ﬂuid to maintain adequate intravascular volume, cardiac output, and, ultimately, oxygen delivery to tissues at a time when normal physiological functions are altered by surgical stress and anesthetic

agents.67 Maintenance ﬂuid requirements vary considerably within the neonatal period itself, but may be taken as being approximately 4 ml/kg/hour for infants older than 5 days of age. Assuming there is no preoperative ﬂuid deﬁcit, an i.v. infusion set at the usual maintenance rate should be commenced prior to induction of anesthesia. In practice, this will usually have been done in the ward. The composition of the administered ﬂuid will vary according to the maturity of the baby and preoperative electrolyte and glucose levels. Because of the problems associated with hyperglycemic states in infancy, care should be taken with the use of 10% dextrose infusions.68,69 It is important to take into account the volume of drug dilutents administered during anesthesia and surgery when calculating ﬂuid balance. Blood and ﬂuid loss can be extensive and very difﬁcult to measure during neonatal surgery. The former is best estimated by the use of small volume suction traps, by weighing small numbers of surgical swabs before they dry out, and by serial hematocrit measurements. During lengthy surgery, serum electrolytes and blood glucose should be measured at regular intervals. Urine output may be monitored by the use of adhesive collecting bags or bladder catheterization. Estimated third space loss may be replaced by continuous administration of lactated Ringer’s solution at 3–5 ml/kg/hour. While volume replacement should be undertaken when blood loss is expected to exceed 5–10% of circulating blood volume, concern has been expressed regarding the cost–beneﬁt ratio of colloidal solutions such as albumin.70 Because of the high hematocrit level at birth, red cell replacement is seldom required during most routine neonatal surgical procedures. When required, the blood used should be as fresh as possible. The most convenient and accurate method of administration is by syringe, through a three-way tap in the i.v. line. Adequacy of volume replacement can be assessed by monitoring of blood pressure, central venous pressure, peripheral circulatory state and urine output.

ANESTHESIA FOR SPECIFIC SURGICAL CONDITIONS Esophageal atresia Once a diagnosis of esophageal atresia (with or without ﬁstula) has been made, the blind upper pouch should be continuously aspirated using a Replogle or similar tube. In general, operation may be safely delayed pending improvement of any aspiration pneumonia which has developed.71 Pre-thoracotomy bronchoscopy is practised in some centers and may inﬂuence subsequent management.72 Anesthesia is similar to that for other neonatal

Special considerations for the premature infant 67

procedures, but special care must be taken with positioning of the endotracheal tube, the tip of which should be located above the carina but below any ﬁstula present. Surgical retraction during the operation may compromise either respiratory or cardiac function, so that close monitoring is essential. If serious contamination has not occurred, extubation is usually possible at the end of the procedure.

Congenital diaphragmatic hernia This condition was formerly regarded as one of the great emergencies of pediatric surgical practice, but it is now generally agreed that operation should be postponed until adequate gas exchange has been obtained and the infant is hemodynamically stable.73,74 Positive pressure ventilation using bag and mask should be avoided prior to endotracheal intubation, as expansion of the viscera contained within the hernia will cause further lung compression. Nitrous oxide should be avoided for the same reason. A reasonable anesthetic technique includes controlled ventilation with fentanyl 0.01–0.02 mg/kg, intermediate-acting muscle relaxant and 100% oxygen or oxygen in air as required. Great caution should be exercised in the use of volatile anesthetic agents. Airway pressures should be kept as low as possible. Should advanced ventilatory techniques such as high-frequency oscillation be required in order to achieve preoperative stabilization, these may be safely continued during surgery.75,76 Most infants will require mechanical ventilation in the postoperative period.

Intestinal obstruction The various forms of neonatal intestinal obstruction account for approximately 35% of all surgical procedures in the newborn. The major anesthetic problems are those of ﬂuid and electrolyte imbalance (which must be corrected preoperatively), abdominal distension (causing respiratory embarrassment) and the risk of regurgitation and aspiration of gastric contents into the lungs. Following decompression of the stomach, a rapidsequence induction incorporating preoxygenation, thiopentone and succinycholine with gentle cricoid pressure is advised. Anesthesia is then continued in the usual way.

Exomphalos and gastroschisis Anesthetic concerns include heat and ﬂuid loss from the exposed bowel and the fact that closure of the abdominal wall defect may push the diaphragm cephalad, thus compromising respiratory function. Special care must be taken to keep heat loss to a minimum. Fluid requirements are much greater than in normal neonates. To maintain plasma oncotic pressure,

at least 25% of ﬂuid intake should be given as colloid. The extent of respiratory compromise can assist the anesthetist in advising the surgeon whether or not primary closure is feasible. A proportion of infants, especially after repair of gastroschisis, require postoperative mechanical ventilation.

Congenital lobar emphysema This condition may cause severe respiratory distress in the neonatal period. Induction of anesthesia for lobectomy should be as smooth as possible – struggling may trap large amounts of air in the affected lobe during violent inspiratory efforts.77 Nitrous oxide can also increase the volume of trapped air considerably78 and is contraindicated. Great care should be taken with controlled ventilation because of the risk of pneumothorax.

Myelomeningocele If the defect is large, heat and ﬂuid loss during surgery can pose problems and should be monitored as closely as possible. Surgery is carried out with the infant in the prone position and the chest and pelvis should be supported with pads so that the abdomen remains free from external pressure.

SPECIAL CONSIDERATIONS FOR THE PREMATURE INFANT Congenital defects occur more commonly in preterm infants, so that surgery is frequently required. Organs and enzyme systems are very immature and meticulous attention to detail during anesthetic and surgical management is imperative if survival rates are to be high. The large body surface area and lack of subcutaneous fat make maintenance of body temperature even more difﬁcult than in term infants, so that a high neutral thermal environment is essential. Respiratory fatigue occurs very easily and may be exacerbated by residual lung damage following mechanical ventilation, persistent fetal circulation and oxygen dependency. The response to exogenous vitamin K is less satisfactory than in term infants and there is an increased risk of bleeding. In addition, anemia is common because of reduced erythropoiesis, a short erythrocyte lifespan and iatrogenic causes such as frequent blood sampling. Fluid and electrolyte management can be difﬁcult – insensitive losses are high and hypoglycemia and hypocalcemia occur easily, while renal function and the ability of the cardiovascular system to tolerate ﬂuid loads are reduced. Premature infants with a history of idiopathic apneic episodes preoperatively are more prone than other infants to develop life-threatening apnea during recovery

68 Anesthesia

from anesthesia.79 It has been recommended that infants born prematurely who undergo anesthesia and surgery while less than 60 postconceptual weeks of age should have respiratory monitoring for at least 12 hours postoperatively in order to prevent apnea-related complications.80 I.v. caffeine 5 mg/kg given intravenously at induction appears to reduce the risk of apneic episodes, but respiratory monitoring is still required.81

REFERENCES 1. Besag FMC, Singh MP, Whitelaw AGL. Surgery of the ill, extremely low birth weight infant: should transfer to the operating theatre be avoided? Acta Paediatr Scand 1984; 73:594–5. 2. Frawley G, Bayley G, Chondros P. Laparotomy for necrotizing enterocolitis: intensive care nursery compared with operating theatre. J Paediatr Child Health 1999; 35:291–5. 3. Ayre P. Endotracheal anaesthesia for babies with special reference to hare-lip and cleft palate operations. Anesth Analg 1937; 16:330–3. 4. Rees GJ. Neonatal anaesthesia. Br Med Bull 1958; 14:38–41. 5. Tochen ML. Orotracheal intubation in the newborn infant: a method for determining depth of tube insertion. J Paediatr 1979; 95:1051. 6. Harnett M, Kinirons B, Heffernan A et al. Airway complications in infants: comparison of laryngeal mask airway and the facemask-oral airway. Can J Anaesth 2000; 47:315–18. 7. Bahk J-H, Choi I-H. Tracheal tube insertion through laryngeal mask airway in paediatric patients. Paediatr Anaesth 1999; 9:95–6. 8. Ellis DS, Potluri PK, O’Flaherty JE et al. Difﬁcult airway management in the neonate: a simple method of intubating through a laryngeal mask airway. Paediatr Anaesth 1999; 9:460–2. 9. Delrue V, Veyckemans F, De Potter P. Modiﬁcation of the LMA no. 1 for diode laser photocoagulation in expremature infants. Paediatr Anaesth 2000; 3:345–6. 10. Todres ID, Crone RK. Experience with a modiﬁed laryngoscope in sick infants. Crit Care Med 1981; 9:544–5. 11. Walker I, Lockie J. Basic techniques in anaesthesia. In: Sumner E, Hatch DJ, editors. Paediatric Anaesthesia. London: Arnold, 2000. 12. Anand KJS, Hickey PR. Pain and its effects in the human neonate and fetus. N Engl J Med 1987; 317:1321–9. 13. Anand KJS, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery. Lancet 1987; I:243–7. 14. Salanitre E, Rackow H. The pulmonary exchange of nitrous oxide and halothane in infants. Anesthesiology 1969; 30:388–94. 15. Cook DR. Neonatal anaesthetic pharmacology: a review. Anesth Analg 1974; 53:544–8.

16. Steward DJ, Creighton RE. The uptake and excretion of nitrous oxide in the newborn. Can Anaesth Soc J 1978; 25:215–17. 17. Hatch D, Fletcher M. Anaesthesia and the ventilatory system in infants and young children. Br J Anaesth 1992; 68:398–410. 18. Nicodemus HF, Nassiri-Rahimi C, Bachman L et al. Median effective doses (ED50) of halothane in adults and children. Anesthesiology 1969; 31:344–8. 19. Gregory G, Eger EI, Munson ES. The relationship between age and halothane requirement in man. Anesthesiology 1969; 30:488–91. 20. Lerman J, Robinson S, Willis MM et al. Anesthetic requirements for halothane in young children 0–1 month and 1–6 months of age. Anesthesiology 1983; 59:421–4. 21. Gregory GA, Wade JG, Beihl DR et al. Fetal anaesthetic requirements (MAC) for halothane. Anesth Analg 1983; 62:9–14. 22. Diaz JH, Lockhart CH. Is halothane really safe in infancy? Anesthesiology 1979; 51:S313. 23. Diaz JH. Halothane anesthesia in infancy: identiﬁcation and correlation of preoperative risk factors with intraoperative arterial hypotension and postoperative recovery. J Paediatr Surg 1985; 20:502–7. 24. Friesen H, Wurl JL, Charlton GA. Haemodynamic depression by halothane is age-related in paediatric patients. Paediatr Anaesth 2000; 10:267–72. 25. Sampaio MM, Crean PM, Keilty SR et al. Changes in oxygen saturation during inhalation anaesthesia in children. Br J Anesth 1989; 62:199–201. 26. Raftery S, Warde D. Oxygen saturation during inhalation induction with halothane and isoﬂurane in children: effect of premedication with rectal thiopentone. Br J Anaesth 1990; 64:167–9. 27. Warde D, Nagi H, Raftery S. Respiratory complications and hypoxic episodes during inhalation induction with isoﬂurane in children. Br J Anaesth 1991; 66:327–30. 28. Cameron CB, Robinson S, Gregory GA. The minimum anesthetic concentration of isoﬂurane in children. Anesth Analg 1984; 63:418–20. 29. LeDez KM, Lerman J. The minimum alveolar concentration (MAC) of isoﬂurane in preterm neonates. Anesthesiology 1987; 67:301–7. 30. Wolf AR, Lawson RA, Dryden CM et al. Recovery after desﬂurane anaesthesia in the infant: comparison with isoﬂurane. Br J Anaesth 1996; 76:362–4. 31. Kataria B, Epstein R, Bailey A et al. A comparison of sevoﬂurane to halothane in paediatric surgical patients: results of a multicentre international study. Paediatr Anaesth 1996; 6:283–92. 32. O’Brien K, Robinson DN, Morton NS. Induction and emergence in infants less than 60 weeks post-conceptual age: comparison of thiopental, halothane, sevoﬂurane and desﬂurane. Br J Anaesth 1998; 80:456–9. 33. Brown K, Aun C, Stocks J et al. A comparison of the respiratory effects of sevoﬂurane and halothane in infants and young children. Anesthesiology 1998; 89:86–92.

References 69 34. Eisele JH, Milstein JM and Goetzman BW. Pulmonary vascular responses to nitrous oxide in newborn limbs. Anesth. Analg 1986; 65:62–4. 35. Hickey PR, Hansen DD, Stafford M et al. Pulmonary and systemic haemodynamic effects of nitrous oxide in infants with normal and raised pulmonary vascular resistance. Anesthesiology 1986; 65:374–8. 36. Dubois MC, Troje C, Martin C et al. Anesthesia in the management of pyloric stenosis. Evaluation of the combination of propofol-halogenated anesthetics. Ann Fr Anesth Reanim 1993; 12:566–70. 37. Friesen RH, Henry DB. Cardiovascular changes in preterm neonates receiving isoﬂurane, halothane, fentanyl and ketamine. Anesthesiology 1986; 64:238–42. 38. Delphin E, Jackson D, Rothstein P. Use of succinylcholine during elective pediatric anesthesia should be reevaluated. Anesth Analg 1987; 66:1190–2. 39. Goudsouzian NG, Donlon JV, Savarese JJ et al. Reevaluation of dosage and duration of action of dtubocuraine in the pediatric age group. Anesthesiology 1975; 43:416–25. 40. Goudsouzian NG. Atracurium infusion in infants. Anesthesiology 1988; 68:267–9. 41. Nightingale DA. Use of atracurium in neonatal anaesthesia. Br J Anaesth 1986; 58(Suppl 1):32–36S. 42. Brandom BW, Rudd GD, Cook DR. Clinical pharmacology of atracurium in paediatric patients. Br J Anaesth 1986; 55:117–21S. 43. Brandom BW, Woelfel SK, Cook DR et al. Clinical pharmacology of atracurium in infants. Anesth Analg 1984; 63:309–12. 44. Fisher DM, Miller RD. Neuromuscular effects of vecuronium (ORG NC45) in infants and children during N2O, halothane anesthesia. Anesthesiology 1983; 58:519–25. 45. Brandom BW, Meretoja OA, Simhi E et al. Age related variability in the effects of mivacurium in paediatric surgical patients. Can J Anaesth 1998; 45:410–16. 46. Driessen JJ, Robertson EN, Van Egmond J et al. The timecourse of action and recovery of rocuronium 0.3 mg × kg(–1) in infants and children during halothane anaesthesia measured with acceleromyography. Paediatr Anaesth 2000; 10:493–7. 47. Hain WR, Mason JA. Analgesia for children. Br J Hosp Med 1986; 36:375–8. 48. Cook DR. Paediatric anesthesia: pharmacological considerations. Drugs 1976; 12:212–21. 49. Way WL, Costley EC, Way EL. Respiratory sensitivity of the newborn infant to meperidine and morphine. Clin Pharmacol Ther 1965; 6:454–61. 50. Lynn AM, Slattery JT. Morphine pharmacokinetics in early infancy. Anesthesiology 1987; 66:136–9. 51. Yaster M. The dose response of fentanyl in pediatric anesthesia. Anesthesiology 1987; 66:433–5. 52. Eck JB, Lynn AM. Use of remifentanil in infants. Paediatr Anaesth 1998; 8:437–9. 53. Wee LH, Moriarty A, Cranston A et al. Remifentanil

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infusion for major abdominal surgery in small infants. Paediatr Anaesth 1999; 5:415–18. Wolf AR. Pain, nociception and the developing infant. Paediatr Anaesth 1999; 9:7–17. Purcell-Jones G, Dorman F, Sumner E. The use of opioids in neonates. A retrospective study of 933 cases. Anaesthesia 1987; 42:1316–19. Mahe V, Ecoffey C. Spinal anesthesia with isobaric bupivicaine in infants. Anesthesiology 1988; 68:601–3. Shenkman Z, Hoppenstein D, Litmarrowitz I et al. Spinal anaesthesia in 62 premature, former-premature or young infants – technical aspects and pitfalls. Can J Anaesth 2002; 49:262–9. Krane EJ, Haberkern CM, Jacobson LE. Postoperative apnea, bradycardia and oxygen desaturation in formerly premature infants: prospective comparison of spinal and general anesthesia. Anesth. Analg 1995; 80:7–13. Williams RK, McBride WJ, Abajian JC. Combined spinal and epidural anaesthesia for major abdominal surgery in infants. Can J Anaesth 1997; 44:511–14. Somri M, Gaitini L, Vaida S et al. Postoperative outcome in high-risk infants undergoing herniorrhaphy: comparison between spinal and general anaesthesia. Anaesthesia 1998; 53:762–6. Duncan HP, Zurick NJ, Wolf AR. Should we reconsider awake neonatal intubation? A review of the evidence and treatment strategies. Paediatr Anaesth 2001; 11:135–45. Down SM, Roloff DW, Goldstein GW. Prevention of intraventricular haemorrhage in preterm infants by phenobarbitone. Lancet 1981; ii:215–17. Friesen RH, Honda AT, Thieme RE. Changes in anterior fontanel pressure in preterm neonates during tracheal intubation. Anesth Analg 1987; 66:874–8. Stephens CR, Ahlgren EW, Bennett EJ. Elements of Pediatric Anesthesia. Springﬁeld, Ill: Charles C. Thomas, 1970. Meakin G, Sweet PT, Bevan JC et al. Neostigmine and edrophonium as antagonists of pancuronium in infants and children. Anesthesiology 1983; 59:316–21. Watson A, Visram A. Survey of the use of oesophageal and precordial stethoscopes in current paediatric anaesthetic practice. Paediatr Anaesth 2001; 11:437–42. Leelanukrom R, Cunliffe M. Intraoperative ﬂuid and glucose management in children. Paediatr Anaesth 2000; 10:353–9. Louik C, Mitchell AA, Epstein MF et al. Risk factors for neonatal hyperglycemia associated with 10% dextrose infusion. Am J Dis Child 1985; 139:783–6. Bush GH, Steward DJ. Can persistent cerebral damage be caused by hyperglycaemia? Paediatr Anaesth 1995; 5:385–7. Anon. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. Cochrane Injuries Group Albumin Reviewers. Br Med J 1998; 317:235–40. Spitz L, Kiely E, Brereton RJ. Esophageal atresia: ﬁve year experience with 148 cases. J Paediatr Surg 1987; 22:103–8.

70 Anesthesia 72. Kosloske AN, Jewell PF, Cartwright KC. Crucial bronchoscopic ﬁndings in esophageal atresia and tracheoesophageal ﬁstual. J Paediatr Surg 1988; 23:466–70. 73. Cartlidge PHT, Mann NP, Kapila L. Preoperative stabilisation in congenital diaphragmatic hernia. Arch Dis Child 1986; 61:1226–8. 74. Langer JC, Filler RM, Bohn DJ et al. Timing of surgery for congenital diaphragmatic hernia: is emergency operation necessary? J Paediatr Surg 1988; 23:731–4. 75. Bouchut J-C, Dubois R, Moussa M et al. High frequency oscillatory ventilation during repair of neonatal congenital diaphragmatic hernia. Paediatr Anaesth 2000; 10:377–9. 76. Tobias JD, Burd RS. Anaesthetic management and high frequency oscillatory ventilation. Paediatr Anaesth 2001; 11:483–7.

77. Cote CJ. The anesthetic management of congenital lobar emphysema. Anesthesiology 1978; 49:296–8. 78. Eger EI, Saidman LJ. Hazards of nitrous oxide anesthesia in bowel obstruction and pneumothorax. Anesthesiology 1965; 26:61–6. 79. Liu LMP, Cote CJ, Goudsouzian NG et al. Life threatening apnoea in infants recovering from anesthesia. Anesthesiology 1983; 59:506–10. 80. Kurth CD, Spritzer AR, Broennle AM et al. Postoperative apnoea in preterm infants. Anesthesiology 1987; 66:486–8. 81. Welborn LG, de Soto H, Hannallah RS et al. The use of caffeine in the control of post-anesthetic apnoea in former premature infants. Anesthesiology 1988; 68:769–98.

7 Postoperative management DESMOND BOHN

INTRODUCTION

MONITORING

The past two decades have seen major advances in the management of critically ill newborns. During this period we have seen the introduction of innovative treatments for acute hypoxemic respiratory failure including surfactant replacement therapy, extracorporeal membrane oxygenation (ECMO) and highfrequency oscillatory ventilation (HFOV) which have resulted in improved survival of both term and preterm infants. At the same time advances in surgical and anesthetic management have led to corrective surgery being performed on complex lesions both prenatally and in low birth weight (LBW) infants, placing a demand for higher levels of care in the postoperative period. While the surgery itself may be only of a relatively short duration, success or failure will inevitably depend on the level and skill of the postoperative care. There are some distinct differences in the physiology of the newborn infant compared to the older child which may impact on postoperative management. Pulmonary vascular resistance is elevated in the ﬁrst week of life, which increases the potential right-to-left shunting at ductal level. There are distinct differences in the coagulation system as plasma levels and activities are low at the time of birth and then increase in the ﬁrst few months of life. Total body water is higher in the newborn, especially the preterm infant and the glomerular ﬁltration rate (GFR) is low in the ﬁrst few days of life. Thermoregulation mechanisms are also poorly developed. The newborn increases cardiac output by increasing heart rate because stroke volume is relatively ﬁxed. Finally, there are important hormonal–metabolic responses to surgery which have major implications for analagesia and sedation during and after surgery. While a comprehensive review of these topics is beyond the scope of this chapter the signiﬁcance of these physiological changes to the postoperative care of the newborn will be discussed.

The key to being able to successfully manage a critically ill newborn is the ability to measure and then adjust physiological parameters. For that reason invasive and non-invasive monitoring assume an important role in management in the postoperative period. The newborn, especially the preterm infant, has little tolerance to changes in normal physiological parameters and therefore minimum monitoring requirements should include continuously recorded ECG, rectal temperature, blood pressure by Doppler or automatic non-invasive blood pressure cuff, measurement of respiratory rate and hourly urine output. In addition, in infants with compromised cardiorespiratory function, more sophisticated respiratory and hemodynamic monitoring is required.

RESPIRATORY MONITORING Blood gas measurement Monitoring of respiratory function in the postoperative period requires measurement of gas exchange. The most reliable and accurate method is to measure PaO2, PaCO2 and pH from an arterial sample. The common sites for invasive arterial monitoring are umbilical artery (newborns) and radial or dorsalis pedis arteries in the ﬁrst few months of life. In the newborn, a blood gas drawn from the right radial will measure pre-ductal PaO2 values, whereas the other sites will be post-ductal. On some occasions the left subclavian artery is juxta-ductal and will therefore measure similar values to the right. With the newer generation of automated blood gas machines, samples as small as 0.1 ml are sufﬁcient for a full blood gas and pH proﬁle. This is particularly important in premature infants in whom frequent sampling may necessitate ‘top up’ transfusions. An alternative method of measuring PaCO2, PaO2 and pH is to use ‘arterialized’

72 Postoperative management

capillary blood taken from an area of skin that has been vasodilated by warming, usually the heel. This technique is generally reliable for PaCO2 and pH. With arterial PaO2 levels above 60–70 mmHg, accuracy drops off considerably.

Transcutaneous blood gas monitoring The development of pulse oximetry has made it possible to measure arterial saturation and heart rate on a beatto-beat basis and has proved to be a reliable and effective method of monitoring and trending oxygenation.1,2 The absolute values do not correlate well with those measured at saturations of less than 70% and in low cardiac output states where there is inadequate perfusion for a pulse to be recorded by the probe.3 Careful sensor placement is important to prevent distortion by light and the probes are sensitive to light artifact. It is a useful monitor to record the rapid response of PO2 to interventions such as suctioning and changes in ventilation. Due to the shape of the oxygen hemoglobin dissociation curve, high PaO2 levels (>12.6 kpa) will not be accurately reﬂected by saturation measurements. In the premature neonate (<1000 gm), where high PaO levels may predispose to the development of retinopathy of prematurity (ROP), the transcutaneous PO2 (TcPO2) probe is the preferred method of monitoring oxygenation as it indirectly measures the actual PaO2. The TcPO2 technique uses a modiﬁed Clark electrode with a heating element that raises skin temperature to between 41°C and 44°C in order to augment cutaneous blood ﬂow. These devices correlate well with arterial oxygen in small infants who have little subcutaneous tissue, and are reliable where cardiac output and peripheral perfusion are good.4 However, quality declines in the older child and in those in low cardiac output states. Transcutaneous CO2 (TcPCO2) monitoring uses the modiﬁed Severinghous probe with a heating element, which heats the skin to 41–44°C.5 These have proved to be reliable in small infants. While transcutaneous PO2 and PCO2 monitoring are useful trending devices, absolute values should be occasionally checked against an arterial sample. Greater accuracy is obtained by careful maintenance of the probes and care in calibration and application to the skin. The risk of skin damage from the heating element requires that the measuring site be changed every 4–6 hours

MANAGEMENT OF THE INTUBATED PATIENT Tube size and position Newborns are most commonly managed with nasotracheal tubes rather than oral tubes unless there is some congenital abnormality of or injury to the nasal area that

precludes their use. They provide for greater patient comfort and acceptability and the tube may be more securely fastened to the face and upper lip. In terms of length, the tip of the tube should reach to the level of the clavicles on the chest ﬁlm. Tubes that extend lower may enter a main bronchus, especially during ﬂexion or extension movements of the head. A routine chest ﬁlm should be obtained immediately after intubation or change of tube position to ascertain correct placement. The proximal end of the tube should protrude sufﬁciently far from the nose so that the tube connector does not impinge upon the external nares. Severe excoriation of nares and erosion of cartilage can occur with longterm intubation. In selecting a tube of correct diameter, the size should be sufﬁcient enough to provide a small leak under positive pressure, but not large enough to provide an airtight seal. Tight-ﬁtting tubes left in situ for prolonged periods will lead to tracheal stenosis and vocal cord granuloma formation, requiring tracheostomy and extended postoperative care. At the same time, too large a leak will make positive pressure ventilation extremely difﬁcult. In the term newborn 3 mm, 3.5 mm or 4 mm tubes may be used depending on the size of the infant; 2.5 mm or 2 mm tubes may be used in premature infants, but these are prone to becoming blocked with secretions.

Endotracheal tube suctioning Routine suctioning to maintain the patency of the endotracheal tube and prevent atelectasis is of prime importance in newborns. However, even skillful suctioning can lead to a profound fall in PaO2 and bradycardia, especially in infants who are already hypoxemic. Consequently, prior to suctioning, all patients should have their lungs inﬂated with 100% oxygen by manual hyperventilation. A catheter of a size that does not occlude the lumen of the endotracheal tube should be chosen so that the suctioning does not generate large enough negative pressures to cause atelectasis. End-hole catheters should be used rather than the side-hole type, which can trap and injure the respiratory tract mucosa. Suction should only be applied while the catheter is being withdrawn and for not longer than a few seconds. Between each suctioning, the patient should be ventilated with 100% oxygen. The onset of bradycardia during suctioning is an immediate indication to stop and ventilate with oxygen, as it is almost always indicative of hypoxemia. Endotracheal suctioning should always be performed as a sterile procedure using surgical gloves and a sterile catheter. The objective should be to pass the catheter down as far as it will go to beyond the carina and down either one or the other main bronchus, at the same time stimulating the patient to cough. The catheter tip may be encouraged to pass down either one or the other side by

Mechanical ventilation 73

rotating the head to the opposite side. The presence of unduly thick secretions in the respiratory tract should alert one to the possibility of inadequate humidiﬁcation. Intrapulmonary hemorrhage increases the chances of endotracheal tube blockage substantially and indicates the need for more frequent suctioning.

Humidiﬁcation Humidiﬁcation is one of the least emphasized but most important aspects of respiratory care. The small diameter endotracheal tube in the newborn patient is notoriously prone to blockage from secretions, especially where they become inspissated due to inadequate humidiﬁcation. Too much humidiﬁcation leads to ‘rainout’, as the inspired gas cools during its passage between the humidiﬁer and the infant’s airway and can lead to the absorption of considerable amounts of water. The goal of optimal humidity is to deliver fully saturated gases (44 mg/L H2O) at a temperature of 37°C to the peak of the airway. This can only be achieved with the heated water bath type humidiﬁer as opposed to the nebulizer type, which has little application in neonatal practice. The temperature of the water bath must be raised above body temperature, to about 40°C in order to deliver gases at 35–37°C at the endotracheal (ET) tube. Between the humidiﬁer and the endotracheal tube, considerable condensation of water vapor may occur as the gases cool, which may impede gas ﬂow. This problem has been overcome to some extent with the newer humidiﬁers, which have a heated electric coil inside the inspiratory line. This maintains a consistent temperature throughout the inspiratory line by means of a dual servo mechanism with temperature sensors in both the water bath and at the patient’s airway. There is therefore less cooling of gases in the respirator tubing and inspired gas is delivered to the endotracheal (ET) tube fully saturated and at 37°C. The condenser humidiﬁer or ‘Swedish nose’ is also capable of supplying moisture and preventing heat loss from the respiratory tract. While obviously not as efﬁcient as the water bath type, it is particularly useful for patient transport or for providing humidity to infants who have been intubated for upper airway problems. As the condenser humidiﬁer becomes increasingly saturated, the airway resistance tends to rise and the humidiﬁer must be changed every 24 hours.

RESPIRATORY FUNCTION IN THE NEWBORN The respiratory system is probably the most vulnerable area in the maintenance of a normal physiological milieu. Abnormalities in the cardiovascular, renal and central nervous systems are rapidly reﬂected in changes in function of the respiratory apparatus, which in the

newborn is ill equipped to deal with. The chest wall itself is highly compliant and increasing respiratory efforts, due to a fall in lung compliance, result in increasing chest wall distortion and eventual apnea from respiratory muscle fatigue. Major abdominal or thoracic surgical procedures in the newborn render the infant particularly vulnerable to developing respiratory failure, as surgery frequently has an adverse effect on the mechanics of the respiratory system. Repair of congenital abnormalities such as gastroschisis or congenital diaphragmatic hernia (CDH) frequently result in rises in intra-abdominal pressure, upward displacement of the diaphragm and a fall in total thoracic compliance.4 Normal tidal respiration in the infant occurs around the closing capacity and therefore any loss of lung volume will result in further atelectasis and hypoxemia. Similarly, the use of inhalational anesthetic agents, narcotics and muscle relaxants will adversely affect diaphragmatic function not only during surgery, but have an effect which extends well into the postoperative period. In order to prevent respiratory compromise in the immediate postoperative period, infants undergoing major abdominal or thoracic surgery will beneﬁt from a period of ventilatory support, the duration of which will depend on the maturity of the infant, the underlying surgical problem and the presence or absence of disease or abnormalities within the lung itself.

MECHANICAL VENTILATION Mechanical ventilation of newborn infants came into widespread use in the 1970s, when it was appreciated that long-term intubation was both safe and feasible in small infants and that positive pressure ventilation was not necessarily damaging to the newborn lung. The initial concept was to adapt adult ventilators for use in the infant, using positive pressure to generate a gas ﬂow into the lung, sufﬁcient to expand alveoli by overcoming the opposing forces generated by the elastic properties of the lung (compliance) and the airways (resistance). The most commonly used ventilators in the newborn are the time-cycled, pressure-limited variety. The number of breaths delivered by the respirator is set by the operator while the duration of the inspiratory and expiratory phases of the respiratory cycle can be altered by adjusting the inspiratory time. The respirator cycles from inspiration to expiration when a preset pressure is reached. This preselected pressure is known as the peak inspiratory pressure (PIP), which may vary depending on the pressure needed to expand the lung by overcoming the compliance of the lung and the airway resistance. The airway pressure at end expiration (normally zero during spontaneous breathing) can be increased to 5–20 cmH2O, depending on whether positive end expiratory pressure

74 Postoperative management

(PEEP) is required to maintain lung expansion. The volume delivered by a pressure ventilator will change signiﬁcantly according to conditions within the thorax. A fall in compliance or a rise in airway resistance results in the ventilator rapidly reaching its preselected cycling pressure. A reduction in delivered alveolar ventilation will inevitably follow, which can only be overcome by increasing the preset pressure. If one also takes into account the fact that there is invariably a leak around the ET tube in a newborn infant, changes in compliance and resistance will also increase the amount of wasted ventilation escaping between the tube and tracheal wall. The alternative ventilation system is a time-cycled, volume preset respirator which will deliver a set tidal volume at a preselected rate. In certain machines, the operator chooses the minute volume and ventilatory rate and the tidal volume can be calculated from these two settings. Alternatively, in other types of respirators the tidal volume and rate are selected and the minute volume calculated. As with the pressure-type respirator, the duration of the inspiratory and expiratory time can be adjusted according to conditions within the thorax. A fall in compliance or rise in airway resistance will not result in a fall in alveolar ventilation as the machine will merely increase the pressure in order to overcome these changes. The respirator however will not compensate for leaks around the ET tube and a signiﬁcant proportion of the preset volume will be vented around the tube when there is a large leak. These ventilators are most commonly used for ventilating adult patients where cuffed ET tubes are used, but are increasingly used in children and newborns.

Oxygen uptake The diffusion gradient for oxygen within the lung is high as the PO2 in the pulmonary artery is (PvO2) 5.3 kpa compared with alveolar PO2 (PaO2) of 14 kpa on FiO2 0.21. Despite this favorable gradient, the alveoli must remain open for gas exchange to occur. In the normal lung, due to the hysteresis, the alveoli open during inspiration and remain open during most of expiration and only cease gas exchanging at end expiration. In the diffusely atelectatic lung, of which RDS is a prime example, the alveoli become unstable and tend to collapse at low lung volumes. The degree of alveolar expansion depends to a large part on mean airway pressure (Paw), which is a measure of the average pressure that the alveoli are exposed to during the respiratory cycle. This in turn is determined by a combination of the PIP, PEEP and duration of the inspiratory phase of the respiratory cycle. Attempts to improve oxygenation are based on the manipulation of one or more of these variables in order to increase Paw. The simplest and most time honored of these measures is to increase the amount of PEEP, which was ﬁrst introduced to improve oxygenation in RDS. Abnormalities within the lung that cause a large difference between PaO2 and PaOo2 (A-a DO2) may also be compensated for to a certain extent by increasing the FiO2. However, both oxygen and positive pressure have been implicated in causing the chronic lung injury (BPD) seen in newborns with respiratory distress syndrome (RDS). High PaO2 levels have also been implicated in the development of retinitis of prematurity (ROP). Consequently, there are good reasons for carefully monitoring and controlling oxygen therapy in the newborn.

RESPIRATORY GAS EXCHANGE Carbon dioxide elimination Adequate CO2 elimination depends on the ratio between CO2 production (metabolic rate) and alveolar ventilation (tidal volume – dead space). In the normal situation, the two sides of the equation balance and normal CO2 homeostasis is preserved. An increase in CO2 production can normally be met by increased alveolar ventilation and the newborn achieves this by increasing its respiratory rate. Similarly, abnormalities within the thorax will result primarily in an increase in respiratory rate rather than volume in order to achieve the same alveolar ventilation. In mechanical ventilation, the PaCO2 level can be controlled by adjusting both ventilator rate and the volume delivered by each respiratory cycle (alveolar ventilation = tidal volume – dead space × frequency). With a pressure preset ventilator, minute ventilation is increased by increasing the peak inspiratory pressure (PIP) and rate, while in the volume respirator PaCO2 is controlled by adjusting rate and delivered volume.

VENTILATOR MANAGEMENT OF THE NEWBORN Choosing the options for ventilatory management of the newborn is in a large part determined by conditions within the patient. The objective is to maintain gases within a physiological range (PaO2 8–12 kpa, PaCO2 5–6.5 kpa) using the lowest FiO2 and airway pressure compatible with that aim. This may be relatively simple where the lungs are normal, but may require a completely different strategy in the presence of abnormalities within the abdomen or thorax. Therefore one must take these considerations into account when selecting ventilator settings for the newborn infant. Generally speaking, the term infant with normal respiratory system compliance and airway resistance on a pressure-preset ventilator would require a PIP of 10–20 cmH2O, a rate of 30–40/minite, an FiO2 0.25–0.35 and an inspiratory to expiratory ratio (I:E ratio) of 1:2 or 1:2.5 and a minimum of 3–5 cmH2O PEEP as routine. Using a

Ventilator management of the newborn 75

volume respirator, a tidal volume of 8–10 ml/kg would be adequate in a newborn with normal lungs. Having selected these settings, the adequacy of gas exchange must be veriﬁed by an arterial blood gas sample to ensure that hyperventilation is avoided.

(IVH) and the need for pharmacological paralysis.9 The infants were stratiﬁed for birth weight and the results show there was no difference in outcome except for infants with a birth weight of greater than 2000 g who had a shorter duration of mechanical ventilation associated with the use of SIMV. There was also an increased use of ECMO therapy in the IMV group.

Synchronized ventilation Synchronized mechanical ventilation has evolved from the use of patient triggering in the assist/control mode of mechanical ventilation. The drawback to this system was that it was frequently not sensitive enough to pick up the small negative inspiratory efforts frequently seen in the tachypneic newborn infant. The concept of synchronized mechanical ventilation is to trigger the ventilator’s positive pressure early enough during inspiration to avoid stimulating active expiration against the triggered breath. This type of asynchrony may result in suboptimal gas exchange, increased risk of barotrauma and an increased incidence of intraventricular hemorrhage. One method of overcoming this is to use sedatives or neuromuscular blocking drugs, both of which carry with them an alternative set of problems. Neuromuscular blockade is associated with loss of vasomotor tone and circulatory insufﬁciency, while the immature drug metabolism of the newborn may result in a prolonged effect of sedation. A more ideal solution to this problem is to use a form of synchronized ventilation that does not compete with the patient’s own breathing pattern. Most of these systems have been adapted from designs incorporated into adult ventilators and they include synchronous intermittent mandatory ventilation (SIMV), pressure support ventilation, volume support ventilation and proportional assist ventilation (PAV). Most experience in neonatal intensive care has been with the SIMV mode, with which the ventilator senses either airway ﬂow or pressure and the set rate or mandatory breaths from the ventilator are triggered so they do not interfere with the expiratory phase of respiration. There are an increasing number of studies that have compared synchronized ventilation with conventional intermittent mandatory ventilation (IMV) in neonatal respiratory failure. Jarreau et al.6 have shown that patient triggering decreased the work of breathing in neonates compared with IMV and Donn et al.7 showed that ﬂow synchronization was associated with a shorter time to extubation and decreased patient charges compared with IMV in a randomized prospective trial. Other studies have compared SIMV with conventional IMV in newborn infants. Bernstein et al.8 found increased and more consistent tidal volumes were associated with the use of SIMV. In a large multicenter randomized, controlled trial which enrolled 327 term and preterm infants, SIMV and IMV were compared in terms of outcome (death or survival), need for supplemental oxygen at 28 days, incidence of intraventricular hemorrhage

Weaning from ventilation Weaning from mechanical ventilation has been considerably simpliﬁed by the widespread use of IMV and other forms of ventilatory-assist modes. With these systems the infant may take spontaneous breaths from a gas ﬂow provided either through a demand valve or from a separate spontaneous breathing circuit. In this manner the mandatory breaths are gradually reduced as spontaneous respiratory effort improves, until the infant is breathing entirely spontaneously through a constant positive airway pressure (CPAP) system. The pace of weaning depends on the type of surgery and any additional pathology within the lung, and is set by observing the spontaneous respiratory rate and the measured blood gas response to changes in ventilation settings. In order to tolerate the transition from CPAP to extubation, the infant should be on FiO2 0.4, PEEP 5 cmH2O, with normal blood gases. A more recent innovation has been the introduction of pressure support ventilation, with which each spontaneously initiated breath generates a positive pressure from the machine to a preset inspiratory level.10 This helps to overcome the ﬁxed resistance of small endotracheal tubes.

Hyperventilation and ventilator-associated lung injury Since the ﬁrst introduction of intubation and ventilation for the treatment of neonates with acute respiratory failure, the objective has been to adopt a pattern of ventilation designed to produce gas exchange within normal physiological parameters. Since the original description of the induction of a respiratory alkalosis to reverse ductal shunting in persistent pulmonary hypertension (PPHN),11 hyperventilation became one of the mainstays of treatment. Although there may be a shortterm beneﬁt from this approach, there have been no prospective trials that have shown an improved outcome with the use of hyperventilation. In addition, there is now increasing concern that this may result in serious adverse consequences. The high inﬂation pressures required to reduce the CO2 can frequently result in ventilator-induced injury to the lung, thereby compounding a pulmonary–vascular problem with a pulmonary– parenchymal one. There are numerous animal models of ventilator-induced lung injury where pulmonary edema, hyaline membrane formation and pulmonary epithelial

76 Postoperative management

cell injury can be produced in normal lungs with peak inﬂation pressures as low as 30 cmH2O. As few as six manual inﬂations using high pressure at the time of birth have been shown to induce lung injury in an animal model.12 Wung et al. in 1985 was the ﬁrst to suggest that PPHN could be treated effectively without the use of hyperventilation and showed excellent outcomes with pressure-limited ventilation and hypercarbia.13 This is true not only in the premature lung but also in the dysplastic lung of infants with CDH, which are equally vulnerable to injury.14 There are several series reporting improved survival using a pressure-limited strategy which does not use hyperventilation to treat ductal shunting.15–17 There is also increasing evidence that low PaCO2s may adversely affect cerebral blood ﬂow and injure the developing brain18 and may partly account for the alarmingly high incidence of neurosensory deafness seen in these infants.19–24 Conversely hypercarbia increases cerebral protection in experimental models of neonatal brain injury.18,25 The ﬁrst human randomized trial that addressed the issue of hypercarbia in neonates has shown a decrease in number of days on a ventilator and absence of adverse events when permissive hypercapnia was compared with the conventional approach.26 Finally, in terms of avoidance of ventilator-associated lung injury, there is increasing evidence that the use of nasal CPAP together with early intervention with surfactant improves outcome in premature infants with moderately severe forms of IRDS.27–29

ACUTE HYPOXIC RESPIRATORY FAILURE IN THE NEWBORN: ALTERNATIVE THERAPIES A number of innovative techniques have recently been introduced into the management of acute respiratory failure, which include high-frequency ventilation, inhaled nitric oxide (iNO), and, if all else fails, ECMO. It is very likely that a signiﬁcant number of these therapies are being resorted to as rescue therapy from ventilatorinduced injury. This speculation is supported by the ﬁgures from the Extracorporeal Life Support Organisation (ELSO) registry which show the annual number of cases is actually falling for the ﬁrst time since neonatal ECMO was ﬁrst introduced in the late 1970s. It is likely that we will recognize that the single most important advance in ventilator management will be the recognition that the solution is part of the problem and that the ventilator must adapt to the underlying pathophysiology of the lung rather than to outmoded physiological imperatives.

High-frequency oscillatory ventilation One of the prinicipal strategies for the prevention of ventilator-associated lung injury is the use of HFOV.

This has been tested in a large number of randomized, clinical trials in preterm infants. Although the original National Institute of Health (NIH) study30 suggested that there was an increased incidence of intraventricular hemorrhage associated with its use, subsequent trials have led to a general acceptance that it is a safe and effective form of ventilation without there being any clear demonstrable beneﬁt in terms of increased survival and decreased incidence of chronic lung disease.31–36 This may be because the lung recruitment strategies (the open lung approach) were not aggressive enough or introduced early enough. Most of the protocols in neonatal trials have used levels of mean airway pressure (MAP) of 1–2 cmH2O above that of conventional mechanical ventilation (CMV) increased in small increments. The PROVO trial in 1996,37 which was an early intervention study and used a clearly deﬁned lung recruitment protocol with all patients receiving surfactant, was the ﬁrst to show a reduction in chronic lung disease with HFOV (24 vs 44%), less surfactant usage and decreased hospital stays. However, the rates of chronic lung disease in this study do not compare favorably with a Japanese HFOV study published in 1993,35 in which the rates were 9% and 13%, respectively. This highlights the problem of comparing different modes of ventilation in small randomized studies in which an optimal ‘open lung’ approach with HFOV is compared to a conventional technique where little attempt was made to use a lung recruitment strategy. In addition, no study has compared HFOV with a conventional ventilation approach that uses an optimal lung-recruitment strategy. When this has been done in experimental animals HFOV have been shown to be equally effective in opening the lung.38,39 It should also be emphasized that surfactant-replacement therapy has made a major impact on the mortality rate from neonatal lung disease. Clearly, if one is to use HFOV, early intervention before the lung sustains signiﬁcant damage is key and has been demonstrated by the excellent results published by Rimensberger et al,40 in which premature infants at risk from IRDS were placed on HFOV in the delivery suite. The incidence of chronic lung disease, as deﬁned as oxygen dependency at 36 weeks’ postgestational age, was zero compared to 34% in historical controls. The optimal recruitment strategy also needs to be determined. Copying the recruitment maneuvers (30 cmH2O for 15 seconds) used in the experimental lung lavage model is frequently insufﬁcient to achieve optimal recruitment strategy in premature infants. Thome et al 41 has shown that lung volume recruitment on HFOV is both time and pressure dependent in these patients. He was able to show that stabilization of mean lung volume after modiﬁcation of mean airway pressure took 2–25 minutes (median 9 minutes) in premature infants. HFOV has also proved effective in the management of term and near-term infants with PPHN, meconium aspiration and in preoperative stabilization of infants with CDH.31,42–44

Acute hypoxic respiratory failure in the newborn: alternative therapies 77

High-frequency jet ventilation High-frequency jet ventilation (HFJV) was ﬁrst developed in clinical anesthesia to provide small tidal volume ventilation for procedures involving the larynx and tracheobronchial tree where the ability to achieve a normal CO2 with low airway pressures provided ideal operating conditions. Although HFJV and HFOV operate on the same physiological principles of very small tidal volumes delivered at high rates, they should not be considered as merely two variations on the same theme. HFJV uses a high-pressure gas source to deliver small tidal volumes at frequencies of 1–5 Hz. Apart from the slower rates used in HFJV, the other major difference is that expiration is passive in the former while it is active in HFOV. The published experience with jet ventilation in acute hypoxemic respiratory failure (AHRF) is considerably less than oscillation and until recently only documented its use as rescue therapy in patients with either hypoxemia despite high PEEP or an established air leak. The rationale for the switch is usually the avoidance of further barotrauma by the use of smaller tidal volumes while maintaining a high mean airway pressure, but with lower peak airway pressures. Improvements in oxygenation can be obtained by driving up the MAP but this usually involves some compromise to cardiovascular function because of the transmitted pressure. A randomized, controlled clinical trial of HFJV in neonates with pulmonary interstitial emphysema (PIE) has shown an improvement in PIE and lower mortality rate in infants treated with HFJV compared to conventional ventilation.45 In the past 2 years, several prospective randomized trials have compared HFJV in both premature and term infants with AHRF.46–48 The two studies on premature infants showed conﬂicting results. Keszler et al.46 found better pulmonary outcomes in patients randomized to HFJV without a difference in survival rate while Wiswell48 found no difference in pulmonary outcomes but an increased risk of death and intraventricular hemorrhage associated with the use of HFJV. Engle et al.,47 in a randomized trial in term and near-term infants found improved oxygenation without any difference in survival rate. There are some technical safety concerns about the adequacy of humidiﬁcation in this system as well as reported cases of tracheal damage (necrotizing tracheobronchitis) in severely ill newborn infants. In addition, the airway pressures measured from the catheter within the trachea during HFJV probably represent a serious underestimate of true MAP because of the Bernoulli effect and consequently there is likely to be a signiﬁcant amount of auto-PEEP present.

Inhaled nitric oxide As well as having a key role in the modulation of vascular tone, exogenously administered NO has been shown to

be a highly selective pulmonary vasodilator. When administered by inhalation, NO diffuses rapidly from the alveolus into the endothelial cell and the vascular smooth muscle, where it stimulates guanylate cyclase to produce cGMP. The systemic nitrodilators currently in clinical use work by a similar mechanism but their pulmonary vasodilator effects cannot be separated from the systemic effects. In the case of inhaled nitric oxide (iNO), the vasodilatory properties are conﬁned to the pulmonary circulation because the marked afﬁnity of NO for the hemmoiety of hemoglobin results in its rapid binding and inactivation as soon as it crosses the alveolar capillary membrane, which explains its highly selective effect on the pulmonary vascular bed. A series of randomized, controlled trials (RCTs) have shown that iNO improves oxygenation49–55 and decreases the need for ECMO56–58 in term and near-term infants with PPHN. Although the response may be very dramatic, by no means do all infants respond well to it. This may reﬂect the fact that respiratory failure in this group of patients is not always a single disease entity and individual responses will vary according to the underlying pulmonary pathophysiology. Those infants with pure right-to-left ductal shunting and little parenchymal lung disease would be expected to respond best, while the infant with extensive pulmonary parenchymal disease as a cause of their hypoxemia (e.g. in meconium aspiration) may have little response. Although patients with alveolar capillary dysplasia have a dramatic response, the outcome is always fatal.59 An interesting alternative approach to iNO is to enhance the effect of endogenous production of NO in the vascular endothelium by blocking the inactivation of cGMP by phosphodiesterase inhibition. Two phosphodiesterase inhibitors, dipyridamole and zaprinast, have been shown to decrease pulmonary vascular tone in newborn animal models of pulmonary hypertension,60,61 and both dipyridamole and sildenaﬁl have been successfully used to treat the rebound pulmonary hypertension associated with withdrawal of iNO.62–64 The combination of HFOV and iNO together has proved particularly effective in one RCT.55

Surfactant-replacement therapy Probably the most important advance in neonatal medicine in the past 20 years has been the introduction of surfactant-replacement therapy for the treatment of lung disease of prematurity. This has resulted in a reduction in neonatal mortality without a signiﬁcant impact on the incidence of chronic lung disease.65 This may be because it has not been used with an optimal ventilation strategy that minimizes ongoing lung injury. Also, there are important differences between synthetic and natural surfactants, the latter having surfactant proteins which may have important anti-inﬂammatory

78 Postoperative management

properties. In term and near-term infants the situation is less clear cut. These infants are not surfactant deﬁcient but it may be inactivated by lung injury. Human studies have shown that the use of surfactant replacement therapy in this patient population is associated with decreased need for ECMO.66

Non-invasive ventilation An important advance in the management of respiratory failure in the newborn has been the increasingly widespread use of non-invasive ventilation either in the form of a nasal mask or cannulae. The high gas ﬂow used in this system means that airway pressure remains positive throughout both the inspiratory and expiratory cycle. Functional residual capacity (FRC) is maintained, decreasing the work of breathing and preventing lung collapse. There is an additional potential advantage in that avoiding invasion of the airway reduces the risk of nosocomial lung infections. The system has proved effective in the treatment of lung disease of prematurity both as a primary mode of therapy and as a method of supporting infants after extubation.27–29, 67–70

OVERVIEW A large number of highly innovative therapies have been introduced into the management of neonates with acute respiratory failure in the past few years. Many of these have shown beneﬁt in terms of improvement in physiological parameters without having a signiﬁcant impact on overall mortality, possibly partly due to the fact that, in an age where neonatal mortality is at a low level, many of the studies are underpowered to be able to show a difference.71 When all else fails, we still have the safety net of ECMO therapy to fall back on. Most tertiary care neonatal centers are now reporting a decrease in ECMO usage by 50% or more and these numbers are conﬁrmed by data from the ELSO Registry. The economic impact from this is that hospital charges for neonates with acute respiratory failure who previously required ECMO therapy have now been reduced by 50% or more.72,73 Although this may seem to indicate signiﬁcant progress in this area, the proliferation of these innovative technologies outside the tertiary referral areas means that when these treatments fail, sicker infants are being referred to the ECMO centers for rescue therapy, a reality that needs to be factored in when evaluating these therapies.

improvement in survival seen over the past few years.15–17,74 Newborn infants presenting with this anomaly have a mixture of pulmonary hypolasia, i.e. reduced alveolar number, as well as pulmonary vascular disease consisting of a reduced pulmonary vascular bed and a reactive and potentially reversible component due to the increased smooth muscle in the small pulmonary arterioles. The dysplastic lungs of these infants are highly susceptible to pulmonary barotrauma caused by high peak inﬂation pressures. The end result is hyaline membrane formation and pulmonary alveolar hemorrhage.14 Improved survival has been noted in several centers where the focus has been on the use of low peak airway pressures with less emphasis paid to treatment of right-to-left shunting through the ductus arteriosus and PFO. Attempts to reverse this by inducing alkalosis with hyperventilation will only cause pulmonary barotrauma. Therefore the focus should be on maintaining a pre-ductal SaO2 greater than 90% and not treating right and left shunting at the ductal level with hyperventilation. The objective for mechanical ventilation should be to maintain the PIP at <25 cmH2O without necessarily maintaining a normal PaCO2. It is our practice in this center to switch to HFOV if the PIP is above 25 cmH2O on conventional ventilation as this is a less injurious mode of ventilation. The strategy with HFOV in CDH is very different to that used in other forms of neonatal lung disease. In this instance the lung is hypoplastic and not recruitable and therefore we use a mean airway pressure of no more than 14–16 cmH2O. With this approach we ﬁnd that HFOV is a very efﬁcient way of maintaining normal PaCO2 levels without inﬂicting further injury on the lung. Survival rates of >80% and decreased ECMO use have been reported by centers using this approach.75 Other centers have chosen to use other non-conventional ventilator strategies such as tracheal gas insufﬂation (TGI)76 which uses a very high gas ﬂow delivered through an intratracheal catheter. It is also our practice to obtain a cardiac echo on all CDH infants to rule out structural heart disease and to assess the degree of right-to-left shunting. In most infants the right ventricular pressure is elevated with either bidirectional shunting, indicating that right ventricular pressure is systemic, or pure right-to-left shunting in which case it is supra-systemic. INO has been used extensively in CDH, although it does not seem to be as effective as in other forms of PPHN.77 Other adjuncts to positive pressure ventilation used in this disease include surfactant therapy and prenatal steroids, although neither of these therapies have been of proven beneﬁt in prospective trials.

Ventilatory management of congenital diaphragmatic hernia

POSTOPERATIVE SEDATION AND ANALGESIA

The pre- and postoperative ventilator management of infants with CDH is one of the key factors in the

One of the most important advances in postoperative care in the past decade has been a far greater under-

Cardiovascular homeostasis in the newborn 79

standing of the need for analgesia and sedation in newborns who have had major surgery. There is now strong evidence that neonates exposed to multiple painful procedures either during intrauterine or early in extrauterine life exhibit acute physiological responses which are detrimental.78–80 This has been associated with an increased physiological stress response resulting in hypertension and an increased incidence of intraventricular hemorrhage in preterm newborns. The increased hormonal and metabolic responses to major operations and to painful stimuli associated with procedures in the ICU also have the potential to increase the incidence of morbidity and mortality.81–83 Given the limited endogenous reserves of carbohydrates, proteins and fats in the newborn, it is perhaps not surprising that in the stressed state these reserves are rapidly exhausted. There is also evidence that failure to blunt painful stimuli in the developing nervous system results in changes within the spinal cord with altered long-term sensitivity to pain.84 There are now a number of studies which show that the use of narcotics and anaesthetic drugs can blunt these responses and bring about a decrease in morbidity associated with both surgical procedures and painful interventions in the ICU.85,86 These include reductions in catecholamine levels, lower airway pressures during mechanical ventilation and less acute rises in blood pressure and pulmonary artery pressure.87–89 The most commonly used narcotic agents in neonatal practice are i.v. morphine or fentanyl infusions. These are commonly combined with i.v. benzodiazepines usually in the form of midazalam or lorazepam.

CARDIOVASCULAR HOMEOSTASIS IN THE NEWBORN Cardiac output is a product of heart rate times stroke volume with increases in output dependent on the ability to increase heart rate or vary stroke volume. Stroke volume in turn is inﬂuenced by three inter-related factors: 1 Pre-load or venous return that determines enddiastolic volume 2 After-load or the impedance to left or right ventricular output 3 Contractility or the contractile state of the myocardial muscle, which in turn depends on its end-diastolic ﬁber length and the speed of shortening for a given load. In the newborn, where the myocardium is relatively immature, there is little capacity to increase stroke volume. Therefore, cardiac output is to a large part rate dependent and the neonate will primarily compensate for a fall in output by increasing its heart rate. Blood

pressure reﬂects cardiac output poorly in this age group as this is maintained at the expense of increasing heart and vasoconstriction, until a sudden decompensation and hypotension occurs. In situations where hypovolemia is the cause of low output, a reduction in elevated heart rate is the best guide to the adequacy of volume replacement. Cardiac output may be directly measured in the newborn by using either the thermo or dye dilution, but both techniques require invasive monitoring. For most practical purposes, the combination of heart rate, blood pressure, urine output and peripheral perfusion provide a reasonably accurate estimation of cardiac output. This can be combined with serum lactate and mixed venous oxygen saturation (SvO2) drawn from a central venous line in more critically ill newborns. In these patients measurement of central venous pressure (CVP) is particularly useful in optimizing cardiac output by the adjustment of right atrial ﬁlling pressures. Central venous access may be established through the internal jugular, subclavian or femoral veins in the neonate; the complication rate associated with the different approaches is related to the experience and skill of the operator rather than the approach chosen.90,91 The cannulation of the radial, posterior tibial, dorsalis pedis or femoral arteries with a 22 or 24 gauge cannula will provide a reliable direct arterial pressure measurement together with access to sampling for blood gas, electrolytes and acid–base measurement. Umbilical arterial lines are satisfactory for short-term use only due to the potential to cause renal or gut ischemia if not positioned correctly. The initial approach to the infant with a low CO, indicated by tachycardia, vasoconstriction, oliguria and hypotension, is to increase pre-load by volume expansion with 10–20 ml/kg of crystalloid or albumin and then reassess the effect on the measured parameters assessed. The CVP measurement may prove very useful in this context, as repeat volume increments may be used to increase the ﬁlling pressures to as high as 12–14 mmHg in order to increase output (Fig. 7.1). Failure to raise output by increasing pre-load is an indication of an attempt to decrease after-load or increase contractility by the use of vasoactive drugs.

USE OF VASOACTIVE DRUG THERAPY In order that the correct therapeutic option is chosen when dealing with a low cardiac output state in the newborn, it is important to know what effects vasodilators and inotropes have on the circulation in this situation. Since the objective is improved oxygen delivery at tissue level, changes in heart rate, ﬁlling pressures and afterload, which in turn profoundly affect myocardial work and therefore oxygen consumption, should always be considered when electing to use a particular drug. While one could use a vasoconstricting agent to maintain

80 Postoperative management

Figure 7.1 Effect of increasing right atrial ﬁlling pressures, vasodilator drugs and inotropes on cardiac output (Frank–Starling curve)

blood pressure in an infant in low cardiac output, this would be unsuccessful in most circumstances because this could only be achieved at the expense of a greatly increased after-load, decreased tissue perfusion and oxygen delivery. The aim must be to move the depressed myocardial function curve upwards and to the left as depicted in the Starling curve (Fig. 7.1), either by increasing contractility or by reducing pre-load or afterload. In the case of contractility, this can be achieved by using an inotrope which may cause signiﬁcant increases in heart rate, which the neonate, with its relative freedom from ischemia, is able to tolerate reasonably well. The ideal vasoactive drug would be that which increased contractility and decreased after-load with no change in heart rate, while at the same time maintaining renal and splanchnic perfusion.92

INOTROPES Dopamine Dopamine is an endogenous precursor of norepinephrine with sympathomimetic properties. It has been shown to be useful in the management of shock associated with cardiovascular surgery, sepsis and severe asphyxia with demonstrable inotropic, vasoconstricting and renal vasodilating effects. It has a well-documented range of activity with selective vasodilatory effects on cerebral, mesenteric, coronary and renal vascular beds through stimulation of dopaminergic receptors in a dose range of 0.5–3.0 μg/kg/minute. As the dose increases from 3–10

μg/kg/minute, it directly stimulates β1 receptors of the myocardium causing a rise in blood pressure, CO and heart rate, in addition to indirect stimulation through the release of norepinephrine. As the dose increases from 10–20 μg/kg/minute, progressive α adrenergic stimulation negates the effect of β stimulation, causing a rise in systemic vascular resistance (SVR) and renal vasoconstriction. Dopamine has been shown to be an effective inotrope following cardiopulmonary bypass in children.93,94 Studies on the effective dose in neonates have generally been anecdotal and contradictory.95–99 Evidence has been presented for the need for high-dose dopamine to achieve a measurable clinical effect, yet others have shown demonstrable effects at low doses. On balance it would seem demonstrable clinical beneﬁt can be achieved with dopamine using modest doses (<8 μg/kg/min), with a titratible dose-response increase in effect and little likelihood of side effects. Dopamine can be expected to increase MAP, improve echocardiographically determined indices of ventricular function, and improve urine output with a low incidence of side effects at doses <10 μg/kg/minute. Its effect on ventricular ﬁlling pressures remains uncertain. Dopamine’s effect on systemic vascular resistance appears secondary to the effect on CO at doses <10 μg/kg/minute, where there will be a drop in SVR. At doses above 20 μg/kg/minute there will be an increase in SVR as the effects of dopamine become predominant (see Table 7.1).

Dobutamine Dobutamine is a synthetic analogue of dopamine with predominately β1 effect and relatively weak β2 and α receptor-stimulating activity. In addition, it does not seem to lead to indirect stimulation through release of norepinephrine. In adults at doses of 5–15 μg/kg/minute, it has been shown to increase contractility, CO and MAP, improve tissue perfusion, and unlike dopamine, results in a decrease in cardiac ﬁlling pressures. It has consequently found much favor in the treatment of low cardiac output states in adults with ischemic heart disease. Pulmonic and systemic vascular resistances uniformly fall. It therefore can be described as having pre- and after-load-reducing properties in addition to its inotropic effect. Experience of its use in children generally parallels that of the literature on adult use with an increase in cardiac index and MAP in a dose-dependent fashion with doses from 2–7.5 μg/kg/minute.100–102 Neonatal experience has usually been in the treatment of PPHN, but there is a tendency for signiﬁcant increases in heart rate as well as cardiac output to occur in small infants. As there is no selective renal vasodilating effect, there would appear to be little advantage to using the drug in preference to dopamine in the newborn.

Vasodilators 81

Epinephrine Epinephrine is the ﬁnal product of catecholamine synthesis and has been used in emergency resuscitation for a number of years. It stimulates both α and β receptors in a dose-dependent fashion; in low doses (0.05–0.1 μg/kg/minute) it affects predominately β receptors, resulting in inotropic and chronotropic effects. In higher doses (0.2–1.0 μg/kg/minute) it is a potent vasoconstrictor, the α stimulation increasing MAP and diastolic pressure. This latter effect is the key to its effectiveness in resuscitation, where it can be given as an i.v. bolus, endotracheally, or rarely, intracardiac injection can be used. Epinephrine is a potent inotropic agent for the newborn myocardium; its major disadvantages are tachycardia and an increased SVR. Renal vasoconstriction can impair renal function and mesenteric vasoconstriction may cause bowel ischemia. Although epinephrine is not commonly used as a ﬁrst-choice inotropic agent, there are instances where it can be very useful when the more commonly used inotropes fail to produce an effect. This is most likely due to overwhelming disease and in this instance we ﬁnd that increasing the dopamine to >30 μg/kg/minute rarely produces any improvement in output. In such instances we would commence an adrenaline infusion at 0.05 μg/kg/minute, increasing to 1 μg/kg/minute according to response, frequently combined with vasodilator therapy.

appropriate use of vasodilators will shift the heart to a more favorable Starling curve, so that there is an improved SV for a given ﬁlling pressure (Fig. 7.1). 3 A drop in ﬁlling pressure with preservation of MAP will improve coronary perfusion and thereby improved load tolerance 4 Decreased end-diastolic volume may favorably alter the compliance characteristics of the heart with less pronounced limitation to ﬁlling exerted by either ventricle on the other and on both ventricles by the pericardium. With the newborn infant functioning at a high level of performance and limited reserve capacities as described earlier, acute pre-load or after-load increase, in addition to that imposed by postnatal adaptation, may be particularly harmful. Volume loads from left-to-right shunts, excessive volume administration or vasoconstriction from pharmacologic therapy may all lead to profound cardiovascular decompensation. A number of investigators have documented success with after-load reduction in conditions where inotropes have failed or have described additional beneﬁt in function with the addition of vasodilators to inotropic therapy.103–105

Sodium nitroprusside

Norepinephrine is a potent vasoconstrictor with predominant α agonist effects. As such it is effective in raising blood pressure at the expense of raising after-load on the heart and decreasing peripheral perfusion. It therefore has no place in the routine treatment of low cardiac output. However, in vasodilated septic shock, as seen in Gram-negative sepsis, it can be effective in restoring perfusion to vital organs, the unwanted effects such as decreased splanchnic and renal perfusion notwithstanding. Its potent vasoconstrictor properties require it to be infused via a central vein to prevent skin ischemia and necrosis. The usual dose range is 0.01–0.1 μg/kg/minute.

Sodium nitroprusside (SNP) is a direct-acting arteriolar dilator that reduces SVR by predominantly affecting resistance vessels and in addition reduces ﬁlling pressures by increasing venous capacitance. It is given by continuous i.v. infusion due to its short half-life of 1–2 minutes and is light sensitive. Its effect reverses within minutes of discontinuation. It is metabolized to thiocyanate, which is excreted by the kidneys. Cyanide toxicity can potentially occur if conversion to thiocyanate is impaired with formation of cyanmethemoglobin and reduced red cell oxygen-carrying capacity. Since its predominant effect is on arteriolar resistance vessels and left ventricular (LV) after-load, there may be a reduction in MAP. The dose ranges from 0.5–7 μg/kg/minute. SNP is frequently combined with inotropic drugs, especially where high-dose dopamine or adrenaline infusions are being used, in order to counteract the unwanted vasoconstrictor effects.

VASODILATORS

Phosphodiesterase inhibitors

Norepinephrine

Vasodilators are thought to be of beneﬁt in low cardiac output states through a number of mechanisms: 1 By decreasing impedance to ventricular emptying, resulting in increased stroke volume and decreased end-systolic volume 2 Increasing venous capacitance decreases venous return and therefore end-diastolic pressure;

A more recent innovation in pharmacotherapy for the management of low cardiac output has been the introduction of the phosphodiesterase inhibitors which act by blocking the breakdown of cGMP. This represents an alternative pathway for increasing myocardial performance rather than the traditional route via catecholamines, which can lose their effectiveness due to downregulation of β receptor activity. They also have

82 Postoperative management

important vasodilator properties. There are several studies of the effective use of phosphodiesterase inhibitors in the treatment of low cardiac output following open heart surgery in infants.106–110 The most commonly used drug in this class is milrinone in a dose of 0.33–1 μg/kg/minute. The drug has a long half-life and its metabolism is prolonged in hepatic failure.111

FLUID MANAGEMENT AND RENAL FUNCTION Preserving normal ﬂuid and electrolyte homeostasis is a more signiﬁcant problem in the neonate compared with the older child, as the renal system is somewhat immature in the newborn. The glomerular ﬁltration rate (GFR) is lower in the preterm infant compared with the term infant. However, the term newborn is capable of producing a dilute urine (30–50 mOsm/L) and will maintain a positive sodium balance with normal levels of sodium intake.112 The kidney in the preterm infant, however, is inefﬁcient at conserving sodium. On the other hand, there is also resistance to the effects of ADH and the infant can only concentrate urine to 400–600 mOsm/L. The preterm neonate also has an increase in extracellular ﬂuid volume (ECFV) compared to the term infant and this tends to rapidly expand immediately after birth.113 Fluid balance in the neonate depends on the balance between ﬂuid loss (evaporative, renal and gastrointestinal tract (GIT)) and the intake required for maintaining normal homeostasis organ function and growth. When calculating normal ﬂuid requirements in the newborn, all these factors need to be taken into consideration. Full maintenance ﬂuid requirements for the non-ventilated term newborn start at 60 ml/kg/24 hours in the ﬁrst day of life and increase to 100–150 ml/kg/24 hours by 5–7 days of life in the form of a dextrose/saline solution. Losses from the gastrointestinal (GI) tract due to nasogastric suction should be replaced with normal saline. The stimulus of surgery, the use of anesthetic agents and narcotic drugs, positive pressure ventilation and CPAP will all result in inhibition of ADH secretion and the failure to excrete a dilute urine. The frequent use of hypotonic i.v. solutions results in the accumulation of electrolyte-free water and hyponatremia. In addition, IPPV with humidiﬁcation of the respiratory tract eliminates not only evaporative losses from the respiratory tract but frequently will result in a net ﬂuid gain. For this reason it is common practice to calculate the maintenance requirements for ﬂuid for an infant on a respirator as being 70% of normal requirements in order to prevent ﬂuid retention. A urine output of >1 ml/kg/hour is generally regarded as a manifestation of adequate renal function following surgical procedures in the newborn. However, a period of oliguria in the presence of normal renal function is

not uncommon in the immediate postoperative period, especially where positive pressure ventilation is being used. There is usually a spontaneous diuresis within the ﬁrst 3–5 days after birth but it should be remembered that 7% of normal infants will not pass urine in the ﬁrst 24 hours of life. Persistent oliguria or anuria on the other hand may be associated with renal failure due to either pre-renal, postrenal or intrinsic renal damage. Pre-renal failure is most frequently due to decreased renal plasma ﬂow associated with blood or ﬂuid loss or inadequate ﬂuid resuscitation preoperatively. A ﬂuid challenge of 20 ml/kg of isotonic ﬂuid or 5% albumin will frequently result in restoration of urine output. Although critically ill newborns are frequently hypoalbuminemic and the maintenance of colloid osmotic pressure would seem to be an important factor in decreasing tissue edema, there is some dispute as to the efﬁcacy of albumin compared with crystalloid solutions.114–117 A further ﬂuid bolus/boluses with or without a diuretic may be tried depending on CVP measurement if there is no initial response. Intrinsic renal failure is a more serious complication and more difﬁcult to manage. Causes include congenitally abnormal kidneys (cystic or dysplastic), prolonged intraoperative renal ischemia or vascular abnormalities of the kidney (arterial thrombosis associated with umbilical artery catheters, renal venous thrombosis secondary to dehydration and prolonged hypotension due to sepsis.118 Drugs such as indomethicin and aminoglycoside antibiotics can also cause intrinsic renal damage. This form of renal failure can be differentiated from pre-renal etiology by the ﬁnding of red cells, protein and casts in the urine in association with high urinary sodium losses. Management of acute renal failure consists of eliminating the underlying cause if possible, restricting ﬂuids to urine output plus insensible losses and treating hyperkalemia with dextrose infusions and potassium exchange resins. This is only likely to be a short-term solution as the ﬂuid restriction will also entail restricted calorie intake and a cycle of catabolism with protein breakdown and weight loss. Early institution of renal replacement therapy (RRT) is important in interrupting this process. Peritoneal dialysis is an effective method of removing ﬂuid and potassium in the newborn with persistent renal failure, but may not be feasible after major intraabdominal surgery. Various solutions with differing glucose concentrations are used depending on the requirement for ﬂuid removal. Dialysis is unlikely to be effective unless ﬁll volumes of 10–20 ml/kg can be tolerated without hemodynamic compromise. Efﬁcacy also depends on perfusion of the mesentry and works less well in shocked states. The application of continuous veno-venous hemoﬁltration in small infants has demonstrated that large amounts of ﬂuid can be removed while at the same time maintaining a high calorie intake with

Postoperative hemorrhage 83

i.v. alimentation. Although this requires the insertion of a large double lumen catheter into a central vein and the use of heparin, there are several published case series with good outcomes.119–122

TEMPERATURE REGULATION AND METABOLISM IN THE NEONATE Temperature To maintain a normal body temperature, the neonate has to balance heat loss with heat production. With a large body surface area to body weight ratio, the neonate tends to lose heat rapidly by: 1 Conduction due to direct contact with cold surfaces 2 Convection by the cooling effects of air currents on exposed skin 3 Radiation to nearby objects such as an incubator wall 4 Evaporation of ﬂuid from skin and respiratory tract. Failure to eliminate areas of heat loss result in the infant attempting to raise its heat production by metabolism of brown fat stores and glucose. The preterm infant is poikilothermic and will not defend its body temperature and is therefore particularly vulnerable to the effects of cold injury. These include acidosis, hypoglycemia, increased O2 consumption and weight loss. It is therefore of great importance that the critically ill neonate be protected from the effects of cold stress following surgery. Nursing the infant in an incubator with an internal temperature of 32–36°C will eliminate conductive and convective heat losses. Radiation can be reduced by using double-glazed incubators and evaporative heat losses reduced by humidiﬁcation. Incubators do however limit access to the critically ill infant whereas the radiant warmer bed, while less efﬁcient in conserving heat losses, does provide excellent access. Evaporative and convective heat loss may be reduced with this system by covering the infant with plastic cling ﬁlm stretched between the side walls of the warmer bed.123

METABOLISM IN THE NEWBORN Glucose and calcium Glucose metabolism is not well developed in the newborn period and the critically ill neonate is liable to develop hypoglycemia at times of acute stress, particularly the preterm infant. This may be as a result of: 1 Diminished glycogen stores (inadequate stores in the premature infant or depletion from catecholamine-

stimulated glycogen breakdown release in perinatal stress) 2 Hyperinsulinemia in infants of diabetic mothers 3 Inadequate glucose production in small for gestational age (SGA) infants. Failure to recognize and correct neonatal hypoglycemia will result in seizures and brain damage. In order to prevent this it is recommended that a minimum of 10% dextrose with saline be used in all maintenance ﬂuid infusions in the newborn after surgery. In addition the blood sugar should be regularly measured to prevent hypoglycemia (<1.1 mmol/L in the preterm and <1.7 mmol in the term infant). Persistent hypoglycemia may require further boluses and an increased infusion to 15% dextrose. Where the hypoglycemia is due to delay in glucose release from glycogen stores in the liver, the administration of glucagon 300 μg/kg or steroid may result in a rise in blood sugar.124 Infants receiving highconcentration dextrose infusions have increased blood insulin levels. Abrupt discontinuation of the infusion will result in rebound hypoglycemia and therefore the patient should be weaned gradually. Hypocalcemia is common in the newborn period, but measurements of the total serum calcium do not accurately reﬂect the level of ionized calcium (Ca++) in the blood. Levels of total serum Ca above 1.75 mmol/L rarely cause problems but levels below 1.5 mmol/L may result in seizures, apnea and low cardiac output. Critically ill infants in the ﬁrst 24–48 hours of life, infants of diabetic mothers and newborns who have undergone large volume blood transfusions are all at risk for developing hypocalcemia. Calcium infusions should be given preferentially through central venous lines because of the tendency to cause intense venous irritation and damage to skin.

POSTOPERATIVE HEMORRHAGE The coagulation mechanism in the newborn infant is less well developed than in the older child and adult. Hepatic immaturity leads to decreased levels of vitamin K and a reduction of the vitamin K-dependent coagulation factors (II, VII, IX, X), particularly in the preterm infant. Reductions in these factors do not normally result in impaired hemostasis in the healthy term infant as levels of only 20–30% of most coagulation factors are necessary for normal clot formation. Although the most common form of postoperative bleeding is ‘surgical’ in nature as a result of hemorrhage from small vessels, it may be compounded by a failure of normal coagulation mechanisms, especially in the sick preterm neonate. Normal clot formation in the newborn may also be somewhat inhibited by the fact that although the platelet numbers may be normal, there is frequently some degree of platelet dysfunction, as they demonstrate abnormal

84 Postoperative management

membrane activity and diminished thromboxane A2 activity. In addition, continuous hemorrhage with blood replacement may result in a consumptive coagulopathy due to depletion of clotting factors and platelets.125,126 The clinical approach to the diagnosis and management of the newborn should be based on differentiating between a surgical correctable bleeding problem and an underlying coagulation problem. In the case of nonsurgical bleeding, the PT, PTT, platelet count, ﬁbrinogen level and a measurement of d-dimers will differentiate between a disorder due to inadequate coagulative factor levels and disseminated intravascular coagulation (DIC). The infant with excessive bleeding due to DIC frequently is severely ill with an underlying sepsis, asphyxia or shock. Excessive oozing from puncture sites, gastrointestinal and petechiae are frequently seen. The PT and PTT are prolonged, the platelet count reduced and d-dimers are high. The premature infant is at high risk of developing severe intraventricular hemorrhage secondary to disorders of coagulation. The main objective in treatment is to correct the underlying cause and replace the coagulation factors with fresh frozen plasma (FFP) and platelet transfusions. Heparin was formerly advocated in the treatment of DIC, but has not been shown to be effective. More recently the use of exchange transfusion to remove toxins, d-dimers and provide coagulation factors has become widely accepted although randomized controlled trials have not been shown to decrease mortality.

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causes pulmonary vasodilation in the ovine fetus. Am J Physiol 1995; 269(2 Pt 2):H473–9. 61. Thusu KG, Morin FCr, Russell JA, Steinhorn RH. The cGMP phosphodiesterase inhibitor zaprinast enhances the effect of nitric oxide. Am J Respir Crit Care Med 1995; 152(5 Pt 1):1605–10. 62. Kinsella JP, Torielli F, Ziegler JW, Ivy DD, Abman SH. Dipyridamole augmentation of response to nitric oxide. Lancet 1995; 346:647–8. 63. Thebaud B, Saizou C, Farnoux C, Hartman JF, Mercier JC. Dypiridamole, a cGMP phosphodiesterase inhibitor, transiently improves the response to inhaled nitric oxide in two newborns with congenital diaphragmatic hernia. Intensive Care Med 1999; 25(3):300–3. 64. Atz AM, Wessel DL. Sildenaﬁl ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology 1999; 91(1):307–10. 65. Jobe AH. Pulmonary surfactant therapy. N Engl J Med 1993; 328(12):861–8. 66. Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel JH. Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. Survanta in Term Infants Study Group. J Pediatr 1998; 132(1):40–7. 67. Robertson NJ, Hamilton PA. Randomised trial of elective continuous positive airway pressure (CPAP) compared with rescue CPAP after extubation. Arch Dis Child Fetal Neonatal Ed 1998; 79(1):F58–60. 68. Davis P, Henderson-Smart D. Post-extubation prophylactic nasal continuous positive airway pressure in preterm infants: systematic review and meta-analysis. J Paediatr Child Health 1999; 35(4):367–71. 69. Dassieu G, Brochard L, Benani M, Avenel S, Danan C. Continuous tracheal gas insufﬂation in preterm infants with hyaline membrane disease. A prospective randomized trial. Am J Respir Crit Care Med 2000; 162(3 Pt 1):826–31. 70. Kamper J, Wulff K, Larsen C, Lindequist S. Early treatment with nasal continuous positive airway pressure in very low-birth-weight infants. Acta Paediatr 1993; 82(2):193–7. 71. Jobe A. Too many unvalidated new therapies to prevent chronic lung disease in preterm infants. J Pediatr 1998; 132(2):200–2. 72. Wilson JM, Bower LK, Thompson JE, Fauza DO, Fackler JC. ECMO in evolution: the impact of changing patient demographics and alternative therapies on ECMO. J Pediatr Surg 1996; 31(8):1116–22; discussion 1122–3. 73. Kennaugh JM, Kinsella JP, Abman SH, Hernandez JA, Moreland SG, Rosenberg AA. Impact of new treatments for neonatal pulmonary hypertension on extracorporeal membrane oxygenation use and outcome. J Perinatol 1997; 17(5):366–9. 74. Azarow K, Messineo A, Pearl R, Filler R, Barker G, Bohn D. Congenital diaphragmatic hernia—a tale of two cities: the Toronto experience. J Pediatr Surg 1997; 32(3):395–400.

References 87 75. Reyes C, Chang LK, Waffarn F, Mir H, Warden MJ, Sills J. Delayed repair of congenital diaphragmatic hernia with early high-frequency oscillatory ventilation during preoperative stabilization. J Pediatr Surg 1998; 33(7):1010–14; discussion 1014–16. 76. Wilson JM, Thompson JR, Schnitzer JJ, Bower LK, Lillehei CW, Perlman ND et al. Intratracheal pulmonary ventilation and congenital diaphragmatic hernia: a report of two cases. Journal of Pediatric Surgery 1993; 28(3):484–7. 77. Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Pediatrics 1997; 99(6):838–45. 78. Anand KJ. Neonatal stress responses to anesthesia and surgery. Clin Perinatol 1990; 17(1):207–14. 79. Anand KJ, Hansen DD, Hickey PR. Hormonal-metabolic stress responses in neonates undergoing cardiac surgery. Anesthesiology 1990; 73(4):661–70. 80. Anand KJ, Brown MJ, Causon RC, Christoﬁdes ND, Bloom SR, Aynsley-Green A. Can the human neonate mount an endocrine and metabolic response to surgery? J Pediatr Surg 1985; 20(1):41–8. 81. Pokela ML. Pain relief can reduce hypoxemia in distressed neonates during routine treatment procedures. Pediatrics 1994; 93(3):379–83. 82. Barker DP, Rutter N. Stress, severity of illness, and outcome in ventilated preterm infants. Arch Dis Child Fetal Neonatal Ed 1996; 75(3):F187–90. 83. Pokela ML. Effect of opioid-induced analgesia on betaendorphin, cortisol and glucose responses in neonates with cardiorespiratory problems. Biol Neonate 1993; 64(6):360–7. 84. Anand KJ. Pain, plasticity, and premature birth: a prescription for permanent suffering? Nat Med 2000; 6(9):971–3. 85. Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet 1987; 1(8524):62–6. 86. Anand KJ, Hickey PR. Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med 1992; 326(1):1–9. 87. Jacqz-Aigrain E, Wood C, Robieux I. Pharmacokinetics of midazolam in critically ill neonates. Eur J Clin Pharmacol 1990; 39(2):191–2. 88. Vacanti JP, Crone RK, Murphy JD, Smith SD, Black PR, Reid L et al. The pulmonary hemodynamic response to perioperative anesthesia in the treatment of high-risk infants with congenital diaphragmatic hernia. J Pediatr Surg 1984; 19(6):672–9. 89. Quinn MW, Wild J, Dean HG, Hartley R, Rushforth JA, Puntis JW et al. Randomised double-blind controlled trial of effect of morphine on catecholamine concentrations in ventilated pre-term babies. Lancet 1993; 342(8867):324–7.

90. Groff DB, Ahmed N. Subclavian vein catheterization in the infant. J Pediatr Surg 1974; 9(2):171–4. 91. Prince SR, Sullivan RL, Hackel A. Percutaneous catheterization of the internal jugular vein in infants and children. Anesthesiology 1976; 44(2):170–4. 92. Keeley SR, Bohn DJ. The use of inotropic and afterloadreducing agents in neonates. Clin Perinatol 1988; 15(3):467–89. 93. Driscoll DJ, Gillette PC, McNamara DG. The use of dopamine in children. J Pediatr 1978; 92(2):309–14. 94. Lang P, Williams RG, Norwood WI, Castaneda AR. The hemodynamic effects of dopamine in infants after corrective cardiac surgery. J Pediatr 1980; 96(4):630–4. 95. DiSessa TG, Leitner M, Ti CC, Gluck L, Coen R, Friedman WF. The cardiovascular effects of dopamine in the severely asphyxiated neonate. J Pediatr 1981; 99(5):772–6. 96. Padbury JF, Agata Y, Baylen BG, Ludlow JK, Polk DH, Habib DM et al. Pharmacokinetics of dopamine in critically ill newborn infants. J Pediatr 1990; 117(3):472–6. 97. Padbury JF. Neonatal dopamine pharmacodynamics: lessons from the bedside. J Pediatr 1998; 133(6):719–20. 98. Padbury JF, Agata Y, Baylen BG, Ludlow JK, Polk DH, Goldblatt E et al. Dopamine pharmacokinetics in critically ill newborn infants. J Pediatr 1987; 110(2):293–8. 99. Perez CA, Reimer JM, Schreiber MD, Warburton D, Gregory GA. Effect of high-dose dopamine on urine output in newborn infants. Crit Care Med 1986; 14(12):1045–9. 100. Perkin RM, Levin DL, Webb R, Aquino A, Reedy J. Dobutamine: a hemodynamic evaluation in children with shock. J Pediatr 1982; 100(6):977–83. 101. Driscoll DJ, Gillette PC, Duff DF, Nihill MR, Gutgesell HP, Vargo TA et al. Hemodynamic effects of dobutamine in children. Am J Cardiol 1979; 43(3):581–5. 102. Bohn DJ, Poirier CS, Edmonds JF, Barker GA. Hemodynamic effects of dobutamine after cardiopulmonary bypass in children. Crit Care Med 1980; 8(7):367–71. 103. Stephenson LW, Edmunds LH, Raphaely R, Morrison DF, Hoffman WS, Rubis LJ. Effects of nitroprusside and dopamine on pulmonary arterial vasculature in children after cardiac surgery. Circulation 1979; 60(2 Pt 2):104–10. 104. Butt W, Bohn D, Whyte H. Clinical experience with systemic vasodilator therapy in the newborn infant. Aust Paediatr J 1986; 22(2):117–20. 105. Benitz WE, Malachowski N, Cohen RS, Stevenson DK, Ariagno RL, Sunshine P. Use of sodium nitroprusside in neonates: efﬁcacy and safety. J Pediatr 1985; 106(1):102–10. 106. Chang AC, Atz AM, Wernovsky G, Burke RP, Wessel DL. Milrinone: systemic and pulmonary hemodynamic effects in neonates after cardiac surgery. Crit Care Med 1995; 23(11):1907–14. 107. Lawless S, Burckart G, Diven W, Thompson A, Siewers R. Amrinone in neonates and infants after cardiac surgery. Crit Care Med 1989; 17(8):751–4.

88 Postoperative management 108. Bailey JM, Miller BE, Kanter KR, Tosone SR, Tam VK. A comparison of the hemodynamic effects of amrinone and sodium nitroprusside in infants after cardiac surgery. Anesth Analg 1997; 84(2):294–8. 109. Ramamoorthy C, Anderson GD, Williams GD, Lynn AM. Pharmacokinetics and side effects of milrinone in infants and children after open heart surgery. Anesth Analg 1998; 86(2):283–9. 110. Reinoso-Barbero F, Garcia-Fernandez FJ, Diez-Labajo A, del Cerro MJ, Cordovilla G. Postoperative use of milrinone for Norwood procedure. Paediatr Anaesth 1996; 6(4):342–3. 111. Lindsay CA, Barton P, Lawless S, Kitchen L, Zorka A, Garcia J et al. Pharmacokinetics and pharmacodynamics of milrinone lactate in pediatric patients with septic shock. J Pediatr 1998; 132(2):329–34. 112. Simpson J, Stephenson T. Regulation of extracellular ﬂuid volume in neonates. Early Hum Dev 1993; 34(3):179–90. 113. Engle WD. Evaluation of renal function and acute renal failure in the neonate. Pediatr Clin North Am 1986; 33(1):129–51. 114. Greenough A. Use and misuse of albumin infusions in neonatal care. Eur J Pediatr 1998; 157(9):699–702. 115. So KW, Fok TF, Ng PC, Wong WW, Cheung KL. Randomised controlled trial of colloid or crystalloid in hypotensive preterm infants. Arch Dis Child Fetal Neonatal Ed 1997; 76(1):F43–6. 116. Kanarek KS, Williams PR, Blair C. Concurrent administration of albumin with total parenteral nutrition in sick newborn infants. J Parenter Enteral Nutr 1992; 16(1):49–53.

117. Greenough A, Emery E, Hird MF, Gamsu HR. Randomised controlled trial of albumin infusion in ill preterm infants. Eur J Pediatr 1993; 152(2):157–9. 118. Gouyon JB, Guignard JP. Management of acute renal failure in newborns. Pediatr Nephrol 2000; 14(10–11):1037–44. 119. Reeves JH, Butt WB, Sathe AS. A review of venovenous haemoﬁltration in seriously ill infants. J Paediatr Child Health 1994; 30(1):50–4. 120. Zobel G, Ring E, Kuttnig M, Grubbauer HM. Five years experience with continuous extracorporeal renal support in paediatric intensive care. Intensive Care Med 1991; 17(6):315–19. 121. Bambauer R, Jutzler GA, Philippi H, Jesberger H-J, Limbach H-G, Richter J et al. Hemoﬁltration and plasmapheresis in premature infants, 1988. 122. Bambauer R, Jutzler GA, Jesberger HJ, Lofﬂer G, Limbach HG, Graf N et al. Hemoﬁltration and plasmapheresis in newborns using a small blood pump system. ASAIO Trans 1989; 35(3):578–9. 123. Chahine AA, Ricketts RR. Resuscitation of the surgical neonate. Clin Perinatol 1999; 26(3):693–715. 124. Ogata ES. Carbohydrate metabolism in the fetus and neonate and altered neonatal glucoregulation. Pediatr Clin North Am 1986; 33(1):25–45. 125. Buchanan GR. Coagulation disorders in the neonate. Pediatr Clin North Am 1986; 33(1):203–20. 126. Andrew M, Paes B, Johnston M. Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol Oncol 1990; 12(1):95–104.

8 Fluid and electrolyte balance in the newborn WINIFRED A. GORMAN

INTRODUCTION Appropriate ﬂuid and electrolyte therapy is an essential part of good neonatal care. In order to deliver appropriate quantities of ﬂuid and electrolytes, a thorough understanding of ﬂuid and electrolyte balance in the newborn is essential.

WATER DISTRIBUTION IN THE FETUS AND NEWBORN Body composition alters progressively throughout pregnancy. The body of the very young fetus is composed of 92% water, of which 65% is extracellular and 25% intracellular; less than 1% of the birth weight is composed of fat. There are progressive changes throughout pregnancy as the amount of protein and fat in the body increase. In a fetus of 1000 g birth weight (approximately 28 weeks’ gestation) about 80% of its weight is comprised of water; by full-term the water content is 75% and by 3 months of age (weighing approximately 5000 g) it is 60%.1–3 The total intracellular water content of the fetus and newborn’s body increases directly in proportion to cell mass. In the very immature fetus early in pregnancy, 25% of the weight is intracellular water; this increases to 35% at birth and 40% by 3 months of age. The body fat content increases from about 1% in the very early fetus to 15% at birth and 30% at 3 months of age.1 Fat has a very low water content and this increase in body fat content contributes to the decrease in total body water content.1 The growth-retarded infant whose body content of fat is low, has a greater proportion of body weight as water than the appropriately grown infant.

FUNCTIONAL ADJUSTMENTS TO POSTNATAL LIFE Renal blood ﬂow Functional nephrons are ﬁrst present in the fetus at approximately 8 weeks’ gestation. Nephrons develop in a centrifugal pattern with juxtamedullary nephrons developing ﬁrst. The full complement of glomeruli is present by 34 weeks’ gestation. Renal blood supply arises from the aorta between T12 and L2, a relationship that remains constant between 24 and 44 weeks’ gestation. As the renal arteries divide into segmental end arteries, the renal tissue in their area of distribution is very vulnerable to ischemia, thus follows the recommendation that umbilical artery catheters should not be positioned between T12 and L3.4,5 The renal blood ﬂow and glomerular ﬁltration rate in utero increase gradually with gestational age. Although absolute values increase, blood ﬂow and ﬁltration normalized to fetal weight remain constant, indicating that growth of new nephrons accounts for these increases in the fetus. Vascular resistance is high in the fetal kidney and restricts renal blood ﬂow and glomerular ﬁltration in utero. The proportion of cardiac output that is distributed to the kidneys during fetal life is about 2–3%.4–6 It increases to about 6% during the ﬁrst week of life and approximates 15–18% during the ﬁrst month of life. In adults, the kidneys receive 20–25% of the cardiac output. The low renal blood ﬂow during fetal life results from a high renal vascular resistance. Renal function is modiﬁed substantially after birth as a result of cardiovascular and hormonal inﬂuences. Increased cardiac output and decreased renal vascular resistance are responsible for increased blood ﬂow to the

90 Fluid and electrolyte balance in the newborn

kidneys. For 24 hours after birth, total renal blood ﬂow remains unchanged; however, distribution of intrarenal blood ﬂow changes dramatically, in that there is a shift in blood ﬂow from the inner to the outer cortex. After the ﬁrst day of life, blood ﬂow continues to rise in the outer zone of the cortex, whereas blood ﬂow to the inner cortex remains unchanged. The factors controlling these alterations in renal ﬂow are not fully understood. Factors noted to have an inﬂuence include renal sympathetic innervation, circulating catecholamines, the renin– angiotension systems and prostaglandins.7–9

Glomerular ﬁltration rate Glomerular ﬁltration begins between 9 and 12 weeks’ gestation in the human fetus and is responsible for making urine which contributes to amniotic ﬂuid. In fetal sheep, the glomerular ﬁltration rate (GFR) increases by 2.5 times during the last trimester and parallels the rise in fetal body weight and kidney weight.7–9 At delivery there is a positive correlation between GFR and gestational age in newborns delivered between 27 and 43 weeks’ gestation.10 In the ﬁrst 24 hours after delivery, there is a threefold increase in GFR. This occurs despite the absence of an increase in total renal blood ﬂow to the kidneys or an increase in systemic blood pressure. As mentioned earlier, however, there are dramatic changes in intrarenal blood ﬂow distribution with an increase in blood ﬂow to cortical glomeruli.7,9 The increase in glomerular ﬁltration occurs only in the infant of greater than 34 weeks’ gestation. Infants born before this gestation period fail to demonstrate this rapid rise in GFR; rather only a slow increase with age occurs postnatally so that by 40 weeks’ gestation the preterm infant has a GFR comparable to that of the term infant. The low GFR that characterizes the premature neonate’s renal function makes him intolerant of excessive ﬂuid and electrolyte loads. 8,10–12 Changes in GFR at birth may be inﬂuenced by plasma adrenaline and noradrenaline.13,14 Alterations in renin– angiotensin, prostaglandin, arginine vasopressin15–17and plasma cortisol18 concentration also occur perinatally. Each of these or a combination of these hormones may inﬂuence glomerular ﬁltration by decreasing glomerular vascular resistance and recruiting superﬁcial cortical nephrons.

Water homeostasis The diluting segment of the distal tubule and ascending limb of the loop of Henle develops relatively early in nephrogenesis. When challenged with a water load both the term and the preterm infant can dilute their urine to osmolalities to 50 mOsm/kg and 70 mOsm/kg water. The glomerular ﬁltration, however, is low and this limits the quantity of urine that can be excreted even in

the presence of a potent dilutional capacity. Thus the newborn, both term and preterm, is at risk of ﬂuid overload if presented with more ﬂuid than the kidney can handle. The concentrating ability of the newborn kidney is limited by the osmolality in the medullary interstitium. The newborn kidney of both the term and preterm infant has relatively low osmolality in the renal medulla and this limits the effectiveness of the countercurrent concentrating mechanism in the loop of Henle.11,12 In the term infant, urine can be concentrated to a maximum of 600–700 mOsm/L, considerably less than that of 1200 mOsm/L in the older child or adult. Thus both the preterm and full-term newborn are unable to handle either ﬂuid deprivation or overload, thus underlining the need for accurate assessment of ﬂuid requirements.19 Immediately after birth a physiological acute isotonic volume contraction occurs with the corresponding postnatal weight loss. Weight loss is greater and lasts longer in infants with less advanced gestational age. This volume contraction occurs predominantly in the extracellular water. This has been shown to occur independently of the amount of ﬂuid given postnatally.20 Hartnoll et al.21 studied the inﬂuence of delaying routine sodium supplementation on body composition. Their ﬁndings suggest that early sodium supplementation before a physiologic weight loss had occurred impaired the normal loss of body water from the extracellular ﬂuid compartment and resulted in increased respiratory morbidity.

Insensible water loss Insensible water loss is the continuous invisible loss of water by evaporation that occurs from the skin and lung surface. Account must be taken of an infant’s estimated insensible water loss when estimating total ﬂuid requirements.22

SWEATING Sweating occurs to only a very limited extent in response to a thermal stimulus in the term infant, despite the fact that the full complement of sweat glands is present at birth. Preterm infants below 30 weeks’ gestation do not have thermal sweating in the immediate newborn period,23 despite the absence of well-developed sweat glands by about 28 weeks’ gestation.

TRANSEPIDERMAL WATER LOSS Evaporation of water from the skin surface occurs continuously by diffusion.24,25 The quantity of water lost is determined by a number of factors. First, the relative humidity of the infant’s surrounding atmosphere is a major inﬂuence, particularly in the preterm infant.

Functional adjustments to postnatal life 91

Skin maturation has an inﬂuence on the quantity of water lost by evaporation. The full-term infant has a well-developed layer of keratinized stratum corneum which protects him/her against excess water loss. Keratinization begins at 17 weeks’ gestation and progresses in a non-uniform way throughout gestation, occurring latest on the skin of the abdomen and back.25–27 Transepidermal loss of water from the skin of the preterm infant is greatly increased as gestational age decreases. This is the result of a large ratio of surface area to weight and an immature epidermal barrier to water. This loss from the skin is exaggerated by postnatal trauma to the skin, for example from adhesive tape applied to the skin for attachment of monitors. After birth regardless of gestation the skin matures and skin permeability to water falls. However, in the extremely preterm infant this maturation may be extremely slow and extra cellular water loss has been shown to be higher than normal at 28 days postnatal age.28,29

Prenatal steroids Omar et al. have demonstrated high insensible water losses in preterm infants with a mean gestational age of 26 weeks. Transepidermal water loss gradually decreased over the ﬁrst 7 days of life and was signiﬁcantly lower in infants whose mothers had received prenatal steroids. On the other hand Jain et al. failed to demonstrate any maturational effect of antenatal steroids on transepidermal loss in a group of preterm infants. 30–32 The relative humidity of the infant’s surrounding atmosphere has a major inﬂuence on transepidermal water loss as well as heat loss. Water and heat loss can be at least partially counteracted by humidifying the infant’s surrounding atmosphere within the ﬁrst few days of life.33

Respiratory water loss Respiratory loss represents 39% of insensible water loss in term infants. Inspired air becomes fully saturated with water in the upper respiratory tract. Some water is lost as this air is expired. Tachypnea increases water loss through respiration. The relative humidity of the air before inspiration also has an inﬂuence; the higher the humidity, the less water needs to be added and less is lost. Infants ventilated will have humidiﬁed air delivered and thus the respiratory water loss will be zero.34

Sodium regulation Maintenance of normal serum sodium is principally controlled by the kidneys. Sodium intake must be roughly equivalent to the infant’s needs if a normal serum sodium (135–140 mmol/L) is to be maintained.

Glomerular ﬁltration, as has been described, is low in the preterm infant and increases progressively with gestational age. The amount of sodium that can be excreted is limited by the GFR. In the full-term infant, GFR increases dramatically after birth; however, it does not reach adult levels until approximately 2 years of age. This results in a lower GFR of sodium in the newborn infant, particularly in the preterm infant. Thus the ability of the kidney to excrete a sodium load is diminished as compared with adults and falls progressively with decreasing gestational age.35–37 Tubular function also has a role in renal handling of sodium. At all levels of sodium intake, preterm infants have a higher fractional sodium excretion rate than fullterm infants.37 Extrauterine existence has an accelerating effect on tubular sodium reabsorption but not on GFR, whose maturation is related to postconceptual age. The preterm infant, because of having a low GFR, is unable to excrete a sodium load. This immature function also renders him unable to retain sodium where intake is restricted. Al-Dahhan and colleagues have shown that the preterm infant of less than 30 weeks’ gestation requires a minimum of 5 mmol/kg/day of sodium and the infant of 30–35 weeks’ gestation requires 4 mmol/kg/day to achieve a positive sodium balance and maintain normal serum sodium.36,37 Intestinal absorption of sodium in the very preterm infant is low and improves progressively with increasing gestational age.38 Newborns undergoing intensive care may gain signiﬁcant amounts of ﬂuid and sodium from drugs, bronchial lavage, and ﬂushing of catheters – sources that are often overlooked. Hypernatremia may occasionally result, especially in the very small infant. 39 Hartnoll et al. have studied the inﬂuence of delaying postnatal sodium supplementation in infants of less than 30 weeks’ gestation on body composition and respiratory morbidity. They have shown that delaying routine sodium supplementation in preterm infants lessens respiratory morbidity for as long as 28 days postnatally. This suggests that routine supplementation of sodium without looking at overall ﬂuid balance may be detrimental to the preterm infant who has a limited ability to handle a sodium load.40 Prenatal steroids induce maturation of renal tubular function. Infants who have been exposed to prenatal steroids have an earlier diuresis and natriuresis.30

Renal response to antidiuretic hormone The human fetal pituitary contains antidiuretic hormone (ADH) from 12 weeks’ gestation onwards. Labor and delivery are associated with a surge in ADH secretion. Cord blood levels are elevated. Both term and preterm infants are capable of an appropriate ADH response to stimuli. Although blood levels in newborn infants are

92 Fluid and electrolyte balance in the newborn

elevated to the same extent as in adults, the antidiuretic response to ADH is blunted because a lower concentration gradient in the renal medulla lessens its effectiveness. ADH receptors in the kidneys may also be low in the newborn. Excess ADH can, however, cause a drop in urine output and hyponatremia. 41,42 Factors that result in excess or inappropriate secretion of antidiuretic hormone (SIADH) in the newborn include birth asphyxia,43 painful surgery, hypoxia and severe lung disease. SIADH results in weight gain, hyponatremia and oliguria, with a high urine osmolality and usually a high urine sodium. Treatment is with ﬂuid restriction.

FLUID AND ELECTROLYTE MANAGEMENT Dramatic changes in body composition, skin, renal and neuroendocrine function occur with delivery. Infants admitted to a neonatal intensive care unit who are unable to exclusively feed orally require careful management of ﬂuid and electrolyte balance. Additional difﬁculties may occur if the infant is preterm and if, as frequently happens in babies requiring surgery, there are additional losses from the intestine or the kidneys as a result of a complex surgical problem. When planning maintenance ﬂuid therapy for an infant, all the variables that have already been discussed that may inﬂuence ﬂuid requirements must be taken into account. Any guidelines for ﬂuid and electrolyte therapy must be modiﬁed to suit an individual infant’s requirements. Table 8.1 gives some guidelines that may be used and modiﬁed appropriately.43 Increased ﬂuid requirements may occur in the following circumstances: • Low birth weight (LBW) infants. For the reasons outlined in this chapter the LBW infant, especially the very low birth weight (VLBW) infant, has a very high insensible loss of ﬂuid and thus increased requirements for water. • Phototherapy. Phototherapy increases insensible water loss by evaporation, thus ﬂuid intake should be increased by 10 ml/kg/day in the infant weighing >1500 g and 20 ml/kg/day with birth weights <1500 g.44,45

• Radiant warmer. Nursing in a radiant warmer increases insensible ﬂuid loss (by a mean of 0.94 ml/kg/hour 47) when compared with incubators. This increased water loss is not prevented by using a heat shield but may be prevented by using a plastic blanket.46–48 • Polyuric renal failure. In this rare occurrence, maintenance ﬂuids will require very frequent readjustment (see later). Maintenance ﬂuid therapy may need to be decreased in the following circumstances: • Inappropriate ADH secretion. This may occur following cerebral or pulmonary insult and results in hyponatremia, oliguria and high urine osmolality. Treatment is principally with ﬂuid restriction. • Congestive heart failure and oliguric renal failure are both associated with ﬂuid overload, and ﬂuid restriction is thus an essential part of management. • Patent ductus arteriosus. Closure may be helped by ﬂuid restriction. In assessing the infant’s water requirements, useful guides include changes in weight and urine output, speciﬁc gravity and osmolality, serum sodium and creatinine and blood urea, and osmolality. Normal urine output is 2–4 ml/kg/hour. In the ﬁrst 24 hours of life, urinary output may be very low, or even absent. During recovery from a severe illness associated with ﬂuid retention or edema, polyuria may occur. A physiological diuresis (water loss) of up to 10% of body weight occurs over the ﬁrst 4–5 days of life. This diuresis has the effect of decreasing total body water content, in particular extracellular ﬂuid volume. It is greater in the preterm infant whose total body water content is higher than that of the term infant. No attempt should be made to replace this ﬂuid. This water loss occurs despite usual ﬂuid intakes and is typically accompanied by a negative sodium balance even when sodium is provided; it occurs predominantly on days 2 and 3 of life.49 High ﬂuid intake increases the likelihood of symptomatic patent ductus arteriosus. 50 High ﬂuid intake and or high sodium intake may also increase the likelihood of respiratory complications both in the short term and in the longer term by increasing the frequency of bronchopulmonary dysplasia.51

Table 8.1 Guidelines for initial ﬂuid therapy

Birth weight (kg)

Dextrose (g/100 ml)

Fluid rate (ml/kg/day) <24 hours 24–48 hours >48 hours

<1.0 1.0–1.5 >1.5

5–10 10 10

100–150* 80–100 60–80

120–150 100–120 80–120

140–190 120–160 120–160

*VLBW infants frequently require even higher initial rates of ﬂuid administration and frequent reassessment of serum electrolytes, urine output, and body weight.

Fluid and electrolyte management 93

Prevention of excess water loss by humidifying the infant’s environment, especially if the infant is very preterm, lessens water loss and makes maintenance of ﬂuid balance easier.

Sodium balance No sodium is required during the ﬁrst 24 hours of life, during which time urine and sodium output are low. As discussed earlier, sodium supplementation of 2–4 mmol/kg/day should be given when weight loss of approximately 5–10% of birth weight has occurred. This can be given with a solution containing one-ﬁfth normal saline with dextrose to which additional electrolytes are added as required (Table 8.2).

Table 8.2 Maintenance electrolyte therapy kg/day Sodium Potassium Calcium

2–4 mmol 1–3 mmol 5–10 ml of 10% calcium gluconate (1.125–2.25 mmol calcium)

Hyponatremia may occur in the following circumstances: • Laboratory error • Excess antidiuretic hormone secretion, where low urinary loss of water results in dilutional hyponatremia • Large renal tubular losses of sodium as occurs in extreme prematurity or polyuric renal failure • Congestive heart failure with dilutional hyponatremia • Diuretic therapy with loss of sodium via the renal tubules • Hypoadrenalism: congenital Addison’s disease, septic shock with adrenal failure, salt-wasting adrenogenital syndrome • Maternal hyponatremia 52 • Factitious hyponatremia as a result of hyperglycemia or hyperlipidemia. Hypernatremia may occur in the following circumstances: • Laboratory error • High insensible water loss which is incompletely replaced • High urinary water losses which are not replaced • Maternal hypernatremia • Deﬁciency of antidiuretic hormone. In summary, sodium requirements ordinarily are 2–4 mmol/kg/day. The preterm infant with immature renal tubules and resultant high urinary sodium loss may

require up to 6 mmol/kg/day of sodium. This high urinary sodium loss may continue for up to 4 weeks of age. Serum sodium in the ill newborn, especially if i.v. ﬂuids are required, must be monitored at least once daily in the term baby and 2–3 times daily in the VLBW baby, and appropriate adjustments in ﬂuid therapy must be made to correct any abnormalities in serum sodium.53

Potassium balance Potassium is predominantly an intracellular ion. No potassium is required on the ﬁrst day of life. After this, intakes of 1–3 mmol/kg/day should replace losses and maintain a normal serum potassium of 3.5–5.8 mmol/L (Table 8.2). Potassium must not be given if renal function is compromised. It should be given only with great care in the VLBW infant whose ability to excrete potassium may be limited. Early non-oliguric hyperkalemia may occur in 30–50% of infants with birth weights <1 kg as a result of a potassium shift from intracellular to extracellular space. Hyperkalemia will be exaggerated by hypoxia, metabolic acidosis, catabolic stress and oliguria. The hyperkalemia may be severe enough to cause lifethreatening arrhythmias. 7,54–57 Hyperkalemia may occur in the following circumstances: • Laboratory error or hemolysis of blood sample • Severe metabolic acidosis: with each 0.1 pH drop in serum, serum potassium increases by 0.6 mmol/L • Tissue cell death with release of intracellular potassium • Acute renal failure • VLBW in the absence of renal failure • Adrenal insufﬁciency secondary to acute adrenal failure as in sepsis/shock or congenital adrenal hyperplasia • Severe hemolytic anemia.

TREATMENT OF HYPERKALEMIA (Fig. 8.1) The following guidelines may be used: • Remove all sources of potassium • Correct metabolic acidosis with i.v. sodium bicarbonate • Give calcium gluconate (10%) intravenously to correct hypocalcemia • Give potassium chelator: calcium resonium 1 g/kg, rectally, 6 hourly • Give glucose and insulin intravenously: infuse 10–15% dextrose with soluble insulin. Use cautiously as severe hypoglycemia may result unless infusion is carefully monitored and titrated • Give salbutamol infusion 4 μg/kg intravenously over 20 minutes.58

94 Fluid and electrolyte balance in the newborn Remove all sources of exongenous potassium (K+) Abn

(1) Support cardiac output, CaGluconate, NaHCO3, frusemide, Kayexelate (2) Glucose/Insulin

Abn

(1) CaGluconate, NaHCO3. Check for arrhythmia causes.

CV status

NI ECG

NI NI Abn

Repeat ECG

Rejoin algorithm at renal status

Renal status

Abn

(2) Glucose/insulin, frusemide. Consider repeating step (1) above. Kayexelate

(1) Kayexelate, frusemide (if oliguric) (2) Dialysis double volume exchange NI Yes

(1) NaHCO3, frusemide, glucose/insulin (2) Kayexelate

Yes

(1) Frusemide (2) Kayexelate or Glucose/Insulin

+

[K ] >8 mmol/L No Ongoing K release

No Watch or frusemide In general, if [K+] acceptable for 6 hours, cease therapy but continue monitoring. Drug doses: Calcium gluconate 10% 1–2 ml/kg i.v. Sodium bicarbonate 8.4% (NaHCO3) 1–2 mmol/kg i.v. (dilute to 4.2%) Frusemide 1 mg/kg i.v. Glucose/insulin Bolus: D10W 2 ml/kg and Actrapid 0.05 U/kg Infusion: D10W 2–4 ml/kg/hour and Actrapid 10 U/100 ml D10W or 5% Albumin @ 1 ml/kg/hour Calcium resonium 1 g/kg rectally, used cautiously in the setting of an immature ischemic GI tract. Figure 8.1 Hyperkalemia44 For a given algorithm outcome proceed by administering the entire set of treatments labelled (1). If unsuccessful in lowering [K+] or improving clinical condition, proceed to the next set of treatments, e.g. (2) then (3). (CV = cardiovascular; Nl = Normal, Abn = abnormal.) (Taken from Manual of Neonatal Care. eds Cloherty and Stark. With permission of Lippincott Raven Publishers, USA)

CAUSES OF HYPOKALEMIA Hypokalemia may occur in the following circumstances: • Laboratory error • Alkalosis lowers serum potassium by shifting the potassium load intracellularly, but does not lower total body potassium • Polyuric renal failure

• Gastrointestinal losses through vomiting or diarrhea or pooling of ﬂuid in a ‘third space’, such as dilated loops with intestinal obstruction • Diuretic therapy • Inadequate intake. Hypokalemia predisposes to cardiac arrhythmias, paralytic ileus, urinary retention and respiratory muscle paralysis. Thus potassium balance must be carefully

Fluid and electrolyte management 95

monitored, taking into account the inﬂuence that pH may have on the serum potassium, in that alkalosis shifts potassium which is predominantly an intracellular ion into the cells; acidosis has the reverse effect and both hyper- and hypokalemia will have adverse effects.

Acid–base balance Normal values for pH are similar to those in the adult; however Pco2 and serum bicarbonate are both slightly lower in the newborn infant than in the adult.59,60 The lungs and kidney play important roles in the maintenance of acid–base balance. The lung excretes volatile acid formed during metabolism as CO2. Respiratory failure will cause accumulation of CO2 and respiratory acidosis.

METABOLIC ACIDOSIS The normal kidney has a vital role in regulation of serum bicarbonate. In mature subjects serum bicarbonate is maintained at approximately 25 mmol/L, but preterm infants have a lower threshold.60The kidney also has an important role in the excretion of non-volatile acid (mainly sulphur containing amino acids) produced by metabolism. Causes of metabolic acidosis The causes of metabolic acidosis include: 1 2 3 4 5 6

Perinatal asphyxia Severe hypotension with impaired tissue perfusion Acute renal failure Acute diarrhea and dehydration Excess ileal loss Excess protein administration, e.g. excess amino acids in parenteral nutrition 7 Inborn errors of metabolism (e.g. organic acidemia). Acute metabolic acidosis is common in the critically ill newborn. Treatment is predominantly by treatment of the underlying cause. Sodium bicarbonate may be used for severe acidosis with pH < 7.1 by giving a dose of 1–2 mmol/kg of 4.2% sodium bicarbonate by slow infusion over 30–60 minutes. 61,62 Causes of metabolic alkalosis • Persistent vomiting causes hypochloremic alkalosis and body potassium depletion. This may occur with untreated pyloric stenosis or upper intestinal tract obstruction. Correction is by replacement of ﬂuid, sodium chloride and potassium. Rehydration and correction of depleted electrolytes will be followed by correction of the metabolic alkalosis. • Chronic respiratory acidosis as in bronchopulmonary dysplasia may cause renal re-regulation of sodium bicarbonate level at a higher threshold until pH is normal. Infants with chronic hypercapnia regularly have a serum bicarbonate level of > 30 mmol/L.

In chronic acidosis or alkalosis, the kidneys and lungs do work in tandem with the aim of normalizing pH.

Glucose homeostasis Glucose is the most important substrate for brain metabolism and whereas ketones, glycerol and lactate can be used, a continuous supply of glucose is essential for normal neurological function.63,64 Fetal blood glucose is identical to that of maternal blood glucose since passive transfer of glucose occurs across the placenta. Immediately after delivery, blood glucose falls to approximately 2.5 mmol/L (45 mg/100 ml) in the term infant. Following delivery a combination of hormonal responses (glucagon, growth hormone, thyroxin) and oral feeds or in their absence i.v. ﬂuids, serve to maintain blood glucose within a normal range. Surprisingly, there is no consensus regarding the deﬁnition of hypoglycemia in the neonate.63,64 Blood glucose levels between 2.5 mmol/L (45 mg) and 7.2 mmol/L (130 mg) are accepted as being very safe. Symptomatic hypoglycemia results in cyanosis, apnea, lethargy, seizures or coma. Blood sugar values represent a continuum and there is no speciﬁc value at which brain-damaging hypoglycemia will always occur.63,65 Cornblath recommends using operational ‘thresholds’ as an indication for intervention. These levels are not diagnostic of disease but act as a guideline for when to treat hypoglycemia.64 In the newborn requiring surgery, hypoglycemia is most commonly caused by vomiting or inadequate intake of ﬂuids. Other contributing factors may include prematurity, septicemia, hypothermia, or hyperinsulinism as may occur in an infant of a diabetic mother. Infants with Beckwith–Wiedemann syndrome who frequently may have omphalocele, commonly have elevated blood insulin levels and severe hypoglycemia. Blood sugar in the infant at risk should be monitored at the bedside using a bedside screening glucose analyzer. Blood sugar levels below 2–2.5 mmol/L should be acted upon by giving a feed or giving a bolus of i.v. 10% dextrose as appropriate for the individual infant. Signiﬁcant hypoglycemia should be conﬁrmed by laboratory blood sugar before deﬁnitive action, such as i.v. glucose is given. This is because all screening methods are not completely accurate at low blood sugar levels.

HYPERGLYCEMIA A blood glucose level above 14 mmol/L (250 mg) may cause a hyperosmolar state with glucosuria, osmotic diuresis and dehydration. The risk of intracranial hemorrhage at least in the infant of < 32 weeks’ gestation may be increased by this increased plasma osmolality. Hyperglycemia most commonly occurs in the VLBW infant who is receiving large amounts of ﬂuids to

96 Fluid and electrolyte balance in the newborn

counteract insensible loss and whose ability to metabolize dextrose or glucose is limited. If hyperglycemia occurs, 10% dextrose should be replaced by 5% dextrose. Rarely, infusion of small doses of insulin may be required to counteract intractable hyperglycemia.43

Calcium homeostasis Calcium is the ﬁfth most abundant element in the human body. It has a key role in many physiological processes, including activation and inhibition of enzymes, intracellular regulation of metabolic sequences, secretion and action of hormones, blood coagulation, muscle contraction and nerve transmission.65 Of total body calcium, 99% exists in bone, to which it gives structural support. Calcium is present in the extracellular ﬂuid in three fractions: 30–50% is bound to protein, principally albumin; 5–15% is complexed to citrate, lactate, bicarbonate and inorganic ions; and 5–15% is ionized – this is the metabolically active fraction of calcium. Calcium concentration reported as mg/dL can be converted to molar units by dividing by 4 (e.g. 10 mg/dL converts to 2.5 mmol/L)43,66–68 If serum albumin is low, total serum calcium falls, but the serum level of ionized calcium is unchanged. Hydrogen ions compete with calcium for albuminbinding sites; thus acidosis increases serum ionized calcium levels without inﬂuencing total serum calcium levels. Alkalosis has the reverse effect. Prenatally, calcium is actively transported across the placenta from mother to fetus against a concentration gradient, which results in fetal hypercalcemia at the end of the last trimester and immediately after birth. Cord serum calcium in the full-term infant is approximately 2.75 mmol/L.67 In healthy full-term infants, calcium concentrations decrease for the ﬁrst 24 to 48 hours and reach a low of 1.8–2.1 mmol/L. Thereafter calcium concentrations progressively rise to the mean values observed in older children. This transient drop in serum calcium is exaggerated in the preterm infant.

HYPOCALCEMIA This is deﬁned as a total serum calcium concentration of < 2.0mmol/L in the term infant and < 1.7mmol/L in the preterm infant.66 Normal serum ionized calcium in the newborn infant is 1–1.5 mmol/L.67–69 Causes of hypocalcemia 1 The majority of hypocalcemia occurs in the fullterm and preterm infant in the ﬁrst 3 days of life. It is frequently asymptomatic and transient. 2 Infants of diabetic mothers frequently are hypocalcemic. 3 Additional stresses such as birth asphyxia or septicemia may precipitate hypocalcemia.

4 Genetic disorders such as Di Georges sequence may include hypoparathyroidism which causes hypocalcemia. Less common causes would include maternal hyperthyroidism and frusemide therapy or hypomagnesemia. Clinical manifestations The majority of instances of hypocalcemia is asymptomatic. The symptoms when they occur include jitteriness and seizures. An electrocardiographic Q-Tc interval longer than 0.4 seconds may occur. Management Early asymptomatic mild neonatal hypocalcemia does not require treatment. Infants receiving i.v. ﬂuids should be provided with maintenance calcium gluconate. Brown and colleagues have shown that aggressive attempts at normalizing serum calcium in sick preterm infants may be ineffective and even hazardous, thus at the least in the ﬁrst week of life maintenance of serum calcium at a level of 2.0 mmol/L is adequate.70 Symptomatic hypocalcemia should be treated with a slow infusion of i.v. calcium gluconate. Extreme care should always be taken when infusing calcium as extravasation can cause severe burns to the surrounding skin and subcutaneous tissue. Emergency treatment of hypocalcemia is only required if the infant is symptomatic. Symptoms include jitteriness, seizures, lethargy, poor feeding and vomiting. Symptoms are uncommon at serum calcium levels above 1.8 mmol/L and become common at serum calcium levels below 1.5 mmol/L. Oral calcium supplements in the form of calcium Sandoz 2.5 ml (50 mg)/kg/day may be given with feeds if the infant on feeds has asymptomatic hypocalcemia, requiring treatment. Symptomatic hypocalcemia unresponsive to calcium therapy may be due to hypomagnesemia. This can be treated with 50% magnesium sulphate either intravenously or intramuscularly.71

PREOPERATIVE FLUID AND ELECTROLYTE PROBLEMS IN THE NEONATE Heird and Winters have summarized the metabolic responses of the normal neonate in the ﬁrst weeks of life.72 Preoperatively, infants with abnormalities requiring surgery, especially those of the gastrointestinal tract, may have a variety of electrolyte abnormalities.72–74 If there has been a delay in recognition of gastrointestinal obstruction and the infant has been vomiting for a period of time, he or she will be dehydrated. Upper intestinal obstruction, for example duodenal atresia, results in loss of hydrochloric acid from the stomach, and small amounts of sodium and potassium.

Fluid and electrolyte balance in septic shock 97

The kidney then conserves hydrogen ions at the expense of potassium and sodium. Bicarbonate is excreted by the kidney along with sodium and potassium and the urine pH is alkaline. Potassium and sodium depletion occur. As loss of potassium and sodium progress, and the body stores are diminished, the kidney ceases to excrete these ions with bicarbonate. Sodium and potassium are now conserved by the kidney and hydrogen ion is lost instead. A severe hypochloremic metabolic alkalosis now occurs. Correction must be with adequate ﬂuid-containing sodium chloride and potassium chloride, as body stores of all these ions are depleted. It is not necessary to correct alkalosis with ammonium chloride. Infants with lower intestinal obstruction, such as Hirschsprung’s disease or other intestinal obstructive lesions, may pool large amounts of ﬂuid and electrolytes in dilated intestinal loops; this may result in intravascular dehydration with hyponatremia, hypokalemia and metabolic acidosis. Neonates with necrotizing enterocolitis, peritonitis or septic shock may have ‘third space’ loss of ﬂuid into the peritoneum, pleural ﬂuid or interstitial tissues with resultant hypoproteinemia and marked interstitial edema. Additionally, many of these infants are ventilated, sedated and paralyzed. Immobility resulting from paralysis will accentuate peripheral pooling of interstitial ﬂuid. Intravascular dehydration and hypoproteinemia and hyponatremia will result. Preoperatively, the infant’s hydration should be assessed on the basis of weight, pulse, blood pressure, capillary ﬁlling time, blood urea and electrolytes and urine output, speciﬁc gravity and electrolyte content.

metabolic acidosis. Inappropriate secretion of ADH is common and results from pain and/or ventilation. This will result in ﬂuid retention and hyponatremia; thus care must be taken to avoid overhydration, which will encourage both of these. Respiratory acidosis should be corrected by appropriate ventilation. Metabolic acidosis may occur postoperatively in the infant who is persistently hypotensive or hypoxic or who has ongoing tissue necrosis (i.e. severe necrotizing enterocolitis). This must be addressed by correcting the underlying cause of acidosis and by giving sodium bicarbonate. Fluids lost through nasogastric suctioning or drainage must be replaced at regular intervals by normal saline with maintenance potassium added; if losses are from the small intestine it has been recommended that a small amount of bicarbonate is also added. Where large ﬂuid losses occur from aspiration, calculation of the electrolyte content of these ﬂuids may help plan replacement71,72 (Table 8.3). Most, though not all, investigators agree that some discernible degree of catabolic response in terms of nitrogen excretion occurs in neonates postoperatively. Thus early attention must be given to beginning parenteral nutrition in infants in whom early feeding is not foreseen. The term infant who will be fed enterally within 5 days need not be fed parenterally; however, the VLBW infant (<1500 g) who has very inadequate stores of nutrients must begin parenteral nutrition as soon as he/she is metabolically stable.

Table 8.3 Electrolyte composition of body ﬂuids

Body Fluid

Electrolytes (mEq/L) Na+ K+ CI-

HCO3

PH

Gastric Pancreas Bile Ileostomy Diarrhea

70 140 130 130 50

0 100 40 25–30 50

1 9 8 8 >7

Intraoperative management Careful attention to ﬂuid and electrolyte balance intraoperatively is essential and monitoring of blood pressure, pulse and temperature is also essential. During major procedures, intravascular lines should be used to monitor blood pressure and central venous pressure. Urine output should also be measured and oxygenation and ventilation with blood gases and pulse oximetry. Loss of ﬂuid and heat from exposed peritoneal surfaces should be taken into account and minimized by keeping the operating room sufﬁciently warm. Acute blood loss should be replaced.73

5–15 5 5 15–20 35

120 50–100 100 120 40

Adapted from Wait RB, Kahng KU. Fluids and electroylytes and acid–base balance. In: Greenﬁeld LJ, Mulholland MW, Oldham KKT et al., editors. Surgery ,Scientiﬁc Principles and Practice. Philadelphia: JB Lippincott Co.,1993:22373,74

FLUID AND ELECTROLYTE BALANCE IN SEPTIC SHOCK

Postoperative management Patients who have been adequately managed pre- and intraoperatively will be well hydrated in the immediate postoperative period. If the infant has been hypotensive, transient renal failure with oliguria may occur and must be managed with ﬂuid restriction and correction of electrolyte abnormalities such as hyperkalemia and

Many surgical conditions predispose to sepsis and shock. These include necrotizing enterocolitis, Hirschsprung’s disease with enterocolitis, and volvulus. The risk of septicemia with hypotension is even higher if the infant is also preterm. Shock is a stage of acute cardiovascular dysfunction in which the delivery of oxygen and nutrients is insufﬁcient

98 Fluid and electrolyte balance in the newborn

to meet metabolic demands of the tissues. The mortality rate when shock occurs is high. Endotoxin appears to be the common etiological factor in septic shock.75,76 Metabolic substrates, i.e. oxygen, glucose and fatty acids, are available, but their utilization is impaired; multiple-organ failure is the result. Capillary permeability increases and ﬂuid and protein leak into the interstitial ﬂuid. This results in tissue edema, hypoproteinemia and a fall in intravascular ﬂuid volume. Pulmonary hypertension, followed by marked pulmonary edema, occurs with severe respiratory distress. Myocardial depression results in decreased cardiac output.

Clinical manifestations Bacterial septicemia is frequently fulminant and fatal. A high index of suspicion by the nursing and medical staff is essential. The initial presenting features are subtle and may be recognized only by an experienced nurse or doctor. The infant may merely appear ‘off color’. The early signs of sepsis include lethargy, irritability, apnea and temperature instability.

Management Shock must be reversed with rapid infusion of ﬂuid and colloid to replete the intravascular space. Normal saline or lactated Ringer’s solution at a volume of 10–20 ml/kg should be infused over 20–60 minutes.74 Inotropic agents should be infused to increase cardiac output – dopamine improves cardiac contractility (5–20 μg/kg/minute) and in a low dose (<5 μg/kg/minute) also increases blood ﬂow to the kidneys and the intestine; high doses have the opposite effect. Alternative drugs are dobutamine or isoproterenol. Patients with profound hypotension and myocardial depression may respond only to infusion of epinephrine or norepinephrine. Hyponatremia and hyperkalemia may occur and should be corrected as outlined earlier in this chapter. Hyperkalemia results from oliguria and tissue catabolism; hyponatremia results from increased total body water and inappropriate antidiuretic hormone secretion. There is controversy about the value of i.v. sodium bicarbonate for correction of metabolic acidosis. It is no longer recommended for resuscitation in newborns and although it may correct acidosis in hypotensive shocked infants, this has not been shown to result in improvement in blood pressure or perfusion.61

ACUTE RENAL FAILURE Acute renal failure is common in the seriously ill neonate requiring surgery. It may be prerenal as a result of severe

dehydration, hypotension, abdominal distension or sepsis. It may result from congenital severe intrinsic renal disease. It may be obstructive and result from severe obstruction in the urinary collecting system, e.g. urethral valves.76,77 Prerenal failure is the most common form of acute renal failure in the surgical neonate, and results from a severe decrease in renal perfusion usually as a result of profound hypotension from blood loss, sepsis, severe necrotizing enterocolitis or intestinal obstruction with loss of ﬂuid into dilated intestinal loops. Primary fascial closure of omphalocele or gastroschisis carries the risk of placing the abdominal contents under pressure, which may cause a reduction in cardiac output, hypotension, bowel ischemia, venostasis and postoperative renal failure. Limited data suggests that an intragastric pressure of >20 ml of mercury or an increase in central venous pressure of 4 ml mercury or more indicate the need of a staged repair using a pouch.78 Additionally, newborn infants with abdominal wall defects have signiﬁcantly increased ﬂuid requirements preoperatively as major insensible water losses occur when eviscerated bowel is exposed to air and a perioperative third space is frequently associated. These conditions also favor hypovolemia, hypoperfusion of the kidney and postoperative renal failure. Renal vein or renal artery thrombosis, if bilateral, may be associated with acute renal failure. Treatment is by early aggressive ﬂuid replacement until blood pressure normalizes and then by meticulous adjustment of ﬂuid and electrolyte balance, until recovery of renal function occurs. Peritoneal dialysis may be required until renal function recovers. Recovery is associated with a polyuric phase which also requires ongoing care with replacement of large amounts of water, potassium and sodium via the kidneys. Renal failure due to obstruction and congenital malformations is often associated with severe irreversible renal diseases not compatible with normal extrauterine life. The focus of care must initially be to decide on the appropriateness of active management. Further discussion of renal failure management is outside the scope of this chapter.

CONCLUSION Major changes in body composition and ﬂuid and electrolyte balance occur during the transition to extrauterine life. These changes are even more marked in the preterm infant. The newborn who has a disorder requiring surgery has additional possible disorders of ﬂuid and electrolyte balance. This chapter outlines some aspects of the normal transition in the term and preterm infant, and the additional complications that may occur for the infant requiring surgery. It also provides some guidelines for ﬂuid and electrolyte therapy.

References 99

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100 Fluid and electrolyte balance in the newborn 38. Al-Danhan J, Haycock GB, Chantler C, Stimmler L. Sodium homeostatis in term and preterm neonates. II Gastrointestinal aspects. Arch Dis Child 1983; 58:343–5. 39. Noble-Jamieson CM, Kuzmin P, Airede K. Hidden sources of ﬂuid and sodium intake in ill newborns. Arch Dis Child 1986; 61:695–700. 40. Hartnoll G, Betremieux P, Modi N. Randomised controlled trial of postnatal sodium supplementation on oxygen dependency and body weight in 25–20 week gestational age infants. Arch Dis Child Ed 2000; 82:F19–23. 41. Rees L, Brook C, Shaw J, Forsling M. Hyponatraemia in the ﬁrst week of life in preterm infants. Part I Arginine vasopressin secretion. Arch Dis Child1984; 59:414–22. 42. Gore Ervin M. Perinatal ﬂuid and electrolyte regulation: Role of arginine vasopressin. Semin Perinatalol 1988; 12(2):134–42. 43. Simmons CF Jr. Fluid and electrolyte management. In: Coherty JP, Stark AR, editors. Manual of Neonatal Care. Philadelphia: Lippincott-Raven, 1988:9,87–100. 44. William OH, Karecki H. Phototherapy and insensible water loss in the newborn infant. Am J Dis Child 1972; 124:230–2. 45. Bell EF et al. Combined effect of radiant warmer and phototherapy on insensible water loss in low birth weight infants. J Peds 1979; 94:810–13. 46. Baumgart S. Reduction of oxygen consumption, insensible water loss, and radiant heat demand with use of a plastic blanket for low birth weight infants under radiant warmers. Pediatrics 1984; 75:89–99. 47. Flenady VJ, Woodgate PG. Radiant warmers versus incubators for regulating body temperature in newborn infants. Cochrane Library. 48. Meyer M, Payton M, Salmon A, Hitchinson C, de Klerk A. A clinical comparison of radiant warmer and incubator care for preterm infants from birth to 1800 grams. Pediatrics 2001; 108:395–401. 49. Lorenz JM, Kleniman LI, Kotagal UR, Reller MD. Water balance in very low birth weight infants: relationship to water and sodium intake and effect on outcome. J Pediatr 1982; 101:423–32. 50. Bell EF, Wharburton D, Stonestreet BS et al. Effect of ﬂuid administration on the development of symptomatic patent ductus arteriosus and congestive heart failure in premature infants. N Engl J Med 1990; 302:598–604. 51. Brown E, Start A, Sosemoko I et al. Bronchopulmonary dysplasia: possible relationships to pulmonary edema. J Pediatr 1978; 92:982–4. 52. Singhi S, Kalghatgi S. Iatrogenic neonatal and maternal hyponatraemia following oxytocin and aqueous glucose infusion during labour. Br J Obstet Gynaecol 1985; 92:356–63. 53. Lorenz JM, Kleinman L, Ghazala A, Markarian K. Phases of ﬂuid and electrolyte homeostasis in the extremely low birth weight infant. Pediatrics 1995; 96(3):484–9. 54. Lorenz JM, Kleinman A, Markarian K. Potassium metabolism in extremely low birth weight infants in the ﬁrst week of life. J Pediatr 1997; 131:81–6.

55. Sato K, Kondo T, Iwao H, Honda S, Ueda K. Internal potassium shift in premature infant: cause of nonoliguric hyperkalaemia. J Pediatr January 1995; 126:109–13. 56. Stefano JL, Norman ME, Morales MC, Goplerud JM, Ishra OP, Delivoria-Papadopoulos M. Decreased erythrocyte Na+, K(+)-ATPase activity associated with cellular potassium loss in extremely low birth weight infants with nonologuric hyperkalemia. J Pediatr 1993; 122:277–81. 57. Kluckow M, Evans N. Low systemic blood ﬂow and hyperkalemia in pretern infants. Journal Pediatr 2001; 139:227–31. 58. Murdoch IA, Dos Anjos R, Haycock GB. Treatment of hyperkalaemia with intravenous salbutamol. Arch Dis Child 1991; 66:527–8. 59. Schwartz GJ, Evan AP. Development of solute transport in rabbit proximal tubule. HCO and glucose absorbtion. Am J Physiol 1983; 245:F382–90. 60. Ramiro-Tolentino SB, Markarian K, Kleinman LI. Renal bicarbonate excretion in extremely low birth weight infants. Pediatrics 1996; 98(2):256–61. 61. Burchﬁeld DJ. Medication use in neonatal resuscitation. Clin Perinatol 1999; 26:683–91. 62. Cooper DJ, Walley KR, Wiggs BR et al. Bicarbonate does not improve haemodynamics in critically ill patients who have lactic acidosis. Ann Int Med 1990; 112:492–8. 63. Koh THG, Eyre JA, Aynsley-Green A. Neonatal hypoglycaemia – the controversy regarding deﬁnition. Arch Dis Child 1988; 63:1386–98. 64. Cornblath M, Hawdon J, William A, Aynsley-Green A, Ward-Platt M, Schwartz R, Kalhan S. Controversies regarding deﬁnition of neonatal hypoglycemia: Suggested operational thresholds. Pediatrics 2000; 105(5):1141–4. 65. Koh THG, Aynsley-Green A, Tarbit M, Eyre JA. Neural dysfunction during hypoglycaemia. Arch Dis Child 1988; 63:1353–8. 66. Scott SM, Ladenson JH, Aguanna JJ, Walgate J, Hillmann L. Effect of calcium therapy in the sick premature infant with early neonatal hypocalcemia. J Pediatr 1984; 104:747–51. 67. Pitkin RM. Endocrine regulation of calcium homeostatis during pregnancy. Clin Perinatol 1983; 10( 3):575–87. 68. Namgun GR, Bainbridge R, Cruz MR, Tsang RC.Disorders of calcium and phosphorous metabolism in infants and children. 1988; 12:253–71. 69. Solden SJ, Hicks JM. Pediatric reference ranges. Washington: AA Press, 1995:39. 70. Brown D, Steranka B, Taylolr F. Treatment of early-onset neonatal hypocalcemia, effects on serum calcium and ionized calcium. Am J Dis Child 1981; 135:24–28. 71. Tsang RC. Calcium, phosphorous and magnesium. Metabolism. In: Polin RA, Fox WA, editors. Fetal and Neonatal Physiology. Philadelphia: Saunders, 1995. 72. Heird WC, Winters R. The body ﬂuids in paediatrics. In: Winters R, editor. Fluid Therapy for the Pediatric Surgical Patient. Boston: Little Brown, 1983. 73. Rice HE, Caty MG, Glick PL. Fluid therapy for the pediatric surgical patient. Pediatr Clin N Am 1988; 45(Aug):719–27.

References 101 74. Wait RB, Kahng KU. Fluids and electrolytes and acid-base balance. In: Greenﬁeld LJ, MuljOlland MW, Oldham KT et al. editors. Surgery Scientiﬁc Principles and Practice. Philadelphia: JB Lippincott Co., 1993:23. 75. Butt W. Septic shock. Pediatr Clin N Am Vol, 2001; 48(3):601–19. 76. Toth-Heyn P, Drukker A, Guignard JP. The stressed neonatal kidney: from pathophysiology to clinical

management of neonatal vasomotor nephropathy. Pediatr Nephrol 2000; 14:22–239. 77. Gouyon JB, Guignard JP. Management of acute renal failure in newborns. Pediatr Nephrol 2000; 14:1037–44. 78. Yaster M, Scherer T, Stone M et al. Prediction of successful primary closure of congenital abdominal wall defects using intraoperative measurements. J Pediatr Surg 1989; 24:1217–20

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9 Nutrition AGOSTINO PIERRO

INTRODUCTION The newborn infant is in a ‘critical epoch’ of development not only for the organism as a whole but also for the individual organs and most signiﬁcantly for the brain.1 Adequate nutrition in the neonatal period is necessary to avoid the adverse effects of malnutrition on morbidity and mortality2 and to minimize the future menace of stunted mental and physical development.1 The survival rate of newborn infants affected by isolated congenital gastrointestinal abnormalities such as intestinal atresia, meconium ileus, omphalocele and gastroschisis has improved considerably over the past 20 years and is now in excess of 90% in most pediatric surgical centers. It is impossible to accurately quantify the contribution of improved nutritional management on the survival rate of these neonates. However the introduction of parenteral nutrition and advancement in nutritional management are certainly among the main factors responsible for this improvement.

HISTORICAL BACKGROUND The ﬁrst person to attempt to deliver nutrition intravenously was Sir Christopher Wren, the architect of St Paul’s Cathedral in London. He used hollow goose quills to infuse wine into dogs. Claude Bernard in the 18th century infused numerous substrates into animals and laid down the foundations of the scientiﬁc understanding of carbohydrate utilization in humans. In the 1930s Elman3 delivered the ﬁrst successful infusion of protein hydrolysates in humans. In 1949, Rhoads and Vars developed an apparatus for the continuous i.v. infusion of nutrients into dogs.4 The ﬁrst report of successful total parenteral nutrition in an infant was published in 1944 by Helfrick and Abelson.5 During the next 20 years, total parenteral nutrition in infants and children was without success because the solutions could not be infused into peripheral veins and insufﬁcient calories were provided

to allow the administered amino acids to be anabolyzed.6 In 1968 Dudrick et al.7 described a method to implant a catheter in the superior vena cava to deliver nutrients for prolonged periods. Using this system, Dudrick et al. showed that adequate growth and development could be achieved in beagle puppies and in a surgical infant.7 Following these initial reports Filler et al. reported the ﬁrst series of surgical neonates with gastrointestinal abnormalities treated with long-term total parenteral nutrition (TPN).8 The ﬁrst systematic investigations on the use of i.v. fat emulsions were carried out in Japan during the 1920s and 1930s.6 However the use of i.v. fat emulsions did not gain popularity because of the serious toxic reactions that occurred. The major breakthrough in the clinical use of i.v. fat emulsions came in 1962, when Wretlind described the soybean fat emulsion Intralipid still in use in many centers.9 During the 1970s and 1980s studies have been conducted in neonates receiving TPN, which led to signiﬁcant improvements in the technique and reduction of complications. The last 10 years have seen considerable changes in the nutritional management of surgical neonates. Various investigators have highlighted the importance of introducing as soon as possible enteral nutrition in surgical neonates. The beneﬁcial effects of minimal enteral feeding on the immune system, infection rate and liver function have been elucidated.

BODY COMPOSITION Newborns grow very rapidly and have lower caloric reserves than adults, and therefore do not tolerate prolonged periods of starvation. The body composition of newborns is markedly different from that of adults. The total body water varies from 86% of body weight at 28 weeks’ gestation to 69% at 40 weeks’ gestation and 60% in adulthood. This decline in body water also reﬂects an increase in energy content of the body. The ratio between minimal metabolic rate to non-protein energy reserve is only 1:2 at 28 weeks’ gestation; it

104 Nutrition

decreases to 1:29 for term infants and 1:100 for the adult.1 This justiﬁes the urgent need after birth for adequate caloric intake in very-low-birth-weight (VLBW) infants. Full-term neonates have a higher content of endogenous fat (approximately 600 g) and therefore can tolerate a few days of undernutrition.

ENERGY METABOLISM Newborns have a signiﬁcantly higher metabolic rate and energy requirement per unit body weight than children and adults10 (Fig. 9.1). They require approximately 40–70 kcal/kg/day for maintenance metabolism, 50–70 kcal/kg/day for growth (tissue synthesis and energy stored), and up to 20 kcal/kg/day to cover energy losses in excreta11,12 (Fig. 9.2). Computerization and miniaturization of indirect calorimeters have allowed the noninvasive investigation of energy metabolism in neonates.10,11,13,14 The total energy requirements for a newborn fed enterally is 100–120 kcal/kg/day, compared to 60–80 kcal/kg/day for a 10-year-old and 30–40 kcal/kg/day for a 20-year-old. Newborns receiving TPN

require fewer calories (80–100 kcal/kg/day). This is due to the absence of energy losses in excreta and to the fact that energy is not required for thermoregulation when the infant is nursed in a thermoneutral environment using a double-insulated incubator. Although the energy expenditure may double during periods of activity, including crying, most surgical infants are at rest 80–90% of the time.11 Signiﬁcant differences in resting energy expenditure (REE) have been reported among full-term surgical newborns (range 33.3–50.8 kcal/kg/day),11 and between premature and full-term babies. A full-term infant requires 100–120 kcal/kg/day, and a premature infant 110–160 kcal/kg/day11,15 (Fig. 9.1). These variations in maintenance metabolism explain the different growth rates frequently observed in surgical neonates receiving similar caloric intakes, and probably represent differences in metabolically active tissue mass, i.e. organ and muscle size. Several equations have been published to predict energy expenditure in adults.16 In stable surgical neonates, REE can be predicted from parameters such as weight, heart rate and age using the following equation:13 REE(cal/min) = –74.436 +(34.661 × body weight in kg) + (0.496 × heart rate in b.p.m.) + (0.178 × age in days) (r=0.92; F = 230.07; signiﬁcance F<0.00001).

The major predictor of REE in the above equation is body weight, which is also the strongest individual predictor of REE, and which represents the total mass of living tissue. The other predictors are heart rate, which provides an indirect measure of the hemodynamic and metabolic status of the infant, and postnatal age, which has been shown to inﬂuence REE in the ﬁrst few weeks of life.

Operative trauma Figure 9.1 Total energy requirement according to age. (Reprinted from J Pediatr Surg, Metabolism and Nutritional Support in the Surgical Neonate, 2002; 37(6):811–22, with permission from Elsevier Science)

Figure 9.2 Partition of energy metabolism in surgical newborns (Reprinted from J Pediatr Surg, Metabolism and Nutritional Support in the Surgical Neonate, 2002; 37(6):811–22, with permission from Elsevier Science)

In contrast with adults the energy requirement of infants and children undergoing major operations seems to be modiﬁed minimally by the operative trauma per se. In adults, trauma or surgery causes a brief ‘ebb’ period of a depressed metabolic rate followed by a ‘ﬂow phase’ characterized by an increase in oxygen consumption to support the massive exchanges of substrate between organs.17 In newborns, major abdominal surgery causes a moderate (15%) and immediate (peak at 4 hours) elevation of oxygen consumption and resting energy expenditure and a rapid return to baseline 12–24 hours postoperatively.18 There is no further increase in energy expenditure in the ﬁrst 5–7 days following an operation.18,19 The timing of these changes corresponds with the postoperative increase in catecholamine levels described by Anand et al.20 The maximum endocrine and biochemical changes are observed immediately after the operation and gradually return to normal over the next 24 hours. Interestingly, infants having a major operation after the second day of life have a signiﬁcantly greater increase in resting energy expenditure than infants undergoing

Energy metabolism 105

surgery within the ﬁrst 48 hours of life. A possible explanation for this may be the secretion of endogenous opioids by the newborn. It has been suggested that nociceptive stimuli during the operation are responsible for the endocrine and metabolic stress response, and that these stimuli may be inhibited by opioids.20,21 This is supported by studies showing that moderate doses of opioids blunt the endocrine and metabolic responses to operative stress in infancy.20,21 The levels of endogenous opioids in the cord blood of newborns are ﬁve times higher than plasma levels in resting adults.22 Thus, it is possible that the reduced metabolic stress response observed in infants less than 48 hours old is related to higher circulating levels of endogenous opioids. This may constitute a protective mechanism blunting the response to stress in the perinatal period. Chwals et al.23 demonstrated that the postoperative increase in energy expenditure can result from severe underlying acute illness, which frequently necessitates surgery (i.e. sepsis or intense inﬂammation). Resting energy expenditure is directly proportional to growth rate in healthy infants, and growth is retarded during times of acute metabolic stress. These authors suggest that energy is utilized for growth recovery following the resolution of the acute injury response in surgical infants. The authors indicate that serial measurement of postoperative resting energy expenditure can be used to stratify injury severity and may be an effective parameter to monitor the return of normal growth metabolism in surgical infants. Studies in adult surgical patients have shown that operative stress causes marked changes in protein metabolism characterized by a postoperative increase in protein degradation, a negative nitrogen balance,24,25 and a decrease in muscle protein synthesis.26 Powis et al.27 investigated substrate utilization and protein metabolism kinetics in infants and young children who had undergone major operations. Patients were studied for 4 hours preoperatively and for the ﬁrst 6 hours following surgery. The respiratory quotient fell signiﬁcantly postoperatively, reﬂecting mobilization of endogenous fat. However there were no signiﬁcant differences in the rates of whole-body protein ﬂux, protein synthesis, amino acid oxidation and protein degradation, between the preoperative and postoperative time, indicating that infants and children do not increase their whole-body protein turnover after major operations. It is possible that infants and children are able to convert energy expended on growth to energy directed to wound repair and healing, thereby avoiding the overall increase in energy expenditure and catabolism seen in the adult.14,27,28

Critical illness and sepsis Nutritional problems in infants and children requiring surgery are not unusual. The real nutritional challenge is

not represented by the operation per se but by the clinical condition of the patient. Examples include intrauterine growth retardation (IUGR) in small-for-gestation-age (SGA) preterm infants, infants who have suffered massive intestinal resection for necrotizing enterocolitis, and infants with motility disorders of the intestine following surgery for atresia, malrotation and midgut volvulus, meconium ileus or gastroschisis. Nutritional integrity, particularly in the neonatal period, should be maintained regardless of the severity of the illness or organ failure, especially in neonates due to their limited energy and protein stores. Infants and children require nutrition for maintenance of protein status as well as for growth and wound healing. One considerable challenge in pediatrics is represented by nutritional support during critical illness and sepsis. Keshen et al.29 have shown that parenterally fed neonates on extracorporeal life support are in hypermetabolic and protein catabolic states. These authors recommend the provision of additional protein and non-protein calories to attenuate the net protein losses. Sepsis is an intriguing pathological condition associated with many complex metabolic and physiological alterations.30 Studies in adults have shown that the metabolic response to sepsis is characterized by hypermetabolism as documented by an increase in resting energy expenditure up to 49% above that predicted.31 In addition, increased tissue catabolism,31 gluconeogenesis and hepatic release of glucose32 have been described. Energy is largely derived from endogenous fat, and the increased protein catabolism provides precursors for enhanced hepatic gluconeogenesis.32 In adult patients with sepsis it has been shown that: 1 During the ﬁrst 10 days from the onset of sepsis, 67% of the protein loss derives from skeletal muscle; after this time protein loss is predominantly from viscera31 2 Fat mobilization is far greater than fat oxidation, implying considerable cycling.33 At a later stage in sepsis, impaired oxidative metabolism and major metabolic abnormalities develop34 and exogenous fat utilization may become impaired.35 The interaction between exogenous lipid administration, immune response and tissue catabolism deserves further investigation.34 The existing knowledge on the metabolic response to sepsis in infants is limited. A recent metabolic study in septic neonates with necrotizing enterocolitis by Powis et al.14 failed to show any increase in whole-body protein turnover, synthesis and catabolism. The metabolic rate and hormonal response to stress and sepsis in infants may be different from that of adults and therefore it is not possible to adapt recommendations made for adults to the neonatal population. It is possible that neonates divert the products of protein synthesis and breakdown from growth into tissue repair. This may explain the lack

106 Nutrition

of growth commonly observed in infants with critical illness or sepsis. Further studies are needed in this ﬁeld to delineate the metabolic response of neonates and children to trauma and sepsis, explore the relationship between nutrition and immunity and to design the most appropriate diet.

PARENTERAL NUTRITION Indications Parenteral nutrition should be utilized when enteral feeding is impossible, inadequate or hazardous for more than 4–5 days. The most frequent indication in neonatal surgery is intestinal obstruction due to congenital anomalies. Frequently after an operation on the gastrointestinal tract, adequate enteral feeding cannot be achieved for more than 1 week and parenteral nutrition becomes necessary. This modality of therapy has improved signiﬁcantly the survival rate of newborns with gastroschisis, a condition that requires i.v. administration of nutrients for 2–3 weeks. Parenteral nutrition is also used in cases of necrotizing enterocolitis, shortbowel syndrome, and respiratory distress.

Fluid requirements A newborn deprived of oral ﬂuids will lose body ﬂuids and electrolytes in urine, stools, sweat and evaporative losses from the lungs and skin. The insensible water losses from the skin are particularly high (up to 80–100 ml/kg/day) in LBW infants.36 This is due to the very large surface area relative to body weight, the very thin and permeable epidermidis, reduced subcutaneous fat, and large proportion of total body water and extracellular water.36 The preterm infant requires larger amounts of ﬂuid to replace the high obligatory renal water excretion due to the limited ability to concentrate urine. The maintenance requirements can be calculated as follows: water losses = insensible (lungs + skin) + urine + stool + sweat + drainages ﬂuid requirements = losses + water for tissue synthesis – water from oxidation

The average water losses in newborns weighing > 2.5 kg are 100 ml/kg/day. In neonates with a weight < 1.5 kg the losses can be as high as 170 ml/kg/day. The water for tissue synthesis can be calculated from the daily weight gain: if this is 20 g/kg and the total body water is 80%, then 16 g/kg/day of water is required. This amount of water requirement is approximately offset by the water production from fuel oxidation. In surgical newborns it is not unusual to see signiﬁcant water losses from gastric

drainage and gastrointestinal stoma. These should be replaced on a ml-per-ml basis. Factors that increase the ﬂuid requirements are: 1 2 3 4 5

Use of a radiant warmer Phototherapy Fever Respiratory distress I.v. feeding.

In order to reduce water losses it is important to use double-walled incubators, to place the infant in relatively high humidity, to use warm, humidiﬁed air via the endotracheal tube, and in premature babies to cover the body surface with an impermeable plastic sheet. On the ﬁrst day of life, preterm newborns weighing < 1.5 kg should receive 80 ml/kg/day. Term neonates with a weight exceeding 1.5 kg should receive 60 ml/kg/day. This amount should be increased progressively day-by-day adjusting the requirements on the basis of the individual needs. Daily weight, ﬂuid balance (intake–output), urine osmolality, and serum electrolytes help to deﬁne the patient’s water requirements. Complications such as patent ductus arteriosus, necrotizing enterocolitis, pulmonary edema, and bronchopulmonary dysplasia are related to overhydration of high-risk infants and can be avoided by a careful monitoring of the above-mentioned parameters.

Components of parenteral nutrition The parenteral nutrition formulation includes carbohydrate, fat, protein, electrolytes, vitamins, trace elements and water. The caloric needs for TPN are provided by carbohydrate and lipid. Protein is not used as a source of calories, since the catabolism of protein to produce energy is an uneconomic metabolic process compared to the oxidation of carbohydrate and fat which produces more energy at a lower metabolic cost. The ideal TPN regimen therefore should provide enough amino acids for protein turnover and tissue growth, and sufﬁcient calories to minimize protein oxidation for energy.

CARBOHYDRATE Glucose is the natural energy source for body cells and is the primary energy substrate in parenteral nutrition. The amount of glucose that can be infused safely depends on the clinical condition and maturity of the infant. The ability of neonates to metabolize glucose may be impaired by prematurity and low birth weight. Carbohydrate conversion to fat (lipogenesis) occurs when glucose intake exceeds metabolic needs. The risks associated with this process are twofold: accumulation of the newly synthesized fat in the liver,37 and aggravation of respiratory acidosis resulting from increased CO2 production, particularly in patients with compromised pulmonary function.38

Parenteral nutrition 107

Jones et al.39 have shown that in surgical infants receiving parenteral nutrition there is a negative linear relationship between glucose intake (g/kg/day) and fat utilization (oxidation and conversion to fat) expressed in g/kg/day (y=4.547–0.254x; r=–0.937; P<0.0001). From this equation it was calculated that ‘net fat synthesis from glucose’ exceeds ‘net fat oxidation’ when the glucose intake is greater than 18 g/kg/day (Fig. 9.3). Jones et al.39 have also found a signiﬁcant relationship between glucose intake and CO2 production (ml/kg/min) (y= 3.849+0.183x; r=0.825; P<0.0001). The slope of this relationship was steeper when glucose intake exceeded 18 g/kg/day (y=2.62+0.244x; r=0.746; P<0.05), than when glucose intake was less than 18 g/kg/day (y= 5.30+0.069x; r=0.264; P=0.461). The conversion of glucose to fat thus results in a signiﬁcantly increased production of CO2. Glucose intake exceeding 18 g/kg/day is also associated with a signiﬁcant increase in respiratory rate and plasma triglyceride levels. In summary: 1 Glucose intake is the principle determinant of carbohydrate and fat utilization. 2 The maximal oxidative capacity for glucose in surgical infants is 18 g/kg/day, which is equivalent to the energy expenditure of the infant. 3 If glucose is given in excess of maximal oxidative capacity: ∑ Net fat oxidation ceases ∑ Net fat synthesis begins ∑ The thermogenic effect of glucose increases and the efﬁciency with which glucose is metabolized decreases ∑ Carbon dioxide production increases, and respiratory rate increases ∑ Plasma triglyceride levels increase.

FAT Since the 1960s, safe commercial i.v. fat emulsions have become widely used. These preparations have a high caloric value (9 kcal/g of fat), prevent essential fatty acid deﬁciency,41,42 and are isotonic, allowing adequate calories to be given via a peripheral vein.43 A number of studies in both adults and infants have indicated that a combined infusion of glucose and lipids might confer a metabolic advantage over a glucose infusion alone, because it lowers the metabolic rate and increases the efﬁciency of energy utilization.44–46 Fat tolerance has been extensively studied by monitoring fat clearance from plasma. However, clearance from plasma does not imply that the fat is being utilized to meet energy requirements, since it may be being stored instead.40,47 Pierro et al. have studied i.v. fat utilization by performing an ‘Intralipid utilization test’.40 This consisted of infusing for 4 hours Intralipid 10% in isocaloric and isovolemic amounts to the previously given mixture of glucose and amino acids. Gas exchange was measured by indirect calorimetry to calculate the patient’s O2 consumption and CO2 production, and net fat utilization (Fig. 9.4). The study showed that: (1) surgical infants adapt rapidly (within 2 hours) to the i.v. infusion of fat; (2) more than 80% of the exogenous fat can be oxidized; (3) CO2 production is reduced during fat infusion as a consequence of the cessation of carbohydrate conversion to fat (lipogenesis).40 This study did not measure the rate of fat utilization during a mixed i.v. diet including carbohydrate, amino acids and fat. More recent studies on stable surgical newborns receiving ﬁxed amounts of carbohydrate and amino acids and variable amounts of i.v. long-chain triglycerides (LCTs) fat emulsion have shown that at a carbohydrate intake of

It is advisable therefore in stable surgical newborns requiring parenteral nutrition to not exceed 18 g/kg/day of i.v. glucose intake.39,40

Figure 9.3 Linear relationship between glucose intake and fat utilization (r=–0.9; P<0.0001). Lipogenesis is signiﬁcant when glucose intake exceeds 18 g/kg/day (Reprinted from Pierro et al. J Pediatr Surg 2002; 37(6):811–22), with permission from Elsevier Science)39

Figure 9.4 Intralipid utilization test: surgical newborns adapt very rapidly to the infusion of i.v. fat. At 2 hours after the administration of i.v. fat they utilize approximately 3 g/kg/day. The oxidation of exogenous fat is associated with a signiﬁcant reduction in CO2 production. Fat utilization open . symbols; CO2 production.V CO2 closed symbols) (Reprinted from J Pediatr Surg, Metabolism and Nutritional Support in the Surgical Neonate, 2002; 37(6):811–22, with permission from Elsevier Science)

108 Nutrition

15 g/kg/day (56.3 kcal/kg/day), the proportion of energy metabolism derived from fat oxidation does not exceed 20% even with a fat intake as high as 6 g/kg/day. At a carbohydrate intake of 10 g/kg/day this proportion can be as high as 50%.48 This study seems to indicate that during parenteral nutrition in surgical infants the majority of the i.v. fat infused is not oxidized but deposited. Net fat oxidation seems to be signiﬁcantly inﬂuenced by the carbohydrate intake and the resting energy expenditure of the neonate. When the intake of glucose calories exceeds the resting energy expenditure of the infant, net fat oxidation is minimal regardless of fat intake.48 In order to use i.v. fat as an energy source (i.e. oxidation to CO2 and H2O), it is necessary to maintain carbohydrate intake below basal energy requirements. Commonly used fat emulsions for parenteral nutrition in pediatrics are based on LCTs. The rate of i.v. fat oxidation during TPN can be theoretically enhanced by the addition to the i.v. diet of L-carnitine and/or medium-chain triglycerides (MCTs). Important differences have been observed between MCTs and LCTs with respect to physical and metabolic properties. MCTs are cleared from the bloodstream at a faster rate and are oxidized more completely for energy production than LCTs. Therefore, they seem to serve as a preferential energy source for the body. The current author has recently investigated the effects of MCT on i.v. fat utilization during TPN in stable surgical newborns. Two groups of surgical infants receiving TPN were studied: one group received LCT-based (100% LCT) fat emulsion and the other group received an isocaloric amount of MCT-based (50% MCT + 50% LCT) fat emulsion. In infants receiving carbohydrate calories in excess of measured resting energy expenditure (56 kcal/kg/day), net fat oxidation was not enhanced by the administration of MCT-based fat emulsion. Conversely in infants receiving carbohydrate calories below resting energy expenditure (41 kcal/kg/day), the administration of MCT fat emulsion increased net fat oxidation from 0.6±0.2 to 1.7±0.2 g/kg/day. The administration of MCT-based fat emulsion did not increase the metabolic rate of the infants.

PROTEIN In contrast to healthy adults who exist in a state of neutral nitrogen balance, infants need to be in positive nitrogen balance in order to achieve satisfactory growth and development. Infants are efﬁcient at retaining nitrogen, and can retain up to 80% of the metabolizable protein intake on both oral and i.v. diets.49–51 Protein metabolism is dependent upon both protein and energy intake. The inﬂuence of dietary protein is well established. An increased protein intake has been shown to enhance protein synthesis,52,53 reduce endogenous protein breakdown,54 and thus enhance net protein retention.50,54 The protein requirements of newborns are

between 2.5 and 3.0 g/kg/day. The nitrogen source of TPN is usually provided as a mixture of cristalline amino acids. The solutions commercially available contain the eight known essential amino acids plus histidine, which is known to be essential in children.55 Complications like azotemia, hyperammonemia, and metabolic acidosis have been described in patients receiving high levels of i.v. amino acids.36 These complications are rarely seen with amino acid intake of 2–3 g/kg/day.56 In patients with severe malnutrition or with additional losses (i.e. those with a jejunostomy or ileostomy), the protein requirements are higher.55 The inﬂuence of non-protein energy intake on protein metabolism is more controversial. Protein retention can be enhanced by giving carbohydrate or fat,57–62 which are thus said to be protein sparing. Although some studies have suggested that the protein-sparing effect of carbohydrate is greater than that of fat,57–59 others have suggested that the protein-sparing effect of fat may be either equivalent to, or greater than, that of carbohydrate.60–62 The addition of fat calories to the i.v. diet of surgical newborns reduces protein oxidation, protein contribution to the energy expenditure, and increases protein retention.62 In order to further investigate this positive effect on protein metabolism the author studied the various components of whole-protein metabolism by the combined technique of indirect calorimetry and stable isotope (13C-leucine) tracer technique. Two groups of neonates receiving isonitrogenous and isocaloric TPN were studied: one group received a high fat diet and the other a high carbohydrate diet.63,64 There was no signiﬁcant difference between the two groups with regard to any of the components of whole-body protein metabolism: protein synthesis, protein breakdown, protein oxidation/excretion, and total protein ﬂux. This study conﬁrms previous observations that infants have high rates of protein turnover, synthesis and breakdown, which may be up to eight times greater than those reported in adults. In newborns receiving parenteral nutrition, synthesis and breakdown of endogenous body protein far exceeded intake and oxidation of exogenous protein. Infants are avid retainers of nitrogen, and carbohydrate and fat have an equivalent effect on protein metabolism. This supports the use of i.v. fat in the i.v. diet of surgical newborns. The ideal quantitative composition of amino acid solutions is still controversial. In newborns, cysteine, taurine, and tyrosine seem to be essential amino acids. However the addition of cysteine in the parenteral nutrition of neonates does not cause any difference in the growth rate and nitrogen retention.50 The essentiality of the earlier mentioned amino acids could be related to the synthesis of neurotransmitter, bile salts and hormones. The consequences of failure to supply these amino acids may be poor long-term neurological or gastrointestinal function.65 The incidence of abnormalities of plasma aminograms during parenteral

Parenteral nutrition 109

nutrition is low. There are no convincing data at the moment to support the selection of one crystalline amino acid solution over another in newborns.

SPECIAL NUTRIENTS: GLUTAMINE Nutrients can modulate immune, metabolic and inﬂammatory responses. Of these nutrients, glutamine is of particular interest. Glutamine is the most abundant free amino acid in the body, where it plays fundamental physiological roles. It is the predominant amino acid supplied to the fetus through the placenta66 and it is normally present in the enteral diet. Glutamine can be synthesized in the human body in substantial amounts and therefore is usually considered to be non-essential. However, in patients with acute and long-term sepsis and/or trauma, glutamine stores decline. This may be due to a combination of reduced glutamine production, possibly reﬂecting low muscle glycogen levels, glucose intolerance, and increased glutamine utilization. During sepsis, the liver and immune system become major glutamine consumers such that net glutamine utilization exceeds production and glutamine becomes ‘conditionally essential’.67,68 In rats, glutamine oxidation supplies a third of the total energy requirement of the gut.69 In humans who have sustained multisystem trauma or sepsis, glutamine concentration is 15% higher in arterial blood than in portal blood, conﬁrming the selective uptake of glutamine in the gut.70 There are several reasons why glutamine may be beneﬁcial for critically ill patients receiving parenteral nutrition. Firstly, glutamine supplementation has been shown to be beneﬁcial, both in vitro and in vivo, for the immune system.71 Glutamine is thought to be an important fuel and regulator of protein synthesis for cells of the immune system. An in vitro study has shown that glutamine supplementation is directly correlated with the host response to a range of different antigens including microrganisms.72,73 Animal studies have demonstrated that the glutamine-supplemented diet compared to standard parenteral nutrition preserves immunity in the respiratory tract, reduces mortality to a lethal bacterial challenge and reduces central venous catheter infection.74 Until recently glutamine has been excluded from parenteral nutrition because of low solubility and instability in solution. However glutamine dipeptides with improved stability and solubility are now available, making it possible to add glutamine to parenteral

nutrition formulation.75 The effect of glutamine supplementation on the prevention of infectious complications has been examined in randomized trials in adult patients receiving either glutamine-supplemented parenteral nutrition or isonitrogenous isocaloric parenteral nutrition. These trials included patients undergoing elective operations for colorectal cancer, patients with multiple trauma,76 critically ill patients77 and patients undergoing bone marrow transplantation.71 All these studies showed that parenteral glutamine administration does reduce infectious complications. Secondly, glutamine has multiple effects on gastrointestinal function. Glutamine deﬁciency leads to gut atrophy and bacterial translocation.77–80 Several studies in animals have investigated the effects of supplementing nutrition with glutamine on the preservation of the gut mucosal barrier during stress.78,80–82 Glutamine prevents deterioration of gut permeability, prevents intestinal mucosal atrophy83 and preserves mucosal structure in patients receiving parenteral nutrition.84,85 Reduced nitrogen loss has been demonstrated in adult patients receiving glutamine-supplemented parenteral nutrition after major abdominal operations.86 Recent studies have shown that in a neonatal animal model, glutamine reverses the liver dysfunction caused by sepsis due to an increase in the production of glutathione, a major intracellular antioxidant, for which glutamine is an important precursor.87,88 There have been several trials of glutamine parenteral nutrition supplementation in adults. However, a recent Cochrane systematic review has identiﬁed only two published randomized, controlled trials of glutamine use in neonates 89,90 including one on parenteral nutrition supplementation.89 This trial did not identify any adverse effects attributable to glutamine.89 Glutamine administration was associated with a reduced duration of artiﬁcial ventilation, hospital admission and parenteral nutrition,89 but effects on immunity or infection and its generalizability to other settings or patient groups remains unclear.91

Guidelines for the prescription of parenteral nutrition The author’s recommendations for the prescription of parenteral nutrition in surgical neonates are summarized in Table 9.1. I.v. calorie intake should be progressively

Table 9.1 Parenteral nutrition formulation Component

Day 1

Daily increment

Maximum dose

Intravenous ﬂuid Carbohydrate Fat Amino acids

80–100 ml/kg/day 10 g/kg/day 1 g/kg/day 1 g/kg/day

According to patient’s needs 4 g/kg/day 1 g/kg/day 1 g/kg/day

180 ml/kg/day 22 g/kg/day 4 g/kg/day 3 g/kg/day

110 Nutrition

increased over a 5-day period. I.v. carbohydrate intake should be increased from 10 g/kg/day on the ﬁrst day of parenteral nutrition to a maximum of 22 g/kg/day. I.v. amino acid intake should be increased from 1 g/kg/day on the ﬁrst day of parenteral nutrition to a maximum of 3 g/kg/day. I.v. fat should be increased from 1 g/kg/day on the ﬁrst day of parenteral nutrition to a maximum of 4 g/kg/day. Non-protein i.v. calorie intake, after achieving stabilization, should vary from 80–120 kcal/kg/day according to weight gain and individual needs.

Complications of parenteral nutrition The complications of parenteral nutrition can be classiﬁed as those that are: 1 2 3 4

Infectious Metabolic Mechanical Hepatic.

INFECTIOUS COMPLICATIONS In spite of signiﬁcant improvement in the management of parenteral nutrition including the introduction of nutrition support teams, recently published infection rates from large children’s hospitals indicate that between 5% and 37% of infants may develop sepsis while receiving parenteral nutrition.92–95 This may lead to impaired liver function,95,96 critical illness and removal of central venous catheters. It has always been assumed that the central venous catheter is the major portal of entry for micro-organisms causing septicemia in patients on parenteral nutrition.93 However, studies in animals97 and surgical neonates95 have reported microbial translocation (migration of micro-organisms from the intestinal lumen to the systemic circulation) during parenteral nutrition. In a study on surgical neonates on parenteral nutrition95 all but one episode of microbial translocation occurred in patients with elevated serum bilirubin levels (cholestasis). Pierro et al.96 have reported that almost half of the surgical infants on parenteral nutrition develop abnormal ﬂora and that all cases of septicemia were preceded by gut colonization with abnormal ﬂora.96 Furthermore, it has been reported 98,99 that parenteral nutrition itself impairs host defense mechanisms and contributes to the occurrence of infection.100 This may be due to individual components of the parenteral nutrition solution, such as lipid emulsion101–104 or due to lack of nutrients, such as glutamine, normally present in the enteral diet. Important factors in reducing the incidence of septic complications are the placing of i.v. catheters under strict aseptic conditions, preparing the parenteral nutrition solutions in pharmacy in aseptic conditions and using meticulous care when catheters are used.

Every 4 days, the dressing on the exit site of the i.v. line should be removed aseptically, the skin should be cleansed with an antiseptic solution, and a sterile dressing reapplied. A 0.22 μ ﬁlter can be placed in-line to remove particulate matter, such as calcium salts or micro-organisms that may have contaminated the solution. All i.v. tubing and the containers of infusate should be changed daily. Chlorexidine 0.5% in 70% alcohol solution should be applied to all joints in the circuit to prevent entry of micro-organisms. Sepsis should be suspected when infants on parenteral nutrition present clinical features of generalized inﬂammation including one or more of the following features: temperature instability, poor perfusion, hypotension, lethargy, tachycardia, respiratory distress, and fever. In these neonates blood culture should be performed from the central venous line and/or from a peripheral vein. The current author suggests starting blind therapy with a combination of teicoplanin and gentamicin at the onset of sepsis. The aminoglycoside can be stopped in case of a Gram-positive micro-organism. In cases of Gram-negative bacillary septicemia, the glycopeptide should be discontinued and replaced by a second- or third-generation cephalosporin. In case of fungemia, liposomal amphotericin B can be administered. If cultures prove to be negative, antibiotics should be discontinued unless the severity of the sepsis warrants a full 5-day course of treatment. In the majority of neonates (80–90%) with positive blood culture, the central venous catheter can be salvaged with a 7-day course of antibiotics. In those patients who do not respond to antibiotic treatment it is advisable to remove the central venous line and insert a peripheral cannula for peripheral parenteral nutrition and i.v. antibiotic administration. A new central venous line should be inserted at least 4–5 days after cessation of the clinical features of generalized inﬂammation.

METABOLIC COMPLICATIONS The metabolic complications most frequently observed in newborns receiving parenteral nutrition are listed in Box 9.1. These complications are related to inappropriate administration of nutrients, ﬂuid, electrolytes, and trace elements or to the inability of the individual patient to metabolize the i.v. diet. Hyperglycemia occurs frequently during the course of parenteral nutrition, particularly while the glucose concentration of the infusate is being increased. Unless 4+ glycosuria or osmotic diuresis occurs, the hyperglycemia is best left untreated because most patients will, within hours, produce adequate endogenous insulin to metabolize the carbohydrate load. The treatment of symptomatic hyperglycemia usually is reduction of the infusion rate. When hyperosmolality occurs, the osmolality of the infusate must be decreased; rarely, insulin will be required.

Parenteral nutrition 111 Box 9.1 Metabolic complications of TPN Carbohydrate administration Hyperglycemia Hypoglycemia Fatty inﬁltration of the liver Hyperosmolarity and osmotic diuresis Increased CO2 production Protein administration Hyperammonemia, azotemia Abnormal plasma aminograms Hepatic dysfunction Cholestatic jaundice Fat administration Hyperlipidemia Fat overload syndrome Displacement of albumin-bound bilirubin by free fatty acids Peroxidation and generation of free radicals Fluid administration Patent ductus arteriosus Pulmonary edema Electrolyte imbalance Sodium, potassium, cholorine, calcium, phosphate Trace element and vitamin deﬁciency

Hypoglycemia usually results from sudden interruption of an infusion containing a high glucose concentration. The treatment is i.v. glucose by bolus or infusion of a 10% solution. High doses of fat or an accidental rapid infusion of fat may lead to fat overload syndrome, characterized by an acute febrile illness with jaundice and abnormal coagulation. Treatment is symptomatic and lipid fusion must be discontinued.105,106 The i.v. administration of fat emulsion in premature infants seems to increase the incidence of bronchopulmonary dysplasia and retinopathy.107 Peroxidation in stored fat emulsions, occlusion stored fat emulsions, and the generation of free radicals during i.v. infusion of fat in premature infants have been reported.108 The release of free radicals may overwhelm the endogenous protective mechanisms, resulting in cellular damage.109

MECHANICAL COMPLICATIONS Mechanical complications related to the i.v. infusion of nutrients are not uncommon. Box 9.2 lists the mechanical complications reported in the literature. Extravasation of parenteral nutrition solution is a common complication of peripheral parenteral nutrition. The ﬁnal concentration of parenteral nutrition for peripheral infusion should not exceed 10% dextrose and 2% amino acids. Unfortunately even a low osmolarity solution is

Box 9.2 Mechanical complications of parenteral nutrition Extravasation of parenteral nutrition solution Blockage of the central venous line Migration of the central venous line Breakage of the infusion line Right atrium thrombosis Cardiac tamponade (perforation of right atrium or vena cava)

detrimental for peripheral veins leading to inﬂammation and extravasation of the solution. This can cause tissue necrosis and infection. Careful monitoring of the infusion site and use of infusion pumps sensitive to changes in pressure can alert the nurse and surgeon to the need for discontinuing the infusion and re-siting of the i.v. cannula. I.v. lines may become clogged from thrombus formation, calcium precipitates, or lipid deposition. A urokinase (5000 U/ml) ﬂush should be tried ﬁrst, allowing for a 20-minute dwelling time. If this is unsuccessful, 0.1 N hydrochloric acid (HCl) or ethanol 70% can be tried. Since the volume of neonatal lines is small, very limited amounts of the above agents need to be used (0.001–0.004 ml/cm). There is disagreement on the ideal position of central venous lines for parenteral nutrition in infants. Some authors advocate the atrium as the ideal position because this would give less chance of catheter dysfunction.110,111 Others believe that placement in the superior vena cava would reduce the risk of perforation.112,113 There are no controlled trials to advise against positioning the tip of the central venous line in the right atrium. The risk of thrombosis of the superior vena cava is not abolished by positioning the tip of the line in the right atrium. In the current author’s opinion, the tip of the central venous line can be positioned either in the superior vena cava or in the right atrium. In small preterm infants the distance between the superior vena cava and the right atrium is very small. Current imaging techniques with the use of i.v. contrast should be able to differentiate between tips of lines located in the superior vena cava from those located in the right atrium. In a survey of 587 CVLs inserted in neonates,114 cardiac tamponade was the cause of death in two neonates (0.3%). In most of the cases reported in literature of cardiac tamponade following CVL insertion, the perforation was thought to be in the right atrium.112,113,115 Cardiac tamponade should be suspected in any patient with a CVL whose condition deteriorates suddenly. Immediate chest X-ray and echocardiogram should be performed to support the diagnosis. However when the patient’s condition is deteriorating rapidly, a diagnostic (and therapeutic as well!) pericardiocentesis should be performed without waiting for other diagnostic measures.116

112 Nutrition

HEPATIC COMPLICATIONS The hepatobiliary complications related to parenteral nutrition remain serious and often life threatening. The commonest hepatobiliary complication of parenteral nutrition in surgical neonates is cholestasis. The incidence of parenteral nutrition-related cholestasis varies widely from as low as 7.4%117 to as high as 84%.118 The etiological factors for the development of cholestatic jaundice in infants requiring parenteral nutrition are still unclear. Peden et al.119 ﬁrst reported in 1971 the development of liver disease in a preterm infant who was receiving parenteral nutrition from birth until the infant’s death at the age of 71 days. At autopsy the infant’s liver revealed cholestasis, bile duct proliferation, and early cirrhosis. The association between cholestasis and parenteral nutrition has been subsequently criticized by Rager and Finegold,120 who from a series of autopsy studies concluded that early fasting, rather than parenteral supplementation, may contribute to impaired hepatobiliary function in the small premature infant. Since these initial reports there have been several other publications on parenteral nutrition-related cholestasis. The frequency of this complication seems to be diminishing.121 However this is probably related to the early initiation of oral feeding rather than to an improvement in the i.v. diet. The clinical presentation of parenteral nutrition-related cholestasis is fairly typical. The infants requiring long-term parenteral nutrition develop progressive jaundice. This is commonly preceded by elevation of biochemical non-speciﬁc tests of hepatic damage, function and excretion. Various clinical factors are thought to contribute to the development of parenteral nutrition-related cholestasis (Box 9.3). These factors include prematurity, low birth weight, duration of parenteral nutrition, immature entero-hepatic circulation, intestinal microﬂora, septicemia, failure to implement enteral nutrition, and number of operations.122,123 Parenteral nutritionrelated cholestasis is a diagnosis of exclusion without any speciﬁc marker yet available. Therefore infants with cholestasis who are receiving or have received parenteral Box 9.3 Patient risk factors for the development of parenteral nutrition-related cholestasis Age Prematurity Immaturity of biliary secretory system Absence of oral/enteral intake Septicemia Bacterial overgrowth in the small bowel Short bowel length Necrotizing enterocolitis Hypoxia Major abdominal operations General anesthesia

nutrition must have an appropriate diagnostic evaluation to exclude other entities. These include bacterial and viral infections, metabolic diseases and congenital anomalies.124 When serial ultrasound examination of liver and gallbladder is performed in infants receiving parenteral nutrition, biliary sludge and cholelithiasis can be detected. Sludge is a dense ﬂuid lying in the dependent portion of the gallbladder, which produces low amplitude echoes.124 The incidence of sludge formation increases with duration of parenteral nutrition. Gallbladder sludge appeared in 18 neonates (44%) after a mean period of 10 days of parenteral nutrition.125 Sludge can progress to ‘sludge balls’ and gallstones. Asymptomatic infants can develop biliary stones and spontaneous resolution of the stones has been described.125 Cholecystitis in infants receiving parenteral nutrition is rare. Serial liver ultrasound examinations of neonates and infants receiving parenteral nutrition are advisable to detect abnormalities and/or to follow the abnormal gallbladder content. Parenteral nutrition-related cholestasis is progressive unless parenteral nutrition is ceased and enteral feeding introduced. Hepatosplenomegaly and severe jaundice are characteristic features of advanced disease. Neither of these signs, however, are pathognomonic for this condition and the diagnosis of hemolytic anemias, infection and metabolic disease should be excluded.124 Portal hypertension may develop and indeed be fatal. Although the parenteral nutrition-related cholestasis resolves with time after discontinuation of parenteral nutrition, in a small percentage of cases it remains intractable and progresses to severe hepatic dysfunction and death.126 In spite of 20 years of clinical experience with parenteral nutrition and several studies in animals and humans, the etiology of parenteral nutrition-related cholestasis remains unclear. Different factors may contribute to the development of the disease. These include the toxicity of parenteral nutrients, lack of enteral feeding, continuous non-pulsatile delivery of nutrients and host factors. Most of the components of parenteral nutrition have been thought to be implicated in the pathogenesis of cholestasis. Hepatic damage from the components of i.v. diet may result from excessive nutrient administration, deﬁcient nutrient administration, toxicity of by-products, and abnormal metabolism in the neonate. The infant’s clinical status inﬂuences the likelihood of parenteral nutrition-related cholestasis development. Box 9.3 lists the most common risk factors. Parenteral nutrition-related cholestasis has a higher incidence in premature infants than in children and adults. This may be due to the immaturity of the biliary secretory system since bile salts pool size, synthesis, and intestinal concentration are low in premature infants in comparison with full-term infants.127 The clinical care of infants and children who require parenteral nutrition and develop progressive jaundice

Parenteral nutrition 113

represents a real challenge. The difﬁculty is compounded by the lack of a full understanding of the pathological mechanisms of parenteral nutrition-related cholestasis. None of the experimental animal models for the disease can be extrapolated to the clinical situation, since the histological ﬁndings in the liver of animals on parenteral nutrition are not similar to those found in the livers of affected human infants and children. Most of the recommendations for prevention and treatment are therefore empirical and often not based on substantial clinical evidence. Prevention of parenteral nutrition-related cholestasis is based on the early usage of enteral feeding and the administration of i.v. feeding only when appropriate and necessary. In most patients the cholestasis resolves gradually as enteral feedings are initiated and parenteral nutrition is discontinued. Continuation of parenteral nutrition is usually associated with exacerbation of the liver damage; therefore every effort should be made to introduce enteral feeding. It has been recently shown that minimal bolus enteral feeding (1 ml/kg) during parenteral nutrition in premature infants induces signiﬁcant gallbladder contraction and after 3 days of starting minimal enteral feeds, the gallbladder volume returns to normal.128 Unfortunately, as a consequence of gut dysfunction, enteral feeding is often not feasible. In these cases the provision of i.v. calories should not be discontinued since malnutrition and increased risk of infection may result. The calorie needs of the patient should be carefully assessed and overfeeding should be avoided. Maini et al.129 suggested that cycling the parenteral nutrition may diminish cholestatic hepatic changes in adults. This may explain the less frequent liver disease in children receiving their parenteral nutrition cyclically at home. Experience with this technique in premature infants is extremely limited but encouraging.130,131 Rebound hypoglycemia is a common complication of this approach. Modiﬁcation of the constituents of parenteral nutrition has been proposed but no prospective trial has demonstrated any beneﬁt in reducing or changing the intake of nutrients. Several reports have described the attempts to use drug therapy to treat or prevent parenteral nutritionrelated cholestasis. Antibiotics such as metronidazole have been proposed to decrease bacterial overgrowth, formation of secondary toxic bile acids and production of endotoxins.132 In a subsequent animal study, however, metronidazole administration did not prevent development of abnormal liver enzymes on parenteral nutrition.133 Choleretics such as phenobarbital have been used with negative results.130 Cholecystokinin has been administered to diminish the gallbladder stasis and promote bile ﬂow. Sitzmann et al.134 have demonstrated in a randomized, double-blind controlled study in adults receiving parenteral nutrition that cholecystokinin given intravenously daily prevents stasis and sludge in the gallbladder. Rintala et al.135 reported the reversal of parenteral nutrition-related cholestasis in seven infants

by i.v. administration of cholecystokinin three times a day for 3–5 days. However all the patients except one were completely weaned from parenteral nutrition before the treatment with cholecystokinin. In rabbits maintained on total parenteral nutrition, daily infusions of cholecystokinin decreased periportal inﬂammation and ﬁbrosis, maintained gallbladder emptying capacity, and improved organic anion secretion, although bile ﬂow and bile acid secretion were not improved, and hepatocyte damage persisted.136 Prospective studies are needed to investigate, in infants and children requiring parenteral nutrition, the effects of exogenous cholecystokinin administration on bile ﬂow and cholestatic jaundice. Ursodeoxycholic acid can be used in infants and children on parenteral nutrition to correct the decreased secretion of endogenous bile acids.121 Ursodeoxycholic acid is non-toxic and acts as a natural bile acid after conjugation. The efﬁcacy of this treatment has been demonstrated in rabbits and sporadic case reports in humans. Controlled studies showing that ursodeoxycholic acid actually decreases morbidity and mortality in infants on long-term parenteral nutrition have not been performed.121 Biliary sludge, cholelithiasis and cholecystitis have been reported with the use of parenteral nutrition. Biliary sludge often resolves with the initiation of enteral feedings and discontinuation of parenteral nutrition. Cholecystectomy is the treatment of choice for patients with acute and symptomatic cholelithiasis and cholecystitis. Rintala et al.137 have proposed laparotomy and operative cholangiography followed by biliary tract irrigation in patients with progressive cholestatic jaundice not responding to medical treatment. In some patients the hepatic disease may progress to cirrhosis, portal hypertension and hepatic failure. In selected cases small bowel and liver transplantation have been used. The introduction of tacrolimus has allowed clinical intestinal transplantation to become feasible. However infectious and immunological problems still cause signiﬁcant morbidity and mortality, even 1–3 years after transplantation.138 The author’s approach to the treatment of parenteral nutrition-related cholestasis is as follows. Once the diagnosis is established and other medical causes of jaundice have been excluded, an ultrasound of liver and extrahepatic biliary tree is repeated to exclude extrahepatic biliary pathology. If cholelithiasis and/or cholecystitis are present, a cholecystectomy with intraoperative cholangiogram is performed. If only biliary sludge is present, an operation is not performed, but serial ultrasound monitoring of the extrahepatic biliary tree is performed to detect stone formation. In the absence of gallbladder disease, the current author vigorously attempts to establish at least minimal bolus enteral feeding to stimulate endogenous cholecystokinin production. Elemental formulas containing medium-

114 Nutrition

chain triglycerides are used to improve intestinal fat absorption. Surveillance cultures of throat, rectum, and stool are taken to detect bacterial overgrowth. If present, selective decontamination of the digestive tract is carried out.139,140 The calorie requirements of the patients are carefully re-evaluated and the carbohydrate intake is limited to the patients’ resting energy expenditure (approximately 50 kcal/kg/day in a full-term neonate). The i.v. fat intake is discontinued for 14 days. If this produces a drop in serum bilirubin level, the lipid intake is limited to 0.5 g/kg/day on alternate days to provide essential fatty acids. Normal lipid intake is resumed if no changes are observed in serum bilirubin level. Complications from fat-soluble vitamins and/or trace element deﬁciencies are minimized with proper monitoring and supplementation. Attempts are made to cycle the i.v. infusion of nutrients by reducing the daily administration of parenteral nutrition to a maximum of 12 hours.

Monitoring of neonates on parenteral nutrition All infants receiving parenteral nutrition must have accurate monitoring of their nutritional state and growth, and for possible metabolic complications. Weight should be measured daily and plotted on a growth chart. Expected weight gain in the full-term newborn is about 20 g/day; acute changes usually reﬂect ﬂuid gain or loss. Head circumference is measured weekly, and length, monthly; these two are charted. Skinfold thickness (subscapular and triceps) and midarm muscle area measurements are not used routinely but are useful for patients on long-term parenteral nutrition in conjunction with other body dimensions141 to assess variations in body composition (total body fat and lean body mass). During the initial period while glucose, protein and fat are being introduced, and during periods of metabolic instability, ﬂuid balance, urine-speciﬁc gravity or osmolality, urine sugar and protein content, and the blood sugar level should be checked every 6 hours. The cumulative volume of blood taken for tests may become signiﬁcant and should be recorded.

Weaning from parenteral nutrition The transition to enteral feeding is begun as soon as intestinal function is judged to be adequate, bearing in mind that if feeding is advanced too quickly, this may compromise digestion and absorption, and increase ﬂuid, electrolyte and nutrient losses. Initial feeds should be hypo-osmolar and small in volume as discussed for enteral nutrition. Increases must be subtle. The parenteral nutrition infusion should be tapered progressively during the transitional period and dis-

continued only when at least 70% of the caloric needs are being tolerated enterally. If there is a severe relapse of malabsorption, enteral feeds should be discontinued until the gut has recovered, after which weaning is begun again.

ENTERAL NUTRITION The energy requirement of an infant fed enterally is greater than the i.v. requirement because of energy lost in the stools and the energy cost of diet-induced thermogenesis. Because individual requirements vary, the energy intake must be adjusted according to the infant’s growth. The protein requirements for full-term infants are 2.5–3.0 g/kg/day. Breast milk from the infant’s mother is preferred because of the anti-infectious protective functions142 and high content of non-protein metabolizable nitrogen, notably urea.143 A standard commercial formula is adequate for full-term infants with a functionally normal gastrointestinal tract, and will provide approximately 0.66 kcal/ml. Premature infants may require a special formula with calories, minerals (notably calcium) and proteins content adjusted for the special needs of these infants.15 Additional calories may be provided as glucose polymer or medium-chain triglycerides. The volume required for enteral feeds is 150–200 ml/kg, adjusted for individual needs. Following an operation, enteral feeds usually can be commenced as soon as there is continuity of function throughout the intestinal tract, demonstrated by the absence of bile in the nasogastric aspirate, a low volume of aspirate (below about 50 ml/day), and the appearance of green stools. The presence of bowel sounds indicates small bowel peristalsis but is not evidence of continuity of function. Infants who have fed before operation should be able to tolerate the same feed after operation. It is not necessary that the initial feed should be a dextrose solution. Feeds should be commenced in small volumes, every 2 or 3 hours, and increased incrementally as tolerated. Infants who are premature or too weak to take oral feeds will need to be fed by gavage. If bolus feeds are not tolerated, a continuous slow feed through a nasogastric tube beginning at 1 or 2 ml/hour is often successful. Gastro-esophageal reﬂux is common in newborns and continuous tube feeds are better tolerated in this situation. A nasoduodenal tube or feeding jejunostomy should be considered when gastric emptying is abnormal. Tolerance of feeds is monitored by recording gastric residual volumes, stool frequency and volume, and the presence or absence in the stool of blood, fat and reducing substances. Documenting the growth of the infant in terms of body weight and head circumference monitors the efﬁcacy of the feeding regimen (see monitoring).

References 115

When malabsorption is anticipated, for example in infants with meconium ileus or necrotizing enterocolitis, or with a shortened length of functional small intestine due to an extensive resection or a proximal enterostomy, a hydrolyzed casein formula may be better tolerated, especially if diluted to reduce the osmolality. An example is Pregestimil, beginning with a one-quarter- or onehalf-strength preparation.

Chemically deﬁned formulae If malabsorption persists, an appropriate speciﬁc formula should be introduced. A soy-based disaccharide-free feed is used when there is disaccharide intolerance resulting in loose stools containing disaccharides. For fat malabsorption, a formula containing MCTs should be used. An elemental formula may be indicated when there is severe malabsorption due to short bowel syndrome or severe mucosal damage as in necrotizing enterocolitis. These preparations contain amino acids, glucose and fats, including MCTs. Dipeptide preparations which include dipeptides as well as amino acids have the advantage of a lower osmolality, are well absorbed and have a more palatable taste.144 For persistent severe malabsorption, a modular diet may be neccesary.145,146 Glucose, amino acid and MCT preparations are provided separately, beginning with the amino acid solution and adding the glucose and then the fats as tolerated. Minerals, trace elements and vitamins are also added. These solutions have a high osmolality and if given too quickly may precipitate dumping syndrome, with diahorrea, abdominal cramps and hypoglycemia. It is important therefore to start with a dilute solution and increase slowly the concentration and volume of each component. This may take several weeks and infants will need parenteral nutritional support during this period. Infants recovering from neonatal necrotizing enterocolitis pose a particular problem as malabsorption may be severe and prolonged. These infants may have had their small bowel resected, in addition to which the remaining bowel may not have healed completely by the time feeds are begun. Feeding may provoke a relapse of the necrotizing enterocolitis and the author recommends a cautious feeding program beginning with 25% Pregestimil at a slow rate.

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10 Vascular access in the newborn JUDA Z. JONA

INTRODUCTION The establishment of specialized units for the care of the newborn, with advanced monitoring, ventilation techniques and support for the ill newborn, has markedly increased their chance for survival.1 Vascular access is one of the tools which has enabled neonatologists and surgeons to provide ongoing therapy for the babies, while at the same time securing avenues for invasive monitoring of the condition and progress of these very ill patients. The therapeutic advantages which the various catheters and cannulae provide include the ability to administer ﬂuids and electrolytes, blood products, drugs and sophisticated nutritional formulas. The monitoring beneﬁts derived from these catheters are mostly for obtaining blood samples for analysis, measuring arterial and venous pressures, and providing minute-by-minute control and response to the various therapeutic modalities, particularly ventilatory. Signiﬁcant clinical advances have been brought about by the introduction of sophisticated and miniaturized monitoring instruments that have been coupled with the development of new catheters and devices for their introduction.2

ARTERIAL CANNULATION Invasive cannulation of the arterial tree has been introduced into clinical medicine in the past three decades. Previously, arterial puncture was done infrequently and great reliance was entrusted to clinical evaluations and heel-stick blood sampling. The modern application of intra-arterial cannulation has provided a great advance in the care and management of newborns. It enables the clinician to monitor continuously the patient’s blood pressure and to obtain, at will, samples of arterial blood for blood gas analysis, which is so vital to the ventilatory and acid–base management of these babies. In addition, all sampling for laboratory tests can be performed without repeated puncture of the babies’ limbs. When

possible, we encourage percutaneous insertion of these catheters, since any surgical ‘cut’down’ has the disadvantages of providing an easy portal for infection, dislodgement and inability to reuse the site in the future.

Maintenance and complications As with all catheters and cannulas, the arterial one must be secured particularly ﬁrmly to the patient and the strictest aseptic handling maintained. Since intra-arterial devices are prone to thrombosis, in all instances, heparinization of the infusate must be used. We customarily use heparin at 1 u/ml, continuously infusing at a slow rate utilizing small-volume pumps. The combination of infusion/sensory apparatus (Spectramed transducer system) is used in our institution and permits sampling and ﬂushing without a need for line disconnection. Puncture site care is carried on at set intervals, which involves povidone-iodine repreparing and resecuring of the cannula. Dampening of the arterial tracing usually indicates malposition or microthrombi formation. In time, endothelial damage will promote more aggressive thrombus formation, but immobilization of the limb and site will reduce the chance of this happening. Complications can, at times, be serious and early recognition through continuous observation may prevent signiﬁcant ill effects. It is therefore advised that the site and the extremity as a whole be inspected frequently. An inadvertently disconnected arterial line may result in exsanguination. Peripheral ischemia, an uncommon problem, can be caused by vasospasm or microthrombic formation, which may become severe enough to cause loss of tissue or digits. This complication is more probable in babies with poor peripheral perfusion or in those on vasoactive drug therapy. Site, or systemic, infections are by far the most common complication. A sepsis rate of about 4% and local infections in 15–18% of patients have been reported.3,4 Careful site management and secure immobilization of the catheter may reduce the chance of infection.5

122 Vascular access in the newborn

Umbilical artery catheterization By and large, umbilical artery catheterization is performed by the neonatologist and/or the pediatrician and rarely an opportunity arises for the surgeon to perform this task. Much has been written in the medical literature6 concerning the technique and positioning of the catheter and the precautions one must take in order to avoid complications. This discussion will not deal with the routine umbilical artery catheterization, but rather with a variant of this technique which is employed quite commonly by pediatric surgeons and involves the transfer of the umbilical artery from its umbilical position to a para-umbilical anterior abdominal wall position. The need for this maneuver arises when one deals with the surgical correction of abdominal defects in babies who will require careful monitoring and prolonged ventilatory support. This is particularly true in premature infants in whom peripheral arterial cannulization is at times impossible and in whom continuous intra-aortic catheterization is essential. When babies with gastroschisis or omphalocele (exomphalos) are taken to the operating room for deﬁnitive primary or staged repair of their abdominal wall defect, it is readily found that direct umbilical artery catheterization is either impossible (omphalocele) or impractical, since these defects involve commonly the umbilical stump and its vicinity. In such situations, transfer of the umbilical artery is called for (Fig. 10.1).

forceps. An appropriately-sized catheter (3 Fr. or 5 Fr. gauge) should be on hand, which is speciﬁcally designed and measured for umbilical artery catheterization. A paramedian and somewhat inferior stab incision is done in an area which will be uninvolved in the surgical closure. A ﬁne-tip hemostat is then advanced through the thickness of the abdominal wall towards the free end of the artery. The artery is grasped and brought to the surface. Care must be taken in order not to twist or angulate the artery sharply, so that the catheter can be advanced smoothly in. The catheterization then progresses as it is done routinely and, at the ﬁrst convenient time, a radiograph is taken in order to ascertain the proper position of the catheter tip in the distal thoracic aorta (in some centers, distal abdominal aortic position is preferred). The cannula is secured to the artery with a 4-0 permanent ligature and is then anchored with the same ligature to the adjacent skin. Removal of the catheter, when its function is terminated, is simple and usually does not involve undue bleeding. When the umbilicus is unsuited for direct catheterization because of dryness or previous manipulations, one can attempt similar cannulation by tracing the infraumbilical course of one of the arteries and bringing it to the surface through a separate small extraperitoneal incision.7 (Fig. 10.2) At the institutions of the Children’s Hospital of Wisconsin and at the NICU–Evanston, this

UA

UV

RAM

UA

OPERATIVE TECHNIQUE At the onset of the operation, the surgeon will carefully dissect the course of the umbilical artery as it descends inferiorly from the umbilical stump towards its union with the iliac artery. This dissection, which is done just below the surface of the peritoneum, need not be carried for a long distance. With proper magniﬁcation, the umbilical artery is isolated as it is held with ﬁne-tip

Inc

UR (a)

(b)

Figure 10.1 Surgical transfer of the umbilical artery catheterization in a newborn with gastroschisis. Umbilical site (arrow head) transposed umbilical artery (arrow)

RAM

Pr

Figure 10.2 Infraumbilical cut down.The umbilical arteries (UA) are exposed through a transverse subumbilical incision (Inc). The arteries run on either side of the urachal remnant (UR) in an extraperitoneal (Pr) position. A. Location of incision. B. Cross-section representing the extraperitoneal – para urachal position of the UA. RAM: Rectus abdominal muscle; UV: Umbilical vein

Arterial cannulation 123

has occurred quite rarely and in most instances we would rather resort to peripheral arterial catheterization.

Radial artery cannulation Radial artery catheterization is a rather commonplace procedure in the hand of the neonatologist in providing access to intra-arterial monitoring. The percutaneous technique is the standard approach to the insertion of the cannula and it is successful in most instances when carried out by an experienced clinician. At times when this is impossible, the surgeon is called to assist in providing cutdown exposure and direct cannulation.

OPERATIVE TECHNIQUE After ascertaining that the circulation to the hand is present via both radial and ulnar arteries (the Tennell test), the baby’s forearm is positioned in pronation on a ﬁxation board with the hand slightly dorsiﬂexed (Fig. 10.3). All other extremities should be restrained in order to prevent unnecessary motion. The wrist area is thoroughly prepared with antiseptic solution and draped with sterile drapes. The position of the radial pulse is then determined and a short incision is made on the volar aspect of the wrist, slightly proximal to the joint. Although we prefer a small transverse incision, some surgeons may ﬁnd it more useful to make a small longitudinal one. Using only a blunt hemostat, the tissues are dissected in a longitudinal manner and the artery is isolated and elevated out of the wound over a ligature. At least 1 cm of artery should be exposed to view. An appropriately sized trocar needle/cannula (Angiocath Arrow or similar product) is then preloaded with heparin solution (10 μ/ml). With proper traction on the distal ligature, the artery is straightened and is held relatively taut (stretching it too much will reduce its calibre and make the insertion more difﬁcult). With the bevel of the needle

pointing upwardly, the artery is punctured and the needle introduced a short distance. Care must be taken and visual inspection must ascertain that the artery is not punctured through-and-through. The sheath of the cannula is then advanced over the needle into the artery and the needle withdrawn. Back-ﬂow of arterial (pulsatile) blood assures successful cannulation. At these institutions, it is recommended not to tie the ligature around the artery in order to prevent occlusion of the artery following the removal of the catheter. Two skin sutures are placed on either side of the cannula, which are used both to approximate the skin edges and also secure the cannula in its position. Tincture of benzoin is then lavishly applied and an adherent plastic sheath (Tegoderm or Opsite) is placed over the protruding part of the catheter and the connecting cannula in order to further secure it to the patient. With proper care, these catheters can be maintained for a long period of time. The complication rate following surgical cannulation of the radial artery should not be much greater than those experienced by the percutaneous technique, except that there is a slight increase of the chance of wound infection for which precautions must be undertaken.

Pedal artery cannulation When the radial arteries are found unsuitable for intraarterial monitoring, the author has used the vessels of the lower extremities, namely the dorsalis pedis and posterior tibial arteries. The former lends itself to percutaneous catheterization, whereas the latter may require surgical cut-down. Of the two, we prefer the posterior tibial artery, since it takes a straight course and it is easy to identify and cannulate. It is located just posterior to the medial malleolus, between the malleolus and the achilles tendon. The technique of insertion of the cannula into either of these two arteries is quite similar to the one done in the radial artery, and the longevity and complication rate of these cannulas are similar too.

Axillary artery cannulation

Figure 10.3 Radial artery cannulation. Note the position of the hand and the direct puncture of the artery without a cutdown (a similar puncture technique is used in peripheral vein cut-down)

The axillary artery is rarely used by the cut-down technique and is reserved mostly for intraoperative monitoring of extremely ill babies. This is done in situations where the peripheral pulses are weak and the need for immediate intra-arterial access exists. We prefer not to maintain these catheters for longer than a few hours because of the threat to the extremity from vasospasm and/or embolization. The technique involves abduction of the arm beyond 90° and ﬁxation of the skin over the medial aspect of the upper arm. Percutaneous insertion is done in the upper half of the arm towards the axilla. The need for surgical exposure of the artery for insertion has never occurred in our practice and we would rather resort to femoral arterial cannulation.

124 Vascular access in the newborn

Femoral artery cannulation The indication for using this route is similar to the one of the axillary route, namely, extreme situations when peripheral circulation is poor and immediate access is necessary. In cannulating the femoral artery, we prefer to use a Seldinger technique (over a guide wire) to make sure that the insertion of the cannula is precise and is positioned in the iliac system. Again, because of threat to the lower extremity from spasm and/or embolization, we prefer to use this route only in extreme emergencies and for as short a period as possible.

VENOUS CATHETERIZATION Artiﬁcial cannulation of the venous system in babies has been available for nearly half a century. Great advancements in utilizing this modality have occurred in recent years with the introduction of non-ferrous (plastic) catheters. The short-term application of i.v. therapy in the newborn is achieved via umbilical vein catheterization or through percutaneous puncture of a peripheral vein. These, however, are a temporary modality when ﬂuids and electrolytes, blood products and the need for exchange transfusion and drug therapy are required for a relatively short duration. Percutaneous catheterization of major veins is occasionally done, especially when the baby is extremely ill and the peripheral vascular bed is contracted. When this fails, surgical exposure and cannulation of various veins may become necessary. Needless to say, for longterm usage, there is near-universal agreement that the surgical mode of introduction is preferred over the percutaneous route.

Percutaneous cannulation As mentioned earlier, percutaneous cannulation is usually undertaken for short-term usage – generally not to exceed 1–2 weeks. This is the most common method of introduction for babies undergoing emergency neonatal operation and those who require short-term i.v. ﬂuid support and/or drug therapy.

Umbilical vein Catheterization of the umbilical vein is rather commonplace in most nurseries and neonatal units, and it can be achieved by trained hands with a great degree of success. There is a time limitation beyond which the umbilicus is unsuitable for further cannulation and in such instances the clinician must resort to other routes. Most physicians agree that umbilical vein catheterization should not be maintained for a lengthy period of time for the fear of

inducting portal vein thrombosis. It is preferred to advance the tip of the catheter along the umbilical vein through the ductus venosus into the proximity of the right atrium. This will permit the administration of a concentrated i.v. solution and reduce the risk of thrombosis. Proper positioning of the catheters and verifying its position by means of radiographs is essential. The technique of this catheterization is a standard neonatal procedure and will not be discussed here. In our surgical practice, umbilical vein catheterization is used most frequently in newborn babies who require resuscitation and transport to our institution over a distance, and in whom ﬂuid administration must be assured throughout the transport. In hospital, it is most commonly used in babies requiring exchange transfusion for various medical reasons. At times, during a course of major abdominal operation, one may need to establish a large bove i.v. channel mostly for an exsanguinating situation. Direct cannulation of the umbilical vein as it courses along the falciform ligament may be a life-saving operation. For that reason, if the umbilical vein has to be divided during the onset of the celiotomy, the vein should be divided in its subumbilical origin, in order to keep a workable length of vessel before it enters the liver parenchyma.

Peripheral veins Here again, percutaneous cannulation is a standard neonatal practice which will not be elaborated upon here, except to mention that the most commonly used veins are the ones on the dorsum of the hands and feet, the scap veins and the antecubital veins. The longevity of percutaneous catheters, however, are known to be short lived and many cannot be maintained far beyond 1 week.

Major vein cannulation8–10 At times of urgent resuscitation or when a neonate is about to undergo a major operation and a large volume of ﬂuid and blood products may be required, we prefer to introduce a larger bore cannulae into a more proximal vein. In their order of usage, we employ the external jugular veins, the internal jugular veins, the femoral veins and the subclavian veins. In our daily practice, however, the distal saphenous vein has been successfully cannulated percutaneously in the majority of babies with a 20-gauge cannula. At times, the vein at the ankle is not always visible, but with prior knowledge of its anatomical location, ‘blind’ introduction can be accomplished. The external jugular vein is our next choice. The insertion here is facilitated by slight lowering of the baby’s head. The introduction may necessitate a guide wire technique if this is found to be difﬁcult. The ﬁxation and maintenance of the external jugular cannula

Surgical introduction 125

is somewhat awkward and it is to be considered only intermediate in its longevity. The internal jugular vein is usually catheterized percutaneously in emergency situations; however, the operator must realize again that the catheter cannot be maintained for more than 1–2 weeks in this position. The technique involving internal jugular cannulation and the anatomical landmarks for its insertion have been described and will not be mentioned here.11 In general, we do not like to cannulate the femoral vein except under extreme situations, since the hazards of thrombosis and infection are quite high and we reserve this technique for very short time use, mainly during resuscitative maneuvers.

Percutaneous central catheter Percutaneous central venous catheterization through a peripheral venous site has gained popularity in our neonatal units. It is done through cannulation of a medium-sized peripheral vein (scalp or antecubital) and threading through it a soft and ﬁne Silastic catheter which is ‘carried’ by the circulation to a central position. This can be achieved even in the severely premature infant and through this ﬁne catheter, not only total parenteral nutrition but also blood and blood products can be administered. The system we use is called Per-Q-Cath, which incorporates a 1.9 Fr. gauge (23 ga) Silastic Elastomere catheter. Repeated radiographs and great patience is required to lead the catheter tip eventually through the superior vena cava to a position near the right atrium. The infection rate is comparable to our surgically implanted catheters. The peculiar organism frequently seen infecting these catheters when they are used in longterm total parenteral nutrition (TPN) is Malassezia furfur. It is an organism which is rarely seen as an offender of other types of catheter. There is excellent long-term satisfaction with this system and it has virtually replaced the need for surgical insertion in the ordinary nursery patient.

SURGICAL INTRODUCTION Peripheral vein cut-down With the advent of improved cannulas for percutaneous peripheral venous insertion, we have found that the need for peripheral cut-down has markedly diminished and nowadays it is reserved mostly for those who have an acute blood or ﬂuid loss, both causing hypovolemia and peripheral venous constriction. At times, just prior to a major surgical maneuver, in order to ensure a large caliber cannula for rapid blood and/or ﬂuid replacement, we are called upon to utilize this technique. The preferred sites of cut-down in order of frequency are the greater saphenous, just above the middle malleolus at

the ankle, the brachiocephalic vein, just above the lateral condyle of the wrist, the veins of the antecubital fossa and the saphenous vein at its proximal position below the femoral canal.

PROCEDURE After proper immobilization of the extremity and thorough skin preparation with povodone–iodine, a small amount of local anesthetic is inﬁltrated at the site. A small transverse incision is then made and the dissection is carried with a hemostat, dissecting bluntly in a longitudinal manner. When the vein is isolated, it is encircled with a small caliber ligature and it is then dissected free to a distance of approximately 1 cm. With traction on the distal ligature, the vein is elevated and is straightened, such that direct puncture of the vein can then be accomplished with a proper cannula that is sheathed over a metal needle (AngioCath). Care must be taken to keep the puncture site tangential enough in order not to penetrate the vein through-and-through, and for that reason strong traction on the ligature must be avoided. Once the cannula is advanced a short distance, the needle is withdrawn and the catheter is then advanced to its full length. A syringe with saline is then utilized to inject the solution into the cannula to make sure that it is positioned properly in the venous system. When this is conﬁrmed, the cannula is afﬁxed in place with the previously placed ligature (we prefer an absorbable material). The skin is then closed on either side of the cannula utilizing silk or nylon material and the cannula is further afﬁxed to the skin site too. A small amount of povodone–iodine ointment is then applied to the wound and the whole wound is dressed with an adherent plastic material (Tegoderm or Opsite) and infusion begun. At times when the vein needs to be dilated in order to accommodate a larger caliber cannula, we place two ligatures around the vein proximally and distally and then perform a small transverse venotomy, which should not exceed one-third of the diameter of the vein. With the help of a catheter introducer, which opens the venotomy site and at the same time dilates it as it is introduced farther into the vein (by virtue of being wedge shaped), a larger cannula can then be introduced (Fig. 10.4). The care and maintenance of these peripheral cutdowns is similar to all other peripheral intravenous sites. Immobilization is a key to prolongation of its service. By and large, we have found that introduction by the cut-down technique does not prolong the longevity over the percutaneous mode.

Central venous catheterization Parenteral nutrition is claimed to be one of the major contributors to the ever-improving survival rates of

126 Vascular access in the newborn

Figure 10.4 Catheter-introducing device opens and dilates the venotomy for catheter introduction

premature infants and neonates. The administration of hyperosmolar solution of glucose and proteins necessitated its introduction into a central vein, where immediate mixing of the i.v. ﬂuids with a large volume of blood can be achieved. This requires the positioning of the tip of the cannula as close to the right atrium as possible and, in some instances, within the lumen of the atrium itself. Parenteral nutrition is offered not only to the severely premature infant and those with debilitating nutritional problems, but more and more as a preventive measure to avert the protein wasting associated with prolonged gastrointestinal malfunction. Whenever possible, we prefer to insert the central cannula in the operating room, in a sterile environment, under general anesthesia, and with the availability of ﬂuoroscopic X-ray apparatus. When we are asked to perform this procedure on premature babies in the neonatal intensive care nursery, it is usually done in the unit itself without utilizing general anesthesia.12

SURGICAL PROCEDURE The patient is positioned supine on the operative table and a small rolled towel is placed under the baby’s shoulders, such that the neck can be extended and rotated away from the operative site. The area is thoroughly prepared and draped as for a regular operation. Care must be taken to expose the entire chest, so that the catheter can be tunnelled adequately. A slight head-down (Trendelenberg) position is advantageous when possible. If the external jugular vein is prominent, we prefer to use this vein rather than the internal jugular. Some centers have preferably used the common facial vein as the site of introduction. A small transverse incision is made in the

region of the desired vein and the vein is exposed with a curved hemostat, using blunt dissection in a longitudinal manner. When the external jugular vein is utilized, we prefer to dissect it to a point slightly behind the clavicle to avoid the branches which may be present between the insertion site and the subclavian vein. In exposing the internal jugular vein, the sternocleidomastoid muscle is split longitudinally between its two heads and the vein is carefully separated and elevated, making sure not to injure or trap the vagus nerve. In severely premature babies with a thin subcutaneous layer, we use a noncuffed catheter, otherwise a Dacron cuff (Broviac) is selected. We like to premeasure the catheter on the baby’s surface to a position slightly above the line of the nipples. A subcutaneous tunnel of 2–3 cm is created, usually from a site selected for being ﬂat and somewhat out of the way. Tunnelling via a large-bore i.v. cannula has been described previously,12 but many operators prefer other devices or techniques. The catheter is then advanced under ﬂuoroscopic control and positioned at the junction of the superior vena cava and the atrium or in a high atrial position. Insertion through the internal jugular vein is straight and usually the catheter assumes its expected route. However, insertion through the external jugular vein may cause the catheter at times to ascend along the internal jugular vein rather than descend towards the heart. If the catheter persists in its misdirected route, it is advisable to rotate the patient’s head towards the site of insertion in order to angulate the junction between the subclavian and internal jugular vein in such a way as to favor a descent of the catheter towards the heart. We then secure the catheter with absorbable suture material to the vein, making sure that we do not impair the ﬂow of the ﬂuid within the catheter itself. Before closing the wound, care must be taken to ensure that there are no sharp angulations of the catheter in the subcutaneous site, such that it will kink and occlude the ﬂow. The wound is closed in two layers, except in the severely premature infant, in which a single layer closure is done. The catheter is additionally secured with a nylon suture at the skin exit site in order to prevent early dislodgement. We prefer to circle the catheter once on the anterior chest wall before afﬁxing it with a see-through adherent plastic sheath (Tegoderm or Opsite). At all times, attention must be paid to preventing air from entering the catheter and the vascular system for fear of systemic embolization (Fig. 10.5a–d).

Inferior vena cava cannulation As mentioned earlier, this route is reserved mostly to the acute situation when immediate resuscitation due to hypovolemia mandates large-volume infusion. There are times, however, when the venous access to the superior vena cava and its tributaries have been utilized, yet the

Surgical introduction 127

(b)

(a)

(c)

(d)

Figure 10.5 (a) Positioning of the baby for the operation: the neck extended and the head rotated away from the site of insertion. (b) Subcutaneous tunnelling of the catheter through the lumen of a large venous catheter. (c) After appropriate venotomy, the catheter is introduced into the vicinity of the right atrium. (d) The completed procedure

patient is in urgent need of i.v. parenteral nutrition. In such instances, we have had to resort to catheterization of the central venous system through the inferior vena cava. The insertion is done through the proximal-most portion of the saphenous vein, just prior to its entrance into the common femoral or, as some authors prefer, via the inferior epigastric vein in the lower abdominal region. The technique of insertion is similar in either case and subcutaneous tunnelling must be undertaken either towards the middle thigh for the saphenous vein or to the ﬂank area in the inferior epigastric insertion. The catheter should be advanced past the hepatic veins into the inferior portion of the right atrium proper in order to assure proper mixing. Since thrombosis of the inferior vena cava may carry with it some visceral consequences, it may be advisable to heparinize the solution and/or the patient lightly. In some pediatric surgical centers they prefer initially to utilize the inferior vena cava route, mentioned here, and with proper

tunnelling, wound care and heparinization have incurred low complication rates.

Azygos vein and right atrium catheterization In several children in whom all peripheral sources for catheterization have been used, we have utilized the azygos vein or the right atrium directly. These operations are more involved and are rarely needed in the newborn patient. The azygos vein is approached through a right fourth intercostal posterolateral thoracotomy carrying the dissection in the extrapleural space, as is done for the exposure and repair of oesophageal atresia. Since this approach may obliterate some of the superior vena cava collaterals, in many instances we resort to direct right atrial cannulation. For right atrial catheterization, a formal right thoracotomy is needed and the catheter is positioned through the atrial appendage after securing

128 Vascular access in the newborn

an appropriately sized purse-string suture. Because of the constant motion of the heart, it is advised to leave a small amount of slack in the line within the pericardial chamber in order to prevent premature dislodgment.

Direct subclavian catheterization Direct subclavian catheterization has been attempted in infants for some time, although only recently has it gained widespread acceptance. Recent literature reported encouraging results regarding the length of use and the incidence of infection in such an insertion. In our practice it is used mostly in the anesthetized baby, who is about to undergo a major surgical procedure. The miniaturization of various kits for this purpose, provide for a safe and relatively easy introduction. Most employ the standard Seldingers’ method of insertion over a guide wire.13,14

Central venous line maintenance The early use of central venous catheters was fraught with many severe complications. We soon came to realize that a designated nurse who is completely in charge of the day-to-day care of these catheters would signiﬁcantly reduce the frequency of expulsion and the rate of infection of these lines. Numerous authors have attested to the beneﬁt derived from having such a person in the pediatric institution. Utmost sterility in connecting and disconnecting the i.v. lines must be maintained at all times. Participants must wash their hands, glove and don a face mask when handling the site. The care of these patients is conducted in such a way as to minimize the interruption of the line itself. The entire i.v. administration system is changed once daily at the same time as a new solution is given. The dressing over the site is changed every 3 days, again by the designated central venous line therapist, who scrubs the area thoroughly with povodone–iodine and applies a sterile dressing to the site. Careful inspection of the skin surrounding the site is mandatory. In severely premature babies, because of the fragility of the epidermis, the see-through adherent plastic sheath (Tegoderm, Opsite) is applied in surgery and is changed less frequently, probably once every 10–14 days.

Complications Technical complications of catheter insertion have been greatly reduced with the attention to details and more so with the routine use of X-ray imaging of the catheter tip position. Cardiac arrhythmias are seen occasionally; most frequently they are due to irritation of the endocardium by the tip of the catheter and/or the chemical impact of the concentrated i.v. solution. Keeping the tip

of the catheter in the superior vena cava/right atrial junction will minimize this problem. Metabolic complications can be greatly minimized by attention to prescribed administration procedures and will not be discussed here. The two most commonly encountered complications nowadays pertain to thrombosis and infection.15–17 In past years, before the widespread usage of Dacron cuffed catheters, catheter expulsion was seen with some regularity (approximately 5% of the time). Biochemical changes should be monitored regularly and corrected.

Thrombosis Catheter tip thrombosis is a rather frequent occurrence which is hallmarked by the inability to withdraw blood freely from the catheter. When this happens, ultrasound or echocardiography often will depict thrombus formation. If there is difﬁculty or cessation of ﬂow in the catheter, the utilization of urokinase or streptokinase (50 μ/kg/hour) may be necessary. Because of concerns for the sources from which UK or SK are obtained, the FDA in the USA has issued a warning for their use. We have switched exclusively to the use of tissue plasminogen activator (TPA), which is by far a more expensive drug.14 Enough volume should be instilled to ﬁll the catheter totally to just beyond its tip. In most instances, successful declotting of the line can be achieved. Small clots, which under observation remain stable need not be a cause for catheter removal, especially in babies in whom TPN therapy is required for a long time. All efforts must be made to maintain the catheter even if anti-thrombotic therapy must be employed repeatedly. Occasionally, a premature baby will manifest ‘consumption coagulopathy’ due to rapid growth of the thrombus. In such a situation, removal of the catheter and, at times, heparin therapy, may be needed.

Infection Line infection and bacteremia or fungemia are by far the commonest cause for premature removal of catheters. This is particularly true in premature babies and in those who are severely stressed. Patients with altered immune states or those who have been on massive wide-spectrum antibiotics are the prime candidates for fungal infection (primarily Candida albicans). The most common offending bacterium in catheter infection is Staphylococcus epidermidis. Where, in the past, this organism was thought to be a mere contaminant, it is recognized nowadays as a true pathogen and should be therefore treated accordingly. In babies who must have a central line for support, i.v. antibiotic therapy with vancomycin is ordinarily curative. It is preferable, however, to remove the catheter, since this will promptly eradicate the infection. Other organisms have occasionally been

References 129

isolated from the catheter and, if they are signiﬁcantly pathogenic, it is advised to remove the catheter as well. Bacterial infection of the subcutaneous tissue surrounding the catheter exit site has also been seen. If the infection remains localized, topical measures and speciﬁc systemic antibiotics may, at times, eradicate the infection without the need for catheter removal. C. albicans fungemia from a catheter source ordinarily must be treated with removal of the catheter.18 A short course of amphotericin B may be added to patients with a compromised immune system. Candida is a frequent offender in the neonatal period in our experience. Embolization of a severed catheter has occurred only once in our experience, and, in that particular patient, pulmonary arteriotomy was necessary in order to retrieve the catheter.

CONCLUSION Improved vascular access in premature and newborn babies has opened new avenues for monitoring and treatment of these precarious patients. With careful attention to the details of insertion and proper maintenance techniques, the complications from these devices can be markedly reduced. The evolution of the modern care of neonates is dependent on further miniaturization of invasive tools, the establishment of sophisticated and sensitive instruments and the abilities of the clinician to assimilate all the new data to improve the care of the newborn meaningfully.

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16. 17.

18.

complications. Radiol Clin North Am 1999; 37(6):1109–25. Chiang VW, Baskin MN. Use and complications of central venous catheters inserted in a pediatric emergency department. Pediatr Emerg Care 2000; 16:230–2. Band JD. Infections caused by arterial catheters used for hemodynamic monitoring. Am J Med 1979; 67:735. Rodgers MC. Diagnostic Tests and technology for Pediatric Intensive Care. In: Pediatric Intensive Care, Baltimore: Williams and Wilkins, 1987:1406–10. Hughes WT, Buescher ES. Umbilical Vessel Catheterization, Exchange Transfusion and Phototherapy. In: Pediatric Procedures, Philadelphia: W.B. Saunders, 1980: 122–7. Sherman N. Umbilical artery cutdown. J Pediatr Surg 1977; 12:723–4. Morgan WW, Harkins GA. Percutaneous introduction of long-term indwelling vascular catheter in infants. J Pediatr Surg 1972; 7:538. Filston HE, Johnson DG. Percutaneous venous cannulation in neonates and infants. Pediatrics 1971; 48:896–901. Bagwell CE, Salzberg AM, Sonnino RE, Haynes JH. Potentially lethal complications of central venous catheter placement. J Ped Surg 2000; 35:709–13. Hall DM, Geefhuysen J. Percutaneous catheterization of the internal jugular vein in infants and children. J Pediatr Surg 1977; 12:719–22. Jona JS. Central venous hyperalimentation in the severely premature baby. In: Puri P, editor. Surgery and Support of Premature Infant Basel: Karger, 1985; 58–65. Goff DB, Ahmed N. Subclavian vein catheterization in the infant. J Pediatr Surg 1974; 9:171–4. Filston HC, Grant JP. A safer system for percutaneous subclavian venous catheterization in newborn infants. J Pediatr Surg 1979; 14:564–70. Grisoni ER, Mehta SK, Connors AF. Thrombosis and infection complicating central venous catheterization. J Pediatr Surg 1986; 21:772–6. Vane DW, Ong B, Rescorla FJ et al. Complication of central venous access in children. Pediatr Surg Int 1990; 5:174–8. Warner BW, Gorgone P, Schilling S. Multiple purpose central venous access in infants less than 1000 grams. J Pediatr Surg 1987; 22:820–2. Salzman MB, Rubin L. Intravenous catheter related infections. Adv Pediatr Infect Dis 1995; 10:37–368.

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11 Radiology in the newborn NOEL S. BLAKE

INTRODUCTION In recent years there have been great advances in surgical techniques, anesthesia and intensive care of the newborn. Imaging modalities have reached a high level of sophistication and the number and range of invasive and interventional radiology techniques has greatly increased also. All these advances have given rise to greater demands on pediatric radiology departments which should be well staffed, funded and equipped to keep up with these developments. It is essential that both conventional radiographic and high-technology imaging facilities be used efﬁciently and rationally. A sequence of investigations should be applied using ﬁrst the simplest and least invasive and irradiating examinations. These may provide the diagnosis before progressing to more complex, invasive and expensive studies, even if they are readily available. Duplication of information obtained from various imaging modalities without inﬂuencing management of the patient should be avoided.

(a)

CONVENTIONAL RADIOGRAPHY Examinations in the newborn should be directed to achieving the required information with the minimum of handling or disturbance, maintaining body temperature and employing measures to limit radiation. Only relevant projections should be obtained in relation to the clinical problem and condition of the baby (Fig. 11.1a,b). Rooms for examinations in newborns should be kept warm – around 80°F (27°C) – and the baby should be removed from the warm protective environment of the incubator for the shortest possible time. Measures to reduce radiation include the use of rare earth-intensifying screens in the cassettes and carbon ﬁber table tops to give lower exposures and shorter times. The beam should be collimated to cover only the area necessary and gonad protection with lead shields is extremely important. Good radiographic technique is

(b) Figure 11.1 Dorsal decubitus view for suspected perforation in necrotizing enterocolitis. (a) Position of baby in incubator for horizontal beam exposure. (b) Resultant radiograph conﬁrming free intraperitoneal gas below anterior abdominal wall. This was achieved with minimal disturbance to the baby

essential to produce radiographs of high quality and avoid the unnecessary extra irradiation and disturbance of babies entailed in repeat exposure.1 Sufﬁciently welltrained and experienced radiographic technicians should be available to ensure high standards.

132 Radiology in the newborn

PORTABLE EXAMINATIONS In recent years a great increase in demand for portable radiographic examinations has occurred. The position of i.v. catheters and endotracheal tubes needs to be checked often and frequent examinations may be required in infants with severe respiratory problems on ventilation.2 Portable X-ray machines have become smaller, more maneuverable and give shorter exposure times. Very good radiographs can now be obtained in critically ill or premature neonates in intensive or special care units without removing them from their incubators. This protects them from heat loss and allows minimal handling. It follows that incubators chosen for special or intensive care baby units should be user-friendly for radiography. A good example of not adhering to the earlier mentioned guidelines is in the case of taking inverted lateral radiographs for anorectal anomalies. The baby is removed from the incubator and held upsidedown by the legs while the exposure is taken. Even apart from the trauma to the infant, it is difﬁcult to obtain a good true lateral view centered at the correct level. A prone lateral view with the buttocks elevated and using a horizontal X-ray beam is a far superior technique. The baby can be left comfortably in this position for a prolonged period to ensure that gas outlines the distal limit of the blind rectal pouch (Fig. 11.2). Lateral decubitus views of the chest or abdomen are readily performed with a horizontal beam, leaving babies in their incubators. Erect views to show pneumothorax or pleural effusion, or to demonstrate ﬂuid levels in dilated bowel loops or free intraperitoneal gas should no longer be necessary.

available as well as a fully equipped resuscitation trolley. Procedures should be carried out quickly but carefully. A satisfactory i.v. infusion should be ensured before commencing any invasive or interventional technique. Developments in computerized digital ﬂuorography in recent years have resulted in the potential for a marked reduction in radiation exposure, more rapid performance of dynamic contrast studies and greatly improved recorded images.3 Digital ﬂuoroscopy units also have the facility to provide a rapid series of exposures up to 8/second. This can be very useful in studies of the swallowing mechanism or of the airway. These images can be obtained with a multiformat camera from videotape recordings of the examinations. Some installations provide image enhancement, processing and digital subtraction facilities, which can be very useful in angiography. Advances in contrast media have occurred in recent years with the development of water-soluble non-ionic media. Such contrast agents can be used with increased safety intravenously, intrathecally for myelography and for gastrointestinal examinations to exclude leakage or obstruction. In cases with suspected aspiration, a nonionic medium can be used safely. By dilution, an isoosmolar solution can be achieved for even greater tolerance in the airway. A good example of this would be in a bolus injection in the upper esophagus in H-type tracheo-esophageal ﬁstula (Fig. 11.3).

FLUOROSCOPIC EXAMINATIONS For investigations in neonates the ﬂuoroscopy room should be warm, with oxygen and suction outlets readily

Figure 11.2 Newborn with imperforate anus in prone position in incubator, with buttocks elevated for lateral view with horizontal beam

Figure 11.3 Prone lateral radiograph of bolus injection in esophagus to demonstrate H-type tracheo-esophageal ﬁstula. Non-ionic contrast diluted to achieve almost iso-osmolar solution was used

Ultrasonography 133

ULTRASONOGRAPHY This relatively inexpensive imaging modality has transformed neonatal diagnosis, especially since readily portable, high-resolution, real-time units were developed. In premature or severely ill babies, sonography can be performed satisfactorily without removing them from their incubators. The principles of minimal handling and maintenance of body temperature apply. Examinations should be carried out efﬁciently to achieve a diagnosis and not aimed at producing ‘pretty pictures’. Antenatal diagnosis of surgical conditions is being made by obstetric sonographers with increasing frequency worldwide.4 Lesions such as hydrocephalus and spina biﬁda can be recognized, as well as cystic or obstructive renal disease and intestinal tract obstructions (Fig. 11.4). Abdominal wall defects such as exomphalos and gastroschisis can be demonstrated in utero also. When diaphragmatic hernia is diagnosed antenatally on sonography, the birth can be arranged in or close to a major pediatric surgery center. Antenatal interventional techniques have been developed recently using ultrasound guidance, e.g. the insertion of stents or to drain obstructed urinary tracts. Cranial sonography is now an integral part of any department dealing with newborn patients. Using realtime sector probes of high frequency, images of excellent detail are obtained. Hydrocephalus is accurately diagnosed and graded using sonography, and serial examinations are helpful in relation to the need for shunting.

Figure 11.4 Antenatal ultrasound image demonstrating duodenal atresia with distended stomach and duodenum (Courtesy of M. El Shaﬁe, Toledo)

One of the most important contributions of highresolution sonography is in the diagnosis and grading of intraventricular hemorrhage (IVH). Early diagnosis of minimal lesions can be achieved in infants at risk. The discovery of IVH can inﬂuence the decision to operate on a newborn with a congenital malformation if IVH is severe (Fig. 11.5). Sonography has a role in the investigation of mass lesions in the neck and mediastinum. Localization, delineation, relationship to surrounding structures and especially differentiation of cystic from solid lesions are the main features achieved (Fig. 11.6). Real-time sonography can be ideal for diagnosing lesions around the diaphragm, including phrenic nerve paralysis. Abdominal sonography is most frequently carried out in the newborn to diagnose or exclude renal disease. Lesions conﬁned to the kidneys include multicystic dysplastic kidney, polycystic disease and hydronephrosis due to obstructions at pelvi-ureteric, uterovesical or urethral valve levels. All these lesions are readily diagnosed with sonography, and severity of obstruction and renal damage can be indicated also. The kidneys are frequently involved in complex syndromes, e.g. VATER syndrome. The spectrum of renal anomalies varies from agenesis (Fig. 11.7) to crossed fused ectopic and duplex kidneys. In space-occupying lesions of the abdomen, sonography should be the ﬁrst investigation. It will differentiate cystic from solid lesions and will frequently give the complete diagnosis, e.g. congenital mesoblastic nephroma, or give a clear indication of the next logical examination. In neonatal jaundice, sonography has a role complementary to that of radionuclide imaging and may give the complete diagnosis, e.g. choledochal cyst. It can certainly demonstrate or exclude dilatation of the biliary duct system (Fig. 11.8).

Figure 11.5 Coronal section of baby with multiple surgical problems relating to VATER syndrome. Severe bilateral IVH is shown; this inﬂuenced surgical management, as there was complex congenital heart disease

134 Radiology in the newborn

(a) Figure 11.7 Renal agenesis. Absence of echo pattern of right kidney in transverse prone sonogram. There was no evidence of an ectopic kidney and absence was conﬁrmed on T-cells–DTPA scan

(b) Figure 11.6 Mediastinal bronchogenic cyst. (a) Chest ﬁlm showing mass in the left superior mediastinum. (b) Ultrasound section demonstrates echo-free cystic lesion

The development of Doppler, duplex Doppler imaging and, more recently, color ﬂow Doppler imaging has been a considerable advance. Doppler studies may have widespread application, e.g. cranial,5 and in intestinal hemodynamics in relation to potential necrotizing enterocolitis.6 In regard to surgical lesions in the newborn, the facility for vascular mapping can be very useful in abdominal masses or in arteriovenous malformations in any site.

Figure 11.8 Longitudinal ultrasound section demonstrating dilated biliary ducts in obstructive jaundice with large choledochal cyst

Recently, a role for color Doppler imaging has been described in cranial neurosurgical procedures intraoperatively.7

NUCLEAR MEDICINE With the great advances in ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI), fewer radionuclide examinations are carried out in major centers now. Functional rather than morpho-

Computed tomography 135

logical studies are usually required. Total and individual renal function can be accurately assessed, but imaging is less clear than in the older infant or child. Technetium DTPA for dynamic scanning is more frequently used and technetium DMSA is for static scans, to demonstrate renal parenchymal function. Hepatobiliary scintigraphy using technetium with derivatives of iminodiacetic acid (IDA) is the deﬁnitive investigation in neonatal jaundice. Excretion is enhanced if phenobarbital is used for 3 days before the examination. This test should differentiate between biliary atresia and other obstructive lesions, and neonatal hepatitis (Fig. 11.9). If the biliary tract is patent, the passage of isotope into the intestine is usually detected within 30 minutes. Imaging with gallium citrate or indium-labeled leucocytes for deep-seated abscesses would very rarely be required in the newborn. Such lesions should usually be detected with ultrasound or CT. Isotope bone scanning can be unreliable in neonatal osteomyelitis and septic arthritis. It is rarely performed in the newborn, but may be used to demonstrate widespread metastases in neuroblastoma. Iodine-131 metaiodobenzylguanidine (MIBG) is now an established isotope which is accumulated in neuroblastoma and other neural tumours. It demonstrates metastases as well as the primary tumour and would be useful in follow-up to assess response to therapy.

COMPUTED TOMOGRAPHY Computed tomography has become an established and vital imaging modality with broad application in the

Figure 11.9 Neonatal jaundice. Technetium HIDA scan demonstrating complete obstruction of common bile duct and accumulation of isotope in choledochal cyst (same case as Fig. 11.8)

newborn and should be available on site in any specialized pediatric unit. Sharp, clear images with high resolution, giving excellent anatomical detail, are achieved with the latest generation of CT scanners. Other features include reduced acquisition times with exposures even less than 1 second, and reduction of artifacts.8 However, radiation dose remains a disadvantage and CT should be reserved in the newborn for speciﬁc indications where sonography or conventional radiography provide insufﬁcient information. For complex cerebral lesions (Fig. 11.10), CT can be deﬁnitive but, if available, MRI now provides greater detail in the brain and spinal cord. Tumors in the neck, chest and abdomen can be fully evaluated with CT, giving accurate staging of malignant lesions and demonstrating metastases. Response of tumors to therapy can also be monitored accurately.9 Examinations should be carefully monitored and technique directed to the individual patient requirement. Oral and i.v. contrast should be employed where indicated and the facility to use alternatives to the standard axial projection may be availed of. Sagittal reconstruction images or direct sagittal or coronal sections may give optimal demonstration of lesions prior to surgery. In esophageal atresia, direct sagittal CT can demonstrate associated tracheo-esophageal ﬁstula and give accurate measurement of the gap between the esophageal segments.10 The baby is placed transversely in the opening of the CT gantry. It follows that a wide opening is advisable in a pediatric CT unit. In anorectal anomalies, a useful role for CT has been described in lesions of equivocal level in relation to the puboccygeal line.11 The method involves selected axial slices and coronal reconstructed images to give the exact level of the blind rectal pouch and also to display the muscle complex of the pelvic ﬂoor.

Figure 11.10 Axial CT brain scan showing gross ventricular distension and distortion. Note dense calciﬁcation in left parieto-occipital region consistent with the clinical diagnosis of toxoplasmosis. The calciﬁcation was not detected on sonography due to proximity to bone

136 Radiology in the newborn

MAGNETIC RESONANCE IMAGING In the relatively short time since the ﬁrst reports of its use in pediatrics appeared, MRI has improved dramatically. Anatomical sections of the body can now be displayed in multiple planes with excellent detail and without ionizing radiation. These are great advantages, especially in pediatrics.12 Recent developments have resulted in shorter acquisition times and smaller magnets of low ﬁeld strength, which are cheaper to buy, install and operate. Open magnets have been developed, giving easier access for manipulation of tubes or lines, and for resuscitation if necessary. In brain imaging, MRI exploits the 14% difference in water content between gray and white matter to demonstrate them much more clearly.13 The latest MRI scanners give exquisite detail in imaging the brain14 (Fig. 11.11) and spinal cord, for which it should be the investigation of choice for suspected space-occupying lesions. Myelography should rarely be necessary for spinal lesions if MRI is available as a non-invasive, radiationfree investigation (Fig. 11.12). In malignant masses in the thorax, abdomen or pelvis, the lesions can be characterized and accurately staged with MRI (Fig. 11.13). Recently antenatal ultrasound and MRI diagnosis of mesoblastic nephroma was described by Irsutti et al. Optimal demonstration was achieved in the coronal plane.15 Response of tumors to therapy can be more frequently monitored with safety using MRI than CT due to radiation exposure. Contrast enhancement of lesions using gadolinium DTPA is now well established. This can be excellent for detecting and characterizing intracranial lesions and tumors of the spinal cord.17 However, there would be limited application of this technique in the newborn in whom brain and spinal cord tumors are rare. Magnetic resonance spectroscopy is a non-invasive and non-irradiating technique with exciting potential. It

Figure 11.11 MRI axial brain scan. Hydrocephalus is shown with marked distension of posterior horns of lateral ventricles

Figure 11.12 Sagittal MRI section demonstrating myelomeningocele and almost entire spinal cord

Figure 11.13 Metastatic sacrococcygeal teratoma. Sagittal T2-weighted image deﬁnes intramedullary tumor expanding the spinal cord at thoracolumbar level

Interventional techniques 137

can be used to measure relative metabolite concentrations in vivo.18

INTERVENTIONAL TECHNIQUES A marked increase has occurred in recent years in the number, range and complexity of interventional procedures in pediatric as well as adult radiology practice. In the gastrointestinal tract, the reduction of intussusception by barium enema or air insufﬂation is long established. However, this is a rare condition in the newborn. The reduction of meconium ileus by Gastrograﬁn enema has been practiced for four decades now and the typical plain ﬁlm and contrast ﬁndings are well known. However, it is worth stressing that complications such as volvulus, peritonitis and perforation must be excluded before a Gastrograﬁn reduction is attempted. The ﬂuoroscopy room should be warm and an i.v. drip must also be checked. In some centers the Gastrograﬁn is diluted with saline to reduce its potential toxicity. The current author prefers to induce full-strength Gastrograﬁn to reﬂux through the ileocecal valve and then follow it with normal saline.19 This permits the full effect of the hypertonic contrast with good imaging in ileal loops while limiting the colonic concentration and total volume of Gastrograﬁn (Fig. 11.14). Balloon catheter dilatation of esophageal strictures in neonates following anastomosis for esophageal atresia is now established in major centers worldwide. The advantages of balloon dilatation over bougienage relate to marked reduction in shear force with radial force

mainly achieving the dilatation.20 An interventional role can apply in imperforate anus of equivocal level. A high or low anomaly is usually categorized with a combination of clinical inspection and plain radiographs, including a horizontal beam lateral view with buttocks elevated. However, an anomaly may appear to be high, with gas well above the pubococcygeal line without any clinical stigmata to support this, such as associated anomalies or sacral dysplasia (Fig. 11.15a,b). An un-

(a)

(b)

Figure 11.14 Gastrograﬁn enema in meconium ileus. Impacted meconium is shown in ileal loops with full concentration of contrast. Normal saline gives washout effect in rectum and distal colon

Figure 11.15 Percutaneous proctogram. (a) In prone lateral ﬁlm with buttocks elevated, gas appears to be arrested well above the pubococcygeal line. Note normal sacrum and there were no other anomalies except imperforate anus. (b) Contrast injected through cannula inserted into rectum has gravitated in lateral erect ﬁlm, conﬁrming a low rectal anomaly and avoiding an unnecessary colostomy

138 Radiology in the newborn

necessary colostomy can be avoided in some of these cases by performing a percutaneous proctogram. A cannula is inserted through the anal region under ﬂuoroscopic control and advanced anterior to the upper sacrum with the baby in the lateral position. Then 5 ml of water-soluble contrast is injected, followed by an erect lateral radiograph. The contrast gravitates and outlines the exact limit of the blind rectal pouch. An associated ﬁstula can also be demonstrated. Balloon dilatation of colonic strictures complicating necrotizing enterocolitis is another established interventional procedure. Percutaneous gastrostomy and placement of a feeding tube in the jejunum is a further useful technique being practiced in many centers. In urinary tract obstruction, percutaneous nephrostomy to relieve the obstruction is widely practiced and is ideally performed under ultrasound control. A single stab technique should be used and a pigtail catheter containing a long needle and stilette can be introduced directly now without using a guide wire. The sharp echo of the needle is readily identiﬁed as it is guided into the dilated collecting system (Fig. 11.16). The performance of biopsies of organs or lesions under ultrasound, ﬂuoroscopic or CT guidance is not strictly interventional, but the aspiration or drainage of abscesses or cysts certainly is. In general, ultrasound is more simple and cheaper to use and avoids irradiation. The role of imaging specialists in procedures involving treatment or inﬂuencing management of patients is rapidly expanding. These techniques often reduce discomfort and morbidity. Hospital stay is frequently shortened and interventional procedures tend to be much more cost-effective than the alternative conventional surgical approach.

Figure 11.16 Percutaneous nephrostomy in congenital pelviureteric obstruction. Note sharp bright echo of needle in grossly dilated renal pelvis

REFERENCES 1. Gyll C, Blake NS. Paediatric Diagnostic Imaging, London, Heinemann, 1986: 44–62. 2. Narla LD, Hom M, Loﬂand GK et al. Evaluation of umbilical catheter and tube placement in premature infants. Radiographics 1991; 11(5):849–63. 3. Wesenberg RL. Limiting radiation exposure a boon to paediatric imaging. Diagn Imag 1987; 5:138–43. 4. Cohen HL, Haller JO, Gross B. Diagnostic sonography of the foetus: a guide to the evaluation of the neonate. Pediatr Ann 1992; 21(2):87, 91–6, 98–9. 5. Raju TN. Cranial Doppler applications in neonatal critical care. Crit Care Clin 1992; 8(1):93–111. 6. Van Bel F, Van Zweiten P, Guit GL et al. Superior mesenteric artery blood ﬂow velocity and estimated volume ﬂow: duplex Doppler ultrasound study of preterm and term neonates. Radiology 1990; 174:165–9. 7. Barr LL, Babcook DS, Crone KR et al. Colour Doppler US imaging during neurosurgical and neuroradiologic procedures. Radiology 1991; 181(2):567–71. 8. Zimmerman RA, Gusnard DA, Bilaniuck LT. Paediatric craniocervical spinal CT. Neuroradiology 1992; 34(2):112–16. 9. Eggli DK, Close P, Dillon PW, Umlauf M, Hopper KD et al. Mesoblastic nephroma. Paediatr Radiol 2000; 30:147–50. 10. Tam PKH, Chan FL, Saing H. Diagnosis and evaluation of oesophageal atresia by direct sagittal CT. Paediatr Radiol 1987; 17:68–70. 11. Krasna IH, Nosher JL, Amorosa JL et al. Localisation of the blind rectal pouch in imperforate anus with the CT scanner. Paediatr Surg Int 1988; 3:114–19. 12. Harwood-Nash. MRI and pediatric neuroradiology: a present perspective. Eur Radiol 1991; 1:3–18. 13. Smith FW. The value of NMR imaging in paediatric practice. Paediatr Radiol 1983; 13:141–7. 14. Christophe M et al. Early MR detection of cortical and subcortical hypoxic-ischaemic encephalopathy in fullterm infants. Pediatr Radiol 1994; 24:581–4. 15. Irsutti M, Puget C, Baunin C, Duga I, Sarramon MF, Guitard J et al. Mesoblastic nephroma. Paediatr Radiol 2000; 30:147–50. 16. Stack JP, Antoun NM, Jenkins JP et al. Gadolinium – DTPA as a contrast agent in magnetic resonance imaging of the brain. Neuroradiology 1988; 30(2):145–54. 17. Rothwell CI, Jaspan T, Worthington BS et al. Gadolinium enhanced magnetic resonance imaging of spinal tumours. Br J Radiol 1989; 62:1067–74. 18. Hope PL, Moorcraft J. Magnetic resonance spectroscopy. Clin Perinatol 1991; 18(3):535–48. 19. Blake NS. Radiological and procedures. In: Gyll C, Blake NS, editors. Paediatric Diagnostic Imaging. London: Heinemann, 1986: 80–2. 20. McLean GK, LeVeen RF. Shear stress in the performance of oesophageal dilation: comparison of balloon dilation and bougienage. Radiology 1989; 172:983–6.

12 Immune system of the newborn DENIS J. REEN

INTRODUCTION The immune system, just like the endocrine and neural systems, is a major inducible biological response system. Its function is to protect the host against pathogenic attack. Nowhere during our entire lifespan are we subjected to more foreign antigenic stimuli for the ﬁrst time than during the early neonatal period, when the newborn passes from the relatively protected environment of the womb to the hostile world of pathogens. The newborn’s immune defense system is therefore a vital response mechanism essential for its protection in the new environment in which it ﬁnds itself. The human neonate, especially those born prematurely, is highly susceptible to serious infections with bacterial, viral and fungal pathogens, including some which do not ordinarily cause systemic disease in immunocompetent older children and adults. Neonates have increased morbidity and morality from bacterial infections, with the incidence of severe infection rising sharply in extremely premature newborn infants weighing less than 1500 g.1 Neonatal sepsis may account for as many as 30% of neonatal deaths.2 The onset of sepsis and meningitis occurs within the ﬁrst 10 days of life in 75% of term infants and 90% of preterm infants.3 The mortality rate from neonatal microbial sepsis varies between 30% and 50%, depending on the organism, immunocompetence of the host and associated complications present at diagnosis.4,5 This reduced capacity of neonates to deal with a variety of infectious agents has been attributed to the relative immaturity of their immune system.

IMMUNE RESPONSES The basis of an adequate immune response resides in the capacity of individual cells of the immune system to recognize and react to the myriad antigens with which we are in continuous contact. The hemopoietic system of pluripotent stem cells is the source of all the major cell

types, which are involved in the immune response. These cells include various lymphocyte sub-sets, macrophages, natural killer cells, monocytes and polymorphonuclear leukocytes. These cells are involved in a complex regulatory network of cell interactions which constitute an immune response, and whose function is to eliminate both self-aberrant molecules and cells, as well as to protect the host from microbial attack. Lymphocyte development occurs along two distinct pathways leading to the production of the two major lymphocyte populations, T-cells and B-cells, which have very different biological effector functions. The thymus is the site of development of T-cells, which are responsible for the range of effector functions collectively termed cellmediated immunity. Cell-mediated immunity ranges from the release of soluble factors such as cytokines, which regulate the activity of all cells of the immune system, to direct cytopathic effect of cytotoxic lymphocytes on viruses or tumor cells. B-lymphocytes, on the other hand, have a more restricted effector function, conﬁned to the synthesis and secretion of humoral antibodies in each of the immunoglobulin classes, IgG, A, M, D and E. More recently, B-lymphocytes have been shown to be capable of presenting antigen to T-cells.6 In man, the site of synthesis of B-lymphocytes is the bone marrow. The different regulatory and effector functions mediated by cells of the immune system represent the capabilities of populations of cells that can be recognized by the presence of different patterns of expression of cellsurface antigens. The availability of monoclonal antibody reagents for the recognition of lineage, differentiation stage, activation phase and effector function of different cell types has contributed enormously to our understanding of the extent of heterogeneity of different cell types within the immune system. This heterogeneity of cell types forms the basis for an international leukocyte typing classiﬁcation system (CD), utilizing monoclonal antibodies which recognize speciﬁc cell-surface markers in order to deﬁne individual leukocyte subsets.7 The more widely used CD antigens, for classifying immune effector cell types, are described in Table 12.1.

140 Immune system of the newborn Table 12.1 Cell surface antigens which identify leukocyte subtypes in the newborn Antigen

Function

T-cells CD2 CD3 CD4 CD5 CD7 CD8

LFA-3 receptor (adhesion) Associated with cell receptor Class II and HIV receptor Co-stimulatory Unknown Class I receptor

B cells CD19 CD20 CD21 CD72

Signal transduction Unknown C3d and EBV receptor (CR2) Ligand for CD5

NK cells CD16 CD56 CD94

IgG receptor (FcRIII) Isoform of N-CAM Unknown

Myeloid/monocytic cells C14 Unknown C15 Unknown CD32 IgG receptor (FcRII) CD35 C3b receptor (CRI)

It is now well established that T-lymphocytes do not recognize native antigen on any pathogen, but rather a processed form of the antigen, in association with self major histocompatibility antigens (MHCs), class I (HLAA,B,C) or class II (HLA-DR/Ia) molecules.8,9 This important processing of foreign antigen is carried out by one of a group of antigen-presenting cells which include macrophages, dendritic cells, Kupffer cells and some Bcells. The proper functioning of these accessory cells is therefore as central to an adequate immune response as that of speciﬁc effector cells, such as the T-lymphocytes. When antigen becomes localized and processed by the antigen-presenting, cell (APC), the complex interaction of APC, T-cells and B-cells begins, which eventually leads to speciﬁc immunological memory, both of T-cells and B-cells as well as to antibody production. Although B-cells can be directly activated by antigen, under experimental conditions, concomitant activation of T-cells is required for the clonal expansion of antigen-speciﬁc B-cells, leading to the generation of long-lived memory B-cells and immunoglobulin-secreting plasma cells.10,11

Cytokines As well as the series of cellular interactions of the immune response, there exists a range of soluble factors, most of them products of lymphoid cells that are critical to the proper functioning of an immune response. Among the major molecular components of the immune

system are the immunoglobulins, cytokines and proteins of the acute phase response and complement system. While immunoglobulin and complement have long been recognized as potent effector molecules of the immune response, the realization that the whole family of cytokine peptides are important regulators of the immune system has only more recently been recognized. The term ‘cytokine’ is used to describe a group of peptides with potent immunoregulatory effects, which are produced and utilized, by individual cells of the immune system, to communicate with each other and to control the environment in which they operate. A description of some of the major characterized cytokines is listed in Table 12.2. Present evidence suggests that cytokines are of immense importance in controlling both local and systemic immune responses, inﬂammation and the regulation of hemopoiesis.12,13 Their most important function appears to be at local level, modulating the behavior of adjacent cells in a paracrine fashion,13 or the cells that secrete them, in an autocrine fashion.14 In addition, especially in the case of TNF-α, IL-1 and IL-6, cytokines may effect endocrine-like activity on distant organs or tissues.15 Cytokines have important biological activity which can be of major clinical beneﬁt, such as stimulation of antimicrobial function, promotion of wound healing and myelostimulation.16,17 With such diverse biological function, an exaggerated or prolonged secretion of these peptides may be detrimental for the host. Speciﬁcally, aberrant secretion of cytokines, such as TNF-α and IL-1, are thought to be responsible for the hemodynamic changes in the host during septic shock and in cachexia of chronic disease.18,19 The availability of recombinant DNA techniques to produce cytokines in almost unlimited quantities and the production of speciﬁc antagonists such as soluble cytokine receptors and IL-1 receptor antagonists, are leading to new and exciting therapeutic potential for these molecules. It is beyond the scope of this chapter, however, to discuss in great detail the enormous complexity of immune regulation ranging from antigen recognition to speciﬁc immune competence to acquired tolerance. However, the basic principles described earlier are fundamental to the proper functioning of the immune response in the newborn.

T-cell responses Many components of the neonate’s immune system are compromised at birth. Several studies in the literature have questioned the stage of maturity of circulating lymphocytes in the newborn. Some parameters of T-cell function in cord blood, however, have been shown to be normal or similar to those of healthy older children. These include the quantity and proportion of Tlymphocytes,20 lymphocyte response to mitogens,21 and

Immune responses 141 Table 12.2 Cytokines Name

Principal cellular source

Principal cellular target

IL-1α+β IL-2 IL-3 IL-4 IL-5 IL-6 IL-7 IL-8 IL-10 IL-12 IL-13 TNF-α TNF-β IFN-α IFN-β IFN-γ TGF-β GM-CSF

Macrophages, ﬁbroblasts, endothelial cells T-cells T-cells T helper cells T helper cells Fibroblasts Stromal cells Macrophages T-cells, activated monocytes Macrophages T helper cells Macrophages, ﬁbroblasts T-cells Macrophages, ﬁbroblasts Fibroblasts T-cells, NK cells T-cells, macrophages, platelets T-cells, endothelial cells

Thymocytes, endothelial cells, neutrophils, T-cells, B-cells T-cells, B-cells Multipotential stem cells T-cells, B-cells, mast cells, macrophages B-cells, eosinophils B-cells, ﬁbroblasts, hepatocytes B-cells Neutrophils T-cell subsets, macrophages T-cells, NK cells B-cells Many cells type Many cells type Many cells type Many cells type Macrophages, T-cells, B-cells Many cell types Multipotential stem cells

production of certain cytokines such as IL-2.22 However, other newborn cellular immune functions have been reported to be depressed. These include, PHA-induced cytotoxicity,23 lymphotoxin production24 as well as reduced cAMP levels.25 The literature, however, would also appear to contain a number of contradictions with respect to reporting many aspects of immune function in the newborn. Such contradictions, which are not uncommon in describing immune function in clinical disease, often arise from the diversity of analytical approaches to quantifying the immune response. There are some studies which have suggested that the percentage of T-lymphocytes in the newborn period is signiﬁcantly lower 1 day and 5 days after birth, compared to adult levels.26 However, the lymphocyte subsets attain normal distribution values by 20 days of age. While lymphocyte responsiveness to mitogens such as PHA has been shown to be equal to that of adult values in the newborn, spontaneous lymphocyte blastogenesis of newborn lymphocytes is signiﬁcantly greater than that of adult lymphocytes.26 This probably reﬂects an ongoing in vivo immune responsiveness in the newborn to its new antigenic environment following delivery. Premature infants of very low birth weight, have signiﬁcantly reduced mitogen responsiveness.27 The autologous mixed lymphocyte response or the proliferative response to mitogenic antibodies such as OKT3 (CD3) monoclonal antibody is diminished in newborns.28,29 There is also evidence, however, that cord blood T-cells can respond to antigens such as Candida and streptokinase to which the mother has been sensitized, as well as reports of fetal reactivity in the absence of a maternal response.30,31 This suggests that the newborn may be sensitized to antigen in utero. Newborn infants, immunized with BCG, are

capable of manifesting delayed-type hypersensitivity responses on subsequent tuberculin skin testing.32 The overall characteristic that distinguishes newborn T-cells from other T-cells at different stages of development is that they are recent thymic emigrants, not long after exiting the thymus.33

Lymphocyte phenotype Functional aberrations of the T-cell system of the newborn have also been characterized using monoclonal antibodies to cell-surface antigens of the CD system of lymphocyte determinants (see Table 12.1). Lymphocyte phenotyping has been used to identify major T-cell proﬁle differences in the newborn compared to adults. There has been a reported incidence of up to 25% of cord blood lymphocytes co-expressing both CD4 helper T-cell and CD8 suppressor T-cell surface markers.34 Cells of this double positive phenotype are common in the thymus, where they are considered to be the precursors of mature helper and suppressor T-cells. However, more recently, using more sensitive ﬂow cytometry-based analytical techniques, workers investigating cord blood samples failed to detect the presence of doubly labelled CD4/CD8-labelled cells.35 Other markers of an immature phenotype of newborn T-cells have been described. The CD38 antigen, which is a marker of immature thymus-derived T-cells, as well as activated lymphocytes, is present in the majority of newborn cord blood lymphocytes.36 This thymocyte-like membrane phenotype can be modulated by the inﬂuence of thymic hormones in vitro.37 In addition to the presence of CD38 thymocyte-associated antigen,

142 Immune system of the newborn

human cord blood contains T-cells of the unusual phenotype which include peanut agglutinin-positive/ CD8-positive as well as some CD3-positive CD1apositive lymphocytes.38 Like CD38, CD1a is a marker present on early thymocytes.38 CD1a-positive cells are especially present in preterm and antenatally stressed infants.39 While the neonate has adequate numbers of CD4 helper T-cells, cord blood T-cells are deﬁcient in their ability to provide help for antibody production, probably at the level of altered cytokine production.40,41 The cellular basis for this functional defect is reﬂected in other phenotypic markers of functional activity. More than 90% of cord blood T-cells carry the CD45RA+ ‘virgin’ cell phenotype marker, compared with 50% of adult T-cells which express CD45RA+.42 In contrast, less than 10% of cord blood lymphocytes express the CD45RA− ‘memory’ T-cell marker compared to a 50% level of expression in adult T-cells.43 This major imbalance in the ratio of CD45RA+/CD45RA−, CD4positive T-cells in the newborn compared to adults may help explain some of the functional differences of newborn cells compared to adult lymphocytes. Regulatory factors contributing to the differences in functional activity and the different phenotypic proﬁles of newborn T-cells compared to adults require further investigation in order to arrive at a fuller understanding of the mechanisms involved.

B-cell responses The newborn’s capacity to produce antibody is signiﬁcantly reduced, both quantitatively and qualitatively, compared to that of an adult. Newborn B-lymphocytes poorly differentiate into immunoglobulin-producing cells.44,45 The mechanisms controlling this aspect of B-cell immunocompetence in the newborn is unknown. Many studies have focused on the ability of cord blood lymphocytes to terminally differentiate into IgG-, IgA- and IgM-producing plasma cells in response to mitogens. However, a delay occurs in B-cell differentiation, resulting in decreased production of plasma cells, markedly diminishing the secretion of antibody, and restriction of secreted antibody to IgM isotype.46 Cord blood Blymphocytes, unlike adult B-cells, usually are unable to differentiate into immunoglobulin plaque-forming cells when cultured with pokeweed mitogen alone, or with killed Staphylococcus aureas Cowan 1 alone.47 However, it appears that these two stimuli can act synergistically to induce a signiﬁcant in vitro plaque-forming cell response in cord blood B-cells. The relative inadequacy of IgG and IgA antibody synthesis cannot be attributed to the lack of precursor Bcells, since lymphocytes bearing these immunoglobulin classes on the surface are present in the fetus and on cord blood B-cells.48,49 The impaired capacity to undergo IgG or IgA synthesis has been attributed to immaturity of

cord blood B-cells, since their activation by polyclonal activators, like pokeweed mitogen, lipopolysaccharide or Epstein–Barr virus, generally results in moderate or reduced levels of IgM synthesis with no IgA, IgG or IgE production.45 However, the question of T-cell immaturity as a signiﬁcant factor in the restricted imunoglobulin isotype production of cord blood B-cells has to be taken into account.40,41 Cord blood mononuclear cells produce normal levels of IgE in vitro, when cultured in the presence of IL-4, indicating that the B-cells are mature in their capacity to switch to IgE-producing cells.50 The defect observed may be associated with the failure of cord blood T-cells to produce detectable levels of IL-4, which has been shown to be responsible for induction of IgE synthesis, both in vitro and in vivo.51 An inadequacy of newborn T-cell help for plasma cell isotype switching to IgG and IgA immunoglobulin-producing cells is also suggested by the observation that IgG and IgA antibody responses are more dependent upon T-cell help than are IgM responses. In a series of experiments, co-culturing adult T-cells and newborn T-cells with adult or newborn B-cells, the addition of adult T-cells greatly enhanced the pokeweed mitogen-driven responses of newborn mononuclear cells, which included IgG and IgA responses.52,53 Cord blood T-cells, however, did not show augmentation of B-cell differentiation when co-cultured with nonT-cells from adults. These data, looked at collectively, would indicate that deﬁcient T-cell function as well as possible deﬁciencies of B-cell function exist in the newborn. The defect in immunoglobulin production may also be contributed to, of course, by suppressor T-cell activity of newborn lymphocytes or even by enhanced suppressor activity of newborn monocytes. The newborn also possesses a major population of CD5-positive52 B-cells, which are only commonly found in patients with autoimmune diseases. It appears that these cells, in the newborn, uniquely express the activation antigens 4F2 and CD25.54 The signiﬁcance of these activated CD5positive B-lymphocytes is however unclear. A particular function of these cells is the production of natural polyspeciﬁc autoantibodies.55 A possible role for these cells in the newborn may therefore be the inﬂuencing of emerging B-cell speciﬁcities.

IMMUNOGLOBULINS The presence of physiological hypogammaglobulinemia has been noted by several investigators in preterm and term infants. Neonates have low levels of IgA and IgM immunoglobulins because of the poor ability of these immunoglobulin classes to cross the placenta.56 Furthermore, all IgG sub-classes are not equally transferred across the placenta, especially the IgG2 and IgG4 subclass levels, which are therefore also relatively low in the newborn.54 The neonate is consequently very susceptible to pyogenic bacterial infections since most of the antibodies that opsonize capsular polysaccharide

Conclusion 143

antigens of pyogenic bacteria are contained in the IgG2 sub-class and IgM immunoglobulin subfraction. Neonates, even during overwhelming sepsis, do not produce type-speciﬁc antibodies.57 This impairment in antibody production appears to be secondary to the defect in the differentiation of B-lymphocytes into immunoglobulin-secreting plasma cells and T-lymphocyte-mediated facilitation of antibody synthesis. There is a marked limitation in infant antibody responses to most bacterial capsular polysaccharides.58 This limitation prevents successful infant immunization with Hib polysaccharide vaccines,59 which fortunately can be circumvented by use of conjugate vaccines shown to be immunogenic in infants.60

ACCESSORY CELLS The crucial role of monocytes/macrophages in the immune response resides in their accessory cell and immunoregulatory functions of both humoral and cellular immunity. Human cord blood contains almost three times as many monocytes as adult blood does and major changes occur in the levels of monocytes during the ﬁrst few weeks of life. Newborn macrophages show poor resistance against facultative intracellular organisms. Newborn monocytes exhibit marked heterogeneity with respect to density. This heterogeneity in density is reﬂected in functional responses in different population of newborn monocytes.61 The most dense population of newborn monocytes appear to have helper function for antibody production, while suppressor function resides in the less dense populations.62 Neonatal blood monocytes are also characterized as having a much lower frequency of class II molecular expression than adult monocytes, which may be related to the selective incapacity of neonates to secrete signiﬁcant levels of IFN-γ.63 The precise role of the monocyte in the newborn’s unique susceptibility to infections with various agents, remains a challenging area for future study. Dendritic cells are the primary antigen-presenting cells for optimum sensitization of naive T-cells to antigen. Newborn dendritic cells have been shown to be deﬁcient in IL-12 (p35) expression, a key regulator of Th1-type Tcell responses.64 The critical role of the neutrophil in host defences against microbial infection has long suggested that defects in this particular cell type might be the cause of the increased susceptibility of the newborn to serious bacterial infections. Recent advances in our understanding of the molecular basis of cell adherence and phagocytosis have provided us with greater insight into the role of the neutrophil in the newborn’s defense system. Numerous in vitro abnormalities include decreased chemotaxis, leukocyte adherence, bacterial killing and depressed oxidative metabolism.65,66 However, most of these neonatal neutrophil functions have been carried out on cord blood, which contains immature forms of

the cells, and therefore care must be taken in interpreting some of the data. Oxidative metabolic function of cord blood monocytes, measured by chemiluminescence, has been shown to be depressed 12–36 hours after birth.67 Cytoskeletal actin polymerization has also been shown to be altered in neonates.68 Decreased adherence of neonatal neutrophils may be caused, at least in part, by the decreased expression of adherence glycoproteins, or by decreased ﬁbronectin content in the plasma membrane of polymorphonuclear leukocytes.69 Humoral defects have also been found in neonates, which may help explain the decreased levels of chemotaxis reported in neonatal polymorphonuclear leukocytes. Such altered humoral factors include decreased levels of complement components70 and ﬁbronectin.71 Phagocytosis by neutrophils from healthy term newborns has been studied by a number of investigators using a wide range of micro-organisms. The general consensus appears to be that neonatal neutrophils exhibit normal phagocytosis of opsonized particles as well as particles that required no opsonization. The major opsonic role of neutrophils for the uptake of antibody or complement-coated micro-organisms is reﬂected in their expression of a number of receptors both for antibody (Fc-receptors) and complement (CR receptors). In newborn cord blood, the levels of these receptors are similar to those in adult polymorphonuclear leukocytes.72,73 The level of expression of Fc receptors is signiﬁcantly more upregulated in response to in vitro stimuli such as f-met-leu-phe (FMLP) on adult PMNs compared to newborn PMNs.68 As is the case with many aspects of lymphocyte and monocyte function we are only beginning to appreciate the subtleties of molecular regulation that may inﬂuence polymorphonuclear leukocyte function as part of the immune responses in the neonate.

CONCLUSION In fetal and neonatal life, many aspects of the immune system reveal several in vivo and in vitro dissimilarities compared to the adult immune system. It is clear that the abnormalities of the immune defense system of the newborn could predispose the infant to serious and often overwhelming bacterial and fungal infections. The molecular and cellular basis for these abnormalities, while partially explained by many of the observations described in this chapter, still remains relatively unclear. The prospects for more speciﬁc and selective immunological intervention as part of the treatment of the immunocompromised neonate undergoing surgery will beneﬁt enormously from ongoing research into the biological basis of immuno-insufﬁciency of the newborn.

144 Immune system of the newborn

REFERENCES 1. Pyati SP, Pildes RS, Rama-murthy RS et al. Decreased Mortality in neonates with early onset group B streptoccocal infection: reality or artifact? J Pediatr 1981; 98:625–7. 2. Wasserman RL. Neonatal sepsis: the potential of granulocyte transfusion. Hosp Pract 1982; 75:95–104. 3. Quie PG. Neonatal septicaemia. Antibiot Chemother 1976; 21:128–34. 4. Gonzalez LA, Hill HR. The current status of intravenous gammaglobulin use in neonates. Pediatr Infect Dis J 1989; 8:315–22. 5. Placzek MM, Whitelaw A. Early and late onset neonatal septicaemia. Arch Dis Childh 1983; 58:728–31. 6. Myers CD. Role of B-cell antigen processing and presentation in the humoral immune response. FASEB J 1991; 5:2547–53. 7. Schlossman ST, Boumsell L, Gilks W et al. Leukocyte Typing V, Oxford University Press, Oxford,1995. 8. Meuer SC, Schlossman SG, Reinherz EL. Clonal analysis of human cytotoxic T lymphocytes: T4+ and T8+ effector T-cells recognise products of different major histocompatibility complex regions. Proc Nat Acad Sci USA 1982; 79:4395–9. 9. Germain RN. The ins and outs of antigen presentation. Nature 1986; 322:687–9. 10. Melchers F, Anderson J,Curbel CM et al. Regulation of B lymphocyte replication and maturation. J Cell Biochem 1982; 19:315–21. 11. Singer A, Hodes RJ. Mechanisms of T-cell–B-cell interaction. Ann Rev Immunol 1983; 1:211–42. 12. Hamblin AS. Lymphokines, IRL Press, Oxford, 1988. 13. Whicker JT, Evans SW. Cytokines in disease. Clin Chem 1990; 36/7:1269–81. 14. Lucas C, Bald LN, Fandly BM et al. The autocrine production of transforming growth factor- during lymphocyte activation: a study with a monoclonal antibody based ELISA. J Immunol 1990; 145:1415–22. 15. Nijsten MW, de Groot ER, ten Duis HJ et al. Serum levels of interleukin-6 and acute phase responses. Lancet 1987; 2:921. 16. Fong Y, Moldawer L, Shires GT et al. The biological characteristics of cytokines and their implication in surgery injury. Surg Gynec Obstet 1990; 170:363–78. 17. Leary AG, Ikeubuchi K, Hirai T. Synergism between interleukin-6 and interleukin-3 in supporting proliferation of human hematopoietic stem cells: comparison with interleukin-1a. Blood 1988; 71:1759–63. 18. Beytler B, Mylsark IW, Cerami A. Passive immunisation against cachectin/Tumor necrosis factor protects mice from the lethal effect of endotoxin. Science 1985; 229:869–71. 19. Schoham S, Davernne D, Cady AB et al. Recombinant tumor necrosis factor and interleukin-1 enhance slowwave sleep. Am J Physical 1987; 253:142–9.

20. Tosato G, Magrath IT, Koski IR, Dooley NJ, Blaese RM. Bcell differentiation and immunoregulatory T-cell function in human cord blood lymphocytes. J Clin Invest 1980; 66:383–8. 21. Puri P, Blacke P, Ren DJ. Lymphocyte transformation after surgery in the neonate. J Paediatr Surg 1980; 15:175–7. 22. Hayward AR, Kurnick J. Newborn T-cell suppression: early appearance, maintenance in culture and lack of growth factor suppression. J Immunol 1981; 125:50–3. 23. Lubens RG, Gard SE, Soderberg-Warner M, Stiehm R. Lectin dependent T lymphocytes and natural killer cytotoxic deﬁciencies in human newborn. Cell Immunol 1982; 74:40–3. 24. Eife RF, Eife G, August CS et al. Lymphotoxin production and blast cell transformation by cord blood lymphocytes: dissociated lymphocyte function in newborn infants. Cell Immunol 1974; 14:435–9. 25. Gupta S, Shwartz SA, Good RA. Subpopulation of human Tcell lymphocytes. VII cellular basis of concanavalin A induced T-cell mediated suppression of immunoglobulin production by B-lymphocytes from normal humans. Cell Immunol 1978; 44:242–9. 26. Puri P, Reen DJ. Host defences in the newborn. Mod Probl Paediatr 1985; 23:13–33. 27. Chandra RK. Inﬂuence of nutrition-immunity axis on perinatal infections. In: Ogra PL, editor. Neonatal Infection. New York: Grune and Stratton, 1984: 229–45. 28. Zamkoff FW, McKenas D, Davy FR. The autologous mixed lymphocyte reaction in cord blood lymphocytes: altered kinetics and magnitude of proliferative response compared to the adult autologous mixed lymphocyte reaction. J Clin Lab Immunol 1985; 16:87. 29. Papadogiannakis N, Johnsen SA, Olding LB. Monocyte regulated hypo responsiveness of human cord blood lymphocytes on OKT3, monoclonal antibody induced mitogenesis. Scand J Immunol 1986; 23:91. 30. Gill TJ, Rabin BS, Kunz HW et al. Immunological aspects of maternal-fetal interactions. In: Cooper MD, Dayton DH, editors. Development of Host Defences. New York: Raven Press, 1977: 287–302. 31. Pabst HF, Godel JC, Spady DW et al. Transfer of maternal speciﬁc cell-mediated immunity to the fetus. Clin Exp Immunol 1987; 68:209–14. 32. Lawton AR, Cooper MD. Ontogeny of immunity. In: Stiehm ER, editor. Immunologic Disorders in Infants and Children. Philadelphia: WB. Saunders, 1989. 33. Hassan J, Reen DJ. Human recent thymic emigrantsidentiﬁcation, expansion, and survival characteristics. J Immunol 2001; 167:1970–6. 34. Foa R, Giubellino M, Fierro M et al. Immature TLymphocytes in human cord blood identiﬁed by monoclonal antibodies: a model for the study of the differentiation pathway of T-cells in humans. Cell Immunol 1984; 89:194–201.

References 145 35. Reason DC, Ebiasawaaa M, Saito H et al. Human cord blood lymphocytes do not simultaneously express Cd4 and Cd8 cell surface markers. Biol Neonatel 1990; 58:87–90. 36. Clement LT, Vink PE, Bradley GE. Novel immunoregulatory functions of phenotypically distinct subpopulations of CD4+ cells in the human neonate. J Immunol 1990; 145:102–8. 37. Gerli R, Bertotto A, Spinozzi F et al. Thymic modulation of CD38 (T10) antigen on human cord blood lymphocytes. Clin Immunol Immunopathol 1987; 45:323. 38. Maccario R, Ferrari FA, Ciana S et al. Receptors for peanut agglutinin on a high percentage of human cord blood lymphocytes: Phenotype characterisation of peanut positive cells. Thymus 1981; 2:239. 39. Meccario R, Nespoli IO, Mingrat G et al. Lymphocyte subpopulations in the neonate: identiﬁcation of an immature subset of OKT8-positive, OKT3-negative cells. J Immunol 1983; 130:1129–32. 40. Splawski JB, Lipsky PE. Cytokine regulation of immunoglobulin secretion by neonatal lymphocytes. J Clin Invest 1991; 88:967–77. 41. Watson W, Oen K, Ramdahin R et al. Immunoglobulin and cytokine production by neonatal lymphocytes. Clin Exp Immunol 1991; 83:169–74. 42. Clement LT, Vink PE, Bradley GE. Novel immunoregulatory function of phenotypically distinct sub-populations of CD4+ cells in the human neonate. J Immunol 1990; 145:102–8. 43. Erkeller-Yuuksel FM, Deneys V,Yuksel B et al. Age-related changes in human blood lymphocyte subpopulation. J Pediatr 1992; 120:216–22. 44. Wu LYF, Blanco A, Cooper MA et al. Ontogeny of B Lymphocyte differentiation induced by pokeweed mitogen. Clin Immunol Immunopathol 1976; 5:208–17. 45. Hayward AR, Lawton AR. Induction of plasma cell differentiation of human fetal lymphocytes: evidence for functional immaturity of T and B cell. J Immunol 1977; 115:1213. 46. Bird AG, Britton S. A new approach to the study of B lymphocyte function using an indirect B cell activator. Immunotl Rec 1984; 45:41. 47. Miller KM, Pittart WB, Sorenson RU. Cord blood B cell differentiation: synergistic effect of pokeweed mitogen and Staphylococcus aureus on in vitro differentiation of B cells from human neonates. Clin Exp Immunol 1984; 56:415. 48. Andersson U, Bird AG, Britton S et al. Humoral and cellular immunity in humans studies at the cell level from birth to 2 years of age. Immunol Rev 1981; 57:5. 49. Durandy A, Fisher A, Griscelli C. Active suppression of B lymphocyte maturation by two different unborn T lymphocyte subsets. J Immunol 1979; 123:2646. 50. Pastorelli G, Rousset F, Pene J et al. Cord blood B-cells are mature in their capacity to switch to IgE producing cells in response to interleukin-4 in vitro. Clin Exp Immunol 1990; 82:114–19.

51. Finkelman SD, Katona IM, Urban JF et al. IL4 is required to generate and sustain in vivo IgE responses. J Immunol 1988; 141:2335–41. 52. Hayward AR, Lawton AR. Induction of plasma cell differentiation of human fetal lymphocytes: evidence for functional immaturity of T- and B-cells. J Immunol 1977; 119:1213–17. 53. Clough JD, Mims LH, Strober W. Deﬁcient IgA antibody responses to arsanilic acid bovine serum albumin (BSA) in neonatally thymectomised rabbits. J Immunol 1971; 107:1624–9. 54. Durandy A, Thuillier S, Forbveille M et al. Phenotypic and functional characteristics of human newborns Blymphocytes. J Immunol 1990; 144:60–5. 55. Raveche ES. Possible immunoregulatory role for CD5+B cells. Clin Immunol Immunopathol 1990; 56:135–50. 56. Cates KL, Rowe JC, Ballow M. The premature infant as a comprised host. Curr Probl Pediatr 1983; 13:5–63. 57. Rijkers GT, Sanders EA, Breukels MA, Zegers BJ. Infant B Cell responses to polysaccharide determinants. Vaccine 1998; 16:1396–4000. 58. Holmes SJ, Granoff DM. The biology of Haemophilus inﬂuenzae type b vaccination failure.J Infect Dis 1992; 165 Suppl A:S121–8. 59. Eskola J, Ward J, Dagan R, Goldblatt D, Zepp F, Fiegrist CA. Combined vaccination of Haemophilus inﬂuenzae type b conjugate and diphtheria-tetanus-pertussis containing acellular pertussis. Lancet 1999; 354:2063–8. 60. Goriely S, Vincart B, Stordeur P, Vekemans J, Willems F, Goldman M, De Wit D. Diﬁcient IL-12 (p350 gene expression by dendritic cells derived from neonatal monocytes. J Immunol 2001; 166:2141–6. 61. Mills EL. Mononuclear phagocyte in the newborn: their relation to the state of relative immunodeﬁciency. Am J Pediatr Haematol Oncol 1983; 5:189–98. 62. Khansari N, Fuiderberg HH. Functional heterogeneity of human cord blood monocytes. Scand J Immunol 1984; 19:337–42. 63. Byson YJ, Winter HS, Gardm SE et al. Deﬁciency of immune interferon production by leukocytes of normal newborns. Cell Immunol 1980; 58:191–206. 64. Sztein MB, Steeg PS, Stiehm R et al. Modulation of human cord blood monocyte DR antigen expression in vitro by lymphokines and interferons. In: Oppenheim JJ, Cohen S, editors. Interleukins, Lymphokines and Cytokines. New York: Academic Press, 1983: 299–305. 65. Beltas S, Goetza B, Spere CP. Decreased adherence, chemotaxis and phagocytic activities of neutrophils from pre-term neonates. Acta Paediatr Scand 1990; 79:1031–8. 66. Anderson DC, Huges BJ, Edwards MS et al. Impaired chemotaxigenesis by Type III group B streptococci in neonatal sera: relationship to diminished concentration of speciﬁc anticapsular antibody and abnormalities. Pediatric Research 1983; 17:496–520. 67. Miels EI, Thompson T, Bjorksten B et al. The Chemiluminescence response and bactericidal activity of

146 Immune system of the newborn polymorphonuclear neutrophils from newborns and their mothers. Paediatrics 1979; 63:429–34. 68. Hilmo A, Howard TH. F-actin content of neonate and adult neutrophils. Blood 1987; 69:429–949. 69 Anderson DC, Becker-Freeman KL, Herdt, B. Adnormal stimulated adherence of neonatal granulocytes: impaired induction of surface Mac-1 by chemotactic factors and secretogogues. Blood 1987; 70:740–50. 70. Thonson U, Trudsson L, Gustavis B. Complement components in 100 newborns and their mothers determined by electro-immunoassays. Acta Path Microbiol Scand Immunol, C, 1983; 91:148–50.

71. Gerdes JS, Douglas SD, Kolski GB et al. Decreased ﬁbronectin biosynthesis by human cord blood mononuclear phagocyte in vitro. J Leuk Biol 1984; 34:91–9. 72. Fleit HB. Fc and complement receptor (CR1 and CR3) expression on neonatal human polymorphonuclear leukocytes. Biol Neonate 1989; 55:156–63. 73. Smith JB, Cambell EE, Ludomirsky A et al. Expression of the complement receptors CR1 and CR3 and the type III Fcγ receptor on neutrophils from newborn infants and from newborn infants and from fetuses with Rh disease. Pediatr Res 1990; 28:120–6.

13 Hematological problems in the neonate OWEN P. SMITH

INTRODUCTION The neonatal period is a time of rapid ﬂux and hematological problems that present during this time as a result of a genetic defect, immaturity or stress and present a major diagnostic and therapeutic challenge to the neonatologist and hematologist alike. The recent explosion in molecular biological techniques has allowed the elucidation of the molecular and cellular mechanisms that give rise to the disorders of platelets, coagulation proteins, and red cells that present in the newborn. Because of the space allotted it is hoped that this chapter will give the reader a broad understanding and appreciation of the major hematological disorders seen in the neonatal period, especially those involving platelets and clotting proteins.

PLATELETS The normal range of the platelet count is similar in fetal life to that seen in adulthood, being in the range of 150 × 109/L to 400 × 109/L. Neonatal thrombocytopenia, deﬁned by a blood platelet count of below 150 × 109/L is common, with a reported frequency of approximately 0.9% in unselected newborns, and 40% in infants in intensive care units.1–3 The differential diagnosis of thrombocytopenia in the neonatal period is similar to thrombocytopenia in older children with a number of exceptions that include the inherited thrombocytopenia group and those that arise due to pathophysiological events unique to the antenatal and perinatal periods. It is important to remember to conﬁrm that the low platelet count is genuine by careful inspection of the blood sample and smear before initiating further investigations. Once established, the approach to the diagnosis of thrombocytopenia should be tailored to the individual infant and mother. For example, assessment of the child’s general well-being is very important as healthy neonates usually have an immune or an inherited

etiology, whereas the presence of lymphadenopathy, hepatosplenomegaly, mass lesions, hemangiomas, bruits and congenital anomalies will point towards a totally different spectrum of causes. It should also be emphasized that obtaining a detailed maternal history to include bleeding problems, pre-eclampsia and drug ingestion in present and past pregnancies and any history of viral infections, or connective tissue disease will save time and indeed unnecessary investigations. The causes of thrombocytopenia are divided into two broad categories: inherited and congenital thrombocytopenia.

INHERITED THROMBOCYTOPENIA The inherited thrombocytopenias comprise a group of platelet formation abnormalities in which platelet numbers are reduced. In the vast majority of patients the platelet count is only mild to moderately reduced (50 × 109/L and 100 × 109/L) and therefore, signiﬁcant spontaneous hemorrhage tends not to be problematical. There are however, a small number of notable exceptions where spontaneous bleeding is a prominent clinical feature of the syndrome. These include Wiskott–Aldrich syndrome (WAS), amegakaryocytic thrombocytopenia and thrombocytopenia with absent radii, where the platelet count is usually very low, and in Bernard–Soulier syndrome (BSS) and Chediak–Higashi syndrome, where there is also a marked platelet dysfunction.4 Immunemediated thrombocytopenia is a major differential diagnosis in children with low platelet counts, and therefore making the correct diagnosis of these conditions is important as it usually prevents the useless and potentially dangerous prescribing of immunosuppressants such as corticosteroids.4,5

BERNARD–SOULIER SYNDROME This is the best characterized inherited thrombocytopenia which has, in association, abnormal platelet

148 Hematological problems in the neonate

function. Typically, there is moderate to severe thrombocytopenia, a prolonged bleeding time and platelet morphology usually reveals ‘giant’ forms. BSS is inherited as an autosomal recessive manner with the underlying molecular defects due to quantitative or qualitative defects in platelet membrane receptors.

PSEUDO-VON WILLEBRAND’S DISEASE This is an autosomal dominant disorder characterized by mild intermittent thrombocytopenia, mild bleeding, absence of high molecular weight von Willebrand factor (vWf) multimers, and increased ristocetin-induced platelet aggregation. It can be differentiated from type 2B vWd, where the mutation resides in the vWf protein by spontaneous aggregation of the patient’s platelets with normal plasma4 (see later).

TYPE 2B vWD This subtype of vWd is clinically and biochemically very similar to pseudo-von Willebrand’s disease (pseudovWd). Type 2B is usually diagnosed by the increased platelet agglutination induced by low concentratons of ristocetin.4

MONTREAL PLATELET SYNDROME This syndrome is characterized by thrombocytopenia, large platelets, spontaneous platelet aggregation, and a reduced response to thrombin-induced aggregation. It can be distinguished from BSS by its autosomal dominant inheritance and a normal platelet agglutinability response to ristocetin.4

GRAY PLATELET SYNDROME This is an extremely rare autosomally inherited syndrome characterized by a markedly reduced platelet alpha-granule content but normal dense bodies and lysosomes. Other features include a prolonged skin bleeding time, morphologically large platelets and highly variable platelet aggregation proﬁles. The thrombocytopenia and bleeding symptoms are usually mild.4,6

PARIS–TROUSSEAU SYNDROME This is a recently described autosomal dominant syndrome comprised of mild thrombocytopenia, a moderate hemorrhagic tendency, giant alpha-granules in a subpopulation of platelets, bone marrow micromegakaryocytes with enhanced megakaryocyte apoptosis and a deletion of the distal part of chromosome 11 at position 11q23 (del (11)(q23.3;qter)).4,6

WISKOTT–ALDRICH SYNDROME WAS is inherited as an X-linked recessive trait and is characterized by eczema, microthrombocytopenia and combined immunodeﬁciency. It is often fatal by the early

teens due to infection, lymphoreticular malignancy or bleeding. Hemorrhagic events in this syndrome are common during the ﬁrst 2 years of life and the reason for this is multifactorial.4,6 Wiskott–Aldrich syndrome variants (X-linked thrombocytopenia) This is a heterogeneous group of thrombocytopenic disorders with X-linked inheritance. The thrombocytopenia is usually less severe in WAS variants and requires no treatment.4,6 Oculocutaneous albinism – Hermansky-Pudlak & Chediak–Higashi syndromes Oculocutaneous albinism denotes a group of inherited disorders characterized by reduced or absent pigmentation of the skin, hair and eyes. Whilst the majority of these patients have an isolated platelet storage pool defect, in some an accompanying low platelet count can occur.4,6 Hermansky-Pudlak syndrome is an autosomal recessive disorder with the classic triad of oculocutaneous albinism (tyrosinase positive), platelet dense-body or combined dense-body and alpha-granule storage pool deﬁciency, and depositions of ceroid-like material in the monocyte–macrophage system. The bleeding tendency is usually mild (related to the storage pool defect and not thrombocytopenia, as the latter is not a feature syndrome), however, excessive bleeding following tooth extractions and tonsillectomy is the rule.4,6 The features of Chediak–Higashi syndrome include: partial oculocutaneous albinism, presence of giant granules in all granule-containing cells, neutropenia, peripheral neuropathy, and platelet storage pool deﬁciency, which usually involves the dense bodies. Thrombocytopenia usually occurs during the accelerated phase of the disease, which involves the development of pancytopenia, hepatosplenomegaly, lymphadenopathy, and extensive tissue inﬁltration with lymphoid cells.4,6

MAY–HEGGLIN ANOMALY This is an autosomal dominant disorder, characterized by giant platelets, variable thrombocytopenia and Dohle-like inclusions within granulocytic cells including monocytes. Platelet function has been reported to be normal in some and impaired in others.4

ALPORT VARIANTS Alports syndrome is associated with the ﬁndings of sensorineural deafness (usually high-tone deafness), hematuria, cataracts and progressive renal failure. The disorder is heterogeneous with the majority having autosomal dominant inheritance. Many variants of Alports syndrome have been described; the three types associated with thrombocytopenia include: Epstein’s syndrome, Fechtner syndrome and Sebastian platelet syndrome.4

Inherited thrombocytopenia 149

Inherited bone marrow failure syndromes THROMBOCYTOPENIA WITH ABSENT RADII Thrombocytopenia with absent radii (TAR) is a rare, autosomal recessive disorder that is usually diagnosed at birth as the vast majority of these patients are thrombocytopenic and have the pathognomonic physical sign of bilateral absent radii. Other skeletal abnormalities involving the ulnae, ﬁngers and lower limbs are also seen but are much less common. TAR differs from Fanconi anemia in several ways; the absent radii are accompanied by the presence of thumbs, the thrombocytopenia is the only cytopenia, there is absence of spontaneous or clastogenic stress-induced chromosomal breakage and evolution to aplastic anemia and leukemia have not been reported.4,7 The majority of children with TAR have recurrent signiﬁcant bleeding episodes in the ﬁrst 6 months of life.4,7 Intracerebral and gastrointestinal hemorrhage are the usual causes of mortality with previously one in four of these children dying by 4 years of age. The majority of these deaths however, occur in the ﬁrst year of life. The mainstay of treatment is judicious use of single-donor platelet concentrates aiming to keep the platelet count above 20 × 109/L, especially in the ﬁrst year of life as this is the time of maximum morbidity and mortality.4,7

AMEGAKARYOCYTIC THROMBOCYTOPENIA Amegakaryocytic thrombocytopenia (AMEGA) is an extremely rare disorder of infancy and early childhood. The thrombocytopenia is non-immune, usually severe and early bone marrow examination shows a normal karyotype, with absent or greatly reduced numbers of megakaryocytes. Platelet transfusions are the main therapeutic intervention from diagnosis.7

FANCONI ANEMIA A premalignant disorder, Fanconi anemia (FA) is inherited as an autosomal recessive trait, with genetic heterogeneity and a gene frequency of about 1 in 600. Thrombocytopenia is usually the ﬁrst cytopenia to appear but rarely in the neonatal period.7

TRISOMY SYNDROMES Moderately severe thrombocytopenia is seen in some cases of trisomy 18 syndrome, trisomy 13 syndrome and to a lesser extent in trisomy 21. Both trisomy 13 and 18 are usually diagnosed at birth as the associated abnormalities are usually quite striking. The majority of these cases die in the neonatal period from non-hemorrhagic sequelae.4

Congenital thrombocytopenia Congenital thrombocytopenia is deﬁned as a low platelet count at birth not resulting from the association of a speciﬁc gene defect, accounting for the majority cases of

neonatal thrombocytopenia. Thrombocytopenia is a common ﬁnding in sick neonates, however, and since the introduction of automated cell counters it is now considered a relatively common (approximately 1%) ﬁnding in apparently normal infants.8 In the vast majority of cases, the thrombocytopenia results from increased platelet destruction, which can arise by several mechanisms, the majority of which are not known.

IMMUNE THROMBOCYTOPENIA Immune-mediated thrombocytopenia is usually seen in term babies that are clinically well and may be responsible for one-third of cases of thrombocytopenia seen in the general neonate population.9 There are two broad groups of conditions: those mediated by an alloimmune mechanism and those with associated autoimmune phenomena.

NEONATAL ALLOIMMUNE THROMBOCYTOPENIA Neonatal alloimmune thrombocytopenia (NAIT) This arises following maternal sensitization to paternal antigens present on fetal platelets. It occurs in approximately 1 in 1500–2000 births, with the mother having a normal platelet count and negative history for bleeding.9 The maternal alloantibody produced does not react with the mother’s platelets but crosses the placenta and destroys fetal platelets. NAIT typically presents as an isolated severe thrombocytopenia in an otherwise healthy child at birth. Severe thrombocytopenia may be present early in gestation and at least 20% of cases suffer intracranial hemorrhage.8 Widespread petechial hemorrhage is present in more than 90% of cases, while cephalohematomata, hematuria and gastrointestinal bleeding occur in a signiﬁcantly smaller number of children.1,4,9 Typically, the platelet count spontaneously returns to the normal range within 3 weeks after birth. The mainstay of treatment for affected infants is washed, irradiated, maternal platelet concentrates.

MATERNAL AUTOIMMUNE THROMBOCYTOPENIA Autoimmune thrombocytopenia (AIT) is due to the passive transfer of autoantibodies from mothers with isolated immune thrombocytopenic purpura (ITP) or it may be seen in association with conditions that have immune dysregulatory features such as maternal systemic lupus erythematosus, hypothyroidism and lymphoproliferative states.9 Approximately 1 in 10 000 pregnancies are complicated by maternal ITP. The risk of signiﬁcant infant morbidity and mortality is minimal, as the infant platelet count is rarely less than 50 × 109/L, ICH rarely, if ever, happens and when it does occur it is not related to birth trauma.9

INTRAUTERINE INFECTIONS (TORCH SYNDROMES) Intrauterine viral infections rarely produce severe thrombocytopenia (< 20 × 109/L) and therefore,

150 Hematological problems in the neonate

therapeutic intervention in the form of platelet concentrate and/or antiviral therapy are only indicated when there is active bleeding, or surgical intervention is being considered.10 In the vast majority of cases the platelet count returns to the normal range within 2–4 weeks after birth but may persist to 4 months of age.

GIANT HEMANGIOMA SYNDROME (KASABACHMERRITT SYNDROME) Kasabach-Merritt syndrome (KMS) is the association of giant cavernous hemangiomata and disseminated intravascular coagulopathy. The consumptive coagulopathy which is seen in approximately 25% of cases of KMS is usually low grade and compensated. However, acceleration into the fulminant form, which is characterized by hypoﬁbrinogenemia, raised d-dimers, red cell microangiopathy and severe thrombocytopenia is not uncommon. Fortunately, spontaneous regression of these tumors occurs in the majority of patients. Treatment modalities that have been used with varying degrees of success including corticosteroids, surgical resection, alpha-interferon, embolization, and radiotherapy. Replacement therapy with platelets, ﬁbrinogen concentrate, fresh-frozen plasma (FFP), cryoprecipitate and antiﬁbrinolytic drugs and antiplatelet agents have a role in the fulminant phase of severe forms.4

HYPERCOAGULABLE STATES Consumptive thrombocytopenia, mainly secondary to DIC following thrombin generation can be the ﬁrst manifestation of an acquired or inherited hypercoagulable state.11

Miscellaneous conditions Other associations of neonatal thrombocytopenia including maternal pre-eclampsia, maternal use of drugs, disseminated intravascular coagulation, primary microangiopathic hemolytic anemias, including hemolytic uremic syndrome, transient abnormal myelopoiesis (TAM) associated with Downs’ syndrome hemophagocytic lymphohistiocytosis, osteopetrosis, congenital leukemia, metastatic neuroblastoma and are covered in more detail elsewhere in the book.

COAGULATION PROTEINS Plasma levels of many of the hemostatic coagulation factors are lower in newborns than in older children and adults.12–15 At the end of gestation, a healthy, normal newborn should have approximately half the adult values of the vitamin K-dependent coagulant factors (factors II, VII, IX and X) and contact factors (factors XII, and XI, prekalikreinin and high molecular weight kininogen).12–15

In pre-term infants these levels are even lower. The natural anticoagulants, antithrombin and protein S are also approximately 50% at term with a similar relationship to gestational age.12–15 The plasma levels of the procoagulant co-factors, factor V and factor VIII and ﬁbrinogen are the same in term infants as is in adults. Like the coagulation system the ﬁbrinolytic system is also physiologically immature in the neonate.12–15

Inherited bleeding disorders Hemophilia A (factor VIII deﬁciency) is the second most common inherited bleeding disorder in man with a frequency of approximately l:5000 male births.16 Hemophilia B or factor IX deﬁciency is approximately one-sixth as common as that of hemophilia A. When there is a family history of hemophilia, it is usually diagnosed early in newborns as the condition is usually suspected. However, one-third to one-half of all individuals with hemophilia A and B arise from the de novo mutations and it may be some time before a ﬁrm diagnosis is made as a signiﬁcant number of these children will be seen in the general pediatric setting.16 Hemophilia has a worldwide distribution, and affects individuals in all racial groups. Hemophilia A and B are clinically indistinguishable. In the severe form the phenotype is characterized by bleeding into the joints and soft tissues. Both the factor VIII and factor IX genes were cloned over l5 years ago and as a result Recombinant factor VIII and factor IX are the treatment of choice.16 Hemorrhagic complications in moderate and severe hemophilia A and B may become obvious after birth, especially if the male child is circumcised. Severity and type of bleeding is related to the absolute level of circulating plasma VIII:C. A minimally effective level for hemostasis is about 25–30% for hemophilia A and 20–25% for hemophilia B. Those with severe deﬁciency (less than l%) usually experience repeated and often spontaneous hemorrhage. While muscular skeletal bleeding is by far the commonest clinical event, other spontaneous hemorrhagic manifestations frequently occur and may be life threatening. Successful treatment in acute or potentially acute (pre-surgical) bleeding is usually achieved with adequate and prompt factor replacement therapy. The level of factor concentrate required to achieve adequate hemostasis will depend on the type of bleeding.16

Other coagulation factor deﬁciencies Deﬁciencies of all coagulation factors have been described. However, it should be remembered that the number of patients with hemophilia A greatly outnumber all of the others put together. Common features to these rarer forms of coagulation factor deﬁciencies

Coagulation proteins 151

have variable bleeding and autosomal recessive inheritance.16,17

way, and platelets; these children also have signiﬁcant platelet function defects.16

ACQUIRED BLEEDING DISORDERS

CONGENITAL HEART DISEASE

The acquired coagulation disorders are far more common than the inherited disorders and are usually associated with multiple coagulation factor deﬁciencies.

A signiﬁcant number of children with congenital heart disease will have coagulation defects. It should be remembered however that in children with cyanotic heart disease with associated polycythemia, the elevation in PT/APTT may be spurious, i.e. may be secondary to a sampling defect as there will be an alteration in the plasma anticoagulant ratio, especially when the hematocrit level is greater than 60%.16

VITAMIN K Vitamin K is crucial for the function of procoagulant factors II, VII, IX and X and the natural anticoagulants protein C and protein S. Vitamin K itself is recycled and when this process is blocked as with warfarin administration, these vitamin K-dependent factors are not produced in adequate amounts.16,18

HEMORRHAGIC DISEASE OF THE NEWBORN This syndrome usually occurs on the second to fourth day of life as a result of decreased synthesis of vitamin Kdependent factors. The etiology of vitamin K deﬁciency in newborns is multifactorial to include reduction of vitamin K stored in the fetus and neonate, functional immaturity of the liver, lack of bacterial synthesis of vitamin K in the gut and low amounts of vitamin K in breast milk.16,18 Most neonates now are given vitamin K at birth. Exceptions to the rule are those children with known G6PD deﬁciency in the family as a signiﬁcant number of these patients will develop frank hemolysis. In those children who present with frank bleeding, vitamin K and infusions of FFP can be given to arrest the blood loss.

LIVER DISEASE The coagulopathy associated with liver disease is complex, involving reduced synthesis of vitamin Kdependent procoagulant factors, non-vitamin Kdependent procoagulant factors, structually abnormal coagulation proteins and a reduced amount of natural anticoagulants.19 A signiﬁcant number of these patients are also vitamin K deﬁcient because of an associated malabsorption. It should also be noted that these patients are usually thrombocytopenic and even though the platelets do circulate, they are usually dysfunctional. Correcting the coagulopathy usually involves replacement of vitamin K, addition of FFP and when volume restriction is imperative, then factor concentrates such as factor VII concentrate and prothromplex concentrate can be given along with platelets and DDAVP.19

CARDIOPULMONARY BYPASS The coagulopathy associated with cardiopulmonary bypass is multifactorial, involving activation of the contact pathway, ﬁbrinolytic pathway, tissue factor path-

VON WILLEBRAND’S DISEASE Von Willebrand disease (vWd) is the commonest inherited bleeding disorder in man with a gene prevalence of approximately 1% of the population.16 There is signiﬁcant phenotypic heterogeneity even among members of the same family. The majority of individuals have type 1 vWd with type 3 vWd being seen in 1–2 per million of the population. Bleeding tends to be predominantly mucocutaneous, so called ‘wet purpura’, the commonest type being epistaxis, easy bruising, gum bleeding following tooth brushing and in adolescent girls, heavy menses. Bleeding into joints is rare and typically only seen in individuals with severe type 3 disease, where the circulating plasma FVIII levels are usually around 2%. The main objective of treatment is to correct the two laboratory hallmarks of the disease, namely, prolonged bleeding time and low FVIII level.16 As most patients have a quantitative defect it is possible to stimulate endogenous release with i.v. DDAVP (Desmopressin). While this treatment is inexpensive and infection free, it does have a number of rare side effects, notably hyponatremia and seizures especially in very young children. Failure to respond occurs in approximately 10–15% of patients, and in those who do not respond, a signiﬁcant number become refractory when the drug is given over an extended period of time (tachyphylaxis).16

Thrombotic states The fetus and neonate are less efﬁcient in generating thrombin and thus thrombotic disease in early childhood is rare and when seen is either secondary to an acquired prothrombotic state or indeed the child has inherited gene defects predisposing to clot formation.12–15,20 When it does occur in childhood it can be fatal or associated with several sequelae such as amputation, organ dysfunction and post-phlebitic syndrome.20 The peak incidence for these thrombotic events is undoubtedly the neonatal period, where the use of indwelling catheters in tertiary care pediatrics is almost the norm.20

152 Hematological problems in the neonate

Acquired states CENTRAL VENOUS CATHETER DEVICES Central venous catheter devices have revolutionized the intensive care management of neonates requiring indwelling vein or artery catheterization. Unfortunately, thrombosis related to their placement continues to be a therapeutically challenging complication in terms of diagnosis, prophylaxis against thrombosis and also treatment of established thrombosis within the catheter. Once clot formation occurs the catheter may be salvaged using either/or antithrombotic or antiﬁbrinolytic agents. However, it should always be remembered that these therapeutics pose special risks in the neonatal age group. It should also be remembered that whilst, although very uncommon, death from venous thromboembolic disease in young children does occur. Therefore early detection of such thrombotic events and adequate treatment are absolutely mandatory in this group of children.

RENAL ARTERY AND VEIN THROMBOSIS Renal artery thrombosis especially in the neonatal period is commonly associated with umbilical artery indwelling on umbilical artery catheters.20 It may be difﬁcult to diagnose and hypertension and heart failure may be the presenting clinical features. There is usually extension of the thrombus to other vascular beds such as the aorta. Its incidence can be as high as one in six neonates and factors that can reduce its incidence include prophylactic anticoagulants, using a smaller size catheter and also concentration of ﬂuids infused.20 Both medical and surgical approaches have been used with variable outcome. Renal vein thrombosis is more common than renal arterial thrombosis in the newborn period. It is associated with birth asphyxia, dehydration, hypotension, cyanotic heart disease, polycythemia, and babies born to diabetic mothers. The commonest presenting features are ﬂank swelling followed by hematuria, microscopic hematuria, renal dysfunction and thrombocytopenia. Usually ultrasound will reveal renal enlargement with or without evidence of venous thrombosis. The use of anticoagulants and thrombolytic agents in this condition continue to be evaluated.20 Survival rates in babies are as high as 80% and renal status after recovery ranges from normal function to renal atrophy, hypertension and chronic renal failure.

ACQUIRED PROTEIC C/S DEFICIENCY Purpura fulminans is a term used to describe an acute, often lethal, syndrome of DIC and purpuric skin.21 Inherited and acquired abnormalities of the protein C pathway, especially protein C deﬁciency, are mainly responsible for the majority of patients with this clinical syndrome.21–23 The treatment of choice is protein C replacement.

ACQUIRED ANTITHROMBIN DEFICIENCY Acquired deﬁciencies of antithrombin have been associated with a large number of diseases, which in turn have an increased rate of venous and arterial thrombosis. Antithrombin concentrates are available and are the treatment of choice during the acute phase of the disease.20

MISCELLANEOUS CONDITIONS Other associations of neonatal thrombosis include: necrotizing enterocolitis, respiratory distress syndrome, heparin-induced thrombocytopenia/thrombosis syndrome (extremely rare in neonates), antiphospholipid antibodies and lupus anticoagulant, extracorporeal membrane oxygenation (ECMO), hemolytic uremic syndrome , birth asphyxia.20

Inherited thrombotic states Genetic defects within the protein C pathway account for the majority of cases of inherited thrombophilia.23

PROTEIN C AND PROTEIN S DEFICIENCY Hereditary protein C (PC) and protein S (PS) deﬁciency (homozygosity or compound heterozygosity) are associated with a high venous thromboembolic risk at birth or in the ﬁrst few months of life. First clinical manifestation is usually skin purpura mainly affecting extremities and in some cases massive large vessel thrombosis can also be a presenting feature. Optimum therapy involves factor replacement (PC concentrate in PC deﬁciency or FFP in PS deﬁciency) and heparin in the acute phase and oral anticoagulation in the long term.23

ANTITHROMBIN III DEFICIENCY Reducing functional defects is also associated with a high risk of venous thromboembolic disease. The homozygous state is extremely rare and appears to be incompatible with life. Presentations of antithrombin deﬁciency in neonates include myocardial infarction at birth, aortic thrombosis, saggital sinus thrombosis and cerebral thrombosis.20

OTHER INHERITED THROMBOPHILIAS Several other inherited gene defects have been associated with increased propensity to clot formation, the commonest being activated protein C resistance (APCR) and factor VR506Q/factor V Leiden, factor II gene variant (prothrombinG20210A), hyperhomocysteinemia.20

Management The indications for use of anticoagulants in infants and children have changed dramatically over the past 20

Anemia 153

years with major advances in tertiary pediatric care such as ECMO, cardiopulmonary bypass, hemodialysis and the use of intra-arterial and i.v. indwelling catheters.20,24,25 The choice of anticoagulant is dependent upon the duration of anticoagulation and therefore in the acute phase heparins, either unfractionated or low molecular weight forms are used, whilst in the longer term oral anticoagulants are the treatment of choice. In more speciﬁc disease states such as inherited or acquired protein C or antithrombin deﬁciencies, factor concentrate replacement as an adjuvant hemostatic support is used more and more. It should be remembered that because the hemostatic system in infancy and throughout childhood is constantly maturing, the anticoagulant effects of unfractionated heparin and warfarin are not predictable and therefore are deemed age dependent.

ANEMIA

usually diagnosed by testing the blood group of the mother and baby together with the presence of maternal allo-antibodies and a positive Coomb’s test. If HDN is due to Rhesus antibodies, the number of circulating nucleated red cells is often very high and thrombocytopenia may be present in those severely affected. If HDN is due to ABO incompatibility, the Hb is often normal and the nucleated red cell count is rarely elevated; however, there are very large numbers of spherocytes, in contrast to a relative paucity of spherocytes in Rhesus disease.

AUTOIMMUNE HEMOLYTIC ANEMIA This is a very uncommon cause of neonatal anemia and it arises when auto-antibodies produced in the mother are directed against fetal red cell antigens causing hemolysis in a similar fashion to neonatal thrombocytopenia secondary to AIT.27

INFANTILE PYKNOCYTOSIS There is a gradual decrease in hemoglobin (Hb) level following birth and throughout the ﬁrst 2 months. This is termed ‘physiological anemia’ and it is a direct consequence of changes in red cell production reﬂecting the increase in oxygenation with adaptation to pulmonary respiration, together with redistribution of blood ﬂow following birth and changes in red cell production.26 When the level of Hb is below the ‘physiological anemic’ range, then a pathological neonatal anemia is present.26 Whilst the majority of cases of anemia occurring in the neonatal period are acquired, a number of inherited disorders that involve gene defects of hemoglobin, red cell membrane and enzymes also present during this period.27 Anemia, whether it be acquired or inherited may present as an incidental ﬁnding on a blood count performed for other reasons, with non-speciﬁc signs of pallor, tachypnea and/or tachycardia, failure to thrive, jaundice, splenomegaly or bleeding. If the anemia is due to a hemolytic process, the jaundice is almost always present.

Acquired anemia

This transient acquired disorder typically presents with jaundice, mild hepatosplenomegaly and anemia in a term baby within a few days or weeks of birth.27 It is not an uncommon cause of moderate anemia in the ﬁrst few weeks of life in term infants. The cause is unknown but some cases appear to be due to selenium deﬁciency. The Hb may fall to as low as 4 g/dL and many neonates require one or two red cell transfusions before the condition resolves spontaneously around 4–6 weeks of age.27

BLOOD LOSS Anemia due to blood loss is the commonest cause of neonatal anemia in pre-term infants. In most cases this is iatrogenic and due to frequent blood sampling. In term infants, blood loss is also not an uncommon cause of anemia and is often occult. This is the commonest cause of otherwise unexplained neonatal anemia. Blood loss may occur before or around delivery due to fetomaternal hemorrhage or twin–twin transfusion; it may occur as a result of bleeding from a ruptured cord or abnormal placenta or there may be bleeding into the baby.

ALLO-IMMUNE HEMOLYTIC ANEMIA Hemolytic disease of the newborn (HDN) is caused by transplacental passage of maternal allo-antibodies.27 The commonest allo-antibodies causing severe hemolytic disease of the newborn are: anti-D, anti-c and anti-Kell, which produce hemolysis in fetuses which carry the D, c and Kell antigens respectively.27 The allo-antibodies are acquired either as a result of blood transfusion prior to or during pregnancy or as a result of allo-immunization during the pregnancy itsesf. Allo-immunization due to anti-D affects around 1200 pregnancies per year and causes at least 50 deaths every year in the UK.27 HDN is

ANEMIA OF PREMATURITY Almost all preterm infants have anemia, the etiology of which is usually multifactorial with reduced red cell lifespan and inappropriately low erythropoietin production being the most important contributing factors.28–31 The best approach is prevention. Whilst blood transfusion is usually carried out especially in babies of less than 28 weeks’ gestation or those requiring prolonged mechanical ventilation, the amount of allogeneic red cell exposure can be signiﬁcantly reduced by reducing blood tests in the child, giving folate and iron to all preterm

154 Hematological problems in the neonate

infants, appropriate use of erythropoietin and compliance with peer reviewed transfusion guidelines.

APPROACH TO MANAGEMENT Only severe or moderate neonatal anemia should be treated with blood transfusion and this decision is made on clinical grounds as well as the Hb in accordance with peer-reviewed guidelines.31 HDN always resolves albeit it may take 1–2 months and in the ﬁrst couple of weeks of life the hemolytic process may be so brisk that the high bilirubin necessitates phototherapy to prevent kernicterus. Blood transfusion may also be required for infantile pyknocytosis and for neonatal anemia due to blood loss.

RED CELL ENZYME DEFICIENCIES These are usually straightforward to diagnose in the neonatal period. A G6PD assay should be performed in cases of prolonged or severe jaundice unless there is an obvious alternative cause. Pyruvate kinase deﬁciency is also diagnosed by assaying red cell enzyme levels; PK assays should be performed in cases of unexplained hydrops, those with hemolytic anemia of unknown cause, and where there is a family history.

MISCELLANEOUS CONDITIONS Other inherited conditions that can present as anemia in the neonatal period include Diamond–Blackfan anemia,32 Pearson’s syndrome,33 congenital dyserythopoietic anemia, 34Aase syndrome, and osteopetrosis.27

Inherited anemia As stated earlier, if the anemia is due to a hemolytic process, jaundice is almost always present. When the hemolytic process is secondary to a red cell membrane disorders then jaundice is usually accompanied by mild to moderate splenomegaly. Jaundice is also frequently seen in neonates with inherited red cell enzyme deﬁciencies, however in glucose-6-phosphate dehydrogenase (G6PD) deﬁciency anemia is not usually present and the hyperbilirubinemia is thought to be most likely of hepatic origin. Most of the hemoglobinopathies, apart from alpha-thalassemia major and hemoglobin-H (HbH) disease do not cause neonatal jaundice.27

RED CELL MEMBRANE DEFECTS These can be difﬁcult to diagnose in the neonatal period especially in the case of the commonest type, hereditary spherocytosis (HS), where the classic blood ﬁlm morphology of numerous spherocytes is indistinguishable from that seen in ABO incompatibility. Spherocytes are also seen in the neonatal period with consumptive coagulopathy, birth asphyxia and when there was signiﬁcant placental insufﬁciency. A positive family history of HS, usually the best piece of additional information that is needed to make the diagnosis as osmotic fragility testing in this age group, is not reliable and should be postponed until the child is between 6 and 12 months of age. Hereditary elliptocytosis is straightforward to diagnose from peripheral red cell morphology.

HEMOGLOBINOPATHIES As globin chain synthesis is in a state of ﬂux between late fetal life and following birth, diagnosing hemoglobinopathy is fraught with difﬁculty in the neonatal period. The hemoglobinopathies that cause neonatal anemia include alpha-thalassemia major (Hb Barts hydrops fetalis) and HbH disease. In sickle cell syndromes the Hb is normal.

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anticoagulant pathway. Thromb Haemost 1993; 70:29–35. Aiach M, Borgel D, Gaussem P et al, Protein C and protein S deﬁciencies. Semin Hematol 1997; 34:205–16. Schlegel N, Hurtund-Roux MF, Beuaﬁls F. Anticoagulation for neonates, infants and children. In: Doupremepuich C, editor. Anticoagulation. 1st edn. New York: SpringerVerlag, 1994, 226–47. Manco-Johnson MJ. Diagnosis and management of thromboses in the perinatal period. Semin Perinatol 1990; 14:393–402. Bifano EM, Smith F, Borer J. Relationship between determinants of oxygen delivery and respiratory abnormalities in preterm infants and anemia. J Pediatr 1992; 120:292–7. Reilly I. Red cell disorders. In: Smith OP, Hann IM, editors. Essential Paediatric Haematology. 1st edn. London: Martin Dunitz, 2002, 168–84. Stockman JA, Anaemia of prematurity: determinants of the erythropoietin response. J Pediatr 1984; 105:786–91. Stockman JA. Anaemia of prematurity: current concepts in the issue of when to transfuse. Pediatr Clin North Am 1986; 33:111–15. Stockman JA, Garcia JF, Oski FA. The anemia of prematurity: factors governing the erythropoietin response. N Engl J Med 1977; 296:647–50. Keyes WG, Donohue PK, Spivak JL et al. Assessing the need for transfusion of premature infants and the role of hematocrit, clinical signs, and erythropoietin level. Pediatrics 1989; 84:412–17. Janov AJ, Leong T, Nathan DG et al. Diamond–Blankfan anemia: natural history and sequelae of treatment. Medicine (Baltimore) 1996; 75:77–82. Rotig A, Cormier V, Blanche S et al. Pearson’s marrowpancreas syndrome: a multisystem mitochondrial disorder in infancy. J Clin Invest 1990; 86:1601–03. Shalev H, Tamary H, Shaft D et al. Neonatal manifestations of congenital dyserythropoietic anemia type 1. J Pediatr 1997; 131:95–8.

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14 Genetics in neonatal surgical practice ANDREW GREEN

NATURE AND STRUCTURE OF A GENE Genetics is traditionally deﬁned as the science of biologic variation, and has been a scientiﬁc discipline for over 100 years. Human genetics makes up a large part of the ﬁeld of genetics, but the principal laws of genetics are universal, and apply equally to all species, including humans. Mendel’s studies in the 19th century were originally felt to have no relevance to humans, and it is only in retrospect that their importance can be seen. Many of the principles of genetics were discovered through the study of smaller organisms, such as bacteria, yeast and fruit ﬂies. The basic genetic mechanisms of cell division, development and differentiation happen in the same way in widely divergent species. Therefore it is impossible to look at human genetics in isolation, and there are large amounts of information from lower species which have bearing on human disorders. The study of the genetics of small organisms has had a profound impact on our understanding of human development, and of how human diseases develop. It is likely that such basic science will continue to contribute signiﬁcantly to the understanding of human genetic disease. This chapter will attempt to outline the basic elements of genetics, describe the types of genetic tests now available to help in neonatal diagnosis, and give an approach to the diagnosis of congenital abnormalities. The basic unit of inheritance for any species is the gene. The original concept of a gene arose long before the relationship between genes and nucleic acids was ever understood. A gene was considered to be a stable heritable element, which conferred a particular property or phenotype onto an individual organism. This element was passed on to subsequent generations of a particular species, and the nature of the phenotype varied according to the nature of the gene. The concept of dominant and recessive traits, which will be discussed later, was derived from studies of inheritance patterns, long before the molecular basis of the gene was understood. A gene can also be considered in another way, as a speciﬁc length of deoxyribonucleic acid (DNA), which

encodes a particular function, in most cases the synthesis of a protein. This also is a stable heritable unit. Each cell in an organism, regardless of its function, has the entire set of genes for that particular organism, but only a proportion of those genes will be active. DNA is found in the nucleus of every cell of an organism as a double helix (Fig. 14.1). Each strand of the double helix has a backbone of alternating phosphate and deoxyribose sugar molecules, with the sugars attached to the 5¢ and 3¢ hydroxyl groups of the phosphate group. Attached to the sugar molecule, lying within the helix, is one of four nitrogen-containing nucleic acid bases. Two of these bases, adenine (A) and P

O

O

O H

O

C 5'

H

BASE

4' H H 3' O –

O

H H

1'

2' H

P

O

O H

C 5'

H

O BASE

4' H H 3' O –

O

P

H H

1'

2' H O

O H H

C 5' 4' H H 3' O

O BASE H H

1'

2' H

Figure 14.1 Structure of a DNA chain. The deoxyribose and phosphate residues are linked to form the sugar-phosphate backbone of DNA

158 Genetics in neonatal surgical practice

guanine (G), are purines, and two are the smaller pyrimidines cytosine (C), and thymine (T). The A and T bases pair together by hydrogen bonding, and the G and C bases similarly pair by hydrogen bonds (Fig. 14.2). The two strands of the double helix are held together by paired A-T or G-C bases of opposite strands of the double helix. The DNA strand can be read in only one direction from 5¢ (left hand) to 3¢ (right hand). The two strands of DNA are complementary to each other, and the sequence of one strand can be predicted from its opposite. If one strand reads 5¢-CAGCGTA-3¢, then the opposite strand must read 5¢-TACGCTG-3¢. The doublestranded sequence would then be written as follows:

to the template strand of DNA. The replication system builds a new strand of DNA based on the template. The new double helix formed as a result will contain one original strand, and a newly synthesized complementary second strand. This is the basic mechanism of DNA replication in all species. Thirdly, the double helix provides a basis for repair of damaged DNA. A damaged base can be replaced, knowing its complementary base is present on the opposite strand. Damage to the sugar-phosphate backbone can also be repaired using the opposite strand as a template.

DECODING THE INFORMATION IN DNA

5¢-CAGCGTA-3¢ 3¢-GTCGCAT-5¢

The simplicity of the double helix structure allows for several important functions for DNA. Firstly, huge amounts of information can be stored in the strand of DNA. If a molecule of DNA is 1 million bases long, then there are 41 000 000 possible sequences for that stretch of DNA. A genome is the complete DNA sequence of an organism. In humans, the estimated genome size is 3 × 109 base pairs (bp). The human genome contains a huge amount of coded information, of which as yet only a small part is known. Secondly, the double helix provides a framework for DNA replication. One strand of DNA acts as a template for the synthesis of a new strand of DNA. The double helix unwinds, allowing DNA replication enzymes access

G

C T

A

G

C

A

A

T

T G

C

Figure 14.2 Double-helix structure of DNA. The double helix of deoxyribose and phosphate molecules is held together by paired purine and pyrimidine bonds

About 90% of the DNA in the human genome does not code for any speciﬁc property. Only about 10% of the genome actually contains coding information in the form of a gene. In simple terms, the genetic code in DNA is transcribed into a molecule called messenger RNA (mRNA). The mRNA is then translated into a protein, which carries out the function encoded by the speciﬁc DNA. A gene has several distinct elements (Fig. 14.3). The major part of the gene is divided into coding regions, called exons, and non-coding regions called introns. Just before (5¢) the ﬁrst exon, there is a promoter which indicates where transcription of a gene should start. There can be several promoters for one gene, and different promoters can be used according to the tissue in which the gene is being expressed, in other words the promoter is tissue speciﬁc. Further 5¢ of the promoter, there can also be enhancers or suppressors, which can increase or decrease the level of transcription of the gene. Not all of the mRNA will code for protein, as some exons will code for mRNA that does not directly encode protein. These areas, known as untranslated regions, can be either at the start (5¢) or the end (3¢) of the mRNA. To express the DNA code, mRNA is used. There are several different types of RNA, but mRNA is the most important in decoding DNA. There are three differences between RNA and DNA. Firstly, the sugar backbone of RNA contains ribose rather than deoxyribose. Secondly, mRNA exists as a single strand, and remains more unstable. Thirdly, in RNA the base uracil (U) is used instead of thymine (T), whereas the other three nucleic acids remain the same. The DNA code in most genes is expressed as a protein, which is a peptide made of the building blocks of individual amino acids. Each amino acid is coded for by a sequence of three DNA bases, known as a codon. For some amino acids, there is more than one codon (Table 14.1). A long series of DNA codons in a gene will thus code for an entire protein. The mRNA codons coding for amino acids are identical to DNA codons, with the substitution of U for T. There is a tightly controlled mechanism for the generation of protein from a DNA template.

Decoding the information in DNA 159 5' untranslated region Exon Intron

Promoters Transcription enhancers initiation site

3' untranslated region

5'

3' AUG translation initiation site

Stop codon (UGA)

Coding region

AAAAAAAA(N)

5' cap

Polyadenine tail

Mature mRNA

Figure 14.3 An idealized gene

Table 14.1 The genetic code

First position

U amino acid

Second position C amino acid A amino acid

G amino acid

Third position

U

UUU UUC UUA UUG CUU CUC CUA CUG AUU AUC AUA AUG GUU GUC GUA GUG

UCC UCU UCA UCG CCU CCC CCA CCG ACU ACC ACA ACG GCU GCC GCA GCG

UGU UGC UGA UGG CGU CGC CGA CGG AGU AGC AGA AGG GGU GGC GGA GGG

U C A G U C A G U C A G U C A G

C

A

G

Phe Phe Leu Leu Leu Leu Leu Leu Ile Ile Ile Met Val Val Val Val

Ser Ser Ser Ser Pro Pro Pro Pro Thr Thr Thr Thr Ala Ala Ala Ala

To decode a gene into protein, the DNA is ﬁrst transcribed into mRNA. A strand (the ‘sense’ strand) of the DNA double helix is used by the enzyme RNA polymerase to synthesize a complementary strand of mRNA. Transcription of mRNA starts from the 5¢ end of the ﬁrst exon of the gene, until the end of the most 3¢ exon. The intervening introns are initially included and the ﬁrst molecule is known as pre-mRNA. The intronic RNA sequences are spliced out, and a 3¢ polyadenine tail is added, producing mature mRNA. The mature mRNA is then transferred from the nucleus to the ribosome to be used as a template for the production of protein. The mature mRNA has both 5¢ and 3¢ untranslated regions. Protein synthesis does not begin at the 5¢ end of the mRNA, but at the ﬁrst 5¢ AUG codon, which codes for the amino acid methionine. Protein translation stops at

UAU UAC UAA UAG CAU CAC CAA CAG AAU AAC AAA AAG GAU GAC GAA GAG

Tyr Tyr Stop Stop His His Gln Gln Asn Asn Lys Lys Asp Asp Glu Glu

Cys Cys Stop Trp Arg Arg Arg Arg Ser Ser Arg Arg Gly Gly Gly Gly

the ﬁrst truncation codon (usually UGA) thereafter (Fig. 14.3). In the ribosome, amino acid-speciﬁc transfer molecules, called transfer RNAs, bind a free molecule of their speciﬁc amino acid. The binding is carried out by an anti-codon in the tRNA, which is complementary to the mRNA that codes for that speciﬁc amino acid. Using its anti-codon, the tRNA binds the speciﬁc mRNA codon for its amino acid. By a complex machinery, the amino acid is then added to a growing peptide chain which will eventually form the mature protein (Fig. 14.4). The 5¢ end of the mRNA corresponds to the NH2 (amino terminus) of the protein, and the 3¢ end of the mRNA corresponds to the COOH (carboxyl terminus) of the protein. Many proteins in higher species are modiﬁed after translation by the addition of phosphate or lipid groups.

160 Genetics in neonatal surgical practice 5'

mRNA 3' C

C

A

A

G

A C

G U

A C

G

G

U

G

U

G

A

C

C

G

G

G

Ribosome

U C U

U G

C Glutamic acid

Transfer-RNA

Arginine

G

Valine

Proline

Figure 14.4 Diagram of protein synthesis from mRNA

CHROMOSOMES AND CELL DIVISION The ﬁrst coiling of DNA is in the form of the double helix. However, there are subsequent higher orders of coiling and packaging of DNA. The ﬁrst order gives a loop of about 146 bp in size, wound around a histone protein. The complex is known as a nucleosome. The highest order of coiling of a large DNA molecule, with its associated histones and other proteins is known as a chromosome. A chromosome consists of one very long double helix of DNA, containing very many genes in millions of base pairs. Humans are diploid, that is to say they have two copies of every chromosome. The normal human chromosome complement is 46, made up of 22 pairs of autosomes (non-sex chromosomes) and two sex chromosomes, either X and Y in a male, or two X chromosomes in a female. Each member of a pair of autosomes contains the same genetic information. The pair of X chromosomes in a female will contain the same genetic information, but X and Y chromosomes in a male only have a small amount of genes in common. A normal human metaphase karyotype is shown in Fig. 14.5. When cells divide, the genetic content must also be duplicated so that the daughter cells have the correct genetic material. Most cell division occurs as mitosis, where one cell divides to give two cells genetically identical to that parent. This is the process which allows the formation of a complete human being from one fertilized embryo, and is also the process by which the cells of many organs are constantly renewed. Mitosis is one short period during a carefully programmed cell cycle (Fig. 14.6). After mitosis, the cell may enter a resting phase (G0), or go on to divide again (G1). A cell in G1 will then go on to synthesize new DNA as described earlier (S phase). There is then a second gap phase (G2) followed by mitosis (M). Prior to mitosis the cell can be said to be in interphase, during which the chromosomes are very elongated. Just before mitosis, in S phase, the chromosomes are dupli-

Figure 14.5 A normal male karyotype

G0 phase

M phase

G2 phase

G1 phase

S phase

Figure 14.6 Cell cycle

cated, and begin to condense as two (sister) chromatids per chromosome. This condensation phase is known as prophase. In the next phase, metaphase, the condensed chromatids line up along the plane of the cell, and spindle ﬁbers develop between the centromeres (narrow waist of each chromatid), and the polar centrioles. Standard analysis of human chromosomes is carried out in metaphase. The chromatids separate, starting from each centromere, and pass to the new daughter cell, in

Chromosome analysis 161

the step called anaphase. By the telophase, the chromatids have reached to opposite poles of the dividing cell, and division completes. Meiosis is the form of division required to form gametes (sperm or oocyte). Gametes are haploid, with only one of each chromosome, 23 chromosomes in the case of humans. This allows the formation of a new diploid organism from two haploid gametes. Meiosis occurs in two stages: meiosis I and meiosis II. The ﬁrst phase of meiosis I, prophase I, is similar to that in mitosis, with the appearance of two condensed chromatids which have duplicated. At this stage, crossing over of genetic material from one chromatid to another can occur. It is estimated that about 1–2 cross-overs occurs per chromosome in each meiosis. This introduces further genetic diversity, ensuring that the inherited chromosomes are different from the chromosomes of the parent. Metaphase I then occurs, where chromatids do not separate, but go to the opposite ends of the cell in anaphase I and telophase I. The cells at this stage are still diploid. The second meiotic division then occurs, where chromatids condense again in prophase II, and line up along the axis of the dividing cell in metaphase II. The chromatids then separate, passing to opposite ends of the cell in anaphase II. The new cells are then haploid, with 23 chromosomes, and the chromatids elongate into thin strands in telophase II.

CHROMOSOME ANALYSIS To examine chromosomes from a patient (a karyotype), dividing cells in culture must be examined. These cells are usually lymphocytes, amniotic ﬂuid cells, or ﬁbroblasts. Cells are arrested in the metaphase stage of mitosis, and stained in such a way that the chromosomes are easily visualized. The usual technique used is Gbanding (using a Giemsa stain), which gives a characteristic positive and negative banding pattern to each chromosome. Each chromosome has a constriction, called a centromere, dividing the chromosome into a short arm (p) and a long arm (q). Each arm has a number of prominent bands, which can then be subdivided into smaller bands. The gene for the ABO blood group is localized to chromosome 9q34. The gene thus lies in the fourth sub-band from the centromere (q34) of the third band from the centromere (q34) on the long arm (q34) of chromosome 9 (9q34). Chromosome abnormalities can broadly be classiﬁed into abnormalities of chromosome number, or a rearrangement of a normal number of chromosomes. The critical issue in most cases for determining the signiﬁcance of a chromosome abnormality is whether the abnormality gives rise to an excess or deﬁciency of the normal diploid state (aneuploidy).

Abnormalities of chromosome number are relatively common, but many are not recognized, as they may result in the early loss of a pregnancy. Triploidy (69 chromosomes) and tetraploidy (92 chromosomes) are relatively common causes of early pregnancy loss. Trisomy, the presence of a single extra chromosome (47 chromosomes), is also a common cause of miscarriage. Speciﬁc trisomies can give rise to an affected neonate, the commonest being trisomy 21 (Down syndrome), trisomy 13 (Patau’s syndrome) and trisomy 18 (Edwards’ syndrome). All these trisomies usually occur as a result of autosomal non-dysjunction in meiotic division of the oocyte. In non-dysjunction, the speciﬁc chromatids fail to separate, resulting in an extra chromosome in one oocyte, and no chromosome in the opposite gamete. A fertilized embryo from the oocyte with an extra chromosome will therefore be trisomic. The fertilized oocyte with an absent chromosome will be monosomic, and be lost as an early miscarriage. Non-dysjunction tends to occur more frequently with increasing maternal age. Non-dysjunction can occur in the male germline, but rarely produces viable offspring. There are numerous types of chromosome rearrangements, the commonest of which are shown in Fig. 14.7. Pericentric and paracentric chromosome inversions are usually balanced, and inherited without any phenotypic effect. Paracentric inversions are usually associated with a low risk of producing a liveborn unbalanced karyotype, but pericentric inversions may carry a higher risk. Insertions, duplications, deletions, isochromosomes and ring chromosomes are all usually aneuploid and associated with signiﬁcant clinical abnormalities. Reciprocal translocations occur where there is exchange of genetic material from one arm of a chromosome in return for genetic material from a different chromosome. Reciprocal translocations are usually balanced, without any clinical effect, but may carry a risk of having a child with problems due to an unbalanced karyotype. Another type of translocation occurs between the acrocentric chromosomes (13–15, 21 and 22), where there is no appreciable coding material on a very small short (p) arm. This is known as a Robertsonian translocation. Robertsonian translocations are one of the commonest human chromosome translocations, and in the balanced form have no clinical effect. A Robertsonian translocation involving chromosomes 14 and 21 is shown in Fig. 14.8. Those who carry a Robertsonian translocation involving chromosome 21 may be at signiﬁcantly higher risk of having a child with Down syndrome as an unbalanced product of the translocation. The same applies to a lesser extent for those carrying a Robertsonian translocation involving chromosome 13, and a subsequent risk of a child with Patau’s syndrome. The nomenclature for reporting a chromosome analysis is strict, and needs to be read carefully. A karyotype is reported initially as the number of chromosomes,

162 Genetics in neonatal surgical practice Normal

Pericentric inversion

Paracentric inversion

Deletion

Isochromosome

A

A

A

B

C

B

B

C

C

B

D

C

C

D

D

C

D

D

Figure 14.7 Different types of chromosome anomaly. A–D represent notional chromosomal loci

D

Reciprocal translocation

Ring chromosome

A

B B A

C C D D

Balanced Robertsonian 14/21 translocation

Normal

14

14

14 21

21

21

Figure 14.8 Robertsonian translocation

regardless of whether those chromosomes are normal or not. The sex chromosomes are then described. If there is no further abnormality, the report is then complete. Any further abnormality is added after the sex chromosomes. A normal male karyotype is thus 46,XY. A male with non-dysjunctional Down syndrome will have the karyotype 47,XY,+ 21, an extra unattached chromosome 21. A male with Down syndrome due to a Robertsonian translocation between chromosomes 14 and 21 will have the karyotype 46,XY,t(14;21), and his carrier mother will have a karyotype 45,XX,t(14;21). A standard laboratory chromosome analysis will be performed on G-banded chromosomes, which will detect many common and less common chromosome abnormalities, and in most cases no further laboratory

work is required. However, recombinant DNA technology has allowed new techniques for chromosome analysis, based on the hybridization of ﬂuorescently labelled fragments of DNA to the DNA of chromosomes, prepared in a standard fashion, immobilized on a glass slide. The slides can then be visualized by eye using a ﬂuorescent microscope, or indirectly by generating an image of the hybridization on computer. This technique is known as ﬂuorescent in situ hybridization (FISH). The information which can be gained from this technique depends on the origin of the fragments of DNA hybridized to the chromosome preparation. Labelled whole chromosome ‘paints’, consisting of DNA exclusively from one chromosome are now commercially available. For example, whole chromosome paints can be used to identify the origin of extra chromosomal material which cannot be identiﬁed using G-banding techniques. Whole chromosome paints are also helpful in determining the origin of subtle complex translocations. It is also now technically possible to use a chromosome 21 paint on uncultured cells in interphase, to look for trisomy 21. A cell would show three ﬂuorescent nuclear dots, representing three chromosomes 21, as opposed to two in the normal situation. Fluorescently labelled small DNA fragments, corresponding to 40–50 kb of DNA from a speciﬁc chromosomal region, can also be hybridized to metaphase chromosomes. Chromosomal deletions which cannot be detected within the resolution of conventional cytogenetic analysis, can be detected by the FISH method. A normal karyotype will give two hybridization signals:

Patterns of inheritance 163

one from the same part of each chromosome. A karyotype containing a submicroscopic chromosomal deletion involving the segment of the chromosome corresponding to the 50 kb DNA fragment will only give one hybridization signal. An example would be the submicroscopic deletion of chromosome 22q11 which occurs in most cases of the Di George spectrum, which can only be seen by FISH analysis of chromosomes. FISH diagnosis of submicroscopic chromosomal deletions is likely to become available for a variety of speciﬁc clinical syndromes.

PATTERNS OF INHERITANCE Single-gene disorders have one of three principal modes of inheritance: autosomal dominant, autosomal recessive, and X-linked recessive. Other rare forms of inheritance include X-linked dominant, and mitochondrial disorders, as well as disorders due to abnormalities of genetic imprinting. Disorders caused by inheritance of unstable elements of DNA are now increasingly being recognized (see later).

Autosomal dominant inheritance Autosomal dominant disorders are characterized by vertical transmission from parent to child, and the hallmark of these conditions is male-to-male transmission of the disease (Fig. 14.9). Those affected with an autosomal dominant disorder have an alteration in one or other copy of their two genes responsible for that condition. Each child of a person with an autosomal dominant disorder has a 50:50 chance of inheriting the gene responsible for the condition from its parent. There are many examples of autosomal dominant disorders, including neuroﬁbromatosis 1 and 2, familial adenomatous polyposis coli, myotonic dystrophy, and

II:1

II:6

III:3

III:4

I:1

I:2

II:2

II:3

II:4

II:5

III:1

III:2

Huntington’s disease. There can often be variability in both expression and penetrance of autosomal dominant disorders. For example, neuroﬁbromatosis 1, an autosomal dominant condition, will almost always manifest in someone who has an altered neuroﬁbromatosis 1 gene. This means that the condition has almost complete penetrance. However, different people can manifest the condition in different ways, with some people showing mild skin lesions, and others with severe intracerebral complications. This means that the expression or expressivity of the condition is very variable. In contrast, only 80% of those who have a single altered gene for the rare hereditary form of retinoblastoma will actually develop an eye tumor. The penetrance in this situation is 80%, but the expression of the altered gene is consistent, as manifested by a retinoblastoma. Autosomal dominant disorders are not commonly seen in neonatal surgical practice. A list of the more frequent conditions is outlined in Table 14.2.

Autosomal recessive inheritance When a child is diagnosed with an autosomal recessive disorder, then both copies of a particular gene responsible for the condition are altered. Both its parents are therefore carriers for that condition, with one normal and one altered gene. Two of the child’s four grandparents is also a carrier, and it is likely that many of the child’s relatives are also unknowingly carriers (Fig. 14.10). In most cases, being a carrier for an autosomal recessive condition has no effect on that person. When both parents are carriers for an alteration in the same gene, then there is a 25% or 1 in 4 chance for each of their children to be affected by the condition. The risk of a healthy carrier sibling of having a child with the same condition depends on the chances of that sibling’s partner also being a carrier. A child of a person with an autosomal recessive disorder will automatically be a carrier. The child’s chances of being affected will depend upon whether its unaffected parent is a carrier for an alteration in the same gene.

= affected Note male-to male transmission and non-penetrance in II:4

Figure 14.9 Autosomal dominant inheritance

= affected = heterozygous carrier

Figure 14.10 Autosomal recessive inheritance

164 Genetics in neonatal surgical practice Table 14.2 Autosomal dominant disorders in neonatal surgical practice System affected

Condition

Gastrointestinal

Hirschsprung’s disease (some cases) Beckwith–Wiedemann syndrome with exomphalos (some cases) Pyloric stenosis (some cases)

Genito-urinary

Vesico-ureteric reﬂux

Skeletal

Stickler’s syndrome Most craniosynostosis syndromes Achondroplasia Osteogenesis imperfecta Limb reduction defects (some cases)

Cardiac

Holt-Oram syndrome Noonan’s syndrome 22q11 microdeletion syndrome

Other

Retinoblastoma

Autosomal recessive disorders are commonly encountered in neonatal practice, and the nature of the disorder depends on the population being seen. Each regional population has its own recessive disorder, where the frequency of carriers for that disorder is highest. For instance, cystic ﬁbrosis is a very common autosomal recessive disorder in western Europe, whereas sickle cell anemia is the commonest autosomal recessive disorder in west Africa. Common examples of autosomal recessive conditions include cystic ﬁbrosis, sickle cell anemia, several of the mucopolysaccharidoses, beta-thalassemia, spinal muscular atrophy and congenital adrenal hyperplasia (Table 14.3). Prenatal diagnosis is available for many of these conditions.

X-linked recessive inheritance In X-linked recessive inheritance, the condition affects almost exclusively males, and females can be carriers (Fig. 14.11). The classic examples of such conditions are hemophilia A and B, Duchenne and Becker muscular dystrophy, and Hunter syndrome. Table 14.3 Autosomal recessive disorders in neonatal surgical practice System affected

Condition

Metabolic

Cystic ﬁbrosis α-1-antitrypsin deﬁciency

Skeletal

Short-rib polydactyly syndrome Jeune’s syndrome Robert’s syndrome

Genito-urinary

Infantile polycystic kidneys Meckel-Gruber syndrome

Endocrine

Congenital adrenal hyperplasia

= affected male = carrier female

Figure 14.11 X-linked recessive inheritance

The daughters of a man with an X-linked recessive condition are all obligate carriers. The sons of a man with an X-linked condition are all normal, as they inherit his Y chromosome, and not his X chromosome. When a woman is a carrier of an X-linked condition, each of her sons has a 50:50 chance of being affected, and each of her daughters has a 50:50 chance of being a carrier. There can be a relatively high mutation rate for some X-linked recessive conditions, and affected boys may not have any family history of the condition. About one-third of cases of boys with Duchenne muscular dystrophy occur as a result of new mutations. Prenatal diagnosis is available for a wide range of X-linked recessive diseases. The more common X-linked disorders in neonatal practice are shown in Table14. 4.

Polygenic inheritance Many congenital conditions do not have a clear mode of inheritance, and can be classed as polygenic or oligogenic, where a disease may arise as a result of the effects of several genes. A good example is cleft lip and palate,

Patterns of inheritance 165 Table 14.4 X-linked recessive disorders in neonatal surgical practice System affected

Condition

Neurological

Hydrocephalus with aqueduct stenosis (some cases)

Hematological

Hemophilia

Skeletal

Amelogenesis imperfecta

Endocrine

Androgen insensitivity syndrome

Metabolic

Adrenoleucodystrophy

which usually occurs in the absence of a family history. However, monozygotic twins have a high concordance for cleft palate, suggesting a genetic inﬂuence. A similar model applies to the genetics of neural tube defects, which arise as a result of the combination of several environmental and genetic factors.

Other forms of inheritance There are also much rarer forms of inheritance, including X-linked dominant, which can be hard to tell apart from autosomal dominant, except that females will be more mildly affected, and there is no male-to-male transmission. An example of an X-linked dominant condition is hypophosphatemic rickets. Mitochondrially inherited diseases show a very unusual pattern of inheritance. Most of the proteins in the mitochondria are encoded for by nuclear genes, but the mitochondria also contain their own small genome of 18 kb, with many copies per cell. The mitochondrial genome replicates independently and far more frequently than the nuclear genome. Several important mitochondrial proteins are encoded by the mitochondrial genome. Mitochondria are only inherited via oocytes, and not sperm. Therefore, where a gene alteration is in the mitochondrial genome, it will pass exclusively down the female line, but both males and females can be affected. The children of an affected male will not inherit their father’s mitochondrial gene alteration. Children with mitochondrial disorders can present with many varied symptoms, including myoclonic seizures, acute acidoses, muscle weakness, deafness or diabetes. A number of point mutations and deletions in the mitochondrial genome have been described in patients with a wide variety of conditions, including myoclonic epilepsy with lactic acidosis and stroke-like episodes (MELAS) or myoclonic epilepsy with ragged red ﬁbers on muscle biopsy (MERRF). To complicate matters further, Leber’s hereditary ophthalmopathy is a mitochondrially inherited condition, with a characteristic mitochondrial mutation, but the expression appears to have an X-linked recessive inﬂuence. Some conditions show a phenomenon known as genetic imprinting. An imprinted gene has been marked

during meiosis, to indicate the parent from which it comes. For some genes, it appears to be important not only to inherit two copies of that gene, but to inherit one from each parent. Some genes may be silenced, depending upon which parent has passed on that gene. A good example is the presence of a small deletion of chromosome 15q, which has a different effect, depending upon which chromosome 15 is deleted. If the deletion occurs on the chromosome inherited from a child’s normal father, the child will develop Prader-Willi syndrome. If the deletion occurs on the chromosome inherited from a child’s normal mother, the child will develop a completely different clinical condition, Angelman’s syndrome. The genes in this area of chromosome 15 are therefore imprinted. In addition, if a child has two maternal copies of chromosome 15 (maternal disomy), but no paternal copy, he or she will also develop Prader–Willi syndrome. Other conditions which show imprinting effects include Russell-Silver syndrome, Beckwith-Wiedemann syndrome, and the rare condition of transient neonatal diabetes mellitus. A new molecular mechanism for genetic disease has been described, of inherited unstable triplet repeat expansions. At least nine different conditions are caused by this phenomenon. In one of these genes, a normal person has a stable number of a repetitive element of three bases of DNA (for example 20 copies of a CAG repeat) in a particular gene. In that case the gene functions normally and the children of that person have the same number of repeats in their gene. An affected person has an increased number of repeats (say 100 copies) in that gene, and the affected children of that person have more serious disease, with perhaps 200 repeats in the gene. The molecular genetic ﬁndings appear to be the genetic correlate of the phenomenon of anticipation, where a condition appears to worsen from generation to generation. The most extreme example is that of congenital myotonic dystrophy, where a minimally affected mother can have a profoundly affected infant. In this case, there is a small repeat expansion of say 150 repeats in the mother, increasing to many hundreds of repeats in her affected infant. This molecular mechanism is responsible for Fragile X syndrome, Huntington’s disease, Friedreich’s ataxia,

166 Genetics in neonatal surgical practice

several forms of spinocerebellar ataxia, and probably several other conditions.

MOLECULAR GENETIC ANALYSIS FOR SINGLE-GENE DISORDERS Laboratory tests for single-gene disorders have been available for a considerable amount of time. Hemoglobin electrophoresis for sickle cell anemia and thalassemia, and enzyme assays for Tay-Sachs’ disease are very effective in resolving clinical issues in individual families. However, an increasing number of speciﬁc DNA-based tests can now be used in diagnosis and prediction of single-gene disorders. The two major techniques used in molecular genetic analysis are the polymerase chain reaction (PCR) and Southern blotting techniques. PCR is a technique which allows ampliﬁcation of a speciﬁc genetic region in large quantities from a small amount of DNA template (Fig. 14.12). The DNA sequence of the region to be ampliﬁed must be known, so that synthetic pieces of singlestranded DNA (oligonucleotide primers) corresponding to the region can be designed and manufactured. The oligonucleotide primers are added in great excess to the DNA template, along with a thermostable DNA polymerase, and free nucleotides (A,C,T,G). The mixture is heated up to cause the two strands of template DNA to separate, and then cooled. As the DNA cools, the oligonucleotides bind to the template sequence, and are extended by the polymerase. A new copy of the template DNA is thus produced. The cycle is repeated 30–40 times, with an exponential increase in the amount of the target sequence.

DNA generated by PCR can be used in many different ways to detect an abnormality in the sequence. There are numerous techniques which are used to screen PCR products for mutations, such as single-stranded conformational assay (SSCA), or denaturing gradient gel electrophoresis (DGGE). In some cases the complete sequence of the PCR product can be directly determined. Speciﬁc PCR assays for mutations have been developed, such as the ampliﬁcation resistant mutation system (ARMS) test, or the use of a speciﬁc DNA restriction enzyme which recognizes a known mutant DNA sequence. Southern blotting is a more protracted procedure involving the digestion of a relatively large amount of DNA by a restriction enzyme. The digested DNA is then electrophoresed through an agarose gel, giving a smear of DNA of different sizes. The DNA is then transferred (blotted) and ﬁxed to a membrane. The ﬁxed DNA is then hybridized to a labelled DNA probe speciﬁc for the gene to be analyzed, and the speciﬁc sizes of DNA to which the probe binds allows determination of the ‘genotype’ (Fig. 14.13). This test is often superseded by PCR technology. There are different degrees to which molecular genetic tests can contribute to clinical diagnosis. Some speciﬁc molecular genetic tests can be used to detect a known pathogenic DNA mutation, and give a diagnosis, even without any knowledge of the patient’s clinical status. For instance, the PCR detection of the ΔF508 deletion in both copies of a person’s cystic ﬁbrosis (CFTR) gene immediately gives a diagnosis of cystic ﬁbrosis. Such Digested DNA separated on agarose gel

DNA transferred and fixed to membrane

+

Primers

Heat

Sequence to be amplified Separation of strands

–

Cycle 1

Primers Membrane hybridized with radiolabelled specific DNA probe

Heat

Separation of strands

Heat

Separation of strands

Figure 14.12 Polymerase chain reaction (PCR)

Radiolabelled probe binds to specific sequences detected by autoradiography

Cycle 2

Cycle 3

Figure 14.13 Southern blotting and hybridization

A clinical genetic approach to diagnosis of malformation syndromes 167

direct mutation tests are possible where both the gene responsible for a condition has been isolated, and speciﬁc pathogenic mutations have been identiﬁed. Similarly a PCR test detects a deletion of exons seven and eight in both alleles of a gene called SMN on chromosome 5q in almost all children with spinal muscular atrophy. Southern blot analysis of DNA from infants with congenital myotonic dystrophy shows a very large expansion in a triplet repeat DNA sequence in the myotonin kinase gene on chromosome 19, as described earlier under ‘Other forms of inheritance’. In other cases, molecular genetic diagnosis can point towards a diagnosis, without conﬁrming it. For instance, the presence of a single ΔF508 CFTR gene mutation in a child with a history suggestive of cystic ﬁbrosis increases the likelihood of the child being affected. In some cases, where either a gene is not known, or very few gene mutations have been identiﬁed in a known gene, gene tracking studies can be performed in a family to predict whether a person in that family is affected. This is known as linkage analysis. Such a study requires careful clinical examination of several family members, to establish whether they are affected or unaffected. Where their clinical status is clear, DNA samples are then obtained. Gene tracking analysis in the family uses the property of normal variation in a gene between different people. Some genetic areas show wide variation between individuals, and a DNA marker from such an area, which can detect many variations, is described as being polymorphic. Each variant of a polymorphic marker is known as an allele. There are now thousands of polymorphic markers covering most of the human genome, and such markers can be found very close to most known genes. There are several types of polymorphic DNA markers, including markers characterized by different numbers of speciﬁc DNA-cutting enzymes recognition sites or restriction fragment length polymorphisms (RFLPs). Other markers detect the variation in number of anonymous elements of repetitive DNA and are called microsatellites or minisatellites. If the two alleles of a polymorphic marker can be distinguished, to discriminate between the two copies of that particular chromosome from where the marker comes, then the marker is informative in that individual. Where a gene location is known but the actual gene has yet to be found, the alleles of informative markers which lie on either side of the gene will be inherited along with each copy of the gene in question. This can be used to predict a child’s clinical status. If one set of alleles is found in the affected members of the family, but not in those unaffected, then the presence or absence of these alleles in the at-risk individual can be used to predict their chances of being affected. An example of linkage analysis for an autosomal recessive disorder is shown in Fig. 14.14. This form of linkage analysis is often used in families with X-linked recessive

2,3

2,4

1,2

3,4

2,3

1,4

?

= affected = carrier Alleles 2 and 3 are associated with a gene mutation and can be used to predict the status of another sib

Figure 14.14 Linkage analysis in an autosomal recessive disorder using an intragenic polymorphic marker

conditions such as Duchenne muscular dystrophy, to predict whether a woman is a carrier. Such linkage analysis can also be used in prenatal diagnosis. Of its nature, linkage analysis is more prone to error than direct mutation testing. This can be due to difﬁculties in assessing a person’s clinical status, and because of the possibility of recombination between the polymorphic markers. However, with the rapid advances in molecular genetics, many more mutations are being found in many different genes, and linkage analysis is often superseded by direct mutation testing. There are many new molecular genetic tests being developed, with the rapid advances in human molecular genetics. It is impossible to cover all such tests in the space available in this chapter, but it is clear that new genetic tests will alter the clinical management of many neonatal conditions.

A CLINICAL GENETIC APPROACH TO DIAGNOSIS OF MALFORMATION SYNDROMES Deﬁnitions One child in 40 (2.5%) is born with a signiﬁcant congenital anomaly and 20–25% of perinatal and childhood mortality is accounted for by congenital anomalies. Only a small number of these anomalies will occur as part of a speciﬁc genetic syndrome. A list of common congenital anomalies and approximate birth incidence is shown in Table 14.5. Awareness of the possibility of a genetic or syndromal association for anomalies is very important for management of the patient, and for advising the whole family. A distinction has also to be drawn between several different forms of abnormality, with appropriate deﬁnitions. A disruption can be deﬁned as an anomaly which is caused by an interference in the structure of a normally

168 Genetics in neonatal surgical practice Table 14.5 Examples of major congenital anomalies

Urethral obstruction, e.g. valve

Renal agenesis

Type

Birth incidence (per 1000 births)

Cardiovascular Ventricular septal defect Atrial septal defect Patent ductus arteriosus Fallot’s tetralogy

10 2.5 1 1 1

Central nervous system Anencephaly Hydrocephalus Microcephaly Lumbosacral spina biﬁda

10 1 1 1 2

Gastrointestinal Cleft lip/palate Diaphragmatic hernia Esophageal atresia Imperforate anus

4 1.5 0.5 0.3 0.2

Limb Transverse amputation

2 0.2

Urogenital Bilateral renal agenesis Polycystic kidneys (infantile) Bladder extrophy

4 2 0.02 0.03

developing organ. A good example would be the digital constrictions and amputations caused by amniotic bands. A deformation can be deﬁned as an anomaly which is caused by an external interference in the structure of a normally developing organ. An example would be talipes equinovarus caused by chronic oligohydramnios, perhaps from an amniotic leak. A malformation can be deﬁned as an anomaly which is caused by an intrinsic failure in the normal development of an organ. Common examples would be congenital heart disease, cleft lip and palate, and neural tube defects. A dysplasia is an abnormal organization of cells in a tissue, often speciﬁc to a particular tissue. For example, achondroplasia is a skeletal dysplasia caused by a mutation in the FGFR3 gene. Most dysplasias are singlegene disorders. A sequence can be deﬁned as a group of anomalies which arise due to one single event. An example would be Potter’s sequence. Potter’s sequence (Fig. 14.15) is the group of anomalies consisting of pulmonary hypoplasia, oligohydramnios, talipes, cleft palate, and hypertelorism. All of these anomalies arise as a result of the failure of urine production in the fetus. The cause of Potter’s syndrome and failure of urine production could be posterior urethral valves, dysplastic or cystic kidneys, or renal agenesis, all of which can have genetic, non-genetic or chromosomal origins. Pierre Robin sequence is the

Reduced urinary output Chronic amniotic leak Oligohydramnios Squashed facial features

Dislocated hips talipes Pulmonary hypoplasia

Death

Figure 14.15 Potter’s sequence

grouping of cleft palate, micrognathia and glossoptosis, which can have at least 30 different causes. A sequence therefore does not have a speciﬁc cause or inheritance pattern. An association can be deﬁned as a clustering of anomalies, which is not a sequence, and which occur more frequently than by chance, but has no prior assumption about causation. A good example is the association of VATER (vertebral anomalies, anal abnormalities, tracheo-esophageal ﬁstula, and radial or renal anomalies). There is no clear cause for VATER, although it can rarely occur in people with chromosome 22q11 microdeletions, and can also rarely be mimicked by Fanconi’s anemia. A syndrome is a description of a group of symptoms and signs, and a pattern of anomalies, where there is often a known cause or an assumption about causation. The looser deﬁnition of ‘syndrome’ to describe an anomaly should be avoided. The term can include chromosomal disorders such as Down syndrome, or single-gene disorders such as van der Woude syndrome, which can cause cleft lip and palate with lower lip pits.

An approach to diagnosis When a child is born with a congenital anomaly, several particular aspects of the history need to be explored. A good family history must be taken, with reference not only to a history of the same anomaly, but other anomalies as well. A family history must include documentation of pregnancy losses, stillbirths and neonatal deaths. Any history of potential teratogens in the pregnancy should be looked for, considering the likely embryological timing of the anomaly. Teratogens can include medications, recreational drugs, maternal diabetes and prolonged maternal hyperthermia. If a child has one congenital anomaly, a very careful examination should be carried out to check for any other more subtle abnormalities or for dysmorphic facial features, e.g. to check for hydrocephalus in an infant with

Further reading 169

a spinal meningomyelocele. If there is more than one malformation or signiﬁcant dysmorphology, a chromosomal analysis should be requested, as chromosomal aneuploidy is a well-recognized cause of multiple malformations. A clinical genetic opinion should also be sought, as a clinical geneticist can often help greatly in achieving a diagnosis, as well as in counselling parents about the likelihood of recurrence of similar problems in other family members. A diagnostic approach to congenital anomalies is outlined in Fig. 14.16. Deformations and disruptions need to be excluded ﬁrst. If the pattern of malformations ﬁts into a well-described sequence, then a cause for that sequence should be sought. If the anomalies do not ﬁt into a sequence, then a syndrome or association diagnosis should be attempted. If a syndrome diagnosis is achieved, it is important to remember that syndromes can be caused by chromosomal disorders, single-gene (monogenic) disorders, or by environmental agents (teratogens). The majority of congenital anomalies have a polygenic or multifactorial origin, and most are isolated (non-

Congenital anomalies

Malformation

Deformation

Malformation sequence

Multiple anomalies not explained by a sequence

Disruption

Malformation syndrome

Chromosomal

Monogenic

Teratogenic

Cause unknown

Figure 14.16 A diagnostic approach to congenital anomalies

syndromal). The causes of congenital abnormalities are outlined in Table 14.6, and it is important to note that about 50% do not have a clear cause. Nonetheless, parents and families want an explanation as to the origin of their child’s anomaly, and it is therefore worthwhile to pursue a diagnosis wherever possible. This chapter is an introduction to the concepts and principles of genetics in neonatal surgical practice. It is not intended to be a comprehensive review of syndromes. Further information can be obtained from the bibliography later, and from many Internet sources.

Table 14.6 Causes of congenital anomalies Type

Relative frequency

Genetic Chromosomal Single gene Multifactorial/polygenic

6% 7.5% 20–30%

Environmental Drugs, infections, maternal illness

5–10%

Unknown

50%

Total

100%

FURTHER READING 1. Watson JD, Hopkins NH, Roberts JW, Steitz JA, Weiner AM. Molecular Biology of the Gene. 5th edn. Menlo Park, CA: Benjamin Cummings Publishing Company, 1993. 2. Strachan T, Read AP. Human Molecular Genetics. Oxford: BIOS Publishers, 1996. 3. Lewin B. Genes V. Oxford: Oxford University Press, 1994. 4. Connor M, Ferguson-Smith M. Essential Medical Genetics. 5th edn. Blackwell Scientiﬁc, Oxford 1997. 5. Mueller RF, Young ID. Emery’s Elements of Medical Genetics. 10th edn. Churchill Livingstone, Edinburgh 2001. 6. Online Mendelian Inheritance in Man. A list of genetic disorders and the latest genetic developments for each condition. Website http://www3.ncbi.nlm.nih.gov /Omim.

170 Genetics in neonatal surgical practice

GLOSSARY 3-prime 5-prime Acrocentric Allele Aneuploidy Anti-codon Autosomal dominant Autosomal recessive Base pair Centromere Chromatid Codon Diploid DNA marker Enhancers Exon Expression FISH Gamete Genetic imprinting Haploid Haplotype Histone Interphase Intron Isochromosome Karyotype Linkage analysis Meiosis Metaphase Microsatellite marker Minisatellite marker Mitosis Non-dysjunction Nucleosome Oligonucleotide primers Paracentric inversion PCR Penetrance Pericentric inversion Promoter Prophase

Distal end of a gene, as indicated by the bond at the 3rd hydroxyl group of the deoxyribose sugar Proximal end of a gene, as indicated by the bond at the 3rd hydroxyl group of the deoxyribose sugar A chromosome with effectively only a long arm – chromosomes 13,14,15,21, and 22 A genetic variation of a gene or DNA marker An excess or deﬁciency of chromosomal material An element of transfer RNA which binds a speciﬁc amino acid Inheritance pattern characterized by transmission through several generations, male-tomale transmission, and a 50:50 risk to the children of any affected person. Inheritance pattern characterized by several affected members of the same generation, with carrier parents and a 1:4 recurrence risk where both parents are carriers Unit of double-stranded DNA Element of chromosome involved in chromosome replication, found as a constriction in the chromosome Condensed chromosome found just before mitosis Three base pair element of DNA encoding an amino acid A complement of two copies of each chromosome per cell A piece of DNA corresponding to a speciﬁc gene or chromosomal segment Elements of DNA which are involved in increasing gene transcription A part of a gene which is transcribed into mRNA The way in which a gene fault manifests clinically Fluorescent in situ hybridization – a new and powerful technique for studying speciﬁc chromosomes or regions of chromosomes A germ cell – sperm or oocyte The marking of a gene according to which parent has passed the gene to its child A complement of one copy of each chromosome per cell (as in sperm or oocyte) A pattern of alleles of DNA markers representing one of the two copies of a chromosomal region A DNA-binding protein important in chromosomal folding Phase of mitosis in which the chromosomes are very elongated The part of a gene between the exons which is not transcribed into mRNA An abnormal chromosome made up of two long or two short arms of a normal chromosome An analysis of the chromosome complement of a cell type The use of polymorphic DNA markers to perform gene tracking studies within a family The process of cell division to give haploid germ cells Phase of mitosis in which the chromosomes are very condensed and easier to analyze A DNA marker which detects variation in number of an anonymous small repetitive element of DNA A DNA marker which detects variation in number of an anonymous medium repetitive element of DNA The normal process of cell division to give two diploid copies of a cell A failure of meiosis, giving two copies of a chromosome in one gamete, and no copy of a chromosome in the other gamete The combination of a histone and its bound DNA Small lengths of synthetic single-stranded DNA of a speciﬁc sequence A rearrangement of chromosomal material within one arm of a chromosome Polymerase chain reaction – a method of generating large amounts of speciﬁc DNA from a small amount of target sequence The number of people known to carry a gene mutation who manifest the condition A rearrangement of chromosomal material around the centromere of a chromosome Element of a gene which is necessary to activate gene transcription Phase of the cell cycle where condensation of the chromosomes occurs, just before metaphase

Glossary 171

Reciprocal translocation Restriction enzyme Restriction fragment length polymorphism Ribosome Ring chromosome Robertsonian translocation Southern blotting Suppressor Telophase Telomere Transcription Translation Triploidy Trisomy X-linked recessive

Exchange of chromosomal segments between different chromosomes An enzyme which cuts double-stranded DNA at a speciﬁc unique short DNA sequence A genetic variation between two copies of the same gene, where one gene may have one copy of a restriction enzyme recognition site, and the other has two copies. This variation can be detected using PCR or Southern blotting. Area of the cell where mRNA is converted into protein An abnormal chromosome in which the tips of the long and short arms have fused A fusion of two acrocentric chromosomes A process of immobilizing DNA to nylon membrane for genetic analysis A DNA element which reduces the expression of a gene The last phase of mitosis The end of a chromosome The process of converting DNA into mRNA The production of protein from a DNA sequence Three of each chromosome, i.e. 69 chromosomes in man One extra chromosome, i.e. 47 chromosomes in man Inheritance characterized by affected males in several generations, and by female carriers

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15 Ethical considerations in newborn surgery JACQUELINE J. GLOVER AND DONNA A. CANIANO

INTRODUCTION In caring for the extremely premature neonate with surgical disease or the infant with multiple, life-threatening congenital anomalies, pediatric surgeons often encounter difﬁcult ethical decisions about the use of advanced, life-sustaining treatments and operative interventions. The imperative to utilize new technology is tempered with concerns about quality of life, informed parental decision making, and access to scarce medical resources. Pediatric surgeons, families and communities ask the difﬁcult ethical question: ‘We can do this particular intervention, but, should we?’ This chapter provides the pediatric surgeon with ethical guidelines to utilize in clinical situations in which therapeutic decisions contain uncertainty or conﬂict and the next steps in the management of an infant that poses challenges for the parents and physicians.

DEFINING THE BEST INTERESTS STANDARD Since neonates and infants cannot make decisions about the appropriate use of technology based on their own personal values, the central ethical question is framed in pediatrics as, ‘What is in the best interests of this infant?’ An answer requires a unique and complex ethical framework that combines a concern for who makes the decision and what decision is appropriate. In the USA, parents are presumed to be the appropriate decision makers for their infants,1 but they are not unqualiﬁed decision makers. Parents and pediatric surgeons must work together to make decisions that are in the ‘best interests’ of infants.2 The term ‘best interests’ is meant to capture a balancing of the beneﬁts and burdens to this infant of a particular intervention.3 In the mainstream medical culture in the USA, the term ‘best interests’ was developed to focus attention on the need to assess the beneﬁts and burdens of treatment for a particular infant from the infant’s perspective. In an

effort to be as objective as possible, only the direct pain and suffering associated with an infant’s condition and/or proposed treatment was to be considered in conjunction with the beneﬁt of continued life. The standard was proposed as a very strict one, regarding treatment as beneﬁcial and in the infant’s best interest unless the infant was dying, the treatment was medically contraindicated, or continued life would be worse for the infant than an early death. A central feature of this narrow understanding of best interests includes its childcenteredness, understood to mean the exclusion from consideration of the negative effects of an impaired infant’s life on other persons, including parents, siblings and society. A second key feature is its emphasis on the infant’s concrete experience of burden in the form of pain and suffering. In addition to the difﬁculties associated with assessing the burdens experienced by an infant, a narrow best interests standard cannot be applied to neonates and infants with neurological deﬁcits so severe as to exclude the possibility of experience of any sort. Infants, who are not responsive to outside stimuli, for example, cannot experience pain and therefore cannot be burdened in the same way as conscious infants. Some ethicists have appropriately pointed out that absence of pain is not the only morally relevant feature.4 A ‘relational potential’ standard is necessary to augment a best interests standard. It is not morally obligatory to sustain life without any capacity for human relationship, even though life is not burdensome per se. Just as the presence of pain unable to be relieved can preclude the attainment of those basic human goods that make life worth living, so the absence of fundamental human capacity can render a life devoid of the same basic human goods.5 For the last few decades, the best interests standard has enjoyed prominence in pediatric ethics in the USA, although its limitations have also been clearly articulated. Critics argue that an infant’s interests are unknowable, that an interests appeal can yield counterintuitive results, and others’ interests also deserve consideration.6

174 Ethical considerations in newborn surgery

For those who favor a best interests standard, it is a way to focus attention on the patient as the primary loyalty of the health care professional, to maximize beneﬁt to the patient,7 to insure that the lives of the disabled are not undervalued, and to guarantee that justice in the form of principles of non-discrimination are applied.4 However, reliance on a narrow best interests standard fails to take into account other moral features that are a necessary part of ethical decision making in pediatrics. The term has been used to oversimplify a distressingly complex set of moral problems. The more one can render an ethical decision unidimensional, and the more factors one can exclude from consideration beforehand, the easier the choice becomes.5 An expanded understanding of best interests must take into consideration several competing ethical values. One value is respect for family autonomy or selfdetermination. Families ought to have the freedom to make important choices about family welfare independent of others. It is not so much that families have a right to make important decisions for their infants, as it is that families have the responsibility to make decisions and provide the necessary ﬁnancial and other types of support. Families are an essential unit of care that is both valuable in themselves, and instrumentally valuable to meet the social goal of caring for children. Since families are presumed to love their children and desire to do what is best for them, they have a unique claim to the decision-making role. Also, families have to live with the consequences of the health care decisions that are made. In a very real sense, the families’ interests are linked with the interests of the neonate or infant.8 An attempt to starkly separate infant and family interests is artiﬁcial and diminishes rather than enhances an understanding of the infant’s well-being. One can understand how the best interests standard developed in the context of imperiled newborns, where there is great uncertainty and no one has a longstanding relationship with the infant. The objectivity sought is comprehensible only because the infant is a stranger to all. Yet even in the case of newborns, most authors agree that parents should be the primary decision makers.9 If family interests were irrelevant, it would be difﬁcult to make sense of such a presumption. Given this presumption in favor of parental decision making, and the fact that most infants are not strangers to their parents, a best interests standard would be better understood to include a more comprehensive understanding of a child-centered decision, one made by a family whose daily lives involve the love and care of their infant. Additionally, the search for the ‘best’ interests of the infant apart from the family has several negative consequences. First of all, it can antagonize parents and turn all parties into adversaries. It can also cut off discussion and planning rather than improve it. Families may not feel free to discuss difﬁculties, and important needs may go unmet. Rather than search for some artiﬁcial ‘best’

interest, all parties should acknowledge the complex goal of promoting the infant’s well-being and the necessary interdependence of families in that endeavor. To exclude the family in a concept of child-centeredness is to reduce the infant to only a physiological organism and wellbeing to pathophysiological function. Another value that is in tension with respect for family decision making is respect for professional integrity. Since ‘best interests’ also contains an important focus on the uniquely medical interests of the infant, professional judgement plays an important role in describing and evaluating the beneﬁts and burdens of health care interventions.10 Pediatric surgeons have independent obligations to the infants who are their patients, to promote their well-being and protect them from harm. They have a professional obligation to promote life and quality of life, and to avoid such harms as killing, premature death, pain and suffering. Yet even based on so-called medical facts, decisions are a complex amalgam of what the infant’s alternative futures will be like, how likely it is that these futures can be gained, and what the infant has to endure to get there. An infant’s present interests in being free from undue burdens must be weighed against all future interests.11 A third important value is that of justice as nondiscrimination.4 How do we understand the interests of a child in himself or herself, independent of how others may value him or her? What does society owe its children as a matter of justice? Infants do not only belong to their families, but they also are members of their community. Communities have an obligation to protect the most vulnerable among them, especially if they are vulnerable to the neglect and abuse of their families. All infants deserve a certain level of health care, independent of what their families might choose for them. The principle of justice also has another important component that is in direct conﬂict with the highly individualistic interpretation of ‘best interests’. In fact, a ‘best interests’ standard is an attempt to narrowly focus decisions on the patient himself or herself and to avoid greater issues of the just distribution of health care resources, but this is impossible. Families and communities struggle to consider what they owe each child, but also to consider what is fair for this child and all children together. Resources of time, effort, services and money are limited within families and communities. Each must consider the impact of choices on the availability of resources for others. There is no doubt that questions of distributive justice are among the most difﬁcult ethical issues that families, professionals, and communities must face. But they will never be resolved if they are simply ignored in the decision-making process. The authors agree that allocation decisions are best made at levels other than at the bedside, as in the formulation of insurance plans and governmental policies. But these corporate allocation decisions will always have implications for bedside care, and must not be ignored.

Applying the best interests standard 175

An expanded ‘best interests’ standard is an attempt to balance the beneﬁts and burdens of a health care intervention according to the values of the parents, pediatric surgeons and the larger society. It should be clear that the model described represents its application in the dominant medical culture in the USA. Firstly, other cultures and countries may have a different understanding of what constitutes family and necessarily include others besides parents. Perhaps others, such as family elders, are the persons designated as decision makers. Secondly, this particular model is based on western notions of the importance of informed consent and respect for the autonomy (self-determination) of the patient, and the family in the case of pediatrics. In other cultures and countries, families may not see their role as decision makers at all, but only in terms of doing what the doctor orders. Also, other cultures and countries may emphasize other core values such as responsibility to the larger family and community rather than autonomy (self-determination). Finally, the model described presumes a certain access to technology that is primarily available in developed nations. A concern for quality of life is different in developed nations where the issue may be the result of technology that is able to save life of diminished quality, as opposed to developing nations where diminished quality of life may be primarily a consequence of inadequate access to basic health care services.

APPLYING THE BEST INTERESTS STANDARD How does the best interests standard work in practice? It must be remembered that the term is just a place holder for a complex structure of values that must themselves be interpreted and applied. It is not possible to use the label ‘best interests’ and expect it to do the moral work for us. It is always necessary to discuss the particular beneﬁts and burdens of an intervention, according to the evaluations of all the parties involved. No one party has a privileged view of the best interests of the infant. Consider for example, an infant born with an imperforate anus. There are no associated anomalies and the infant cannot survive without operative correction. The pediatric surgeon recommends surgery to the parents because surgery would be in the best interests of their infant. The pediatric surgeon means by the use of the term, that the possible beneﬁts to the infant (life, restoration of function, reduction of pain and suffering) outweigh the possible burdens (time in the hospital away from family, risk of death associated with anesthesia, pain and suffering associated with testing and interventions, and risk of compromised function). The calculation of best interests is based on the infant’s diagnosis, prognosis, available treatment options, and the likelihood of their success. The anomaly is fatal without

intervention, and the surgery is relatively low risk with a high likelihood of success. The pediatric surgeon wishes to preserve professional integrity by fulﬁlling the ethical obligations to promote the infant’s welfare by saving the infant’s life and restoring function, and protecting the infant from harm. The pediatric surgeon is acting upon the values of what it means to be a ‘good physician’. Most parents would agree that surgery for an imperforate anus is in the best interests of their infant. Out of their values to be ‘good parents,’ they strive to promote their infant’s welfare and cope with the burdens placed on their infant and upon themselves. Most parents would agree that the outcome is good (life and restored function), and the surgery has a high likelihood of success with minimum burden (surgery, recovery time, and associated costs). Parents who refused such surgery in the USA would most likely be accused of medical neglect, and the power of the state would most likely be used to insure that the infant received the necessary care. In other situations, a pediatric surgeon and parents may agree that stopping life-sustaining treatment would be in the best interests of a particular infant. For example, consider the case of a 23-week-old infant weighing 600 g who develops necrotizing enterocolitis (NEC). Following an operation for NEC that leaves 25 cm of jejunoilieum, the infant develops a grade IV intraventricular hemorrhage, worsening lung disease, and ongoing sepsis. In this case, the mortality rate of the condition is very high, and the infant’s quality of life is affected by the associated neurological and pulmonary complications. A pediatric surgeon and parents would be justiﬁed in withdrawing life support and instituting comfort care for this infant. It could be argued that it would be inappropriate to subject this already vulnerable infant, with little or no potential to interact with the environment, to the substantial burdens of life-sustaining technology for devastating bowel disease. None of the treatments for devastating bowel disease, such as further surgery, the use of total parenteral nutrition (TPN), or a bowel transplant, would improve the infant’s neurological condition. With little or no opportunity to experience things such as pleasure or comfort that we regard as beneﬁts, inﬂicting pain or separation from family could be viewed as disproportionally burdensome or not necessary according to a relational potential standard. Although most health care professionals and parents would agree that further interventions are not in this infant’s best interests, some parents would disagree and insist that ‘everything possible be done’. In the USA, it is a very difﬁcult matter both ethically and legally to stop life-sustaining treatment over the objections of the parents.12 Conﬂict resolution depends on a trusting relationship between the pediatric surgeon and the family. The family must be able to trust the pediatric surgeon so that they can rely on the pediatric surgeon’s judgment. This trust begins with the pediatric surgeon’s honesty: the

176 Ethical considerations in newborn surgery

commitment to disclose all relevant information, to insure that families understand what is being said and to respond to the questions and concerns of the family. Pediatric surgeons must also be compassionate, feeling for the infant and with the family as they endure this critical illness. The family needs to know not only that the pediatric surgeon cares for and about them and their infant, but that the pediatric surgeon will not abandon them on this difﬁcult journey. It is vital in these so-called ‘futility’ cases, to understand just what the family means when they say ‘everything possible is being done’. The conﬂict may be a matter of misunderstanding the diagnosis and prognosis and such false expectations can be often corrected with open, ongoing communication. But sometimes there is a real conﬂict between the values of the pediatric surgeons and the values of the family.

3 Solicit value data from all involved parties. Do conﬂicts exist among the values of the parents, other family members and the physicians? Has the basis for the conﬂict been identiﬁed? 4 Deﬁne the available treatment options. With each option, what is the likelihood of cure or amelioration? What are the risks of an adverse effect? What is a minimum level of professionally acceptable treatment? 5 Evaluate possible treatment options and make a recommendation. Justify your choice according to the values of various parties. 6 Achieve a consensus resolution. Have all parties articulated their viewpoint? Would more factual information help to resolve any disputes? Would a mediator (ethics consultant, ethics committee, or other trusted third party) be helpful?

Taking a values history

Most of the time, ethical conﬂicts between pediatric surgeons and parents can be resolved with further communication, negotiation, and accommodation. But sometimes the conﬂict is so severe that the pediatric surgeons should consider appealing to an outside resource such as an ethics committee or withdrawing from the case based on conscientious objections. The threshold is high for involving the courts in a decision about surgery for a neonate or infant. Pediatric surgeons should invoke the power of the state to secure treatment for an infant only when that treatment is universally regarded as beneﬁcial and the appropriate standard of care, making parental refusal equivalent to medical neglect, as in the previously cited case of the infant with an imperforate anus. The classic case for court intervention involves treatment for a life-threatening condition in which the beneﬁts are substantial and the burdens minimal, such as court-ordered blood transfusions for pediatric patients.14 Courts are also not the appropriate venue when parents demand treatments that the pediatric surgeon regards as not being in the best interests of the infant. Conﬂicts are resolved best at the bedside among the parties who know the infant and the circumstances, and those who will live with the consequences of the decision.

Because families may differ in how they make value judgments about what constitutes an acceptable quality of life for their infants, it is essential to be able to elicit information about values and preferences from families. The authors have found the following questions useful. The questions are intended as subject guides only; each clinician must translate the questions into his or her own style: 1 What is your understanding of your baby’s current condition? 2 How has your baby’s illness affected your family? 3 What is most important in the care of your baby? 4 What do you fear the most? What would you like to avoid? 5 What are your family’s sources of strength and support?

Guidelines for ethical decision making Ethical dilemmas most often arise when parents and pediatric surgeons disagree about what constitutes an acceptable quality of life or what constitutes the best interest of the infant. Whose judgment should prevail? Pediatric surgeons can help insure that their ethical judgments are reliable through the application of an organized process.13 There are multiple versions available in the ethics literature, but they generally all contain the following components: 1 Identify the decision makers. Are the parents involved? Are there non-parental legal guardians? Do the parents have the capacity to make a decision? Who are the involved clinicians? 2 Gather the relevant medical facts. What is the diagnosis? What is the prognosis? Are additional tests necessary for further clariﬁcation? Is there necessary information to be gathered from other clinicians?

ROLE OF CULTURE IN DECISION MAKING The ethical concept of best interests that has been articulated is largely dependent upon the authors’ own experiences in the medical culture in the USA. Some of the most difﬁcult ethical issues that the authors’ have personally faced involve a conﬂict between this western medical notion of best interests and families making decisions for their infants from within other cultures. The following case illustrates how culture may affect parental decisions and the patient–physician relationship.

Role of culture in decision making 177

Case study MS is a 25-day-old infant born at 26 weeks’ gestation, weighing 650 g. He was stable on 50% oxygen and minimal ventilatory settings. He was on continuous feedings using a premature formula. At 25 days of age the infant developed acute abdominal distention, intolerance to feedings, and bloody stools. Urgent consultation with the pediatric surgeon was requested. A radiograph showed diffuse pneumatosis. He was mottled, acidotic, and hypotensive. His laboratory values showed a white blood cell count of 2000, hemoglobin of 7 mg%, and a platelet count of 6000. He received packed red cells and platelets. Blood cultures were drawn and he was started on triple antibiotics. The parents agreed to bedside peritoneal drainage. After 36 hours, MS was clinically stable and the pediatric surgeon advised laparotomy. The parents refused the operation. MS’s parents are from Nigeria and are in the USA on student visas. They have two other healthy children, aged 3 and 5. They plan to return to their native country in 6 months. Both parents visit daily and are concerned about their son. Both the father and mother speak English, but the father’s English is slightly better than the mother’s. Sometimes the father has to translate information for the mother and translate the mother’s statements for the doctors. They ask appropriate questions and seem to understand their son’s medical condition, prognosis, and alternatives for treatment. They desire that their son live, but are strongly opposed to TPN, especially since this technology is not available in Nigeria. They acknowledge that MS is gravely ill and are accepting of his probable death. They say that they agreed to the use of all the previous medical technology because they thought it would save their son’s life. But a life dependent on medical technology is too burdensome. They were expecting that their son would be able to live normally once he got out of the hospital. The parents explain that they have a strong faith in God, and God will decide if their son lives or dies and they will accept whatever happens. They believe that it is not in their power to alter God’s will by the continued use of technology to support a life ‘that was not meant to be’ and that if the boy is not able to eat like a normal infant, than it is better that he go to God. They are supported in this belief by their Nigerian minister and congregation. They have clearly stated their intention to return to Nigeria where life-sustaining technology, such as TPN and specialized nutritional formulas, are unavailable. In addition, in their native country pediatric specialists are unavailable to provide medical and surgical care for an infant with a poorly functioning intestine. What should the pediatric surgeon do? Some may be tempted to resolve this conﬂict in a very legalistic fashion dependent on western notions of medical neglect and their attendant professional obligations to turn to the courts for proper resolution.

Simply stated, ‘You are in the USA – our cultural norms get to override your cultural norms.’ In that sense, this case is no different from any other case that raises the issue of the limits of parental discretion in medical decision making. A narrow best interests standard would seem to require overriding the parents’ decision and forcing the operation. According to informed medical judgment, the infant will most likely die without the surgery, while there is a reasonable probability that the infant’s life can be saved by resection of the diseased bowel. To say that the infant is better off dead is to substantially undervalue the lives of persons with disabilities, including this infant. Some would argue that this case is similar to the case of the infant with an imperforate anus or an infant needing a blood transfusion. To allow this family to choose non-treatment would violate the principle of justice as nondiscrimination. However, there is something particularly compelling about such cases that call participants to value and respect cultural differences. Both the parents and pediatric surgeons are struggling to fulﬁll their role-speciﬁc obligations to be good parents and good physicians. But they literally see their roles quite differently. It is culture that provides the ‘lens’ for each of us to view the world. One deﬁnition of culture states: ‘Culture is a set of guidelines (both explicit and implicit) which individuals inherit as members of a particular society, and which tells them how to view the world, how to experience it emotionally, and how to behave in it in relation to other people, to supernatural forces or gods, and to the natural environment. It also provides them with a way of transmitting symbols, language, art and ritual. To some extent, culture can be seen as an inherited “lens”, through which individuals perceive and understand the world that they inhabit, and learn how to live within it. Growing up within any society is a form of enculturation, whereby the individual slowly acquires the cultural “lens” of that society. Without such a shared perception of the world, both the cohesion and the continuity of any human group would be impossible.’15

It seems obvious from this deﬁnition that there is no way to talk about best interests from outside a cultural perspective. All of our discussion, then, is in some sense cross-cultural. The narrow explication of best interests represents the perspective of the USA, and perhaps predominantly the powerful status of its medical and legal culture. A Nigerian anthropologist commenting on this case might point out that the USA has several unique cultural features. People in the USA tend to think that there is nothing worse than death – at least for a child or young person. Children are to be viewed as little adults – as individuals ﬁrst and then only secondarily as members of a family or community, essentially independent of their

178 Ethical considerations in newborn surgery

families rather than dependent. Their right to grow up and to ultimately make their own choices is primary. US culture is very action oriented: when in doubt – act. The USA is also obsessed by the development and perceived power of technology. Technology and knowledge are primary goods. But the central question is not really whether or not we have a cultural perspective, but whether we can judge some perspectives as better than others. This raises the difﬁcult ethical question of cultural relativity. Cultural relativity refers to the following claims: (1) all moral judgments are relative to the culture in which they arise; (2) moral judgments across cultures are signiﬁcantly different; and (3) there is no way to rank moral judgments across cultures.16 The well-respected physician – ethicist, Edmund Pellegrino, accepts that culture is essential in the context of medical and ethical decisions, but that there are also features of human beings as human beings according to which we can judge among cultures.17 It can be argued that there are some universal features that all cultures either should or would accept. An example would be that moral communities must allow democratic processes and cannot be oppressive.18 The philosopher, Sara Ruddick, identiﬁes three universal maternal interests that are applicable regardless of the particular form they take in a culture. These maternal interests include: (1) preservation; (2) growth; and (3) acceptability.19 Other ethicists identify universal moral principles that underlie our commitments to be tolerant of cultural diversity.20,21 Without some principle of respect for persons, for example, there would be no reason to prefer tolerance of cultural differences. A cultural perspective is particularly important to ethical theorists, who support the inclusion of context and relationship in an ethical analysis, and to those of us working in clinical settings. As Carl Elliot writes: ‘Ethical concepts are tied to a society’s customs, manners, tradition, institutions – all of the concepts that structure and inform the ways in which a member of that society deals with the world. When we forget this, we are in danger of leaving this world of genuine moral experience for the world of moral ﬁction – a simpliﬁed, hypothetical creation less suited for practical difﬁculties than for intellectual convenience.’22

The authors wish to support an ethical analysis that includes culture as an important feature, but also acknowledges the role of the application of universal ethical principles. Like Pellegrino, the authors accept that there are some ethical principles that apply to all humans based on their humanity. Culture is necessary to understand what these principles mean and how they are applied with respect to each of the parties in the conﬂict. It is possible to be respectful of cultural differences and at the same time acknowledge that there are limits. What remains critical is the perceived degree of harm; some

cultural practices may constitute violations of fundamental human rights.23 It is useful to return to the above case and apply the process for ethical decision making with special attention to its cross-cultural features.

CASE ANALYSIS The ethical question in this case is: what should the pediatric surgeon do for MS? What role should culture play in the deliberations? The family in this case clearly values their son’s life and his quality of life. They also value the impact of this infant’s life on their other children, the life of the family as a whole, and their plans to return to their native country. They accepted the initial use of technology in the care of their premature son, in the hope that it would deliver a ‘normal’ infant, free of future dependence on medical technology. They are clear that for them, in a cultural and religious sense, a life dependent on TPN, specialized nutritional feedings, and the prospect of bowel transplantation is unacceptable. For the pediatric surgeon and the other members of the health care team, the preservation of this infant’s life is a goal, but the quality of his life is also a consideration. The laparotomy will allow the pediatric surgeon to assess the severity of the NEC, the amount of diseased bowel, and the prognosis for MS to have functional intestine without the need for prolonged TPN. There are basically three options available in this situation. First, the pediatric surgeon can go forward with all the care that it takes to save this infant’s life. This would include surgery, the use of TPN for as long as necessary, and all efforts to preserve the life of MS, including the possibility for bowel transplantation. This would more than likely include going to court to force the parents to consent to the operation and having a guardian appointed to make medical decisions for MS. This option could result in the permanent loss of parental rights and placement of the infant in the care of the state. In the second option, the pediatric surgeon performs the operation in the hope that there is sufﬁcient residual bowel without the need for long-term TPN and bowel transplantation. If there were clearly not enough viable bowel, MS would be provided with comfort care and allowed to die. If there were sufﬁcient residual bowel, care would proceed as appropriate. A difﬁculty arises if there is a questionable amount of bowel and a trial of TPN would seem to be appropriate. The pediatric surgeon could resect the diseased bowel and proceed with a trial of TPN, discontinuing the use of TPN when it is clear that the bowel is not going to function normally. The third option is not to perform the operation. The infant could be maintained on current levels of support to see whether his bowel will heal on its own, or a comfort care plan could be initiated that would allow the infant to die sooner rather than prolonging the dying process.

Role of culture in decision making 179

The authors think that the ﬁrst option is outside the range of moral justiﬁcation and should not be recommended. The infant is critically ill with a disease that carries high rates of mortality and morbidity. Nontreatment for MS does not rise to the standard of medical neglect. The strongest argument for insisting on treatment rests on the claim that this infant is a member of the community, not only a member of his family. If families will not or cannot take proper care of their children, then we will step in to do so. But who is this ‘we’? If there is no such community support, or insofar as the broader community fails in this responsibility, then the community’ s claim on the family’s choice is diminished. In this case, the Nigerian community (here or in Nigeria) does not make demands on the parents’ choice. They do not see themselves as able, or obligated, to provide these services to MS. But in what sense is MS and his family a member of the US community? An argument can be made that they are community members by virtue of their residence. Yet they are planning to return to Nigeria. The argument that treatment must be forced because of community obligations seems diminished by their departure. We will not be around to provide the support we claim is necessary. But will we provide the necessary support even if they stay? Is it possible for them to stay? Our community claims also seem diminished insofar as the family’s student visa is not renewed, or access to health and social services is limited based on their foreign status. To claim that we are discharging our community obligations only by saving the child’s life, seems to greatly distort the notion of community. But a ﬁnal consideration needs to be mentioned. Couldn’t we discharge our community responsibility by keeping the child here and placing him up for adoption? Then he certainly would become a full member of our community and the concerns raised earlier would no longer apply. Such an action could clearly state that we believe the only appropriate parental choice is to try and save the infant’s life. To choose anything else is to act as bad parents who should be replaced. Yet are they really bad parents? Such a judgment clearly raises serious concerns about cultural norms of parenting, and fails to take culture into consideration. From the parent’s cultural perspective, good parents would not choose surgery and neither would good physicians. This is not standard of care in Nigeria. But how should culture ﬁgure into the deliberations of the pediatric surgeon? It obviously cannot simply be ignored in a grand act of medical and parental imperialism. Also, we should not pay lip service to cultural perspectives, accepting the unusual and exotic only when it also ﬁts into our own value framework. For example, this family could make the choice based on their cultural values only if there were a much higher mortality rate associated with the infant’s condition.

Finally, respect for different cultures cannot simply be some kind of ultimate trump. Automatically deferring to any choices based on cultural differences is to ignore the central values of our own culture. Ironically, it would be a violation of respect for cultural diversity in that our own cultural values are ignored. An attempt at negotiation and compromise is to be preferred. The authors think that the pediatric surgeon should recommend surgery under the second scenario, saving the infant if possible, letting the infant die if appropriate, and negotiating a trial of TPN if necessary. But if this is not acceptable to the parents, the pediatric surgeon should respect the parents’ decision not to have surgery and proceed with a plan of care aimed at keeping the infant comfortable until he either improves or dies. A decision by a pediatric surgeon to conscientiously withdraw from this patient’s care out of concern for his or her own central values, should be respected. The second option is supported by the health care professionals’ and the family’s values. Surgery could save the infant’s life, which all parties value, but it would do so under conditions of a quality of life that are acceptable to the family. Some health care professionals may have problems with this option if a trial of TPN is necessary. It is difﬁcult to establish how long a trial of TPN should last. This difﬁcult negotiation must consider what is medically feasible and also acceptable to the family. Also, many believe that there is a distinction between decisions not to start treatments (withholding) and decisions to stop treatments (withdrawing). Although this distinction is psychologically powerful, it is not ethically or legally valid in the US.23 If health care professionals and parents have sufﬁcient justiﬁcation based on the balance of beneﬁts and burdens not to start a treatment, then they have the same justiﬁcation to stop a treatment once begun. There is a hidden danger in maintaining this distinction between not starting and stopping medical and surgical treatments. Sometimes trials of therapy are not initiated when they are appropriate out of fear that the therapy cannot be stopped once it has begun. Others argue that the provision of nutrition and hydration is different than other medical interventions, such as ventilators and dialysis, which are ‘extraordinary’ and ethically can be withheld or withdrawn. According to this view, the provision of nutrition and hydration is ordinary and is always morally required. The attempt to classify categories of interventions independent of their application to the care of an individual patient is misguided. So-called ‘ordinary’ treatments like antibiotics and the medical provision of hydration and nutrition, can be disproportionally burdensome to certain infants and may be ethically forgone (withheld or withdrawn).24 Many physicians and parents have particular values around the importance of feeding, regarding feeding tubes and TPN as morally equivalent to bottle or breast feeding an infant or to sharing a meal. Yet the provision of TPN is not readily comparable to feeding an infant or

180 Ethical considerations in newborn surgery

to a shared family meal. There are important differences. When hydration and nutrition are provided through medical means, they must be assessed according to the same principles used to evaluate any medical intervention. Decisions must be based on a careful evaluation of the proportionality of the possible beneﬁts and burdens. For this family, TPN is not only burdensome because of the risk of frequent infections and the likelihood of progressive liver disease, but because of what feeding through technology means in their culture, and the ﬁnancial and social burdens to the entire family. The health care team in the USA cannot allocate this family’s scarce resources for them, or for their country of origin.

SUMMARY The best interests standard is a complex amalgam of the values of pediatric surgeons, families, and broader societies. As health care itself becomes increasingly multicultural and international, the need for cross-cultural ethical dialogue increases. There are no ultimate trump cards, just a genuine need for what one philosopher calls ‘communitarian perspectivalism.’16 Any healthy, growing and self-renewing culture continually subjects itself to self-evaluation and evaluation by others. In this regard, the authors wish to point to the need for greater attention to the value of justice in the provision of health care around the globe. This chapter represents a tendency to look at the developed nations and evaluate the issue of not providing the most that can be done. This is obviously an ethical problem for the rich. What about the bigger ethical problem of not providing the basic minimum to infants everywhere – the ethical problem of not providing what poor parents want for their children and cannot afford? Certainly ethical dialogue needs to include what children around the globe are owed as a matter of justice – of fundamental human rights. Access to global health care resources is a problem that affects all persons. The contribution of the medical marketplace to the disproportionate allocation of health care that exists cannot be ignored. Medicine must take responsibility for the emphasis on expanding new technologies in the market rather than meeting basic public health needs, and the disproportionate burden it may place on the economies of developing nations or nations committed to universal access to health care. A global cross-cultural perspective is essential to help expand the concept of ‘best interests’ to include a necessary public health focus.

REFERENCES 1. American Academy of Pediatrics Committee on Bioethics. Informed consent, parental permission, and assent in pediatric practice. Pediatrics 1995; 95:314–17.

2. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Deciding to Forego Life-Sustaining Treatment, 1983, 197–229. 3. The Hastings Center Research Project on the Care of Imperiled Newborns. Hastings Center Report 1987; 17:5–32. 4. McCormick R. To save or let die: the dilemma of modern medicine. JAMA 1974; 29:172–6. 5. Arras JD. Toward an ethic of ambiguity. Hastings Center Report 1984; 14:25–33. 6. Brody H. Commentary. Hastings Center Report 1988; 18:37–39. 7. Bartholome WG. Commentary. Hastings Center Report 1988; 18:39–40. 8. Nelson JL. Taking families seriously. Hastings Center Report 1992; 22:6–12. 9. Ruddick W. Questions parents should resist. In: Kopelman LM, Moskop JC, editors. Children and Health Care: Moral and Social Issues. Dordrecht: Kluwer Academic Publishers, 1989, 221–9. 10. Baylis F, Caniano DA. Medical ethics and the pediatric surgeon. In: Oldham KT, Colombani PM, Foglia RP, editors. Surgery of Infants and Children. Philadelphia: Lipincott-Raven, 1997, 281–388. 11. Buchanan A, Brock D. Deciding for Others: The Ethics of Surrogate Decision Making, Cambridge University Press, Cambridge, 1989, 83–135. 12. Annas GJ. Asking the courts to set the standard of emergency care – the case of Baby K. N Engl J Med 1994; 320:1542–5. 13. Glover JJ, Caniano DA. Ethical issues in treating infants with very low birth weight. Seminars in Pediatric Surgery 2000; 9:56–62. 14. American Academy of Pediatrics Committee on Bioethics. Religious objections to medical care. Pediatrics 1997; 99:279–281. 15. Helman CG. Culture, Health and Illness. Wright Publishing, London, 1990, 2–3. 16. Garcia J. African-American perspectives, cultural relativism, and normative issues: some conceptual questions. In: Flack HE, Pellegrino ED, editors. AfricanAmerican Perspectives in Biomedical Ethics, Washington, DC: Georgetown University Press, 1992, 11–66. 17. Pellegrino ED. Intersections of western biomedical ethics. In: Pellegrino ED, Corsi PMP, editors. Transcultural Dimensions in Medical Ethics, Frederick, Maryland: University Publishing Group, 1992, 13–19. 18. Sherwin SL. No Longer Patient: Feminist Ethics and Health Care, Temple University Press, Philadelphia, 1992, 248–9. 19. Ruddick S. Maternal thinking. In: Trebilcot J, editor. Mothering: Essays in Feminist Theory, Totowa, New Jersey: Rowan & Allanheld, 1983, 213–30. 20. Beauchamp T. Response to Garcia. In: Flack HE, Pellegrino ED, editors. African-American Perspectives in Biomedical Ethics, Washington DC: Georgetown University Press, 1992, 67–8.

References 181 21. Macklin R. Ethical relativism in a multicultural society. Kennedy Institute of Ethics Journal 1998; 8:1–22. 22. Elliot C. Where ethics comes from and what to do about it. Hastings Center Report 1989; 22:28–35. 23. American Academy of Pediatrics Committee on Bioethics

Guidelines on foregoing life-sustaining medical treatment. Pediatrics 1994; 93:532–6. 24. Nelson LJ, Rushton CH. Foregoing medically provided nutrition and hydration in pediatric patients. J Law Med Ethics 1995; 23:33–46.

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16 Minimally invasive neonatal surgery ASHLEY VERNON, TIMOTHY KANE AND KEITH E. GEORGESON

INTRODUCTION The application of minimally invasive surgical techniques to neonates has developed in parallel with its adult counterpart. Limitations in the miniaturization of endosurgical instruments have resulted in a lag in the development and popularity of minimal-access procedures in infants. Signiﬁcant recent advances in the downsizing of surgical instrumentation and the development of reliable and safe techniques have broadened the applicability of endoscopic surgery in neonates. Despite the growing use of minimally invasive procedures in neonates, much of the current literature supporting the safety and applicability of thoracoscopy and laparoscopy is based on case reports and relatively small clinical series of patients. With the growing experience in neonatal endoscopic surgery, it has become clear that neonates tolerate minimally invasive procedures well but have speciﬁc sensitivities to minimal-access invasion that must be recognized in order to achieve successful results. These special sensitivities will be discussed individually in the appropriate sections of this chapter.

THORACOSCOPY The application of thoracoscopy in infants and children began over 20 years ago.1 Currently, the most frequently performed thoracoscopic procedures for infants and children have been for the purpose of pulmonary biopsy for interstitial lung disease. Thoracoscopy has also been used for more extensive pulmonary resections utilizing either segmentectomy or lobectomy for congenital pulmonary lesions including sequestrations, lobar emphysema and cystadenomatoid malformations have been associated with low morbidity rates.2 Bronchogenic cysts, esophageal duplications, thoracic ganglioneuromas and neuroblastomas have been approached

using thoracoscopic methods with excellent visualization and access to these lesions.

Anesthetic consideration in thoracoscopy Like the adaptation of endoscopic instruments for thoracoscopic neonatal operations, the techniques of using anesthesia during delivery have also evolved to ensure patient safety and optimize surgical visualization during thoracoscopy. Peripheral i.v. access is usually adequate for safe thoracoscopy in neonates. Central venous access, although rarely necessary, should be placed on the side of planned thoracoscopy to avoid the potential for bilateral pneumothoraces. Other monitoring devices needed during thoracoscopy include continuous electrocardiography, non-invasive blood pressure monitoring, temperature monitoring, and end-tidal carbon dioxide (ETCO2) measurement. Since ETCO2 monitoring is often inaccurate during thoracoscopic procedures, especially during single-lung ventilation with its physiologic alterations due to dead space and shunt fraction, transcutaneous CO2 monitors are useful and provide a greater margin of safety for thoracoscopic procedures.3 A major problem associated with general anesthesia and positive-pressure ventilation during thoracoscopy is the impairment of visualization and surgical access by lung expansion. In the neonate, single-lung ventilation using selective mainstem intubation of the contralateral bronchus is the primary method used to overcome this problem.4 Other methods of single-lung ventilation include the use of bronchial blockers and cuffed endotracheal tubes. Double-lumen tubes are not available in sizes appropriate for neonates. It is important to monitor the patient for the development of signiﬁcant hypercapnia or hypoxia during one-lung ventilation because this anesthetic technique sometimes results in inadequate oxygenation and ventilation and must be abandoned. If single-lung ventilation cannot be achieved or is not well tolerated by the infant, double-lung ventilation with

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the addition of low-ﬂow (1 L/minute), low-pressure (4–8 mmHg) infusion of CO2 into the thorax on the operative side will often adequately compress the lungs and optimize visualization. This technique is surprisingly well tolerated by most neonates. The major risks of creating this artiﬁcal pneumothorax are the development of hypercarbia and hypoxia due to inadequate ventilation, the sudden onset of hypotension due to inadequate venus return, and the potential development of CO2 embolism. Cardiovascular changes of hypotension and bradycardia are usually quickly reversible by stopping insufﬂation, relieving the pneumothorax and administering ﬂuids to increase pre-load.

Diagnostic thoracoscopy Thoracoscopy for diagnostic purposes is infrequently utilized in the neonate. Most neonatal diagnoses are made by the thoughtful use of diagnostic imaging. However, in carefully selected circumstances, excellent visualization of intrathoracic anatomy can be obtained using thoracoscopy.

Biopsy or resection of lung lesions Pulmonary biopsy is one of the most common operations performed thoracoscopically in infants. Thoracoscopic biopsy has been shown to be useful in the diagnosis of interstitial lung disease, metastatic lesions, or infectious disease of unknown origin. Lung biopsy in neonates is usually performed with a loop ligature placed snugly at the base of the biopsy specimen. The lung peripheral to the ligature is excised sharply leaving a 5 mm cuff. Placement of a chest tube through an access trocar site is optional but recommended. Another effective biopsy technique is to seal the base of the biopsy specimen with an endoscopic Ligasure coagulator (Valleylab, Tyco Healthcare (Boulder, Colorado)). The specimen is then removed peripheral to the coagulated tissue. Thoracoscopic approaches have also been used for resection of congenital cysticadenomatoid malformations and congenital lobar emphysema. The segment or lobe is removed using the Ligasure for sealing of the lung and vessels. Suture ligation is used to secure the bronchus.

safest approach has been ﬁrst to evacuate the cyst followed by subtotal resection of the cyst. Removal of the cyst lining on the esophageal wall completes the procedure. Reinforcement of the esophageal wall is then performed, when needed, using interrupted sutures.8 Mediastinal dissections are almost always carried out with an esophageal dilator in place to minimize potential trauma to the esophagus.

Closure of patent ductus arteriosus There have been multiple reports of thoracoscopic closure of patent ductus arteriosus (PDA). The ﬁrst such report appeared in 1991. Initially, the majority of patients were older than 2 months or over 4 kg in weight.9 As the instrumentation for video-assisted thoracoscopic PDA ligation has improved, the application of this technique in smaller and smaller patients has grown.10 Burke et al.11 has shown that endoscopic PDA ligation in infants weighing <2500 g is safe and effective; in 34 patients there were no operative mortalities. Conversion to open thoracotomy was required in 11%, usually due to difﬁculty in visualization of the PDA.11 The incidence of procedure-related complications of endoscopic PDA ligation such as residual ductal ﬂow and recurrent laryngeal nerve injury are similar to those of open techniques.11

Esophageal atresia Several pediatric surgical groups have demonstrated the ability to repair esophageal atresia with tracheoesophageal ﬁstula using thoracoscopic methods. Some of the observed complications have been anastomotic leaks

Mediastinal masses Thoracoscopic resection of bronchogenic cysts and esophageal duplication cysts have become commonplace in the neonate.5–7 Complete resection of bronchogenic cysts by a thoracoscopy approach is usually straightforward. Adjacent structures are clearly visualized and avoided. Occasionally, esophageal duplication cysts and the esophagus share a common wall. In these cases, the

Figure 16.1 Ligation of TEF and repair of esophageal atresia. Note the clip (arrow) on the tracheo-esophageal ﬁstula. The esophageal anastomisis was performed thoracoscopically

Laparoscopy 185

and stenoses. It is too early to judge whether this technique will be as beneﬁcial as the standard open thoracotomy method of tracheo-esophageal ﬁstula repair. Perhaps this is an area that will beneﬁt from the development of microscopic robotic instruments.

Diaphragmatic hernia repair The repair of Bochdalek and Morgagni diaphragmatic hernias using thoracoscopic methods has been described in anecdotal case reports, usually in older infants and children. Repair of symptomatic congenital diaphragmatic hernias in the newborn has not yet been described. Video-assisted plication for eventration of the diaphragm or phrenic nerve paralysis has become commonplace. No large series have been reported to date but the success of thoracoscopic diaphragmatic plication appears to be equivalent to that of open methods.

LAPAROSCOPY Pneumoperitoneum CO2 has been shown to be a useful insufﬂating gas in adults and infants because it is nonﬂammable, has moderate absorption and has predictable and nontoxic physiological effects when absorbed. The physiological effects of CO2 pneumoperitoneum may be more pronounced in infants than in larger patients. Interest in studying these effects has grown as more laparoscopic procedures are being applied to patients in this age group. Two primary reasons have been proposed for the pronounced effects of CO2 pneumoperitoneum in neonates when compared to adults. Higher levels of dissolved CO2 are seen in neonates during laparoscopic procedures (as signaled by increased end-tidal CO2). This response is thought to be due to an increased peritoneal absorptive surface area in comparison to body weight. Secondly, the absorption of CO2 through the peritoneal surface may be more efﬁcient in neonates. The efﬁciency is likely to be due to decreased fat and closer proximity of the blood vessels to the peritoneal lining. The result is hypercapnia and respiratory acidosis if not anticipated. For the most part, the hypercapnia associated with CO2 pneumoperitoneum is overcome by increasing minute ventilation and ‘blowing off ’ CO2 during the laparoscopic procedure. Some evidence suggests that the ventilatory rate may need to be increased by between 20–30% (Tan, 1992)12 and up to 50–75%13 to maintain normocarbia. In a series of 65 laparoscopic neonatal procedures (in patients 2–30 days old), hyperventilation was necessary to correct elevated end-tidal CO2.14 The

major postoperative risk is that the neonate will be unable to maintain increased ventilatory effort during the immediate postoperative period when CO2 levels are still high, but the diaphragm is sluggish due to inhaled and i.v. anesthetic agents. Prolonged postoperative intubation and ventilation may be necessary in some neonates after the pneumoperitoneum has been evacuated.

Increased intra-abdominal pressure It has been shown in adults that increased abdominal pressure can be tolerated to levels of 15 mmHg. At this level of intra-abdominal pressure, there is usually no compromise to venous return. In fact, at low levels of intra-abdominal pressure the venous return is actually augmented as blood is ‘squeezed’ out of the splanchnic venous bed. The cardiovascular effects of increased abdominal pressure may be different in neonates. An animal neonatal model using newborn piglets was used to study the cardiovascular effects of increased abdominal pressure. Using a pulmonary artery catheter, a progressive decrease in cardiac index was noticed in this neonatal model as pressure was increased above 15 mmHg. At higher pressures, in addition to inferior vena caval (IVC) compression, collaterals are also compressed, accounting for even more profound hypotension than would be explained by IVC compression alone. This study documents the sensitivity of the newborn piglet to increased abdominal pressure and emphasizes the importance of maintaining somewhat lower pressures in human neonates.15 Gueugniaud et al.16 studied 12 healthy infants aged 6–30 months using transesophageal echo aortic Doppler. With a pneumoperitoneum of 10 mmHg and increased minute ventilation to prevent hypercapnia, they noted a decrease in cardiac performance (67% reduction in aortic blood ﬂow and stroke volume) and an increase in systemic vascular resistance (162%). These changes were not associated with any deleterious cardiac effects in the short period of study. Others have found no clinically signiﬁcant effects with short procedures and pneumoperitoneum of less than 15 mmHg. Tobias et al.17 studied 53 children aged 1 month to 7 years who underwent diagnostic inguinal laparoscopy. End-tidal CO2 increased from 32 to 35 and normalized within 10 minutes postoperatively. The patients did not require hyperventilation and ventilatory settings were unchanged during the investigation. These minimal alterations in vital signs were attributed to the brief surgical times, limiting intra-abdominal pressure to 15 mmHg, and avoiding the Trendelenburg’s position. Sfez (1995)18 studied 25 children undergoing laparoscopic fundoplication with over two-thirds of the patients having underlying respiratory disease. Of the

186 Minimally invasive neonatal surgery

patients included in the study, 25% had transient hypoxia postoperatively and three patients had positional hypotension and bradycardia. Upward displacement of the paralyzed diaphragm following creation of pneumoperitoneum can lead to pulmonary atelectasis, which might not be clinically apparent perioperatively owing to positive-pressure ventilation (PPV). With resumption of spontaneous ventilation, however, these patients can become hypoxemic and require PPV until the collapsed lung reexpands.

Abdominal access There are some reports of an increased incidence of access injuries in infants due to the proximity of important intra-abdominal structures in small patients. The insertion of the Veress needle or initial trocar into major vessels can be avoided by strict adherence to the basic principles of insertion. Although there has been no trocar insertion technique proven to be the safest, it appears that the radially expanding trocars are safe. We prefer to use a radially expanding trocar as the initialaccess trocar. Reusable trocars can then be more safely inserted under direct vision. Slippage of trocars can be a major problem, especially in pediatric laparoscopic surgery.19 These complications can be managed in a variety of effective ways. Our preference is to use the radially expanding 5 mm trocars. For trocars 4 mm and smaller, the authors use reusable trocars and suture them to the abdominal wall using a rubber cuff made from a red rubber catheter. The catheter is cut to a 1 cm length segment, slipped over the end of the trocar and positioned at the appropriate level on the trocar. The trocar can then be moved in and out relative to the cuff.

Abdominal procedures Although laparoscopic surgery has been somewhat slower to progress in neonates than in older patients, there are a few laparoscopic procedures that are routinely performed at selected centers. There is a large amount of experience in pyloromyotomy, fundoplication, colon and pelvic procedures.

Figure 16.2 Laparoscopic pyloromyotomy. Note the absence of bleeding and the intact pyloric mucosa

Overall, laparoscopic pyloromyotomy has an acceptable complication rate and operative time which is equivalent to that with the open procedure. Fujimoto et al.23 noted that there are signiﬁcantly lower levels of IL-6 in patients undergoing laparoscopy as compared to those undergoing open pyloromyotomy, implying decreased surgical stress. The major drawback of the laparoscopic procedure is that it is currently more costly than its open counterpart. In a series of 301 patients undergoing pyloromyotomy at The Children’s Hospital of Alabama, Birmingham, Alabama (129 laparoscopic and 172 open pyloromyotomies), operative times were shorter for the laparoscopic group (23.5 minutes) compared to those of the open group (28.5 minutes). Additionally, the postoperative length of stay was shorter for the laparoscopic group (31.4 hours) compared to the open group (41.1 hours). The complications were similar for both groups, with ﬁve perforations and one incomplete pyloromyotomy in the laparoscopic group and four perforations in the open group. The cost per patient for the laparoscopic group was signiﬁcantly higher than for the open group: $4240±$1626 vs $3786±$1405 (P<0.05). In conclusion, laparoscopic pyloromyotomy has become a commonplace procedure. It appears to be equally as safe and effective as open pyloromyotomy. The advantages appear to be a faster recovery, a shorter hospitalization time, equivalent operative times, and better cosmetic outcomes. Despite these advantages, the cost of laparoscopic pyloromyotomy continues to be higher than for the open procedure and this remains the current focus for improvement.

Pyloromyotomy Fundoplication Alain et al. ﬁrst described laparoscopic pyloromyotomy in 199120 and subsequently reported 70 other patients in 1996.21 Downey22 reviewed 226 pyloromyotomies published up to the time of his review in 1998. This cumulative review revealed perforation rates and operative times similar to those obtained with the open procedure.

Laparoscopic fundoplication is being performed with increasing frequency in neonates. A study conducted at three children’s hospitals reviewed the fundoplications performed on all patients younger than 3 months of age or weighing less than 3 kg. Information was compiled on

References 187

104 patients of whom 82 had a gastrostomy tube placement in addition to the fundoplication. The mean patient age was 68 days and the mean operative time was 60 minutes. Eleven complications occurred in these 104 patients. Four complications were related to the laparoscopy, four to the gastrostomy, one to poor patient selection, and two to the fundoplication. One patient with a malpositioned gastrostomy tube had emesis at the time of the report; otherwise all patients had no clinical evidence of gastro-esophageal reﬂux with a mean followup of 5 months. There was one death from a gastrostomy tube leak in an infant with trisomy 18. This study shows that laparoscopic Nissen fundoplication can be done safely and effectively in very young patients. Care should be taken to apply fundoplication only to those patients who cannot be safely or adequately treated using medical management.

Other upper gastrointestinal procedures

Endorectal pull-through

Pelvic pathology

Laparoscopy-assisted endorectal pull-through for Hirschsprung’s disease is being performed in increasing numbers of the neonatal record.24–26 The procedure is performed using three small abdominal ports. The transition zone is identiﬁed by seromuscular biopsies obtained laparoscopically. In patients with a rectosigmoid colon transition zone, the intra-abdominal portion of the aganglionic bowel is devascularized using a hook electrocautery. In patients with the longer segments of aganglionic colon, a pedicle preserving the marginal artery is fashioned as far proximal as necessary to bring the colon pedicle down without tension to form the neorectum. The rectal mobilization is performed transanally using an endorectal sleeve technique. The anastomosis is performed transanally 0.5 cm above the dentate line. The early clinical outcomes after a one-stage laparoscopy-assisted endorectal pull-through have been reported in 80 patients aged 3 days to 96 months and appear to reduce perioperative complications and postoperative recovery time.25 Most of these patients were too young to evaluate fecal continence. However, the author’s impression is that fecal continence after this procedure is equivalent to that after procedures performed in an open fashion. Successful techniques for performing laparoscopy-assisted Duhamel and Swenson pull-through procedures have also been reported in neonates. Endoscopic assisted pull-through for high imperforate anus27 also deserves a mention. This procedure is useful in patients with intermediate- and highimperforate anus. The anatomy of the pelvic ﬂoor is seen clearly using the laparoscope. The perineal dissection is aided by transillumination of the perineal muscles using an intra-abdominal light source. The senior author has performed 20 of these operations. The follow-up is too short to obtain information regarding continence.

A variety of treatment options for ovarian cysts can be pursued laparoscopically. These options include decompression, excision, fenestration, oophorectomy, and adnexal detorsion and ﬁxation.28–33 The use of laparoscopic dissection of the pelvic portion of a sacrococcygeal teratoma has been described by Bax and van der Zee.34 The author’s have also performed the pelvic dissection laparoscopically in two patients with sacrococcygeal teratoma and concur with Bax that the intra-abdominal and pelvic portions of teratomas are expediently managed with laparoscopic assistance.

Laparoscopic procedures for malrotation have been performed in many pediatric surgical centers. The operation is technically simple. The duodenum is released from Ladd’s bands starting just distal to the pylorus and the dissection is continued distally. Further bands are also released to allow the cecum to fall over the left side of the abdomen. We have attached the distal duodenum and proximal jejunum to Gerota’s fascia on the right side using interrupted sutures to help maintain a widened mesentery. The follow-up is too short to tell whether the diminished adhesion formation caused by the laparoscopic approach will allow late volvulus. Other conditions which have been corrected laparoscopically in the neonate include the repair of duodenal atresia and division of obstructive bands.

CONCLUSION Neonatal minimally invasive surgery is becoming an increasingly effective tool for infants requiring surgical correction of their afﬂictions. Eventually, the authors are conﬁdent that most intracavitary surgical conditions in neonates will be approached using these techniques.

REFERENCES 1. Rodgers BM, Moazam F, Talbert JL. Thoracoscopy in children. Ann Surg 1979; 189(2):176–80. 2. Rothenberg SS. Thoracoscopy in infants and children. Semin Pediatr Surg 1998; 7(4):194–201. 3. Tobias JD, Wilson Jr WR, Meyer DJ. Transcutaneous monitoring of carbon dioxide tension after cardiothoracic surgery in infants and children. Anesth Analg 1999; 88(3):531–4. 4. Tobias JD. Thoracoscopy in the pediatric patient. Anesthesiol Clin North America 2001; 19(1):173–86, viii.

188 Minimally invasive neonatal surgery 5. Michel JL et al. Thoracoscopic treatment of mediastinal cysts in children. J Pediatr Surg 1998; 33(12):1745–8. 6. Schier F, Waldschmidt J. Thoracoscopy in children. J Pediatr Surg 1996; 31(12):1640–3. 7. Dillon PW, Cilley RE, Krummel TM. Video-assisted thoracoscopic excision of intrathoracic masses in children: report of two cases. Surg Laparosc Endosc 1993; 3(5):433–6. 8. Rodgers BM. Thoracoscopic procedures in children. Semin Pediatr Surg 1993; 2(3):182–9. 9. Rothenberg SS et al. Thoracoscopic closure of patent ductus arteriosus: a less traumatic and more costeffective technique. J Pediatr Surg 1995; 30(7):1057–60. 10. Laborde F et al. Video-assisted thoracoscopic surgical interruption: the technique of choice for patent ductus arteriosus. Routine experience in 230 pediatric cases. J Thorac Cardiovasc Surg 1995; 110(6):1681–4; discussion 1684–5. 11. Burke RP et al. Video-assisted thoracoscopic surgery for patent ductus arteriosus in low birth weight neonates and infants. Pediatrics 1999; 104(2 Pt 1):227–30. 12. Tan PL, Lee TL, Tweed WA. Carbon dioxide absorption and gas exchange during pelvic laparoscopy. Can J Anaes 1992; 39(7):677–81. 13. Liu SY et al. Prospective analysis of cardiopulmonary responses to laparoscopic cholecystectomy. J Laparoendosc Surg 1991; 1(5):241–6. 14. Fujimoto T et al. Laparoscopic surgery in newborn infants. Surg Endosc 1999; 13(8):773–7. 15. Lynch FP et al. Cardiovascular effects of increased intraabdominal pressure in newborn piglets. J Pediatr Surg 1974; 9(5):621–6. 16. Gueugniaud PY et al. The hemodynamic effects of pneumoperitoneum during laparoscopic surgery in healthy infants: assessment by continuous esophageal aortic blood ﬂow echo-Doppler. Anesth Analg 1998; 86(2):290–3. 17. Tobias JD et al. Cardiorespiratory changes in children during laparoscopy. J Pediatr Surg 1995; 30(1):33–6. 18. Sfez M, Guerard A, Desruelle P. Cardiorespiratory changes during laparoscopic fundoplication in children. Paediatr Anaesth 1995; 5(2):89–95. 19. Bax NM, van der Zee DC. Trocar ﬁxation during endoscopic surgery in infants and children. Surg Endosc 1998; 12(2):181–2.

20. Alain JL et al. [Pyloric stenosis in infants. New surgical approaches]. Ann Pediatr (Paris) 1991; 38(9):630–2. 21. Alain JL et al. Laparoscopic pyloromyotomy for infantile hypertrophic stenosis. J Pediatr Surg 1996; 31(8):1197–8. 22. Downey EC, Jr. Laparoscopic pyloromyotomy. Semin Pediatr Surg 1998; 7(4):220–4. 23. Fujimoto T et al. Laparoscopic extramucosal pyloromyotomy versus open pyloromyotomy for infantile hypertrophic pyloric stenosis: which is better? J Pediatr Surg 1999; 34(2):370–2. 24. Georgeson KE, Fuenfer MM, Hardin WD. Primary laparoscopic pull-through for Hirschsprung’s disease in infants and children. J Pediatr Surg 1995; 30(7):1017–21; discussion 1021–2. 25. Georgeson KE et al. Primary laparoscopic-assisted endorectal colon pull-through for Hirschsprung’s disease: a new gold standard. Ann Surg 1999; 229(5):678–82; discussion 682–3. 26. Jona JZ et al. Laparoscopic pull-through procedure for Hirschsprung’s disease. Semin Pediatr Surg 1998; 7(4):228–31. 27. Georgeson KE, Inge TH, Albanese CT. Laparoscopically assisted anorectal pull-through for high imperforate anus – a new technique. J Pediatr Surg 2000; 35(6):927–30; discussion 930–1. 28. Davidoff AM et al. Laparoscopic oophorectomy in children. J Laparoendosc Surg 1996; 6 Suppl 1:S115–19. 29. Dolgin SE. Ovarian masses in the newborn. Semin Pediatr Surg 2000; 9(3):121–7. 30. Esposito C et al. Laparoscopic management of ovarian cysts in newborns. Surg Endosc 1998; 12(9):1152–4. 31. Mahomed A, Jibril A, Youngson G. Laparoscopic management of a large ovarian cyst in the neonate. Surg Endosc 1998; 12(10):1272–4. 32. Decker PA, Chammas J, Sato TT. Laparoscopic diagnosis and management of ovarian torsion in the newborn. Jsls 1999; 3(2):141–3. 33. Templeman CL et al. Laparoscopic management of neonatal ovarian cysts. J Am Assoc Gynecol Laparosc 2000; 7(3):401–4. 34. Bax NM, van der Zee DC. Laparoscopic clipping of the median sacral artery in huge sacrococcygeal teratomas. Surg Endosc 1998; 12(6):882–3.

17 Fetal surgery JYOJI YOSHIZAWA, LOURENÇO SBRAGIA AND MICHAEL R. HARRISON

INTRODUCTION In the past two decades, major advances in fetal imaging and diagnostic procedures have stripped the veil of mystery from the once secretive fetus and have dramatically changed our understanding and management of many prenatally diagnosed malformations. Early diagnosis and close follow-up of fetuses with congenital malformations have allowed us to deﬁne the disease’s natural history, determine the clinical features that affect clinical outcome, and plan management approaches to improve prognosis. Increasingly sophisticated ultrasonography can identify a growing number of disorders and structural defects at an early enough stage to be amenable to prenatal intervention. Selection criteria for in utero intervention were deﬁned, and anesthetic, tocolytic regimen, and surgical techniques for hysterotomy and fetal surgery were developed and reﬁned.1–5 As a result of this investment in basic and clinical research, the fetus has claimed a role as an independent patient.

MATERNAL–FETAL RISKS Fetal surgery is ﬁrst and foremost predicated on responsibility to the mother and her family since she, as well as her unborn child, is a patient in this setting. The risk-tobeneﬁt ratio favors the fetus with a lethal malformation since without intervention the mortality rate is 100% and with intervention survival is possible. It is not, however, that easily justiﬁed for the mother who is essentially an innocent bystander whose physical health is usually not jeopardized by her unborn baby’s condition. For this reason it was paramount to prove that any intervention through the mother could be done safely. This was tested in the most rigorous animal model, the non-human primate whose anatomy and physiology quite closely resemble that of the human pregnancy.6,7 The ﬁrst technical issue addressed was how to safely open and close the gravid uterus such that bleeding and membrane

separation were prevented and a water-tight closure attained. This was solved with an absorbable stapling device and special back-biting retractors for the uterine edges.8 Closing the uterus is performed in two layers with absorbable sutures, supplemented with ﬁbrin glue. Next, a means to monitor the fetus and uterine activity after the procedure was needed. This was solved by developing a relatively large radiotelemeter that is placed inside the fetus within a submuscular pocket.9 It monitors fetal heart rate, temperature, and uterine pressure (contractions). This is presently being miniaturized such that it can be passed down a trocar during fetoscopic procedures and it will just ﬂoat in the amniotic ﬂuid, sending out signals that are translated onto a real-time bedside computer (Harrison MR, personal communication). There has never been a maternal death during or after fetal intervention. Maternal morbidity is related to preterm labor and its treatment.10–13 The most common side effect of tocolytic therapy, pulmonary edema, occurs while the pregnant patient is receiving high doses. Although reversible, this complication emphasizes the need for close monitoring in an intensive care setting.14,15 It has been rarely seen after fetoscopic procedures since they incite less uterine irritability compared to open fetal surgery. During open fetal surgery, the hysterotomy is often not performed in the lower uterine segment due to fetal and placental position and because the lower uterine segment is not fully developed in the second trimester. Thus, delivery after fetal surgery and for all future deliveries must be by cesarean section to avoid the risk of uterine scar dehiscence during labor. This is not, however, necessary after fetoscopic procedures. Fortunately, the ability to carry and deliver subsequent pregnancies does not appear to be jeopardized by fetal surgery. In a recent survey of fetal surgical patients, 27 mothers have attempted pregnancy after fetal surgery, 25 conceived and delivered normal children. Two, both of whom had a strong preoperative history of infertility, failed to conceive.16

190 Fetal surgery

provides hemostasis and seals the membranes to the myometrium.8 The appropriate part of the fetus is then exposed. Warm lactated Ringer’s solution is continuously infused around the fetus and the open uterus to maintain fetal body temperature. For fetal monitoring in open fetal surgery, a sterile pulse oximeter is used and a radiotelemetric device that is implanted submuscularly (usually on the chest wall) records the fetal electrocardiogram, temperature and intrauterine amniotic pressure.9 After repair of the defect, the fetus is returned to the womb and amniotic ﬂuid is restored with warm saline containing an antibiotic such as nafcillin. The uterine incision is closed with two layers of absorbable sutures. Fibrin glue is used to help seal the uterine incision.

FETAL SURGICAL TECHNIQUES The development of both open and minimal-access fetal surgical techniques continues to evolve.12 Anesthesia of the mother and her baby is established with halogenated agents, which also provide profound uterine relaxation. Additionally, an epidural catheter is inserted to enhance postoperative pain control. In the operating room, the mother is positioned in the left-lateral decubitus position to avoid inferior vena caval compression by the gravid uterus. Maternal monitoring is accomplished with standard techniques including pulse oximetry, a radial arterial catheter, a blood pressure cuff, large-bore i.v. catheters, measurement of urine output, and an electrocardiogram. The two principal routes of access to the fetus will be discussed later.

Minimal-access fetal surgery – FETENDO Although fetoscopic techniques for direct optical visualization of the fetus are not new, recent modiﬁcations of existing postnatal endoscopic techniques and development of new fetoscopic instruments have resulted in minimal-access fetal surgery (FETENDO). The FETENDO strategy may preserve fetal homeostasis by protecting the intrauterine physiological milieu, and avoiding the morbidity of a uterine incision such as preterm labor and postoperative bleeding.17 The mother is placed in a modiﬁed lithotomy position. Anesthetic techniques, tocolytic therapy, and maternal monitoring are as described earlier. Pre- and intraoperative sonography maps the position of the placenta and the fetus and guides trocar placement. An anterior placenta usually requires a low transverse abdominal incision to expose the uterus; trocars are placed superiorly and posteriorly. Continuous irrigation using a pump irrigation system via the sheath of the hysteroscope is crucial to optimize visibility (Fig. 17.1). This system maintains a constant intrauterine ﬂuid

Open fetal surgery The timing of open fetal surgery is dependent on the malformation being treated and the pathophysiologic course encompassing that disorder. Commonly, accurate early diagnosis and the fragility of fetal tissue become limiting factors at less than 18 weeks’ gestation. After 30 weeks’ gestation, manipulations on the uterus are associated with a high risk of premature rupture of the membranes (PROM) and preterm labor. It is then more reasonable to deliver the fetus and treat the malformation with standard postnatal care. A low abdominal transverse incision is used to visualize the uterus. After identiﬁcation of the fetal position and placental location with intraoperative ultrasound, the fetus is given an intramuscularly administered narcotic and paralytic agent. Depending on the placental location, an anterior or posterior hysterotomy is performed using a specially developed absorbable uterine stapler device that

Irrigation telescope Heater In Out

Pressure Pump head

Temp

Out Increase fluid LR

Pu rge

In

HE

In Decrease fluid t

Ou

Waste

Figure 17.1 Warmed lactated Ringer’s solution is circulated through the inner sheath of the hysteroscope and exits at the lighted tip. Amniotic ﬂuid can be suctioned via the outer sheath. The irrigation/aspiration volume can be carefully regulated using the pump

Fetal malformation amenable to surgical correction 191

volume, avoids risk of air embolus with gas distention of the uterus, ensures a continuously washed operative ﬁeld, improves visibilitiy by exchanging the cloudy amniotic ﬂuid with lactated Ringer’s solution, and keeps the fetus warm. One of the difﬁcult obstacles of FETENDO is the manipulating of the fetus into the correct position and keeping it there for the duration of the procedure. This very often frustrating problem is best illustrated by the development of FETENDO tracheal occlusion to treat CDH, where a chin stitch (Fig. 17.2) is used to keep the fetal neck exposed by extending the head.17,18 At the end of the procedure, amniotic ﬂuid volume is assessed by sonography and optimized. Antibiotics are infused, the trocars are withdrawn and the puncture site is closed with an absorbable suture and ﬁbrin glue.

Sonogram

T-bar

Trocar

Chin suture

Tracheal screw

Figure 17.2 Under sonographic guidance, (1) the fetus’ neck is exposed and head stabilized by placing a transuterine chin suture, and (2) a T-bar is placed in the fetal trachea to aid in localizing the midline fetal neck. After anterior tracheal dissection, a tracheal ‘screw’ (inset) is placed in the tracheal wall and anterior traction applied, allowing safe posterolateral tracheal dissection. Subsequently, the trachea is occluded with a titanium clip

POSTOPERATIVE MANAGEMENT Daily fetal sonography and echocardiography are substitutes for direct fetal physical examination in the postoperative course. Continuous epidural analgesics ease maternal stress and aid tocolysis. The hospital stay ranges from 2–7 days, depending on the procedure and whether or not a maternal laparotomy was performed. Preterm labor, the Achilles’ heel of fetal intervention, remains the primary cause of maternal morbidity and fetal death. The pathophysiology of preterm labor after hysterotomy is incompletely understood. Currently, tocolytic regimen begins with administration of indomethacin to the mother prior to surgery and despite best

efforts, the development of appropriate postoperative tocolysis is a difﬁcult and frustrating clinical problem.10–12 Treatment with terbutaline, magnesium sulfate, indomethacin, or nifedipine has been relatively ineffective for preterm labor induced by a hysterotomy, in contrast to their value in spontaneous labor. Outpatient tocolysis is administrated with oral or s.c. (via a pump) terbutaline or oral nifedipine. Fetal sonograms are performed at least weekly. Cesarean delivery is performed when membranes rupture or labor cannot be controlled, usually before 36 weeks’ gestation.

FETAL MALFORMATION AMENABLE TO SURGICAL CORRECTION Prenatal diagnosis has deﬁned a ‘hidden’ mortality rate for some lesions, such as congenital diaphragmatic hernia (CDH), bilateral hydronephrosis, sacrococcygeal teratoma (SCT), and congenital cystic adenomatoid malformation (CCAM) of the lung. These lesions, when ﬁrst evaluated and treated postnatally, demonstrate a favorable selection bias because the most severely affected fetuses often die in utero or immediately after birth. Although most prenatally diagnosed malformations are best managed by appropriate medical and surgical therapy after maternal transport and planned delivery at a tertiary care center, an expanding number of simple anatomical abnormalities with predictable, lethal consequences have been successfully corrected before birth. The development of minimal-access fetal surgery techniques, along with improvements in the treatment and/or prevention of preterm labor may enable the transition from treating only life-threatening defects to treating non-life-threatening, but substantially morbid malformations, namely myelomeningocele.

Obstructive uropathy Obstructive uropathy occurs in 1 in 1000 live births.19 Unilateral urinary obstruction (e.g. ureteropelvic junction obstruction) has a good prognosis and usually does not require fetal intervention. Fetuses with bilateral obstruction, principally male fetuses with posterior urethral valves, are potential candidates for prenatal intervention based on the degree and duration of the obstruction.20 Newborns with partial bilateral obstruction may have only mild and reversible hydronephrosis. However, children born at term with a high-grade obstruction may already have advanced hydronephrosis and renal dysplasia that is incompatible with life. The outcome of patients with urinary tract obstruction is principally dependent on the development of oligohydramnios. Decreased fetal urine production leads to oligohydramnios, which can cause pulmonary hypoplasia

192 Fetal surgery

that, if long standing, may be fatal at birth (Potter sequence). The presence of oligohydramnios is a predictor for a mortality approaching that associated with urinary tract obstruction. Fetuses with oligohydramnios identiﬁed in the early second trimester have a mortality rate in excess of 90%.21,22 Prenatal ultrasound diagnosis is very accurate in the detection of fetal hydronephrosis and in determining the level of the urinary obstruction. When sonography demonstrates bilateral hydronephrosis, the initial assessment of fetal renal function is the determination of the quantity of amniotic ﬂuid. Because the majority of amniotic ﬂuid in middle and late pregnancy is the product of fetal urination, the presence of a normal amniotic ﬂuid implies the production and excretion of urine by at least one functioning kidney. Decreasing amniotic ﬂuid volume on serial ultrasound examinations in the setting of bilateral hydronephrosis is usually an indicator of deteriorating renal function. Renal function can then be assessed in two ways: by the appearance of the renal parenchyma on ultrasound, and by the laboratory analysis of urine via bladder aspiration. The presence of cortical cysts or increased echogenicity is highly predictive of renal dysplasia; the absence of these ﬁndings, however, does not preclude it.23 Direct sampling of fetal urine provides critical information about fetal renal function. Normal fetal urinary chemistry (Table 17.1) includes a urinary sodium less than 100 mEq/dL, chloride less than 90 mEq/dL, osmolarity less than 200 mOsm/L, and β2-microglobulin less than 4 mg/dL.20,21 Values greater than these indicate that the fetal kidney is unable to reabsorb these molecules and predicts poor postnatal renal function. Three successive bladder aspirations must be performed, each separated by at least 24 hours. The ﬁrst one empties stagnant bladder urine, the second empties the urine that was stagnant in the collecting system, and the third is most reﬂective of kidney function. The important dilemma in the management of fetuses with hydronephrosis is how to select fetuses with dilated urinary tracts that have a problem so severe that renal and pulmonary function may be compromised at birth, and yet renal function that is preserved enough to proﬁt from prenatal intervention. Only fetuses who present with (or develop) oligohydramnios with normal renal function (via urine electrolytes and protein), are less than 30 weeks’

gestation, and have no associated anomalies are considered for prenatal intervention. The aim of prenatal intervention is to bypass or directly treat the obstruction. If the urinary tract is adequately drained, restoration of amniotic ﬂuid will enhance fetal lung growth and abrogate any further renal function deterioration. Methods of urinary tract decompression include percutaneous vesico-amniotic shunt placement, fetoscopic vesicostomy, open vesicostomy, and fetoscopic fulguration of posterior urethral valves.19,24 Presently the most widely used and accepted means of treating bladder outlet obstruction is by percutaneous insertion of a double-J vesicoamniotic shunt.

Congenital diaphragmatic hernia (CDH) CDH is a simple anatomical defect, in which abdominal viscera herniate into the hemithorax, most often through a posterolateral defect in the diaphragm. Despite advances in prenatal care, maternal transport, neonatal resuscitation and the availability of extracorporeal membrane oxygenation (ECMO) the devastating physiological consequences due to pulmonary hypoplasia and hypertension are associated with a high neonatal mortality rate and appreciable long-term morbidity.1,2 It has been demonstrated in the fetal sheep model that compression of the lungs during the last trimester, either with an intrathoracic balloon or by creation of a diaphragmatic hernia, results in fatal pulmonary hypoplasia.25,26 Removal of the compression allowed progression of pulmonary growth and development, and increased the chances for survival. The prenatal diagnosis of CDH is established by sonographic demonstration of herniated abdominal contents such as loops of the bowel, stomach, or the left lobe of the liver. Unfortunately, while the function of certain fetal organs, such as fetal heart or fetal kidneys, can be assessed in utero, the fetal lungs do not exchange gas and thus cannot be directly assessed. Thus, several sonographically detectable predictors of the severity of a CDH have been proposed. The two most important parameters are the lung-to-head ratio (LHR)27 and the position of the left lobe of the liver.28 The LHR is the calculated volume of the contralateral lung (the ipsilateral lung cannot be identiﬁed with a CDH) indexed to

Table 17.1 Prognostic criteria* for the fetus with bilateral obstructive uropathy Predicted function Poor Good

Sodium (mEq/L)

Chloride (mEq/L)

Osmolarity (mOsm)

Output (ml/hour)

>100 <100

>90 <90

>210 <210

<2 >2

* Fetal urine composition and volume.

Fetal malformation amenable to surgical correction 193

head circumference to adjust for gestational age. Fetuses with an LHR of more than 1.4 have a favorable prognosis with tertiary postnatal care and are not candidates for fetal intervention. Fetuses with a major portion of the left lobe of the liver herniated into the hemithorax have an approximate 50% chance of survival, whereas those with liver in the normal abdominal position have a greater than 90% chance of survival.28 This determination is technically challenging, requiring color Doppler to visualize the position of the branches of the left portal vein. These prognostic indicators allow careful selection of severely affected fetuses who may beneﬁt from fetal intervention. The prenatal treatment strategy for CDH has undergone continuous development since the ﬁrst attempted CDH repair in 1986.29,30 Open fetal surgery, a procedure where a hysterotomy was performed and the diaphragm was directly repaired was associated with many technical problems. The reduction of a herniated lobe of the liver during repair resulted in a kinking of the intraabdominal umbilical vein, cutting off blood ﬂow from the placenta and led to fetal demise. Data from a National Institutes of Health- (NIH) funded prospective clinical trial demonstrated that repair of the diaphragm for those without liver herniation worked but was no better than standard postnatal care.31 For those with the more severe form (liver herniation), complete repair was not technically feasible. It was this technical problem that forced a redirection in thinking about how to treat fetuses with the most severe CDH. An accident of nature supplied us with a new paradigm for treating these fetuses. It has long been noted that fetuses with congenital high airway obstruction syndrome (CHAOS) due to laryngeal or tracheal atresia have large, hyperplastic lungs due to overdistention by lung ﬂuid.32 Laboratory studies not only conﬁrmed that this model is reproducible, but that the lungs that are physically larger are also functionally better. This concept is now being tested using fetoscopic techniques for temporary occlusion of the fetal trachea using titanium clips to accelerate fetal lung growth.33–37 The preliminary data have shown this technique to have great promise and has formed the basis for an ongoing NIHsponsored clinical trial comparing tracheal occlusion at 26 weeks’ gestation vs standard postnatal care for those fetuses with an LHR < 1.4 and liver herniation. The strategy for removal of the tracheal clips is called the EXIT (ex utero Intrapartum Treatment) procedure.38 During this procedure a hysterotomy is performed, the fetal head and shoulders are delivered, but the cord is not clamped (Fig. 17.3). During this period of placental support, the baby is bronchoscoped by one surgeon while the other removes the occluding clips and sutures the neck incision closed. The child is then intubated, surfactant is delivered and mechanical ventilation (by hand) begun. Once the oxygen saturation increases, the cord is cut and the infant delivered.

Bronchoscope

2.5 endotracheal tube Broviac catheter

Pulse oximeter

Cord blood access

Figure 17.3 Essential elements of the EXIT procedure

Congenital cystic adenomatoid malformation (CCAM) CCAM of the lung is the most common type of fetal thoracic mass that can be detected by prenatal ultrasound at as early as 16 weeks’ gestation, with the majority of cases being diagnosed before 22 weeks’ gestation.39 It is a hamartoma of the lung which is usually unilateral and lobar. The differential diagnosis includes pulmonary sequestration, congenital diaphragmatic hernia, other congenital cystic malformations (e.g. bronchogenic, enteric, neurogenic cyst), and CHAOS. CCAMs have a broad spectrum of clinical severity. They may enlarge signiﬁcantly, may remain the same size, or in fact, disappear prenatally.39,40 They lead to fetal demise in 100% when sufﬁcient cardiac and great vessel compression lead to hydrops. However, size and/or degree of mediastinal shift alone are not predictive of hydrops. Experimentally, the pathophysiogical consequences and the rationale for in utero treatment of CCAM have been elucidated.25,41,42 The abnormal physiology (hydrops) is reversible by removing the mass. Open fetal surgical resection of the massively enlarged pulmonary lobe (fetal lobectomy) at 21–29 weeks’ gestation in 13 hydrophic CCAM cases with 62% survivors.43 The rarer microcystic lesions can be decompressed percutaneously by needle aspiration or a thoracoamniotic shunt.44

194 Fetal surgery

Sacrococcygeal teratoma Sacrococcygeal teratoma (SCT) occurs in 1 of 40 000 livebirths.45 The natural history of prenatally diagnosed SCT is very different from neonatal SCT. The well-established prognostic indicators found for neonatal SCT do not apply when SCT is detected in the fetus.46 Malignant invasion, the primary cause of death in neonatal SCT, is rare in utero.47 The physiological consequences of fetal SCT are associated with the development of high-output cardiac failure due to a ‘vascular steal’ phenomenon through solid, highly vascular tumors.48 Only 10% of fetal SCT causes hydrops and, if untreated, results in 100% mortality.49 Furthermore, SCT may lead to a potentially devastating maternal complication called maternal mirror syndrome (Ballantine syndrome).50 In this syndrome, the mother experiences progressive symptoms suggestive of pre-eclampsia, including vomiting, hypertension, peripheral edema, proteinuria, and pulmonary edema due to the release of placental vasoactive factors or endothelial cell toxins from the edematous placenta. This syndrome is reversed only by delivering the child and the placenta, but not by removing the SCT prenatally. Prenatal sonographic diagnosis of SCT is based upon the demonstration of a characteristic caudal and/or intra-abdominal mass and has been reported as early as 14 weeks’ gestation.51 With widespread application of sophisticated obstetric sonography at midgestation, the majority of SCTs can be diagnosed in utero. Fetal SCTs can be either cystic, solid or mixed in appearance.52 The differential diagnosis includes myelomeningocele and obstructive uropathy. Color ﬂow Doppler ultrasound of large vascular tumors may demonstrate markedly increased distal aortic blood ﬂow and shunting of blood away from the placenta and to the tumor. There are two reported long-term survivors.53,54 In one series open fetal surgery was performed for ﬁve hydropic fetuses with large SCTs.53 Despite aggressive tocolytic therapy, preterm labor and delivery remained a severe problem in all ﬁve cases. Three of the neonates initially did very well. However, one died from an air embolism during resection of the residual tumor, and the second neonate died on the day of planned discharge from a central venous catheter complication. The remaining child is now developing normally at home. Currently, efforts are aimed at developing a minimally invasive approach that reverses the physiology via coagulation of the tumor’s major blood supply, not by tumor debulking.55 We have performed a ultrasoundguided percutaneous minimally invasive technique to coagulate the blood vessels in three fetuses.56

Twin-to-twin transfusion syndrome Twin-to-twin transfusion syndrome (TTTS) is the most common complication in monochorionic twin preg-

nancies, occurring in 5–35% of these pregnancies. Associated anomalies are extremely rare, but TTTS is associated with a high risk of miscarriage, brain damage, perinatal death and morbidity in survivors.57 Unequal sharing of the monochorionic placenta can usually be demonstrated sonographically; the smaller twin’s placental cord insertion is often marginal or velamentous, whereas the larger twin’s cord inserts into the placenta centrally.58 Vascular anastomoses on the placental surface exist between the two twins. If these are unbalanced, a net shunting of blood occurs due to arteriovenous anastomoses. Commonly, ultrasound can demonstrate severe oligohydramnios or anhydramnios in the pump twin’s sac (‘stuck twin’). The differential diagnosis for a ‘stuck twin’ includes uteroplacental dysfunction, discordant aneuploidy, structural urinary tract malformations, or congenital infection. The recipient develops polyhydramnios, pulmonary hypertension, and cardiomyopathy caused by chronic volume overload. Arteriovenous anastomoses can sometimes be demonstrated using Doppler sonography. The vessels in question are unpaired vessels with ﬂow from the donor to recipient. Spectral Doppler interrogation will demonstrate the characteristic pulsatile arterial blood ﬂow on the donor’s side, whereas the vessel will show a continuous venous ﬂow on the recipient’s side. The initial treatment is one or more amniocenteses of the recipient sac. For those nonresponders or those recipients who present with or develop hydrops, fetoscopic YAG-laser ablation of communicating anastomoses is performed. Some investigators elect to coagulate all vessels seen crossing the inter-twin septum,59 whereas others aim to coagulate only the unpaired inter-twin communicating vessels.60,61

Myelomeningocele Myelomeningocele (MMC), or spina biﬁda, is a midline defect resulting in exposure of the contents of the neural canal. Usually the defect is located in the dorsal portion of the lumbosacral vertebrae. Between 1500 and 2000 babies are born with MMC in the USA every year. More than 80% of children with MMC may be identiﬁed before birth with maternal serum alphafetoprotein screening.62 Direct sonographic visualization of the abnormal fetal spine can usually be accomplished by 16 weeks’ gestation. Other sonographic ﬁndings include frontal bone scalloping (lemon sign), abnormality of the cerebellum (banana sign), Chiari II malformation, hydrocephaly, microcephaly and encephalocele. The rationale for prenatal intervention is based on the observation that lower extremity function present in early pregnancy is progressively lost in later gestation. Several animal experiments have demonstrated that intrauterine repair of myelomeningocele may preserve

References 195

peripheral neurological function.63–68 Furthermore, experimental studies indicate that the Chiari II malformation, which is nearly always associated with myelomeningocele, may be prevented by prenatal repair.69 Recent clinical experience has demonstrated that open fetal surgery may improve neurological function and more dramatically resolve the hindbrain herniation associated with myelomeningocele.70–74 These early studies appear promising but the variable natural history, lack of accurate prenatal indicators of neurological function, absence of matched controls and long-term followup hampers the assessment of beneﬁts of prenatal intervention. An NIH-sponsored multicenter trial of fetal MMC repair is presently underway.

Congenital high airway obstruction CHAOS is usually caused by laryngeal or tracheal atresia, rarely by isolated tracheal stenosis, mucosal web or extrinsically by compression by a large cervical mass (e.g. teratoma, lymphangioma). Regardless of etiology, fetal upper airway obstruction prevents the normal egress of lung ﬂuid that is produced peripherally out of the airway, into the amniotic space. This ﬂuid is normally produced under a pressure that favors its movement out of the mouth, aided in part by fetal breathing movements. The resultant sonographic ﬁndings include large overdistended (ﬂuid-ﬁlled) echogenic lungs which compress the mediastinum, bilaterally ﬂattened or everted diaphragms, dilated large airways distal to the obstruction, and fetal ascites and/or hydrops due to heart and great vessel compression.75 If hydrops does not develop in utero, fetuses affected with CHAOS may be treated using the ex utero intrapartum treatment (EXIT) procedure, which maintains the baby on placental support while an airway is established by orotracheal intubation or tracheostomy.38 For fetuses who develop hydrops, early delivery or prenatal tracheostomy are options, depending on gestational age. There are three known survivors of prenatally diagnosed CHAOS.76–78

Amniotic band syndrome The incidence of amniotic band syndrome is 1 in 1200–15 000 live births. Early rupture of the amnion results in mesodermic bands which emanate from the chorionic side of the amnion and insert on the fetal body. These bands may lead to amputations, constrictions and postural deformities secondary to immobilization and have been replicated in an experimental model.79 The earlier the band occurs, the more severe the resulting lesion. Amniotic rupture in the ﬁrst weeks of pregnancy may result in cranio-facial and visceral defects, whereas during the second trimester, the fetal morbidity ranges from formation of syndactyly to limb

amputation. It may be fatal if umbilical cord constriction occurs.80 Mild forms of this syndrome do not warrant fetoscopic intervention at the moment given the potential fetal and maternal morbidity. There are two reported cases of fetoscopic lysis of amniotic bands.81

FUTURE OF FETAL SURGERY Increasingly sophisticated techniques for prenatal diagnosis have revolutionized the ﬁeld of fetal medicine. The fetus has come a long way from the biblical ‘seed’ and mystical ‘homunculus’, to an individual with medical problems that can be diagnosed and treated. The short but eventful history of fetal surgical intervention offers new hope for the fetus with an isolated congenital malformation. The great promise of fetal therapy is that for some diseases, the earliest possible intervention (i.e. before birth) will produce the best possible outcome, i.e. the best quality of life for the resources expended. However, the promise of cost-effective, preventive fetal therapy can be subverted by misguided clinical applications, e.g. a complex in utero procedure that ‘half-saves’ an otherwise doomed fetus for a life of intensive (and expensive) care. Enthusiasm for fetal intervention must be tempered by reverence for the interests of the mother and her family, by careful study of the disease in experimental fetal animals and untreated human fetuses, and by a willingness to abandon therapy that does not prove effective and cost-effective in properly controlled trials.

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References 197 42. Adzick NS, Hu LM, Davies P. Compensatory lung growth after pneumoectomy in fetal lambs: a morphometric study. Surgical Forum 1986; 37:309. 43. Adzick NS, Harrison MR, Crombleholme TM, Flake AW, Howell LJ. Fetal lung lesions: management and outcome. Am J Obstet Gynecol 1998; 179:884–9. 44. Blott M, Nicolaides KH, Greenough A. Postnatal respiratory function after chronic drainage of fetal pulmonary cyst. Am J Obstet Gynecol 1988; 159:858–9. 45. Bale PM. Sacrococcygeal developmental abnormalities and tumors in children. Perspect Pediatr Pathol 1984; 1:9–56. 46. Flake AW. Fetal sacrococcygeal teratoma. Semin Pediatr Surg 1993; 2:113–20. 47. Graf JL, Housley HAT, Albanese CT, Adzick NS, Harrison MR. A surprising histological evolution of preterm sacrococcygeal teratoma. J Pediatr Surg 1998; 33:177–9. 48. Bond SJ, Harrison MR, Schmidt KG et al. Death due to high-output cardiac failure in fetal sacrococcygeal teratoma. J Pediatr Surg 1990; 25:1287–91. 49. Langer JC, Harrison MR, Schnmidt KG et al. Fetal hydrops and death from sacrococcygeal teratoma: rationale for fetal surgery. Am J Obstet Gynecol 1989; 160:1145–50. 50. Kuhlmann RS, Warsof SL, Levy DL, Flake AW, Harrison MR. Fetal sacrococcygeal teratoma. J Pediatr Surg 1986; 21:563–6. 51. Holzgreve W, Mahony BS, Glick PL et al. Sonographic demonstration of fetal sacrococcygeal teratoma. Prenat Diag 1985; 5:245–57. 52. Westerburg B, Feldstein VA, Sandberg PL, Lopoo JB, Harrison MR, Albanese CT. Sonographic prognostic factors in fetuses with sacrococcygeal teratoma. J Pediatr Surg 2000; 35:322–6. 53. Graf JL, Albanese CT, Jennings RW, Farrell JA, Harrison MR. Successful fetal sacrococcygeal teratoma resection in a hydropic fetus. J Pediatr Surg 2000; 35:1489–91. 54. Adzick NS, Crombleholme TM, Morgan MA et al. A rapidly growing fetal teratoma. Lancet 1997; 349:538. 55. Westerburg BW, Chiba T, Gantert et al. Radiofrequency ablation of liver in the fetal sheep: A model for treatment of sacroccygeal teratoma in the fetus. Surg Forum 1998; 49:461–3. 56. Paek B, Jennings RW, Farmer DL et al. Radiofrequency ablation of human fetal sacroccocygeal teratoma. Am J Obstet Gynecol (in press). 57. Blickstein I. The twin–twin transfusion syndrome. Obstet Gynecol 1990; 76:714–22. 58. Fries MH, Goldstein RB, Kilpatrick SJ, Golbus MS, Callen PW, Filly RA. The role of velamentous cord insertion in the etiology of twin–twin transfusion syndrome. Obstet Gynecol 1993; 81:569–74. 59. Hecher K, Plath H, Bregenzer T, Hansmann M, Hackeloer BJ. Endoscopic laser surgery versus serial amniocentesis in the treatment of severe twin–twin transfusion syndrome (In Progress Citation). Am J Obstet Gynecol 1999; 180:717–24.

60. De Lia JE, Kuhlman RS, Harsted TW, Cruikshank DP. Fetoscopic laser ablation of placental vessels in severe previable twin–twin transfusion syndrome. Am J Obstet Gynecol 1995; 172:1202–8. 61. Feldstein VA, Machin GA, Albanese CT, Sandberg P, Farrell J, Farmer D, Harrison MR. Twin-twin transfusion syndrome: The SELECT procedure. Fetal Diagn Ther (in press). 62. Brock DJ, Sutcliffe RG. Alpha-fetoprotein in antenatal diagnosis of anencephaly and spina biﬁda. Lancet 1972; 2:197. 63. Heffez DS, Aryanpur J, Rotellini NAC et al. Intrauterine repair of experimental surgically created dysraphism. Neurosurg 1993; 32:1005–10. 64. Meuli M, Meuli-Simmen C, Hutchins GM et al. In utero surgery rescues neurologic function at birth in sheep with spina biﬁda. J Pediatr Surg 1995; 30:342–7. 65. Hutchins GM, Meuli M, Meuli-Simmen C, Jordan MA, Heffez DS, Blakemore KJ. Acquired spinal cord injury in human fetuses with myelomeningocele. Pediatr Path Lab Med 1996; 16:701–2. 66. Heffez DS, Aryanpur J, Hutchins GM et al. The paralysis associated with myelomeningocele: Experimental data implicating a preventable spinal cord injury. Neurosurg 1990; 26:987–92. 67. Meuli M, Meuli-Simmen C, Yingling CD, Hutchins GM, Seller MJ, Harrison MR, Adzick NS. Creation of myelomeningocele in utero: A model of functional damage from spinal cord exposure in fetal sheep. J Pediatr Surg 1995; 30:1028–32. 68. Michejda M. Intrauterine treatment of spina biﬁda: Primate model. Z Kinderchir 1984; 39:259–61. 69. Jennings RW, Wilkinson C, Westerberg B et al. Chari malformation develops in surgically created myelomeningocele, and is prevented by repair of the myelomeningocele in fetal lambs. Am J Obstet Gynecol (in press). 70. Bruner JP, Richard WO, Tulipan NB, Arney TL. Endoscopic coverage of fetal myelomeningocele in utero. Am J Obst Gynecol 1999; 180:153–8. 71. Ulipan N, Hernanz-Schulman M, Bruner JP. Reduced hindbrain herniation after intrauterine myelomeningocele repair: a report of four cases. Pediatr Neurosurg 1998; 29:274–8. 72. Adzick NS, Sutton LN, Crombleholme TM, Flake AW. Successful fetal surgery for spina biﬁda. Lancet 1998; 352:1675–6. 73. Bruner JP, Tulipan N, Paschall RL et al. Fetal surgery for myelomeningocele and the incidence of shuntdependent hydrocephalus. JAMA 1999; 282:1819–25. 74. Sutton LN, Adzick NS, Bilaniuk LT et al. Improvement in hindbrain herniation demonstrated by serial fetal magnetic resonance imaging following fetal surgery for myelomeningocele. JAMA 1999; 282:1826–31. 75. Martinez-Ferro M, Hedrick MH, Flake AW, Harrison MR, Adzick NS. Prenatal diagnosis of congenital high airway obstruction (CHAOS): potential for perinatal intervention. J Pediatr Surg 1994; 29:271–4.

198 Fetal surgery 76. Crombleholme TM, Sylvester K, Flake AW, Adzick NS. Salvage of a fetus with congenital high airway obstruction syndrome by ex utero intrapartum treatment (EXIT) procedure. Fetal Diagn Ther 2000; 15:280–2. 77. Paek B, Saito J, Callan P et al. CHAOS controlled: Successful fetal intervention for complete high airway obstruction syndrome. Fetal Diagn Ther (in press). 78. DeCou JM, Jones DC, Jacobs HD, Touloukian RJ. Successful ex utero intrapartum treatment (EXIT) procedure for congenital high airway obstruction syndrome (CHAOS) owing to laryngeal atresia. J Pediatr Surg 1998; 33:1563–5.

79. Crombleholme TM, Dirkes K, Whitney TM, Alman B, Garmel S, Conn RJ. Amniotic band syndrome in fetal lambs. I: Fetoscopic release and morphometric outcome. J Pediatr Surg 1995; 30:974–8. 80. Strauss A, Hasbargen U, Paek B, Bauerfeind I, Hepp H. Intrauterine fetal demise caused by amniotic band syndrome after standard amniocentesis. Fetal Diag Ther 2000; 15:4–7. 81. Quintero RA, Morales WJ, Phillips J, Kalter CS, Ngel JL. In utero lysis of amniotic bands. Ultrasound Obstet Gynecol 1997; 10:316–20.

2 Head and neck

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18 Choanal atresia in the newborn FRANCESCO COZZI AND DENIS A. COZZI INTRODUCTION Atresia of the choanae is a relatively rare congenital anomaly in which one or both choanae are obstructed by a membranous or bony plate, either partially or completely. The condition is variously reported as occurring one in 5000–10 000 births.1–3 Approximately 50% of cases are associated with other cranio-facial developmental anomalies such as Treacher Collins’ syndrome, anomalies of pharyngeal arches derivatives, CHARGE association. The latter association is an acronym of colobomata (retinal and/or iridial), heart disease, atresia choanae, retarded growth and development, genital anomalies in males and ear anomalies including deafness. An anomalous contribution of the cephalic neural crest cells to the embryogenesis of either the face or the autonomic nervous system, may explain why choanal atresia is nearly always associated with either minor facial anomalies or autonomic disorders.4 A disturbance of the mesodermal migration of the neural crest cells may also explain the frequent association with other major congenital anomalies.

PHYSIOPATHOLOGY In infants with complete nasal obstruction, it is widely accepted that the mechanism leading to asphyxia is the inability to open the mouth and start oral breathing.5–7 During inspiration, the lips and cheeks are drawn in and the tongue is sucked backwards and upwards to the hard palate, producing a sealing. During expiration, the soft palate is pushed against the base of the tongue, producing a complete obstruction as can be judged by a paradox dilatation of hypopharynx during expiration. This soft tissue sealing must be broken to avoid asphyxial death.6,7 The concept that the infant is an obligatory nasal breather has been recently challenged because nearly all normal infants are able to switch from nasal to oral respiration if nasal occlusion is not realized before the

infant starts to breathe through the mouth.8 Therefore, it is not the inability to mouth-breathe but the inability to sustain adequate mouth-breathing that may be the main cause of respiratory problems in infants with choanal atresia.8,9 During normal breathing, intrathoracic inspiratory depression does not result in collapse of musculomembranous pharyngeal walls because a neuromuscular mechanism acts, prior to inspiration, to stiffen the ﬂoppy structures of pharynx.10 The action of genioglossus plays a crucial role in maintaining the patency of the oropharyngeal airway because the tongue is a dynamic ﬂap valve which may easily obstruct the oropharyngeal airway when negative inspiratory pressure overcomes the genioglossus force.11 The autonomic control of forces acting on the upper airway muscles may present a developmental delay. The control may be also disturbed by factors that increase the negative intrathoracic pressure (respiratory tract infection, crying, exercise, etc.) and decrease the upper airway dilating muscle activity (sleeping, anesthetic, sedative, etc.). Infants present with a wide spectrum of neuromuscular activity of upper airway dilating muscles. Those at the lower end of the spectrum may experience respiratory difﬁculties even during a simple rhinitis. Conversely, infants at the upper end of the spectrum may remain asymptomatic even if affected by bilateral choanal atresia. In infancy, any type of nasal obstruction which results in a decreased inspiratory pressure overcoming the airway maintaining the genioglossus action causes recurrent episodes of functional upper airway obstruction during inspiration.12–14 Inspiratory dyspnea is the result of recurrent partial functional obstruction (glossoptosishypopnea). Apneic spells are the result of a complete functional obstruction due to a sealing of the tongue to the hard palate (vacuum-glossoptosis-apnea). Severe inspiratory dyspnea causes alveolar hypoventilation, which leads to hypoxemia, hypercapnia, and respiratory acidosis.13 Moderate inspiratory dyspnea causes a lower airway instability leading to miliary atelectasis (not detected by chest ﬁlms) with hypoxemia without hypercapnia.13

202 Choanal atresia in the newborn

The inspiratory dyspnea is often associated with an expiratory dyspnea, traditionally attributed to a passive functional obstruction due to approximation of the soft palate to the base of the tongue.6,7 The new concept is that the expiratory obstruction, at least in part, is due to an active braking of the expiratory ﬂow.14 Grunting expiration is a useful breathing strategy to avoid collapse of widespread areas of the lung and consequent right-toleft shunt. In infants with nasal obstruction and inspiratory dyspnea, active braking of the expiratory ﬂow may be particularly important since a large intrapulmonary shunt may play a role in the pathogenesis of apparent life-threatening episodes (ALTEs) with severe hypoxemia.15

CLINICAL FEATURES Babies with symptomatic choanal atresia or stenosis present clinical manifestations13,16,17 which are remarkably similar to those found in infants with other facial or thoracic malformations (congenital micrognathia, esophageal atresia, vascular ring, etc.). The common syndrome is due to a maturational dysautonomia affecting one or more autonomic functions. Nearly all infants with symptomatic choanal atresia or stenosis present with a disorder of autonomic control of respiration. The respiratory problems are characterized by recurrent episodes of partial or complete glossoptotic pharyngeal obstruction. The inspiratory dyspnea (polypnea, noisy inspirations, retractions, glossoptosis, retrognathia, opisthotonus, poor or absent air entry) is often associated with an expiratory dyspnea (paradox ballooning of soft tissues of the neck during expiration, barrel chest, hyperphonesis, wheezing and/or grunting). Lifethreatening episodes of complete airway obstruction due to glossoptosis are relieved by crying. The respiratory distress is very often associated with an abnormal autonomic control of sucking and/or swallowing, gastro-esophageal reﬂux and vomiting. About onethird of the patients present life-threatening cyanotic attacks which may occur during or soon after feeding, during crying or during suctioning of the pharynx. Infants with choanal obstruction may have additional autonomic disturbances such as life-threatening reﬂex bradycardia or tachycardia, life-threatening hyperthermia, hyperhydrosis, sialorrhea etc. Main complications include acute or chronic hypoxemia with or without hypercapnia, failure to thrive, pulmonary edema, cor pulmonale, asphyxic brain damage and sudden death.

DIAGNOSIS Relief of respiratory distress by keeping open the oropharyngeal airway excludes an obstruction at the

level of the larynx or trachea. Worsening of respiratory distress by pulling the tongue forward and concomitantly closing the mouth excludes a pharyngeal obstruction due to glossoptosis, and conﬁrms clinically the diagnosis of nasal obstruction. Complete or incomplete patency of the nasal cavity can be assessed by observing the movements of a thin wisp of cotton held in front of each side of the nares. A diagnosis of congenital choanal obstruction can be conﬁrmed by unsuccessful attempts to pass a No. 8 French catheter from the nose into the pharynx. When the catheter or metal sound is advanced along the ﬂoor of the nose next to the septum, it will encounter an obstruction at the level of the posterior choana. To discover whether the obstruction is complete or incomplete, a lateral skull X-ray can be taken while the patient is in the supine position and after injection of contrast medium. Computed tomography (CT) scanning gives excellent resolution of the anatomy of the nasal cavities.3 The information that CT scanning provides on the presence of a narrowing of the posterior part of the bony nasal cavity or on the thickness of the bony atretic plate, assists in the choice of technique for surgical correction in older patients. A deﬁnitive diagnosis of bilateral or unilateral choanal atresia or stenosis can be established by anterior and posterior rhinoscopy, using ﬂexible bronchoscopes or nasopharyngoscopes or nasopharyngeal mirrors. The differential diagnosis of nasopharyngeal abnormalities in infants with impaired nasopharyngeal airway includes traumatic birth lesions of the nose and nasal septum, rhinitis, turbinate hypertrophy, encephaloceles, polyps or tumors, and enlarged adenoids.18,19

PREOPERATIVE TREATMENT Both bilateral and unilateral symptomatic choanal atresia or stenosis require immediate treatment to avoid the risk of severe neonatal asphyxia. An oral airway with an obturator or McGovern nipple20 should be used as an emergency procedure to assure satisfactory ventilation. An orogastric tube can be used to maintain the airway open and to feed the infant. Orotracheal intubation is an option. A tracheostomy should always be avoided. Temporary use of an oral airway will allow the surgical correction of more urgent associated anomalies. Although the timing of deﬁnitive surgical repair has long been controversial, most recent writers1,2,13,21,22 have reemphasized that early establishment of a patent nasal airway minimizes the constant risk of fatal asphyxia. In addition, during the ﬁrst few months of life the soft bony atretic plate can be easily perforated, and early repair avoids a long hospital stay.

Technique of operation 203

TECHNIQUE OF OPERATION During the neonatal period the transnasal procedure is best because it is easily performed with minimal risk of facial growth disturbance. The most commonly used technique is endonasal perforation with blunt dilators followed by placement of tubes in the choanae. The tubes serve as a stent across the atretic area to prevent stenosis and as a nasopharyngeal airway.9 In the past, this technique fell into disuse because of a high frequency of recurrence of stenosis and difﬁculty in keeping the tubes clean. However, if nasal stenting is managed properly, a satisfactory and deﬁnitive repair can be made. Our surgical approach encompasses the following steps: 1 The infant is placed in the supine position on the operating table. Extension of head and neck is avoided. Anesthesia is given via an endotracheal tube passed through the mouth and ﬁxed to one side of the midline (Fig. 18.1). The surgeon sits or stands on the right side of the patient. The assistant sits or stands on the left side, keeps the mouth open and pulls the tongue forward using a laryngoscope; its light permits an excellent view of the pharyngeal cavity, which is kept clear with an angled sucker. 2 Pediatric urethral sounds are used to perforate the obstructing plate (Fig. 18.2). They have the ideal curvature to follow the sloping contour of the nasal ﬂoor and can prevent neurological injuries. 3 A No. 4 French sound is suitable for perforation of either membranous or bony atretic plate. The sound is passed along the ﬂoor of the nose (Fig. 18.3), staying against the septum to avoid penetrating the basisphenoid (a). When the obstruction plate is

Figure 18.1 Laryngoscope blade retracting the tongue forward, its light providing an excellent view of the pharyngeal cavity

Figure 18.2 Pediatric urethral sounds of various sizes

b

a

Figure 18.3 (a) The sound is passed along the ﬂoor of the nose, staying against the septum to avoid penetrating the basisphenoid. (b) When the obstruction plate is encountered, the sound is forced through it

encountered, the sound is forced through it (b). The direction of the sound can be followed by a ﬁnger introduced into the nasopharynx or by means of endoscopy. The perforation is then gradually dilated, avoiding spinal injuries by carefully following with dilators the gentle curve of the nasal ﬂoor. The limiting factor in the dilatation is the size of the anterior nares. 4 In bilateral cases two separate plastic No. 14 or 16 French feeding tubes with end-holes (Fig. 18.4) are fashioned long enough to allow a 1 cm protrusion into the nasopharynx (a). The proximal part of the connector is cut and discarded (b). The distal end of the tubes is sharpened with a pencil sharpener (c). 5 To facilitate placement, a No. 8 French gauge suction catheter is placed inside the tube and then passed from the nose into the pharynx. The tube is then railroaded onto it (Fig. 18.5). In bilateral choanal obstruction, two separate tubes are used.

204 Choanal atresia in the newborn

a

b

c

Figure 18.6 Anchoring of the tube to the forehead by an adhesive dressing Figure 18.4 (a) A No. 14 French plastic feeding tube. (b) The proximal part of the tube has been cut and discarded. (c) The distal end of the tube is sharpened with a pencil sharpener

become stenotic and if the nasopharyngeal airway is adequate, the stent is left out for an increasing number of hours until the infant can be weaned from the tubes day and night. Recurrent choanal stenosis is managed by repeated dilatations. In spite of widely patent choanae, some infants require use of the tubes for several months as a nasopharyngeal airway during sleep. Recently, transnasal repair of choanal atresia using a rod-lens telescope has been used with low morbidity.21,22

REFERENCES

Figure 18.5 The tube being railroaded from the nose into the pharynx

6 A silk suture is placed through the proximal part of the connector and taped to the central part of the forehead (Fig. 18.6). Pressure necrosis of the columella and alar rim should be avoided. This method of stenting has the advantage that the tube can easily be replaced. No antibiotics are used. Tube patency is maintained by instillation of 0.5 ml isotonic saline followed by suctioning. The tubes are removed once a day for thorough cleaning. Parents usually have no difﬁculty mastering the endonasal stent, so the infant can be sent home very soon with adequate medical and nursing supervision. Portable suction machines are used at home to facilitate parental care. After 2 months, the nasal tubes are removed and left out for 1 hour in the morning. If the choanae do not

1. Schwartz ML, Savetsky L. Choanal atresia: clinical features, surgical approach, and long term follow-up. Laryngoscope 1986; 96:1335–9. 2. Stahl RS, Jurkiewicz MJ. Congenital posterior choanal atresia. Pediatrics 1985; 76:429–36. 3. Shirkhoda A, Bigger WP. Choanal atresia. A case report illustrating the use of computed tomography. Radiology 1982; 142:93–4. 4. Cozzi F, Myers NA, Piacenti S et al. Maturational dysautonomia and facial anomalies associated with esophageal atresia: support for neural crest involvement. J Pediatr Surg 1993; 28:798–801. 5. Richardson CW. Congenital atresia of the post-nasal oriﬁce. Lancet 1914; 2:439–44. 6. Whitehouse WM, Holt JF. Paradoxical expiratory ballooning of the hypopharynx in siblings with bilateral choanal atresia. Radiology 1952; 59:216–20. 7. Hough JVD. The mechanism of asphyxia in bilateral choanal atresia: the technique of its surgical correction in the newborn. South Med J 1955; 48:588–94. 8. Rodenstein DO, Perlmutter N, Stanescu DC. Infants are not obligatory nasal breathers. Am Rev Respir Dis 1985; 131:343–7. 9. Cozzi F. Glossoptosis as a cause of apnoeic spells in infants with choanal atresia. Lancet 1977; 2:830–1.

References 205 10. Brouillette RT, Thach BT. A neuromuscular mechanism maintaining airway patency. J Appl Physiol 1979; 46:772–9. 11. Remmers JE, de Groot WJ, Sawerland EK et al. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol 1978; 44:931–8. 12. Cozzi F. Familial obstructive sleep apnea. N Engl J Med 1979; 300:506–7. 13. Cozzi F, Pierro A. Glossoptosis-apnea syndrome in infancy. Pediatrics 1985; 75:836–43. 14. Cozzi F, Bonanni M, Cozzi DA et al. Assessment of pulmonary mechanics and breathing patterns during posturally induced glossoptosis in infants. Arch Dis Childh 1996; 74:512–16. 15. Poets CF, Samuels MP, Southall DP. Potential role of intrapulmonary shunting in the genesis of hypoxemic episodes in infants and young children. Pediatrics 1992; 90:388–91.

16. Cozzi F, Stainer M, Rosati D et al. Clinical manifestations of choanal atresia. J Pediatr Surg 1988; 23:203–6. 17. Cozzi F, Myers NA, Madonna L et al. Esophageal atresia, choanal atresia, and dysautonomia. J Pediatr Surg 1991; 26:548–52. 18. Benjamin B. Evaluation of choanal atresia. Ann Otol Rhinol Laryngol 1985; 94:429–32. 19. Lantz HJ, Birck HG. Surgical correction of choanal atresia in the neonate. Laryngoscope 1981; 91:1629–34. 20. McGovern FH. Bilateral choanal atresia in the newborn: a new method of medical management. Laryngoscope 1961; 71:480–3. 21. Lazar RH, Younis RT. Transnasal repair of choanal atresia using telescope. Arch Otolaryngol 1995; 121:517–20. 22. Friedman NR, Mitchell RB, Bailey CM et al. Management and outcome of choanal atresia correction. Int J Pediat Otorhinolaryngol 2000; 52:45–51.

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19 Pierre Robin sequence EVELYN H. DYKES

INTRODUCTION The inclusion of a chapter on Pierre Robin sequence (or syndrome) in a textbook of operative surgery may be seen by some as outdated, since current management of this condition includes little in the way of surgical procedure. Nevertheless, as a time-honored ‘surgical’ cause of neonatal respiratory distress, the condition is worthy of mention, if only to draw attention to the changes which have taken place in the treatment of these infants.

HISTORY, INCIDENCE AND ETIOLOGY The combination of micrognathia and glossoptosis causing respiratory distress and failure to thrive during the neonatal period was recognized by Pierre Robin in 1926.1 It was 4 years later that Eley and Farber described four patients with these features, exacerbated by the presence of a cleft palate.2 They cited other reports, published as early as 1891, of similar conditions, and recognition of this cause of infantile respiratory distress was born. It is not clear why the eponym of Pierre Robin was applied to the condition and its description as a ‘syndrome’ is not strictly correct. A more accurate representation of the development of the features is gained by the term ‘sequence’ or ‘anomalad’,3,4 but the original eponym persists and is likely to do so for some time. The cardinal features of the Pierre Robin sequence (PRS) are micrognathia, glossoptosis and respiratory obstruction. The latter may be severe and persistent, stimulating immediate attention, or it may be intermittent, related to feeding or posture. Though not initially described by Robin himself, cleft palate is a frequent association2,5,6 – indeed some authors believe it to be a prerequisite of the diagnosis.7,8,9 This confusion has resulted in wide variations in the reported incidence of PRS, but long-term studies in the UK and Australia suggest that it may occur with a frequency of at least 1:8500 live births.7,10

The etiology of the structural defects in PRS is equally controversial. Mandibular hypoplasia is likely to be the primary lesion, resulting in posterior displacement of the tongue into the pharynx (glossoptosis) and frequently also upward displacement, causing cleft palate. Since relative mandibular hypoplasia with glossal displacement is a normal ﬁnding up to the seventh month of fetal life,11 it is presumed that the anomaly results from an insult to mandibular growth at this time. The nature of the insult is uncertain: mechanical compression (as in oligohydramnios), vascular accident, neuromuscular, metabolic and genetic abnormalities have all been proposed and substantiated either experimentally or clinically.12–14 A logical assumption is that a variety of factors may lead to persistent mandibular hypoplasia with the resulting postnatal manifestations.15,16 The severity and persistence of the clinical entity is probably related to the nature of the insult, as illustrated by the difference in outcome between ‘syndromic’ and ‘non-syndromic’ micrognathia.8,13,17

CLINICAL FEATURES AND MANAGEMENT More important than etiologic theorization is the early recognition of the features predisposing to glossoptotic upper airway obstruction. The infant with classical PRS presents a classic ‘bird-like’ facies (Fig. 19.1) with a small receding chin and a ﬂattened nasal base.18 The palate may be high and arched, or may have a complete or submucosal cleft. There may be associated abnormalities of other systems. Measurement of the jaw index has been used to deﬁne micrognathia; infants with PRS have an average jaw index over 3.6 times the normal values .19 With recent improvements in prenatal ultrasound, the diagnosis may be made prenatally.20–23 The presence of a family history of cleft lip or palate, or of PRS itself, should prompt careful examination of the fetal mandible. If fetal micrognathia is detected, a search for other abnormalities should ensue.

208 Pierre Robin sequence

Figure 19.2 (a) Receding chin of Pierre Robin facies; (b) glossoptosis in Pierre Robin anomalad obstructs breathing

Figure 19.1 Typical Pierre Robin facies with receding chin (Courtesy Mr P.A.M. Raine)

AIRWAY MANAGEMENT It should be noted that even minor degrees of micrognathia can result in glossoptosis. Airway obstruction can occur at or immediately after birth, but may take much longer (up to 3 weeks) to become apparent.24 The intermittence of the obstruction demands special vigilance, even in infants with apparently minimal defects. Since most of the complications of PRS are directly related to delayed or inadequate airway management, early diagnosis is mandatory if a favorable outcome is to be achieved.25–27 Airway obstruction in PRS is due to a narrowing or complete obstruction of the pharyngeal air passage by a posteriorly displaced tongue (Fig. 19.2). Upper airway obstruction is identiﬁed by increased respiratory effort, stridor, subcostal recession, and cyanotic or apneic spells. Choking attacks or cyanosis during feeds indicate inadequate airway protection or obstruction. In the apparently asymptomatic infant, repeated attacks of aspiration suggest an intermittent airway difﬁculty. Transcutaneous Po2 monitoring or continuous pulse oximetry may help to identify obstructive episodes.28 The infant displaying such signs should be nursed prone with the head to one side (Fig. 19.3). Level positioning is important – a head-up tilt may aggravate the tendency to glossoptosis, while head-down can stimulate gastro-esophageal reﬂux and aspiration.29 All nursing procedures such as bathing, changing and feeding can be performed with the baby in this position. If necessary, the child can be fed in the mother’s or nurse’s lap – again in the prone position. Ventral suspension of

Figure 19.3 Correct nursing position – prone with head level

the head by a stockinette cap may be of assistance (Fig. 19.4) but adds little to expert postural care. These measures are adequate for the majority of children with glossoptotic obstruction. However in some infants, persistence of respiratory difﬁculty necessitates further intervention. In such children a nasopharyngeal airway should be inserted without delay.30 It is not necessary to intubate the vocal cords, but merely to preserve the pharyngeal airway and, as such, a simple oral airway (Fig. 19.5a) may sufﬁce, at least as a temporary measure, until a formal nasopharyngeal (NP) airway can be obtained. An ordinary Portex endotracheal tube (Portex Inc., Wilmington, MA, USA) cut to the appropriate length, is inserted by the nasal route and securely strapped in place (Fig. 19.5b). Tunstall connectors (Penlon Inc., Cleveland, OH, USA) (Fig. 19.5c), if available, reduce the need for excessive facial trauma from adhesive tape30 but other types of connector, if secure, will serve equally well. The length of the NP airway is critical. The tip of the tube should be just above the epiglottis, thereby bypassing the tongue obstruction (Fig. 19.6) and the position should be conﬁrmed by lateral radiograph following insertion. Since the tube lies above the vocal cords, humidiﬁcation of inspired air is advantageous but not essential. A ‘Swedish nosepiece’ is too cumbersome for tiny infants and may result in dislodgement of the air-

Airway management 209

(a)

(b) Figure 19.4 Ventral suspension of head allowing jaw and tongue to fall forward, thus clearing airway (Courtesy Mr P.A.M. Raine)

way. Tube patency must be maintained, especially before feeds, and regular suctioning with prior installation of 0.5 ml normal saline is necessary. Recently, a modiﬁcation of the traditional NP tube has been described,31 which is claimed to reduce the dead space and airway resistance, and consequently may be better tolerated. If the NP airway is unsuccessful, more invasive measures may be required. Endotracheal intubation is a difﬁcult procedure in children with PRS and should be performed by someone skilled in intubating small infants. A selection of laryngoscope blades may be required,32,33 and occasionally ﬁberoptic techniques have been needed.34 An alternative to intubation is the laryngeal mask airway (LMA).35,36 This is a useful mechanism for short-term support during resuscitation or anesthesia, but is not appropriate for long-term maintenance. Once an endotracheal tube is inserted, humidiﬁcation of inspired gas is essential to prevent encrusting of the lumen with dried secretions. With proper nasotracheal tube care, it is possible to nurse the infant in this way for several weeks, until growth allows removal of the tube and a return to postural management. Previously described surgical procedures such as glossopexy or lip–tongue anastomosis offer no advantage over the NP airway other than to alleviate the need for assiduous nursing. As such they have little place in the present management of PRS, except in underdeveloped countries, where nurses are scarce and tracheostomy is undesirable. The reader in such situations is referred to

(c) Figure 19.5 (a) Infant oral airway; (b) nasopharyngeal airway; (c) Tunstall connector which allows ﬁxation of tube with minimal facial strapping

other sources for a description of the operative techniques.37,38 Tracheostomy carries a signiﬁcant morbidity rate in the small child39,40 and should be avoided if at all possible. Difﬁculty in maintaining the position of the NP airway, or rarely, persistent obstruction despite appropriate use of the NP airway, may result in a need for surgical management, in which event, tracheostomy is preferable to glossopexy.27 Since the glossoptosis of PRS is a temporary phenomenon which usually resolves with growth, endotracheal intubation will obviate the need

210 Pierre Robin sequence (a) (a)

(a)

(b)

Figure 19.6 (a) Narrowing of pharyngeal airway by posteriorly displaced tongue; (b) correct positioning of nasopharyngeal airway with tip of tube above epiglottis

for surgery, but a desire that the infant be orally fed or nursed more easily may take precedence. In this event, the procedure should be performed by a surgeon skilled in pediatric tracheostomy, since the operation differs in some detail from that used in adults (see Chapter 16).

(b)

Figure 19.7 (a) Standard nipple; (b) standard nipple with enlarged X-cut

ment to compensate for up to a tenfold increase in respiratory work.30 Indeed, failure to gain weight despite maximum nutritional intake should suggest the need for more aggressive airway management.43 The availability of total parenteral nutrition should prevent any instances of failure to thrive, but it is only rarely needed if other aspects are correctly managed.

MANAGEMENT OF ASSOCIATED ANOMALIES Nutritional management Failure to thrive was recognized by Pierre Robin and others as a frequent accompaniment of glossoptotic airway obstruction.1,2 Feeding difﬁculties are compounded if a cleft palate is present. Nevertheless, with skilled nursing, simple measures may sufﬁce to overcome these problems. As described earlier, maintenance of the airway is vital during feeding. To this end the infant may be bottle fed in the prone position, with forward placement of the jaw (and therefore also the tongue) encouraged by the thumb and second ﬁnger of the feeder. Care must be taken to avoid compromising the airway further by the injudicious placement of these ﬁngers! A lamb’s feeding teat has been favored by some, but others suggest that a standard nipple (Fig. 19.7a) with an enlarged x-cut (Fig. 19.7b) is better; the former produces a uniformly increased milk ﬂow, while the latter allows the infant to increase ﬂow on demand, with minimal effort.29 If oral feeding fails, gavage feeding may be required. In this event, the nasogastric tube should be withdrawn between feeds to reduce the likelihood of reﬂux and aspiration.29 A feeding gastrostomy relieves the need for repeated tube placement, and can be created via the percutaneous route, but the possibility of creating gastro-esophageal reﬂux should be considered.41,42 Adequate caloric intake is critical for PRS infants. Since the resolution of the airway problem is directly related to mandibular growth, it is important to achieve the maximum growth rate possible. Only recently has the increased work of breathing been appreciated in terms of calorie consumption; it may be necessary to provide these children with several times the normal caloric require-

Abnormalities of other systems are frequently seen with PRS18,44–46 and each infant should be carefully examined and investigated with this in mind.

Genetic syndromes Micrognathia and glossoptosis are components of numerous genetic syndromes.13 Identiﬁcation of inherited or inheritable defects is important, not only because of the need for parental counselling in such cases, but also because the outcome in children with ‘syndromal’ PRS is signiﬁcantly worse than in those in whom PRS is an isolated abnormality.8,10,13,46,47 The inheritance of PRS itself is unproven. While there are reports of familial PRS, most cases occur sporadically.10,44–46

Cleft palate Depending on the diagnostic criteria used, cleft of the soft or hard palate occurs in up to 80% of infants recognized to have PRS.6 Since the cleft is usually restricted to the palate and does not involve the lip, surgical reconstruction is not required during the neonatal period. The feeding maneuvers described will permit adequate nutrition in cleft babies; prostheses are not indicated in these children and may result in accidental airway obstruction. All infants with cleft palate may experience speech and hearing difﬁculties during development and PRS cases are no exception.45,46 The child with PRS and an associated cleft palate should be followed up carefully long after the respiratory difﬁculty has resolved, prefer-

Complications and outcome 211

ably in a center where a multidisciplinary ‘cleft clinic’ is readily available, since auditory assessment, speech therapy and orthodontic treatment are all required. This approach will minimize the educational and communication problems previously seen in so many of these children.

Skeletal anomalies Limb defects are seen in 11–21% of children with PRS.45,46 Common anomalies are talipes equinovarus, syndactyly, short or absent digits and hypoplastic long bones. Occipito-atlanto-axial instability has been described,47 emphasizing the need for experience in those who undertake the intubation of such patients. Orthopedic and radiological consultation should be sought in children with suspected skeletal problems. Rare neuromuscular defects can also occur, resulting in a tendency for glossoptosis to persist despite mandibular growth.13

Cardiovascular anomalies Intrinsic cardiac defects are found in up to 20% of infants with PRS.45,46,48 Septal defects are common but more complex lesions can occur. A thorough cardiovascular examination should be requested in PRS babies, particularly since the airway difﬁculties may aggravate the cardiac status.49

Ocular anomalies Retinal detachment and micrognathia occur as part of Stickler syndrome50 but 10% of infants with nonsyndromic PRS also have eye defects such as strabismus, ptosis and microphthalmia. More severe defects such as cataract and congenital glaucoma have also been reported, and ophthalmological consultation is recommended in all cases.45,46,51

will achieve normal or near-normal proportions, and the glossoptosis will resolve.8,18,54 One study has suggested that there is no signiﬁcant difference in proportional mandibular growth during the ﬁrst year of life between PRS infants and controls,55 but in the majority of affected infants, symptoms are relieved within a few months. Airway protection during this period is vital. The previously documented high incidence of mental retardation in PRS patients was almost certainly due to unrecognized episodes of hypoxia; with good airway management this complication is uncommon.45,46 Undiagnosed hypoxia may also lead to pulmonary vasoconstriction, with resultant pulmonary hypertension and cor pulmonale.49 Some instances of sudden death in PRS are likely to have been due to this problem; the presence of cardiomegaly on a chest X-ray (Fig. 19.8) should alert the physician to the possibility that hypoxic episodes have been overlooked, and appropriate steps should be taken immediately. Although airway patency improves with growth, there remains a potential for obstruction, particularly after invasive procedures such as intubation or cleft palate repair.33 In some children, obstruction may occur during sleep, causing occasional apnea with potentially hazardous consequences.53,56,57 A degree of mandibular hypoplasia may persist for several years, resulting in malocclusion and the need for dental treatment.6,10 The overall mortality rate in infants with PRS is approximately 25%. The majority of deaths (70%) occur in children with associated anomalies, particularly those with cardiac defects or an underlying syndrome.10,45,46 These facts must be considered when counselling parents of affected children. With good medical and nursing care, the prognosis for children with isolated PRS should be excellent.58

Nasal obstruction Choanal atresia is a rare accompaniment of PRS18,52 but may complicate the respiratory difﬁculties in small infants who do not mouth-breathe. It is important to ensure nasal patency, especially if one nostril is to be utilized for a nasogastric feeding tube. Choanal obstruction in itself can lead to glossoptosis, with consequences identical to those of PRS.53

COMPLICATIONS AND OUTCOME In isolated PRS, the long-term outcome is directly related to the quality of the management at the onset of symptoms. With adequate nutrition, mandibular growth

Figure 19.8 Chest X-ray in infant with Pierre Robin sequence showing cardiomegaly due to pulmonary hypertension (Courtesy Mr P.A.M. Raine)

212 Pierre Robin sequence

REFERENCES 1. Robin P. Glossoptosis due to atresia and hypotrophy of the mandible. Am J Dis Child 1934; 48:541–7. 2. Eley RC, Farber S. Hypoplasia of the mandible (micrognathy). Am J Dis Child 1930; 39:1167–75. 3. Lancet. Classiﬁcation and nomenclature of malformation. Lancet 1974; 1:798. 4. Lancet. Classiﬁcation and nomenclature of morphological defects. Lancet 1975; 1:513. 5. McCollum DW, Witkop CJ. The face and oral structures. In: Rubin A, editor. Handbook of Congenital Malformations. Philadelphia: WB Saunders, 1967: 145–6. 6. Millard DR. Mandibular Surgery. In: Cleft Craft. Vol 3. Alveolar and Palatal Deformities. Baltimore: Williams and Wilkins, 1980: 901–31. 7. Bush PG, Williams AJ. Incidence of the Robin anomalad (Pierre Robin syndrome). Br J Plast Surg 1983; 36:434–7. 8. Pashayan HM, Lewis MB. Clinical experience with the Robin sequence. Cleft Palate J 1984; 21:270–6. 9. Marques IL, Barbieri MA, Bettiol H. Etiopathogenesis of isolated Robin sequence. Cleft Palate Craniofac J 1998; 35:517–25. 10. Shefﬁeld LJ, Resiss JA, Strohm K et al. A genetic follow-up study of 64 patients with the Pierre Robin complex. Am J Med Genet 1987; 28:25–36. 11. Stark R. Development of the face. In: Hueston JT, editor. Transactions of the 5th International Congress of Plastic and Reconstructive Surgery. Sydney: Butterworths, 1971: 123–30. 12. Franklin AW. Special syndromes. In: Norman AP, editor. Congenital Abnormalities in Infancy. 2nd edn. Oxford: Blackwell, 1971: 350–91. 13. Carey JC, Fineman RM, Ziter FA. The Robin sequence as a consequence of malformation, dysplasia, and neuromuscular syndromes. J Pediatr 1982; 101:858–64. 14. Edwards JRG, Newall DR. The Pierre Robin syndrome assessed in the light of recent research. Br J Plast Surg 1985; 38:339–42. 15. Cohen MM. The Robin anomalad: its non-speciﬁcity and associated syndromes. J Oral Surg 1976; 34:587–93. 16. Cohen MM Jr. Robin sequences and complexes: causal heterogeneity and pathogenetic/phenotypic variability. Am J Med Genet 1999; 84:311–15. 17. Shprintzen RJ. The implications of the diagnosis of Robin sequence. Cleft Palate Craniofac J 1992; 29:205–9. 18. Nyhan WL, Sakati NO. Pierre Robin syndrome. In: Genetic and Malformations syndromes in Clinical Medicine. Chicago: Year Book, 1976: 446–8. 19. Van der Haven I, Mulder JW, van der Wal KG et al. The jaw index: new guide deﬁning micrognathia in newborns. Cleft Palate Craniofac J 1997; 34:240–1. 20. Pilu G, Romero R, Reece EA et al. The prenatal diagnosis of the Robin anomalad. Am J Obstet Gynecol 1986; 154:630–2. 21. Malinger G, Rosen N, Archiron R et al. Pierre Robin sequence associated with amniotic band syndrome.

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Ultrasonographic diagnosis and pathogenesis. Prenat Diagn 1987; 7:455–9. Bromley B, Benacerraf BR. Fetal micrognathia: associated anomalies and outcome. J Ultrasound Med 1994; 13:529–33. Hsieh YY, Chang CC, Tsai HD et al. The prenatal diagnosis of Pierre Robin sequence. Prenat Diagn 1999; 19:567–9. Ogborn MR, Pemberton PJ. Late development of airway obstruction in the Robin anomalad (Pierre Robin syndrome) in the newborn. Aust Paediatr J 1985; 21:199–200. Sher AE. Mechanisms of airway obstruction in Robin sequence: implications for treatment. Cleft Palate Craniofac J 1992; 29:224–31. Myer CM III, Reed JM, Cotton RT, Willging JP, Shott SR. Airway management in Pierre Robin sequence. Otolaryngol Head Neck Surg 1998; 118:630–5. Bath AP, Bull PD. Management of upper airway obstruction in Pierre Robin sequence. J Laryngol Otol 1997; 111:1155–7. Freed G, Pearlman MA, Brown AS et al. Polysomnographic indications for surgical intervention in Pierre Robin sequence: acute airway management and follow-up studies after cleft palate repair and take-down of tonguelip adhesion. Cleft Palate J 1988; 25:151–5. Lewis MB, Pashayan HM. Management of infants with Robin anomaly. Clin Paediatr 1980; 19:519–28. Heaf DP, Helms PJ, Dinwiddie R et al. Nasopharyngeal airways in Pierre Robin syndrome. J Paediatr 1982; 100:698–703. Chang AB, Masters IB, Williams GR, Harris M, O’Neil MC. A modiﬁed nasopharyngeal tube to relieve high upper airway obstruction. Pediatr Pulmonol 2000; 29:299–306. Hatch DJ, Sumner E. Anaesthesia – basic pronciples. In: Neonatal Anaesthesia and Perioperative care. 2nd edn. London: Edward Arnold, 1986: 85–124. Hatch DJ. Anaesthesia for paediatric surgery. In: Summer E, Hatch DJ, editors. Textbook of Paediatric Anaesthesia Practice. Baillière Tindall, 1989: 275–304. Howardy-Hansen P, Berthelsen P. Fibreoptic bronchoscopic nasotracheal intubation of a neonate with Pierre Robin syndrome. Anaesthesia 1988; 43:121–2. Baraka A. Laryngeal mask airway for resuscitation of a newborn with Pierre Robin. Anaesthesiology 1995; 83:645–6. Osses H, Poblete M, Asenjo F. Laryngeal mask for difﬁcult intubation in children. Paediatr Anaesth 1999; 9:399–401. Routledge RT. The Pierre Robin Syndrome: a surgical emergency in the neonatal period. Br J Plast Surg 1960; 13:204–18. Parsons RW, Smith DJ. A modiﬁed lip-tongue adhesion for Pierre Robin anomalad. Cleft Palate J 1980; 17:144–7. Otherson HB. Trachea, lungs and pleural cavity. In: Welch KJ, editor. Complications of Paediatric Surgery: Prevention and Management. Philadelphia: WB Saunders, 1982: 184–98.

References 213 40. Dempster JH, Dykes EH, Brown WC et al. Tracheostomy in childhood. J Roy Coll Surg Edinb 1986; 31:359–63. 41. Spitz L, Kiely E, Brereton RJ. Esophageal atresia: ﬁve year experience with 148 cases. J Pediatr Surg 1987; 22:103–8. 42. Langer JC, Wesson DW, Ein SH et al. Feeding gastrostomy in neurologically impaired children: is an antireﬂux procedure necessary? J Pediatr Gastroenterol Nutr 1988; 7:837–41. 43. Parsons RW, Smith DJ. Rule of thumb criteria for tonguelip adhesion in Pierre Robin anomalad. Plast Reconstr Surg 1982; 70:210–12. 44. Warkany J. Some syndromes affecting the face. In: Congenital Malformations. Chicago: Year Book, 1971: 650–8. 45. Williams AJ, Williams MA, Walker CA et al. Robin anomalad (Pierre Robin syndrome) – a follow-up study. Arch Dis Childh 1981; 56:663–8. 46. Elliot M, Studen-Pavlovich D, Ranalli DN. Prevalence of selected pediatric conditions in children with Pierre Robin syndrome. Pediatr Dent 1995; 17:106–11. 47. Gamble JG, Rinsky LA. Combined occipito-atlanto-axial hypermobility with anterior and posterior arch defects of the atlas in Pierre Robin syndrome. J Pediatr Orthop 1985; 5:475–8. 48. Pearl W. Congenital heart disease in the Pierre Robin syndrome. Pediatr Cardiol 1982; 2:307–9. 49. Dykes EH, Raine PAM, Arthur DS et al. Pierre Robin

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syndrome and pulmonary hypertension. J Pediatr Surg 1985; 20:49–52. Opitz JM, France T, Herrman J et al. The Stickler syndrome. N Eng J Med 1972; 286:546–7. Smith JL, Stowe FR. The Pierre Robin syndrome (glossoptosis, micrognathia, cleft palate). Pediatrics 1961; 27:128–33. Borovik HR, Kveton JF. Pierre Robin Syndrome combined with unilateral choanal atresia. Otolaryngol Head Neck Surg 1987; 96:67–70. Cozzi F, Pierro A. Glossoptosis-apnoea syndrome in infancy. Pediatrics 1985; 75:836–43. Pruzansky S, Richmond JB. Growth of the mandible in infants with micrognathia: clinical implications. Am J Dis Child 1954; 88:29–42. Vegter F, Hage JJ, Mulder JW. Pierre Robin syndrome: mandibular growth during the ﬁrst year of life. Ann Plast Surg 1999; 42:154–7. Spier S, Rivlin J, Rowe RD et al. Sleep in Pierre Robin syndrome. Chest 1986; 90:711–15. Frohberg U, Lange RT. Surgical treatment of Robin sequence and sleep apnea syndrome; case report and review of the literature. J Oral Maxillofac Surg 1993; 51:1274–7. Bull MJ, Givan DC, Sadove AM et al. Improved outcome in Pierre Robin sequence: effect of multidisciplinary management. Pediatrics 1990; 86:294–301.

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20 Macroglossia GEORGE G. YOUNGSON

INTRODUCTION Tongue enlargement or macroglossia is one of the few disease processes to affect this structure and is deﬁned as a resting tongue which protrudes beyond the teeth, or in the case of the neonate, the alveolar ridge.1 Pseudomacroglossia arises when the tongue itself is normal, but relative protrusion occurs because of a small mandible, as seen in Down’s syndrome and Pierre Robin syndrome.2 When displaced because of adjacent pathology such as cystic hygroma, cysts into the lingual thyroglossal duct, neuroﬁbromatosis, or tumors such as rhabdomyosarcoma, the term ‘secondary macroglossia’ can be used. The causes of primary macroglossia include hypothyroidism and lymphangioma, hemangioma, idiopathic hyperplasia and chromosomal abnormalities. Macroglossia is one of the most constant features of the Beckwith–Wiedemann syndrome, which is characterized by an omphalocele, or umbilical hernia with associated visceromegaly, somatic gigantism or hemi-hypertrophy and hypoglycemia.3

(a)

PRESENTATION Lymphangioma is the commonest cause of macroglossia to present in the neonatal period and may be diagnosed by prenatal ultrasound when associated with Beckwith– Wiedemann syndrome.4 The clinical features of the condition include noisy breathing and drooling, and when difﬁculties in feeding occur, then failure to thrive and poor weight gain feature (Fig. 20.1 a,b). When lymphangioma is the cause, verrucous lesions may appear on the surface and these exude a serous discharge. Minor trauma to this tissue then results in intralesional hemorrhage and/or sepsis (usually cellulitic from group B hemolytic Streptococcus). In this event abrupt enlargement may compromise the airway and produce a life-threatening emergency (Fig. 20.2).

(b) Figure 20.1 a,b Lymphangioma of the tongue occluding the oral cavity in a 4-week-old neonate

216 Macroglossia

care requirements of the other features of this condition. Similarly surgical intervention is inappropriate if hypothyroidism is the primary diagnosis. However massive enlargement may precipitate the need for early intervention and the challenge of anesthesia and endotracheal intubation point towards the need for tracheostomy.

SURGERY

Figure 20.2 Intra-lesional hemorrhage into a lingual lymphangioma producing respiratory obstruction

If treatment is inappropriately delayed, protracted dental defects include prognathism, anterior open bite, and an increased angle between the ramus and body of the mandible.5 Speech defects occur and articulation is subsequently defective, especially expression of consonants which are precluded by inadequate tongue movement as a consequence of the increased bulk in a limited cavity. Regression of macroglossia is not a regular feature when it is due to lymphangioma and a conservative approach to the lesion has no merit.

EVALUATION Investigation, following thorough physical examination for secondary causes of macroglossia comprises thyroid function testing, echocardiography and karyotype analysis. Magnetic resonance imaging to detail the extent of tongue involvement is indicated if the volume of lingual tissue affected is not clinically apparent. If airway occlusion with associated respiratory distress exists, then pulse oximetry and side-stream capnography may help in the management of such critical cases. This is a rare circumstance. Biopsy is rarely indicated.

MANAGEMENT Multidisciplinary involvement is, as ever, helpful with speech therapists, dieticians and pediatric dentists valuable contributors to patient and parental management. When the tongue is particularly large, nursing the infant in the lateral or prone position assists in airway management and skin care, especially if drooling is a prominent feature. When part of the Beckwith– Wiedemann syndrome, the tongue is seldom grossly enlarged and treatment must be seen in context of the

Alternatives to reduction glossectomy include intravascular photocoagulation6 and embolism7 of vascular tongue anomalies and but early surgery (preferably before 7 months of age)8 confers optimal opportunity for rehabilitation of tongue movement and avoids complications such as glossitis, hemorrhage and secondary speech and maxillofacial abnormalities. Clearly postponing surgery in the newborn period is preferable for avoidance of unnecessary morbidity but the timing thereafter is a matter of individual clinical judgment. Steroid treatment confers temporary beneﬁt during management of the acute airway obstruction and penicillin-based antibiotic therapy is indicated for treatment of septic complications. These problems however are usually seen later in infancy and childhood rather than the neonatal period and result from inappropriate delay of surgery. Reduction glossectomy is the mainstay of treatment and options include central wedge resection, circumferential wedge resection or a combined transoral and transcervical approach for a massive inﬁltrative lymphangioma.9 The aims of reduction are to allow intra-oral position of the tongue in the ﬂoor of the mouth to restore normal tongue movement, and to permit speech and deglutition. Implicit in these objectives is the fact that surgery should be conservative and a repeat tapering procedure is preferable to removal of excess tissue.

TECHNIQUE V-shaped resection of the anterior tongue has been previously described.10 The principles involve careful hemostasis by use of a tourniquet effect as described later by Dr Upadhyaya or alternatively use of a Neodymium-YAG laser or harmonic scalpel.

OPERATION Nasal intubation or tracheostomy secures airway protection. The head is placed in a silicone ring and the neck extended. The peri-oral tissues are prepared with

References 217

0.5% chlorhexidine in aqueous solution and drapes applied. A traction suture (3/0 polydioxanone) is placed on the apex of the tongue and two hemostatic/traction sutures tied over silicone rubber dams at the base of the tongue (Fig. 20.3). 0 polydioxanone on a 30-mm round-bodied needle is used for this maneuver. Traction on these three sutures provides the necessary exposure and hemostasis sufﬁcient for central wedge resection. The resection should not usually extend into the posterior third, where the extrinsic muscles of the tongue are inserted. The lateral margins of the incision extend from the level of the anterior gum, with the tongue in a resting position, to the apex, and this incision is bevelled such that more ventral than dorsal tissue is removed. This re-creates the natural concavity of the central tongue (Fig. 20.4). A straight needle is a useful adjunct to creating this bevel.

Figure 20.5 The remaining lateral segments of the tongue approximated in the midline

A

L

The divided lingual arteries are ligated. Restoration of the tongue ﬂaps and the midline is performed with Vicryl incorporating mucosa and a few millimeters of muscle (Fig. 20.5). The opportunity to place a percutaneous gastrostomy should be taken if protracted delay in feeding is anticipated.

M

Figure 20.3 Traction sutures allow good exposure and good hemostasis during reduction glossectomy

PERIOPERATIVE CARE Antibiotics should be continued into the postoperative period to provide prophylaxis against sepsis in the ﬂoor of the mouth. Oral hygiene is maintained with chlorhexidine or saline oral toilet. The appropriate tracheostomy care, if required, is given and secondary orthodontic and speech therapy follow-up arranged.

REFERENCES

Figure 20.4 Wedge of tissue incorporating more of the dorsal than ventral aspect of the tongue is removed

1. Gupta OP. Congenital macroglossia. Arch Otolaryngol 1971; 94:381–82. 2. Murthy P, Laing M. Macroglossia. Br Med J 1994; 309:1386–87. 3. Vogel JE, Mulliken JB, Kaban LB. Macroglossia: a review of the condition and a new classiﬁcation. Plast Reconstr Surg 1986; 78:715–23. 4. Harker CP, Winter T, Mack L. Prenatal diagnosis of Beckwith–Wiedemann syndrome. Am J Roentgenol 1997; 168:520–2. 5. Rizer FM, Scheckter GL, Richardson MA. Macroglossia: aetiological considerations and management techniques. Int J Pediatr Otorhinolarygol 1985; 81:225–36. 6. Chang CJ, Fisher DM, Chen YR. Intralesional photocoagulation of vascular anomalies of the tongue. Br J Plast Surg 1999; 52:178–81.

218 Macroglossia 7. Slaba S, Herbreteau D, Jhaveri HS et al. Therapeutic approach to arterio-venous malformations of the tongue. Euro Radiol 1998; 8:280–5. 8. Shafer AD. Primary macroglossia. Clin Pediatr 1968; 7:357–65.

9. Dinerman WS, Myers EN. Lymphangiomatous Macroglossia. Laryngoscope 1976; 86:291–6. 10. Upadhyaya P, Upadhyaya P. Partial glossectomy for macroglossia. J Pediatr Surg 1986; 21:457.

21 Tracheostomy in infants THOM E. LOBE

INTRODUCTION Both the ﬁelds of neonatology and technology have made great advances over the last few decades. Because of the routine use of surfactant and steroids, it is now rare to see an infant dependent on a ventilator for lung disease alone, and it is neither unusual nor unsafe to leave an infant on a ventilator with an endotracheal tube in place for months on end. Most infants who need a tracheostomy do so because of an inadequate airway. These infants otherwise are ready to go home or to a facility for technologically dependent children, but still require ventilatory assistance. This chapter will discuss the indications for and techniques for insertion and maintenance of a tracheostomy in infants.

Patients with a congenitally stenotic airway or tracheal agenesis are special cases. In the case of agenesis, an emergency tracheostomy may be necessary where the trachea re-establishes distally. Usually, however, these patients can be ventilated best using a mask because the bronchi come off the esophagus and an esophageal tube can cause obstruction. There are several acquired conditions that require tracheostomy including infection, papillomatosis, neuromuscular failure, chronic aspiration and subglottic stenosis. Occasionally the management of a tumor such as a cervical teratoma or sarcoma in infancy will mandate a tracheostomy. More likely a hemangioma or lymphangioma will compromise the airway to the extent that a more stable airway is needed. Rarely, trauma will prompt the surgeon to perform a tracheostomy. This can be related to birth trauma, child abuse or accidents.

INDICATIONS FOR TRACHEOSTOMY The indications for tracheostomy in infants fall into ﬁve main categories: (1) airway immaturity, (2) obstructing congenital anomalies, (3) acquired obstructions, (4) tumors and (5) trauma. The immature airway manifests itself as laryngomalacia, tracheomalacia or a combination of the two conditions. These infants present with inspiratory stridor and some degree of nasal ﬂaring and chest retractions. Other related conditions are congenital vocal cord paralysis, which is usually due to a central nervous system deﬁcit, phrenic nerve injury, which may be associated with a difﬁcult delivery and recurrent laryngeal nerve injury, which may occur after ligation of a patent ductus arteriosus. Some patients with choanal atresia and Pierre Robin syndrome may be candidates for tracheostomy. Other cranio-facial deformities such as Freeman Sheldon syndrome, Cerebro-costo-mandibular syndrome, arthrogyposis multiplex congenita and others also may require a tracheostomy for airway maintenance.

PREOPERATIVE EVALUATION Most infants who need a tracheostomy already have an endotracheal tube in place. Infants suspected of laryngotracheomalacia may require direct laryngoscopy and/or bronchoscopy to assess the situation. The surgeon should make certain of the coagulation status, hemoglobin level and electrolytes as indicated by the patient’s condition. The nutritional status of the patient should also be taken into consideration. Poor nutrition will complicate nearly any condition in infancy and may weigh in favor of an earlier tracheostomy than would be indicated otherwise. When an infant is not intubated, but is under consideration for tracheostomy, the extent to which the child maintains oxygenation and demonstrates adequate ventilation as judged by the Pco2 measured by transcutaneous monitoring will determine the need for a more direct assessment before a decision for tracheostomy is made.

220 Tracheostomy in infants

Finally, patients with persistent aspiration, despite correction of any gastroesophageal reﬂux, may necessitate a tracheostomy to prevent severe pulmonary consequences.

TECHNIQUE The infant is placed supine on the operating table, sufﬁciently toward the foot of the table so that the surgeon can access the infant’s neck easily, but not so far down on the table that the anesthesiologist cannot reach the patient to manipulate the endotracheal tube when required. These cases should be done under a general anesthetic unless the infant is so ill as to be unable to tolerate the drugs. Even so, an anesthesiologist or anesthetist should maintain control of the airway while the surgeon is exposing and manipulating the trachea. The patient’s cardiorespiratory status should be monitored during the case. This should consist of a cardiac monitor for heart rate, a blood pressure monitor, and ideally a pulse oximeter to assess the infant’s oxygenation. If there is any question as to the status of the airway, bronchoscopy should be performed to assure that the tracheal lumen will accept a tracheostomy without difﬁculty. Special issues, such as a tracheostomy to stent an airway for severe tracheomalacia can be assessed by bronchoscopy to determine the proper length of the proposed cannula, which may have to be specially ordered. In some cases it may be necessary to use an ordinary endotracheal tube placed through the cervical incision and secured to the skin of the neck until this temporary tracheostomy cannula can be replaced with the specially ordered device. When positioning the infant on the operating table, the neck should be extended sufﬁciently to allow complete access to the neck. Sometimes, on chubby infants, it is still difﬁcult to see the entire neck, despite the best attempts. A roll should be placed under the infant’s shoulders to facilitate proper positioning (Fig. 21.1). The endotracheal tube should be secured so that the anesthesiologist can easily remove the tube at the appropriate time. This means that any tape should be loosened beforehand. If there is a feeding tube in place, it should be removed so that it does not interfere with endotracheal tube manipulation. When the infant is properly positioned and monitored, the entire neck from the lower lip to below the nipples should be prepped with a suitable surgical prep and draped. The superior most surgical drape should allow easy access to the patient by the anesthesiologist. Once prepped and draped, the surgeon should carefully palpate the infant’s neck to locate the trachea that

Figure 21.1 Position of infant for tracheostomy. The shoulders are elevated on a roll; the head is hyperextended on the neck and supported by a doughnut-form support

hopefully is in the midline. The surgeon must remember that the infant’s trachea is quite mobile and compressible, and may be difﬁcult to palpate. The anesthesiologist can jiggle the endotracheal tube from above to assist with its location. At our institution, we make our incision in the lower neck crease, about the width of one ﬁnger above the jugular notch. A transverse incision is preferable. If the incision is too low you will end up in the mediastinum and the cannula will be placed too low in the trachea. We ﬁrst score the skin with a scalpel, then use a needle-point electrocautery device to deepen the incision, taking care not to burn the skin. This incision is extended through the subcutaneous fascia and platysma muscle, which is quite thin in the small infant. It is helpful to insert two right-angled retractors in the corners of this incision to better expose the operative site. Next, we use two atraumatic forceps to grasp the cervical fascia on either side of the midline and open it vertically in the midline. We extend this incision inferiorly to the jugular notch and superiorly to the thyroid gland. The strap muscles, immediately beneath the anterior cervical fascia similarly are separated in the midline. Usually, there are few to no blood vessels in the dissection thus far. Occasionally, the surgeon will encounter a few small vessels that cross the midline. These should be cauterized and divided as they are encountered. Once these muscles are separated, we place the two retractors deep to the muscle edges and gently retract laterally to better expose the trachea below. Sometimes it is necessary to free the muscle edges sufﬁciently to allow room for the blade of the retractor to gain a secure purchase. The trachea should be visualized easily. If not, then palpation in the wound with manipulation of the endotracheal tube by the anesthesiologist will help locate the trachea. The proposed tracheostomy cannula should be selected, opened and its outer diameter visually checked

Technique 221

against the exposed trachea to judge the correctness of its size. If it seems that the initial selection was incorrect, then a tracheostomy cannula of a more appropriate size should be selected. The pre-tracheal fascia should be scored with the cautery to coagulate any tiny vessels on the surface of the trachea in the midline. Again, the blades of the retractors should be deep in the wound on either side of the trachea for optimal exposure. A suture of 4-0 Prolene or its equivalent should be placed on either side of the midline scored anterior trachea (Fig. 21.2). Each suture incorporates one or two tracheal rings. These sutures are not tied onto the tracheal wall, but can be tied at their ends and should be left 6–8 cm in length. At the end of the case, these sutures should be taped securely to the anterior chest wall and used to locate the tracheal incision in the event of a postoperative emergency in which the newly placed tracheostomy cannula dislodges. These sutures also can be used to hold open the edges of the tracheal incision for ease of placement of the tracheostomy cannula at operation. The surgeon should request that the endotracheal tube be loosened and prepared for removal. Using a No. 11 blade, a vertical incision is made through the tracheal wall along the score mark (Fig. 21.3). Two or three tracheal rings should be divided, usually rings 2, 3 and 4. Rarely, it is necessary to divide the isthmus of the thyroid gland for proper tracheostomy positioning. A transverse tracheal incision or removal of a tracheal ring is likely to result in a tracheal deformity and thus should be avoided. Suction should be available in case blood or secretions interfere with the surgeon’s view of the tracheal lumen.

Thyroid isthmus 2

3 Traction sutures placed

4

Figure 21.2 Traction sutures of ﬁne silk are placed around the 3rd tracheal ring to stabilize the trachea before incision. The sutures are tied in loose loops and later taped to the anterior chest wall. The sutures are left in place for 4 days as a precaution against accidental decannulation postoperatively

E.T. tube

Cartilages incised

Figure 21.3 The trachea should be opened through a midline vertical incision across 2–3 tracheal rings. The incision must be long enough to avoid excess tube pressure against the cartilages. A tight tube can result in pressure deformity and reabsorption of cartilage

The tip of the cannula to be inserted should be lubricated with a water-soluble surgical lubricant and positioned over the incision, poised for insertion when the endotracheal tube is withdrawn. The surgeon should then ask the anesthesiologist to withdraw the endotracheal tube sufﬁciently to clear the lumen so that the tracheostomy cannula can be inserted and directed caudally toward the carina. One way to avoid misplacement is to insert a suction catheter through the lumen, beyond the tip of the cannula (Fig. 21.4). The suction catheter then can be inserted into the tracheal lumen ﬁrst and serve as a guide over which the cannula can be passed. This technique also is useful should the cannula become dislodged after the procedure. If, for any reason, the tracheostomy cannula does not ﬁt easily into the trachea, it should be removed and the endotracheal tube advanced beyond the tracheal incision so that ventilation will not be compromised. This might occur if the diameter of the tracheal lumen has been over estimated and the previously selected tracheostomy is too large to ﬁt into the trachea. In the latter case, a smaller cannula should be selected. As soon as the cannula is in place, the obturator or suction catheter should be removed and the anesthesiologist should disconnect the ventilator hose from the endotracheal tube and connect it to the tracheostomy cannula. Once that is done, the anesthesiologist should administer several deep breaths to the patient to conﬁrm that the cannula is in the proper place and that the infant can be ventilated satisfactorily. If it appears that although the cannula width is appropriate, the cannula is too long

222 Tracheostomy in infants

E.T. tube

Trachea placed over catheter

Catheter introduced into trachea

Figure 21.4 Tube insertion into the trachea is accomplished by shifting the endotracheal tube up to the cephalad margin of the new stoma, inserting a tracheal suction catheter into the trachea through the newly established opening, and then advancing the tracheostomy tube over the catheter in the trachea. This is safer than using the tube obturator, the short tip of which sometimes slips out of the stoma and allows the tracheostomy tube to pass anterior to the trachea and into the mediastinum

Traction taped to chest

Figure 21.5 Prevention of accidental decannulation is the surgeon’s responsibility. The tube should be taped to the anterior chest for 4 days in case an unexpected tube change should become necessary

PERIOPERATIVE MANAGEMENT and its tip rests on the carina, then several pieces of gauze can be used to build up the gap between the neck and the tracheostomy collar, thus backing the tip of the cannula away from the carina. Once adequate ventilation is conﬁrmed, then the endotracheal tube can be removed completely. Once the cannula is connected to the ventilator, the cervical wings of the body of the cannula need to be secured to the patient. We don’t rely on a tie placed around the neck, but accomplish this with the aid of sutures. For each wing, a suture of 3-0 silk or its equivalent is passed through the skin of the neck, then through the upper edge of the wing of the cannula (midway between the midline and the end of the wing), through the lower edge of the wing, then again through the skin. When this suture is tied, the skin will be drawn over the wing and usually will cover it. After these sutures are placed, both wings will be securely ﬁxed to the skin of the neck. The two ties that were placed in the anterior tracheal wall should now be taped securely to the anterior chest wall in such a fashion that ensures that their ends are easily accessible in case they are needed in an emergency to reinsert the cannula (Fig. 21.5). Finally, the umbilical tape or tie that usually comes with the cannula is passed through the holes in the end of the wings and tied around the neck to further secure the cannula. This should be tied in back of the neck. A simple gauze dressing with antibiotic ointment applied is placed underneath the wings of the cannula over the cervical incision to complete the procedure. We send our infants to the intensive care unit after a fresh tracheostomy in case of emergency.

If the skin of the patient’s neck is infected with a bacterial or fungal infection, this should be cleared before any operation is undertaken unless emergency tracheostomy is required to save an infant’s life. In patients with short, fat necks, it may be necessary to place the infant in a position of neck extension to facilitate clearing any skin infection or breakdown that is due to chronic moisture. Simply exposing the infant’s neck to air for drying often is sufﬁcient to clear any problem. Immediately after the tracheostomy is secured, the roll under the patient’s neck should be removed and a radiograph of the chest should be reviewed before the patient is removed from the operating room. This is important to make certain that the tip of the cannula is sufﬁciently clear of the carina and will not become obstructed as the patient’s neck is manipulated. The fresh tracheostomy should be left in place for about 10 days before it is disturbed. At least once each day, the site should be cleaned with a cotton applicator soaked in a solution of hydrogen peroxide, and an antibiotic ointment should be applied to the incision site. The sutures securing the tracheostomy should be left untouched for the initial 10-day period, after which they can be cut. The sutures to the edges of the tracheal incision should be left until the tracheostomy is changed successfully for the ﬁrst time. If the patient is unusually agitated or the ventilator tubing is so heavy that dislodging the cannula is highly likely, then sedation or paralysis may be helpful until the wound has matured and reinsertion can be done more safely.

Complications 223

After the cannula is free and the umbilical tape is untied, the cannula can be removed and replaced. Ideally, the parents or ultimate caretakers should observe the exchange, particularly if the patient is close to discharge. If a temporary endotracheal tube is being replaced with a specially ordered tracheostomy cannula, the new cannula should be inserted as described earlier. Once it is obvious that the cannula can be changed with ease, is in its proper position and that the patient can be ventilated, it is safe to remove the sutures to the edges of tracheal incision. Suctioning of the newly placed tracheostomy should be done as often as necessary, particularly immediately after the procedure. Care must be taken, however, to restrict the passage of the suction catheter to no further than the tip of the cannula. Routine suctioning beyond the tip of the cannula promotes the development of granulation tissue that may obstruct the airway later on.

HOME INSTRUCTION AND CARE Patients should be discharged home with an extra tracheostomy cannula in case a problem occurs. The caretakers should be instructed and checked out on tracheotomy change and cardiopulmonary resuscitation (CPR). They should know how to suction the cannula and be sent home with a suction machine. They should know how to use an Ambu bag for ventilation in conjunction with suctioning. An air ﬁlter should be attached to the tracheostomy cannula if a ventilating device or some other moisturizing device is not otherwise connected. Of course, the family or caretakers must know how to use and trouble shoot in case of problems whilst using any of these devices. It is often helpful to arrange for home nursing visits until the family becomes familiar and comfortable with the new devices; this is especially true when it comes time for the ﬁrst scheduled tracheostomy change if it is to be done at home. The physician may choose to do the ﬁrst tracheostomy change in the ofﬁce and take the opportunity to further instruct and reassure the family or caretakers.

COMPLICATIONS Hemorrhage is an unusual complication that can occur at the time of operation or as a delayed event. When hemorrhage occurs at operation, it can be controlled easily with electrocautery or vessel ligation. Rarely, especially in the newborn, the thyroid gland is near the incision site on the anterior trachea and is inadvertently divided or lacerated. The resultant hemorrhage usually can be controlled with sutures or electrocautery.

Late hemorrhage often is more problematic and can be more serious. First, it must be ascertained whether the hemorrhage is from the tracheal lumen or from the incision. This can be accomplished by suctioning the cannula and inspecting the wound. Occasionally a small skin vessel will bleed briskly but can be easily seen and controlled with a simple suture or even with an injection of 1% Lidocaine containing 1:100 000 epinephrine. More problematic is the possibility of hemorrhage from one of the great vessels, such as the innominate vein or artery. This can occur from erosion of the vessels when the cannula ﬁts too snugly in the thoracic inlet and partially compresses the vessels against the manubrium or clavicle. This type of hemorrhage often presents with a so-called ‘herald bleed,’ which starts briskly but stops, and usually requires a trip to the operating room to repair the damaged vessel. Aside from hemorrhage, the cannula can become dislodged. We are compulsive about securing the cannula in place using the techniques described earlier in order to avoid this complication. Even so, despite our best efforts, a suture will pull loose or one of the plastic wings will tear, allowing the cannula to dislodge. Fortunately, we keep our infants in the intensive care unit during the immediate postoperative period. We anticipate that if the cannula becomes dislodged, it will be noticed immediately. Replacing the cannula in the immediate postoperative period can be a treacherous ordeal that under ideal circumstances should be done by someone familiar with cannula insertion. If a surgeon or intensivist is readily available, then one of them should replace the cannula and re-secure the device. The sutures to the tracheal incision should be taped in such a manner as to be easy to access, untape and retract to expose the tracheal lumen. Good lighting is essential to see well and either the obturator should be inserted into the cannula before reinsertion is attempted or a suction catheter should be used as a guide. It is very undesirable to force the cannula outside the trachea. Proper positioning is assured by administering a deep breath or two with an Ambu bag once the cannula is in place. If the chest does not rise immediately, chances are that the cannula is not in the proper place and should be replaced. A chest radiograph should be taken to assure proper cannula position. It is not usually necessary to use instruments to reinsert the cannula because the sutures attached to the edges of the tracheal incision should lead directly to the opening in the trachea. If difﬁculty arises, two small right-angled retractors should be sufﬁcient to complete the job. Infection is an unusual complication and should be treated with the appropriate antimicrobials according to culture results. Injury to the vagus nerves or, more likely, the recurrent laryngeal nerves can occur. In experienced hands with a surgeon well versed in the anatomy of the infant’s neck, this injury should be rare.

224 Tracheostomy in infants

While unlikely, it is possible to place the cannula into the esophagus. This can occur if the trachea is retracted out of the ﬁeld and the esophagus is entered in error. If this occurs, then the esophagus should be repaired primarily and a drain should be placed. The tracheostomy cannula then can be inserted properly. Endotracheal granulation tissue can result from the chronic irritation of the tip of the tracheostomy cannula against the tracheal wall or from the repeated suctioning of the trachea. It is common for granulation tissue to develop at the stoma. This can be exophytic at the level of the skin, or can be intralumenal. The exophytic granulation tissue at the skin should be cauterized with silver nitrate during an outpatient visit. This may need to be carried out every month or so if bothersome hemorrhage or chronic irritation with infection is present. If the granulation tissue develops immediately within the trachea at the stoma, it usually can be left alone until it is time for decannulation. Only if the granulation tissue is so bulky that it interferes with routine tracheostomy changes or causes signiﬁcant hemorrhage should it be removed before decannulation is contemplated. The development of granulation tissue at the tip of the cannula can present with obstruction, sometimes resulting in a ‘ball-valve’ effect, with trapped air and difﬁculty with ventilation. This can be diagnosed by slipping a ﬂexible bronchoscope through the cannula to visualize the tracheal lumen beyond the tip of the cannula. If the results of this diagnostic maneuver are unclear, rigid bronchoscopy may be necessary. We believe that this type of granulation tissue is best removed with laser. Our preference is for the KTP/532 laser or an equivalent wavelength that operates using a ﬂexible ﬁber. The technique for laser vaporization of granulation tissue is beyond the scope of this discussion.

SPECIAL SITUATIONS Occasionally, there exist special circumstances which require careful thought and planning. Such is the case with tracheal stenosis. Simple acquired subglottic stenosis can be easily managed with a tracheostomy inserted as described except for the size of the endotracheal tube. A small endotracheal tube may be difﬁcult to palpate, however, thus locating the trachea may be difﬁcult. With a particularly stenotic airway, mask ventilation may be the only way to maintain ventilation. The most difﬁcult part of the case is locating the trachea without an endotracheal tube. For patients with distal tracheal stenosis, tracheostomy insertion may be inappropriate. While beyond the scope of this discussion, the infant should be carefully studied if this diagnosis is suspected. Usually, plain radiographs of the chest may lead one to suspect the diagnosis.

Computerized tomography or bronchoscopy may be required for conﬁrmation. When the distal trachea is stenotic in an infant who is difﬁcult to ventilate, a conventional tracheostomy cannula is inappropriate and may interfere with tracheal reconstruction. Patients who are candidates for congenital heart surgery and in whom the ultimate need for a tracheostomy is anticipated, may be best managed by completing the cardiac surgery before tracheostomy is performed. Otherwise, the sternal incision is so close to the tracheostomy site that the risk of cardiac infection is greatly increased.

DECANNULATION Decannulation usually is anticipated well in advance. Its timing depends to a large degree on the indication for the tracheostomy. Patients with severe subglottic stenoses may have their tracheostomy removed at the time of their laryngoplasty. The timing of this procedure, then, depends on the surgeon and may occur any time between 4–6 months and 2 years, or later. In patients whose tracheostomy was placed because of tracheomalacia, it would be unusual to attempt decannulation before the infant is 1 year of age. The infant should undergo periodic bronchoscopic examination to assess the status of the malacia. Once it is certain that the airway is sufﬁciently mature as to be able to maintain its patency, decannulation can be attempted. The ﬁrst step is to make certain that the airway is mature and free of any potential obstructing lesions such as granulation tissue. This is best accomplished with rigid bronchoscopy. Any residual malacia or granulation tissue can be documented and dealt with as needed. At the time of attempted decannulation, we bring the patient to the operating room, positioned as described earlier for insertion of the cannula with the neck extended, and perform the bronchoscopy. In order to assess whether malacia is present, the patient should not be paralyzed and the anesthesia should be light. This is to determine whether the airway remains patent, with the patient breathing spontaneously. Once committed to decannulation, the bronchoscope and neck roll should be removed and the patient is observed for any difﬁculty such as severe chest retraction or deoxygenation that would suggest the continued need for the tracheostomy. If, on the other hand, the patient ventilates with ease, then the patient should be fully awakened and allowed to recover in a unit that permits careful observation. We usually keep these patients in the hospital overnight, or longer if there is any concern, to assure that the tracheostomy is no longer required. Once the cannula is removed, a snug dressing of plain or petroleum jelly-saturated gauze is secured over the

References 225

tracheostomy stoma to occlude it. The caretakers or parents should be instructed on how to change this dressing until the stoma closes completely. Occasionally, we encounter a stoma that does not close spontaneously. If, after several months, the stoma remains open and appears unlikely to close, and it is certain that the infant no longer is at risk for needing another tracheostomy, then operative closure of the stoma as an outpatient procedure can be performed. Usually, this is simply a matter of excising the stoma and placing a simple stitch or two in the anterior trachea. A larger persistent opening may require an anterior wedge excision for repair. This may necessitate admission to the hospital. If, after the patient leaves the operating room decannulated, the infant becomes fatigued or demonstrates other signs of respiratory distress, the dressing can be removed and another cannula should be reinserted. A smaller cannula size can be inserted if desired. This technique often is used to serially wean a patient to progressively smaller-sized cannulae until decannulation is certain to be successful. If, after decannulation, it is necessary to reinsert a tracheostomy, the procedure should be done in the operating room. While this is usually done with an endotracheal tube in place, there are some patients for whom it may be undesirable to insert an endotracheal tube. This avoids airway irritation and prevents re-stenosis. That being the case, the surgeon can inject a local anesthetic around the stoma, dilate the stoma with Hegar dilators (or possibly make a small incision with a No. 11 scalpel blade), and reinsert a cannula of an appropriate size. This maneuver should only be attempted if the anesthesiologist can maintain an adequate airway during the procedure.

REFERENCES 1. Aberdeen E, Downes JJ. Artiﬁcial airways in children. Surg Clin N Am 1974; 54:1155–70. 2. Aberdeen E. Tracheostomy and tracheostomy care in infants. Proc R Soc Med 1965; 58:900–4.

3. Jones JW, Reynolds M, Hewitt RL et al. Tracheoinnominate artery erosion: successful surgical management of a devastating complication. Ann Surg 1976; 184:194–204. 4. Ardran GM, Casut LJ. Delayed decannulation in children. J Laryngol 1963; 77:555–6. 5. Diamant H, Kinman J, Okmina L. Decannulation in children. Laryngoscope 1963; 71:404–14. 6. Smythe PM. The problem of detubating an infant with a tracheostomy. J Pediatr 1964; 65:446–53. 7. Montgomery EE. Tracheotomy in croup and diphtheria. Arch Pediatr 1885; 2:577–86. 8. Jackson C. High tracheostomy and other errors, the chief causes of chronic laryngeal stenosis. Surg Gynecol Obstet 1921; 32:392–8. 9. Foster S, Hoskins D. Home care of the child with a tracheotomy tube. Clin N Am 1981; 28:855–7. 10. Ruben RJ, Newton L, Jornsay D et al. Home care of the pediatric patient with a tracheotomy. Ann Otol Rhinol Laryngol 1982; 91:633–40. 11. Klotz DA, Hengerer AS. Safety of pediatric bedside tracheostomy in the intensive care unit. Arch Otolaryngol Head Neck Surg 2001; 127:950–5. 12. Walner DL, Loewen MS, Kumura RE. Neonatal subglottic stenosis – incidence and trends. Laryngoscope 2001; 111:48–51. 13. Crombleholme TM, Sylvester K, Flake AW, Adzick NS. Salvage of a fetus with congenital high airway obstruction syndrome by ex utero intrapartum treatment (EXIT) procedure. Fetal Diagn Therm 2000; 15:280–2. 14. Bui TH, Grunewald C, Frenchkner B, Kuylenstierna R, Dahlgren G, Edner A, Granstrom L, Sellden H. Successful EXIT (ex utero intrapartum treatment) procedure in a fetus diagnosed prenatally with congenital high-airway obstruction syndrome due to laryngeal atresia. Eur J Pediatr Surg 2000; 10:328–33. 15. Skelton VA, Goodwin A. Perinatal management of a neonate with airway obstruction caused by rhabdomyosarcoma of the tongue. Br J Anaesth 1999; 83:951–5. 16. Park JY, Suskind DL, Prater D, Muntz HR, Lusk RP. Maturation of the paediatric tracheostomy stoma: effect on complications. Ann Otol Rhinol Laryngol 1999; 108:1115–19.

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22 Miscellaneous conditions of the neck and oral cavity ANIES MAHOMED

CYSTS AND SINUSES OF THE NECK Congenital cysts and sinuses of the neck often result from persistence of remnants of embryological structures into postnatal life. These include cartilaginous structures of the cartilaginous skeleton, branchial cleft remnants and thyroglossal duct cysts. These anomalies rarely produce symptoms during the neonatal period. Sinuses and cartilaginous remnants are seen in infants, but cysts usually do not appear until later in childhood.

PREAURICULAR PITS, SINUSES AND ACCESSORY AURICLES Figure 22.1 Multiple accessory auricles in typical position

These lesions, which are familial and frequently bilateral, result from aberrant development of the auditory tubercles.1 Preauricular sinuses are common with an incidence of 15.5–43.7 per 10 000 births.2 These sinuses may present as an ectoderm lined sinus ‘pit’ containing tiny hairs, a skin tag, or a skin tag containing cartilage, called an ‘accessory tragus’. Preauricular sinuses most commonly present anterior to the tragus or in the ascending helical rim.3 Most of these lesions remain asymptomatic, but when problematic frequently present with drainage which may occur spontaneously or following infection. Infection should be treated in the ﬁrst instance with oral or i.v. antibiotics and following recovery, the sinus tract should be excised. Infected lesions may need to be incised and drained before deﬁnitive therapy, which in this context is complicated by a higher recurrence rate.4 Magnetic resonance imaging should be considered in all patients with a suspected ﬁrst branchial cleft anomaly. Accessory auricles are situated in the line of fusion between maxillary and mandibular processes of the ﬁrst branchial arch and are managed by complete excision (Fig. 22.1). Surgery can be safely postponed until after infancy.

BRANCHIAL CYSTS AND SINUSES Most branchial cyst and sinus remnants are derived from the ﬁrst and the second branchial clefts. First branchial anomalies are considered to be less common than those of the second cleft.5 However, those arising from the third branchial apparatus have seldom been reported.6,7

First branchial cleft anomaly These lesions are uncommon, but usually present as a cystic swelling below the lobule of the ear, associated with a sinus opening just behind the ramus of the mandible. Uncommonly, the ﬁrst cleft anomaly may manifest as a true ﬁstula originating about the site of the external auditory meatus and opening into the pharynx behind the posterior tonsillar fossa.8 The congenital tract has an unpredictable path in relation to the facial nerve.

228 Miscellaneous conditions of the neck and oral cavity

The diagnosis is established by careful cervical, parotid and auricular examination. Magnetic resonance imaging (MRI) allows assessment of the extent of the anomaly, especially in the parotid area, and high resolution computed tomographic (CT) imaging shows its exact relationship with the external auditory canal and the middle ear.9 Early resection should be considered as the planes of dissection are more likely to be intact, thereby facilitating facial nerve identiﬁcation and complete removal of the congenital tract.3 Repeated infections make subsequent surgery more difﬁcult by placing the facial nerve at greater risk. Wide exposure is therefore necessary and in most cases this involves a standard parotidectomy incision.

Second branchial cleft anomaly Branchial cyst and sinus remnants of the second branchial cleft present along the anterior border of the sternocleidomastoid muscle, usually in the middle or lower third of the neck. Sometimes the ﬁrst indication of a branchial cleft remnant may be evidence of infection. The treatment of choice is surgical excision of the cyst or sinus tract. The condition rarely presents in infancy and surgery can safely be postponed until the child is 2–3 years old.

Figure 22.2 MRI scan showing congenital lateral cervical cyst (arrow) in sagittal view with vertical extent from the hypopharynx to superior mediastinum

Thyroglossal duct cysts and sinuses Third branchial cleft anomaly The main presentation of a persistent third branchial cleft is as a congenital lateral cervical cyst. These cysts are rare, found exclusively on the left side of the neck and may have components arising from the fourth branchial apparatus. Typically, the cyst presents in the ﬁrst few days of life as a visibly enlarging lesion in the left side of the neck. Because of its size, pressure on the contiguous aerodigestive tract results in stridor with respiratory compromise and difﬁculty in feeding. Infection commonly induces a rapid increase in size but in instances where there is a large pharyngeal communication, it may also occur secondary to crying or feeding.6 Investigations include, cervical X-ray, which may demonstrate the presence of air sometimes with a ﬂuid level in the cyst, MRI which is useful in delineating the extent of the lesion (Fig. 22.2), and endoscopy for location and cannulation of the internal opening of the cyst.10,11 Management needs to be expeditious because of the potential for a sudden increase in the size of the cyst. Surgery involves complete cyst excision with ligation of the internal communication ﬂush with the pharyngeal wall. Histology of the cyst lining demonstrates both ecto- and endodermal components. In addition the presence of intramural thymic tissue as well as Hassal’s corpuscles and rarely thyroid tissue may be noted.6

These lesions result from persistence of the thyroglossal duct after the thyroid migrates from the foramen cecum to its ﬁnal location in the neck. It may rarely present at the base of the tongue in the newborn, where it may interfere with respiration.1 Classically, thyroglossal cysts present later than infancy and in the midline just below the hyoid bone. Treatment is by surgical excision and the excised specimen must include the central part of the hyoid bone and a core of soft tissue extending from the thyroglossal cyst to the foramen cecum.12

Congenital midline cervical clefts Congenital midline cervical clefts are rarely reported. The etiology of these clefts is obscure and it is not clear if it is of pharyngeal cleft origin with failure of fusion of the right and left arch ectodermis or the result of some intrauterine physical insult.8 The cleft consists of a mucosa-covered central depression with a skin tag superiorly.13 The adjacent skin is tethered by scar tissue and the trough ends in a blind pit inferiorly. Treatment consists of excision with z-plasty reconstruction.1 There are a number of other rare conditions which cause cystic neck masses in the neonate. These include persistent pharyngeal pouch derivatives, air-ﬁlled bronchogenic cysts, and laryngocele.

Lesions of the tongue and oral cavity 229

LESIONS OF THE TONGUE AND ORAL CAVITY There are a great variety of lesions of the tongue and oral cavity which may require surgical intervention in infancy. The differential diagnoses include tumors (malignant, teratoma, cystic hygroma, lymphangioma, hemangioma) epulis, dermoid cysts, thyroglossal duct cysts, duplication cysts, ranula, gastric and glial choristoma, hamartomas and lingual thyroid.

Tumors Malignant tumors of the tongue and oropharynx are extremely rare in the newborn. Approximately 5% of germ cell tumors arise in the extracranial head and neck region but malignancy at these sites is rare. The majority however are congenital and have been described in the pharynx, nasopharynx, paranasal sinuses and orbit. Obstruction of the pharynx antenatally may result in maternal polyhydramnios or fetal hydrops.14 Postnatally respiratory and esophageal obstruction may necessitate intubation and surgical decompression. Of head and neck rhabdomyosarcomas, 30% arise in intraoral and pharyngeal structures, but congenital involvement of the tongue has been documented in only a few cases. Presentation varies depending on the site; dysphagia, cough, and acute respiratory obstruction requiring tracheostomy have been described. Total excision of the lesion may sometimes be accomplished.15 Other rare tumors such as congenital malignant rhabdoid tumor and ﬁbrosarcomas have also been reported to occur in the oral cavity.16

Epignathus

multidisciplinary team comprising a neonatologist, anesthesiologist, pediatric surgeon and gynecologist. Delivery by cesarian section if the tumor is large, is recommended.20.21,23

CLINICAL PRESENTATION Epignathia are commonly recognized at birth or shortly thereafter because they are usually large in size, ﬁll the oral cavity, sometimes protrude from the mouth and cause respiratory distress (Fig. 22.3). These masses display varying degrees of maturity and may rarely have recognizable fetal parts.24 Inspiratory retractions of the chest wall, diminished breath sounds and cyanosis on room air, may occur shortly after birth and indicate worsening upper airway obstruction.25

PREOPERATIVE PREPARATION The preoperative management of newborns with epignathus should include early establishment of a reliable upper airway and exclusion of midline congenital central nervous system lesions. The airway should be secured immediately after delivery by endo- or nasotracheal intubation. In difﬁcult cases with large obstructing lesions, cricothyrotomy or tracheostomy may be undertaken as a life-saving procedure.18 X-ray examination of the skull may demonstrate areas of calciﬁcation compatible with a teratoma, occasional cranial asymmetry or other malformations such as cleft palate.26 CT scanning or MRI will deﬁne the extent of the lesion, determine the site of attachment, identify cysts and calciﬁcation as well as exclude CNS defects. It may be difﬁcult to demonstrate the precise origin of the tumors because they blend imperceptibly into normal tissues at sites where access is difﬁcult and where there are vital neural and vascular structures.

Epignathus is a rare congenital teratoid tumor protruding from the mouth and distorting orofacial anatomy. The tumor arises from the palate or pharynx in the region of the basisphenoid (Rathke’s pouch). They occur predominantly in girls. The etiology is unknown, but the more popular theory states that it may arise from pluripotential cells in the region of Rathke’s pouch that grow in a disorganized manner.17 Elements from all three germinal layers are represented. These tumors are benign in histology, but result in a high degree of morbidity and sometimes mortality by virtue of their size and location.18

(b)

ANTENATAL DIAGNOSIS Epignathus has been diagnosed antenatally.19–22 The typical sonographic appearance of epignathus are mixed echogenic lesions with areas of cystyic and solid tissue as well as associated calciﬁcation. Polyhydramnios is a common ﬁnding and may be due to the obstruction of the fetal oropharynx. Antenatal diagnosis is critical to a good outcome, as it allows for adequate assembly of a

(a) (c)

Figure 22.3 Epignathus. (a) A large tumor protruding from the mouth. (b) Arising from the palate. (c) Attached to the retropharyngeal region

230 Miscellaneous conditions of the neck and oral cavity

TREATMENT Surgical excision consists of an oral approach to excise the tumor at its base once encephalocele and intracranial tumor have been ruled out. Excision can be undertaken directly or assisted by endoscopy.18 If the base is of modest size, simple cautery can be employed and the defect so created can be covered with a ﬂap of mucosa elevated from the buccal sulcus, taking care to avoid damage to the point of entry of the parotid duct. Serial measurement of alphafetoprotein levels is essential to ensure complete excision and to monitor for recurrence.

PROGNOSIS The survival of these otherwise normal children was poor prior to the widespread use of prenatal ultrasonography but prenatal planning and proper postnatal specialist care has resulted in an excellent prognosis.22 Prolonged follow-up is necessary to correct speech impediments, facial deformities, dental irregularities and malocclusion of the jaw.

Cystic hygroma Cystic hygromas of the tongue are almost always associated with diffuse involvement of the ﬂoor of the mouth and neck. Antenatal ultrasonography has allowed for in utero diagnosis as well as facilitating adequate postnatal resuscitation. Presentation at birth is complicated by severe respiratory distress and marked salivation, indicating a difﬁculty in swallowing. These lesions have been treated successfully with OK432 (lyophilized mixture of Group A Streptococcus pyogenes).27 The best operative approach consists of staged resections for tongue, sublingual space and neck lesions.28 Good results have also been reported after laser surgery.29

Laser photocoagulation has been successfully employed in some patients to control tongue size but simple debulking does result in a high recurrence rate.32,33 These lesions may also appear in the lips (microchelitis), ﬂoor of mouth or the buccal mucosa.31,32

Hemangioma Large capillary hemangiomas of the tongue may cause difﬁculty in swallowing and breathing, which can be life threatening. Rarely, they may occur on the palate and present with feeding difﬁculty.34 Treatment with corticosteroids and interferon has resulted in a dramatic response in patients with rapidly enlarging capillary hemangiomas.34,35 Impressive results have also been obtained in recent years with laser application.36 Small hemangiomas which are asymptomatic are treated expectantly and usually regress spontaneously.

Congenital epulis Epulis, also referred to as congenital granular cell tumor of the gingiva, is a rare benign soft tissue tumor arising from the alveolar margin of the upper or lower jaw (Fig. 22.4). The tumor is present at birth and is mostly seen in females. It is sessile or partially pedunculated, encapsulated, bluish-red in colour and usually measures 2–5 cm in diameter; it is attached to the incisor or canine region of the mandibular or maxillary alveolus.37–39 The tumor consists principally of large eosinophilic granular cells arranged in solid nests that are separated by thin ﬁbrovascular areas. In addition, there are some spindleshaped cells and polygonal cells among the neoplastic granular cells.39 Rarely, the tumor may be large enough to produce feeding and respiratory difﬁculties.40 Spontaneous regression of this lesion has been described.31 However these are usually a cause of concern to parents

Lymphangioma Lymphangioma is the most common cause of macroglossia in infancy.30 The tumor may be conﬁned to a part of the tongue or there may be diffuse involvement. Typically, lymphangioma of the tongue is present as multiple small translucent cysts, giving a warty appearance. Deeper lesions may show no surface changes.31 Macroglossia secondary to lymphangioma can cause airway obstruction, swallowing difﬁculty, malocclusion and speech problems.32 Infection and trauma may result in recurrent tongue enlargement. Precise preoperative evaluation of extent with ultrasound, CT or MRI is mandatory. Surgical removal of the tumor is the treatment of choice. Satisfactory results are obtained by excising a sufﬁcient amount of tumor to enable re-shaping the contour of the tongue in order to enable proper speech and deglutition. Orthodontic problems are reduced and a reasonable cosmetic result is achieved.

Figure 22.4 Ranula of the sublingual duct displacing the tongue to the right

Lesions of the tongue and oral cavity 231

and for this reason surgical excision is recommended. Recurrences are extremely rare.

Dermoid cysts Dermoid cysts are congenital lesions derived from ectodermal differentiation of multipotential cells. About 30% of those occurring in the head and neck regions are located in the ﬂoor of the mouth. Lingual dermoids are rare entities. These cysts present clinically as swellings in the middle of the posterior aspect of the tongue, commonly on its dorsal aspect.41 Rarely these cysts may attain a massive size and interfere with feeding and breathing.42,43 Treatment consists of surgical excision of the cyst. Preoperative radiography with injection of contrast material to outline the anatomical extension of the cyst has been found to be useful during surgery.28 Malignant degeneration of dermoid cysts is possible but extremely rare.31

Figure 22.5 Newborn with a large epulis arising from the maxillary alveolar margin

Duplication cysts Intraoral duplication cysts are rare and only a few cases have been reported in the literature.44 The cysts are usually located at the base of the tongue. Diagnosis may be established antenatally, especially when the cyst is large and this allows for therapeutic aspiration, which improves access to the oropharynx for intubation at birth. Because of the potential for airway obstruction and respiratory difﬁculties at birth, it is important that preparations for tracheostomy are made in case oral intubation proves impossible. Surgical excision is the treatment of choice. Histology reveals a columnar lined mucosa consistent with enteric duplication cysts.45

(a)

Ranula Ranula is a term applied to a retention cyst of the sublingual gland. It results from partial obstruction of the sublingual salivary duct leading to dilatation of the more proximal duct. The cyst is round or oval in shape and located beneath the tongue (Fig. 22.5). It may occur congenitally and be evident on antenatal ultrasound scans.46,47 When large they interfere with respiration and feeding. Treatment of ranula consists of marsupialization of the cyst. The operative technique is demonstrated in Fig. 22.6.

Line of incision (b)

Lingual gastric choristoma Congenital rests of gastric epithelium may occur in a variety of head and neck locations. It has also been described to occur in association with intestinal epithelium as enterocytomas.48,49 These are rare lesions

Mucosa (c)

Figure 22.6 (a) Large ranula occupying the ﬂoor of the mouth. (b) Line of incision. (c) Continuous 4-0 Vicryl stitch to complete marsupialization

232 Miscellaneous conditions of the neck and oral cavity

with a predilection for affecting males. Presenting symptoms include: an asymptomatic cyst, bleeding ulcer, feeding difﬁculties and partial airway obstruction.50 Surgical excision is the preferred choice of treatment, however CO2 laser excision has been demonstrated to be a safe alternative.51

Lingual thyroid Lingual thyroid occurs when the thyroid gland fails to descend to its normal cervical location. Approximately one in 600 000 live births present in childhood or adolescence with a lingual thyroid.52 In a review of over 400 cases of undescended thyroid, 90% were found within the tongue and 10% in the anterior neck above the hyoid bone.53 The posterior part of the tongue around the foramen cecum is the most common site of the lingual thyroid. It is more common in females. Symptoms usually consist of dysphagia and dyspnea. Diagnosis is conﬁrmed by radioactive iodine scintigraphy. Of patients with lingual thyroids, 75% have no other functional thyroid tissue.31 Therefore, testing for location of thyroid tissue in addition to gland function is indicated. Treatment consists of complete excision of the lingual thyroid followed by life-long thyroid hormone therapy. Autotransplantation of the excised lingual gland or pedicle transfer, retaining a vascular pedicle and moving part of the thyroid into the neck, has been successful in several cases.54,55

Torticollis Torticollis in the neonate results from a ﬁbrous mass or tumor in the sternomastoid muscle (Fig. 22.7).

Although various theories have been proposed, the exact cause of the sternomastoid tumor is not clear. A widely accepted explanation is that birth trauma during a breech or difﬁcult delivery causes rupture of the sternomastoid muscle or its fascial sheath, resulting in ﬁbrous tissue which leads to shortening of the muscle. An alternative popular hypothesis is that the condition is the sequel of an intrauterine or perinatal compartment syndrome.56 The presence of torticollis is suspected from the infant’s abnormal posture, with the head tilted to the side of the lesion and rotation of the face to the opposite side. Plagiocephaly and facial asymmetry may be accompanying features. On palpation of the neck a 1–2 cm diameter, hard, immobile spindle-shaped mass can be felt in the mid-portion of the sternomastoid muscle. It usually develops 14–21 days after birth. Most (97%) present before the age of 3 months.57 Diagnosis of a sternocleidomastoid tumor can be conﬁrmed by ultrasonography. The echogenicity of the mass could be hyperechoic, isoechoic or hypoechoic relative to normal muscle. A hypoechoic rim is, however, frequently present.58 Treatment in the neonate involves active stretching exercises undertaken mainly by the parents but supervised by physiotherapists and pediatric surgeons. The involved muscle should be stretched to an over-corrected position by gentle, even and persistent motion with the infant lying in a supine position. The head is ﬂexed forward and away from the affected side and the chin is rotated toward the affected side. Most infants (80%) treated conservatively show complete recovery within 2–3 months. The poor outcome group and untreated cases that develop facial asymmetry, plagiocephaly and scoliosis,59 necessitate surgical release of the sternocleidomastoid muscle. Multiple surgical procedures for sternocleidomastoid tumors have been described and include, simple open myotomy, extensive release of the sternocleidomastoid muscle, myoplasties, bipolar release, or radical resections.57 The overall outcome is excellent.

Congenital goiter

Figure 22.7 Right sternomastoid tumor in a 3-week-old infant

The majority of neonatal goiters result from maternal ingestion of goitrogens. In the newborn infant, the most commonly implicated drugs are iodides and thiourea derivatives used for treatment of maternal thyrotoxicosis. Congenital goiter has also been described in a newborn with Prader-Willi syndrome.60 Most goiters in newborns are of the hyperplastic type and disappear a few weeks after birth. Ultrasonography is a useful noninvasive investigation in assessing the size of the goiter as well as the response to therapy.61 Rarely, goiters may be large enough to produce severe respiratory distress by tracheal compression. These patients may require division of the isthmus, or subtotal thyroidectomy to relieve tracheal compression. Follicular carcinoma has

References 233

been described in a neonatal dyshormogenetic hyperplastic goiter. Total thyroidectomy is necessary in this instance.62

Salivary gland tumors Fewer than 5% of all salivary gland tumors occur in children and are exceedingly rare in neonates. Histopathologically, Batsakis et al. categorized the perinatal salivary gland tumors into four groups.63,64 The ﬁrst group includes histologically benign tumors that have adult counterparts such as pleomorphic and monomorphic adenomas. The second group comprises the hamartomatous tumors. The third group includes epithelial enlarged-type tumors and are referred to either as sialoblastomas or embryomas. This group is the most common variety of perinatal salivary gland tumor and surgery without chemotherapy or irridiation is the treatment of choice. These lesions have a tendency for local recurrence.65 The last group, which are extremely rare, include the malignant salivary gland tumors of the newborn.66 Most congenital forms are carcinomatous in nature. MRI or CT is the method of choice for the radiological examination of masses in or around the salivary glands.65,67 These investigations provide exact anatomical detail, demonstrating the precise location of a mass within the parotid gland from which its probable impact on the position of the facial nerve may be inferred. Congenital malignant tumors of the parotid gland require conservative parotidectomy with preservation of the seventh nerve. The outlook after surgery for congenital malignant tumors of the parotid gland is excellent. Hemangioma and lymphangioma are the two most common benign neoplasms affecting the parotid gland in infants. These tumors are more common in female infants and are usually present at birth or appear during the ﬁrst month of life. They are usually conﬁned to the intracapsular portion of the gland, occasionally originate in adjacent tissues and extend into the gland. Capillary hemangioma is the most common vascular anomaly involving the parotid gland. These tumors demonstrate rapid growth in the ﬁrst few months of life with a tendency to complete regression by 4–5 years of age.8 The lack of distinctive clinical ﬁndings by which benign and malignant parotid tumors can be distinguished suggests the need for preliminary cautious biopsy. If the lesion is a non-threatening hemangioma with no component of lymphangioma, no treatment is indicated because satisfactory involution occurs within 3–4 years. High-dose corticosteroids, interferon therapy, transcutaneous arterial embolization and laser therapy have been successfully employed in life-threatening hemangiomas.68–71 Patients with intracapsular parotid lymphangioma or juxtaparotid lymphangioma require surgical removal of the tumor.

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234 Miscellaneous conditions of the neck and oral cavity 21. Loderio JG, Feinstein SJ, Molonea RA et al. Antenatal diagnosis of epignathus. A case report. J Reprod Med 1989; 34:997–9. 22. Jerella JT, Finberg FJ. Obstruction of the neonatal airway from teratomas. Surg Gynecol Obstet 1990; 170:126–31. 23. Todd DW, Votava HJ, Telander RL, Shoemaker CT. Giant epignatus, a case report. Minn Med 1991; 74:27–8. 24. Senyuz OF, Rizalar R, Celayir S et al. Fetus in fetu or giant epignatus protruding from the mouth. J Pediatr Surg 1992; 27:1493–5. 25. Sauter ER, Diaz JH, Arensman RM et al. The perioperative management of neonates with congenital oropharyngeal teratomas. J Pediatr Surg 1990; 25:925–8. 26. Valente A, Grant JO, Orr JD, Brereton RJ. Neonatal tonsillar teratoma. J Pediatr Surg 1988; 23:364–6. 27. Suzuki N, Tsuchida Y, Kuroiwa M, Ikeda H, Mohara J, Hatakeyama S, Koizumi T. Prenatally diagnosed cystic lymphangioma in infants. J Pediatr Surg 1998; 33:1599–1604. 28. Velak FT, Klotz DH, Hill CH et al. Tongue lesions in children. J Pediatr Surg 1975; 14:238–46. 29. Dixon JA, Davis RK, Gilbertson JJ. Laser photocoagulation of vascular malformations of the tongue. Laryngoscope 1986; 96:537–41. 30. Fonkalsrud EW. Malformations of the lymphatic system and hemangiomas. In: Holder TM, Ashworth KW, editors. Pediatric Surgery. Philadelphia, London: Saunders, 1980: 1054–60. 31. Dilley DC, Sieger MA, Budnick S. Diagnosis and treating common oral pathologies. Ped Clin N Am 1991; 5:1227–64. 32. Alqahtani A, Nguyen LT, Flageole H, Shaw K, Laberge JM. 25 Year experience with lymphangiomas in children. J Pediatr Surg 1999; 34:1164–8. 33. Balakrishnan A, Bailey CM. Lymphangioma of the tongue. A review of pathogenesis, treatment and the use of surface laser photocoagulation. J Laryngol Otol 1991; 105:924–9. 34. Lale AM, Jani P, Coleman M, Ellis PDM. A palatal haemangioma in a child. J Laryngol Otol 1998; 112:677–8. 35. Edgerton MJ. Treatment of hemangiomas with special reference to the role of steroid therapy. Ann Surg 1976; 183:517–32. 36. Irving IM. In: Lister J, Irving M, editors. Neonatal Surgery. London: Butterworths, 1990: 112–13. 37. Eppley BL, Sadove AM, Campbell A. Obstructive congenital epulis in a newborn. Ann Plastic Surg 1991; 27:152–5. 38. Chiba T, Okayama G. Congenital epulis of the newborn: report of a case with a review of the Japanese literature. Archiv fur Japanische Chirurgie 1990; 59:408–511. 39. Takahashi H, Fujita S, Satoh H, Okabe H. Immunohistochemical study of congenital gingival granular cell tumor (congenital epulis). J Oral Pathol Med 1990; 19:492–6.

40. Tokar B, Boneval C, Mirapoglu S, Tetikkurt S, Aksoyek S, Salman T. Congenital granulosa-cell tumor of the gingiva. Pediatr Surg Int 1998; 13(8):594–6. 41. Reddy VS, Radhakrishna K, Rao PLNG. Lingual dermoid. J Pediatr Surg 1991; 26:389–90. 42. Dahlman B, Livadatis A. Congenital cyst of the anterior half of the tongue. Z Kinderchir 1980; 29:244–7. 43. Tepas JJ, Deen HG, McArter R et al. Giant cystic chorista of the head and neck in a neonate. J Pediatr Surg 1988; 17:184–6. 44. Brown S, Kerr Willson R. Intra-oral duplication cyst. J Pediatr Surg 1978; 13:95–6. 45. Chen MK, Gross E, Lobe TE. Perinatal management of enteric duplication cysts of the tongue. Am J Perinatol 1997; 14:161–3. 46. Fernandez Moya JM, Cifuentes Sulzberger S, Diaz Racasens J, Ramos C, Sanz R, Perez Tejerizo G. Antenatal diagnosis and management of a ranula. Ultrasound in Obstet Gynecology 1998; 11:147–8. 47. Steelman R, Weisse M, Ramadan H. Congenital ranula. Clin Pediatr 1998; 37:205–6. 48. Grime PD. Giant enterocytoma within an infant’s tongue. J Laryngol Otol 1990; 104:814–18. 49. Said-Al-Naif N, Fantasia JE, Sciubba JJ, Ruggiero S, Sachs S. Heterotopic oral gastrointestinal cyst: report of 2 cases and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endo 1999; 88:80–6. 50. Burton DM, Kearns DB, Seid AB, Pranksy SM, Billman G. Tongue gastric choristoma: failure to localise by technetium – 99m pertechnetate scan. Int J Pediatr Otorhino Laryngol 1992; 24:91–5. 51. Aydogan B, Kiroglu M, Soylu L, Aydin O, Satar M, Kiroglu F, Tunali N. Gastric cysts of the oral cavity. Int Journal Pediatr Otorhinolaryngol 1998; 45(3):255–8. 52. Gillis D, Brnjac L, Perlman K, Sochett EB, Daneman D. Frequency and characteristics of lingual thyroid not detected by screening. J Pediatr Endocrinol & Metab 1998; 11:229–33. 53. Wertz ML. Management of undescended lingual and subhyoid thyroid glands. Laryngoscope 1974; 84:507–21. 54. Steinwald OP, Muehrcke RC, Economou SG. Surgical correction of complete lingual ectopia of the thyroid gland. Surg Clin N Am 1970; 50:1177–86. 55. Davis RK. An alternative management of lingual thyroid: Excision implantation. J Ped Surg 1973; 8:869–70. 56. Lawrence WT, Azizkhan RG. Congenital muscular torticollis: A spectrum of pathology. Ann Plast Surg 1989; 23:523–30. 57. Cheng JCY, Tang SP, Chen TMK. Sternocleidomastoid pseudotumour and congenital muscular torticollis in infants: A prospective study of 510 cases. J Pediatr 1999; 134:712–16. 58. Chan YL, Cheng JC, Metrewelt C. Ultrasonography of congenital muscular torticollis. Pediatr Radiol 1992; 22:356–60.

References 235 59. Bredenkams JK, Hoover LA, Berke GS, Shaw A. Congenital muscular torticollis. A spectrum of disease. Arch Otolaryngol Head Neck Surg 1990; 116:212–16. 60. Insoft RM, Hurvitz J, Estrella E, Krishnamoorthy KS. Prader-Willi syndrome associated with fetal goitre: a case report. Am J Perinatol 1999; 16:29–31. 61. Bachrack LK, Daneman D, Daneman A et al. Use of ultrasound in childhood thyroid disorders. J Pediatr 1983; 103:547–52. 62. Medeiros-Neto G, Gil- Da- Costa MJ, Santos CL, Medina AM, Silva JC, Tsou RM, Sobrinho-Silmoes M. Metastic thyroid carcinoma arising from congenital goitre due to mutation in the thyroperoxidase gene. J Clin Endocrinol Metabol 1998; 83:4162–6. 63. Batsakis JG, Frankenthaler R. Embryoma (sialoblastoma) of salivary glands. Ann Otol Rhinol Laryngol 1992; 101:958–60. 64. Batsakis JG, Makay B, Ryka AF, Seifert RW. Perinatal salivary gland tumours (embryoma). J Laryngol Otol 1988; 102:1007–11. 65. Som PM, Brandwein M, Silvers AR, Rothschild MA.

66. 67. 68.

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Sialoblastoma (embryoma): MR ﬁndings of a rare pediatric salivary gland tumor. AJNR 1997; 18:847–50. Bianci A, Cudmore RE. Salivary gland tumours in children. J Pediatr Surg 1978; 13:519–21. Robinov K, Kell Jr T, Gordon PH. CT of the salivary glands. Radiol Clin N Am 1984; 22:145–59. Hosono S, Ohno T, Kimoto H et al. Successful transcutaneous arterial embolisation of a giant hemangioma associated with high output cardiac failure and Kassabach-Merrit syndrome in a neonate: A case report. J Perinat Med 1999; 27:399–403. Grienwald JH, Burke DK, Bonthius DJ, Bauman NM, Smith RJH. Arch Otolaryngol Head Neck Surg 1999; 125:21–7. Hasan Q, Tan ST, Gush J, Peters SG, Davis PF. Steroid therapy of a proliferating hemangioma: Histochemical and molecular changes. Pediatrics 2000; 105:117–21. Wacker FK, Cholewa D, Roggan A, Schilling A, Waldschmidt J, Wolf KJ. Vascular lesions in children: percutaneous MR imaging-guided interstitial Nd:YAG laser therapy – preliminary experience. Radiolog 1998; 208:789–94.

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3 Chest

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23 Congenital thoracic deformities ROBERT C. SHAMBERGER

INTRODUCTION Congenital thoracic deformities comprise a broad spectrum of abnormalities. They include the rare complete and incomplete sternal defects: thoracic ectopia cordis, thoraco-abdominal ectopia cordis (Cantrell’s pentalogy) and biﬁd sternum. More frequent are the deformities of the ribs including pectus excavatum, pectus carinatum and Poland’s syndrome, which are rarely repaired in infancy. Asphyxiating thoracic dystrophy (Juene’s syndrome) and spondylothoracic dysplasia (Jarcho-Levin syndrome) are seldom treated surgically and never with a long-term successful result.

ECTOPIA CORDIS The heart is in an extrathoracic position in ectopia cordis. Infants with this anomaly are classiﬁed by the precise location of the heart. Cervical ectopia cordis, in which the heart protrudes at the base of the neck, occurs in association with other severe deformities of the fetus and is the rarest form of ectopia cordis. There are no survivors with this lesion to date and many affected fetuses are stillborn. Thoracic ectopia cordis, the classic ‘naked heart’, includes infants with an entirely bare heart which is outside the thorax with cephalic orientation of the cardiac apex. It protrudes through a central sternal defect and lacks parietal pericardium and overlying skin. The condition may be associated with a separate epigastric omphalocele or upper abdominal wall defect. Thoracic ectopia cordis must be distinguished from cleft sternum, in which the heart is covered by normal skin in an orthotopic intrathoracic position and is anatomically normal. The heart is covered by skin or an omphalocele-like membrane in thoraco-abdominal ectopia cordis. A constellation of anomalies is often present in conjunction with thoraco-abdominal ectopia cordis, often called Cantrell pentalogy. These anomalies of the heart and

midline parietal wall include partial absence or cleft of the lower sternum, an anterior diaphragmatic defect (absence of the septum transversum), a pericardial defect corresponding to that of the diaphragm, and an upper abdominal defect ranging from an epigastric omphalocele or ventral hernia, to diastasis recti. The heart may be partially herniated into the abdominal cavity or a diverticulum of the ventricle may prolapse through the defect. In contrast with thoracic ectopia cordis, the heart is covered and lacks severe anterior displacement and cephalic orientation. The world literature on ectopia cordis has been extensively reviewed.1 Ectopia cordis can be readily deﬁned by prenatal ultrasound from the early stages of gestation, which facilitates perinatal planning and preparation.2,3 Intrinsic cardiac anomalies are often best demonstrated by in utero studies and other associated anomalies can be deﬁned as well to facilitate discussion with parents regarding prognosis.

Thoracic ectopia cordis The dramatic presentation of the heart, naked and beating upon the chest wall has stimulated many case reports. There are anecdotal reports of attempted repair, but few successes are described. Survival is limited by a generally lethal combination of associated intrinsic cardiac malformations and abnormal rotation of the heart with the apex pointing cephalad (Fig. 23.1).4 The ﬁrst successful repair of ectopia cordis was achieved by Koop in 1975, as reported by Saxena.5 An infant with a normal heart had skin ﬂap coverage at 5 hours of age, with inferior mobilization of the anterior attachments of the diaphragm. The sternal bands were 2 in (51 mm) apart and could not be approximated primarily without cardiac compression and compromise. At 7 months of age an acrylic resin of Dacron and Marlex mesh was inserted to widen the sternal cleft with primary skin closure. Necrosis of the skin ﬂaps complicated the postoperative course, with infection of the prosthetic material requiring its subsequent removal. This child still

240 Congenital thoracic deformities

Figure 23.1 Infant with thoracic ectopia cordis. Heart lies anterior to the thoracic cavity and apex is directed cephalad

survives at age 12 years and is reported to be entirely well.6 The success of this operation in three other patients is reported (Table 23.1).7–9 Dobell’s case is of note in that surgical correction was also performed in two stages.7 Skin ﬂap coverage was provided while the patient was a newborn. At 19 months of age, rib strut grafts were placed over the sternal defect and covered with pectoral muscle ﬂaps. The pericardium was divided from its anterior attachments to the chest wall, allowing the heart to fall back partially into the thoracic cavity. Lillehei (as reported by Hornberger) achieved successful repair of the only infant with an intrinsic cardiac anomaly, tetralogy of Fallot with pulmonary atresia.9 Skin ﬂaps were mobilized for coverage in the perinatal period with a Blalock-Taussig shunt at 4 days of age and a complete repair with aortic homograft at 2 years of age. The unifying theme of successfully managed cases is construction of a partial anterior chest cavity surrounding the heart and avoidance of attempts to return the heart to an orthotopic location. A combination of thoracic ectopia cordis and a separate omphalocele with an intervening bridge of normal skin is particularly difﬁcult to manage. In this group of patients, adequate skin and abdominal wall

components to cover both areas is lacking and no survivors exist. If a successful outcome is to be accomplished in infants with thoracic ectopia cordis, early deﬁnition of the associated cardiac malformation is necessary. Prenatal echocardiography will often deﬁne the cardiac lesion and is more successful than echocardiograms performed after birth with the ultrasound probe placed directly on the cardiac surface, which are complicated by cardiac motion and interference by air. Cardiac catheterization with angiography may be required in infants not diagnosed by antenatal studies. If the cardiac malformation is correctable, the infant should be taken directly to the operating room from the cardiac catheterization laboratory for cardiac repair. Some form of cardiac enclosure must then be provided. Use of prosthetic materials is associated with a high incidence of sepsis and death, especially when prosthetic materials have been used in cardiac repair.

Thoraco-abdominal ectopia cordis (Cantrell’s pentalogy) The required features of the pentalogy of Cantrell are a cleft lower sternum, a half-moon anterior diaphragmatic defect due to failure of development of the septum transversum, absence of the parietal pericardium, adjacent or completely separate omphalocele, ventral hernia or diastasis recti, and in most patients a major form of congenital heart disease, most commonly tetralogy of Fallot or diverticulum from the left ventricle (Fig. 23.2). A complete summary of all reported cardiac anomalies has been presented.1 This condition was precisely described by Wilson in 179810 with the ﬁrst repair attempted by Arndt in 189611 and the ﬁrst successful repair by Weiting in 1912.12 The anomaly was reviewed by Major in 195313 and later by Cantrell et al. in 1958.14 Immediate neonatal intervention is required in patients with a large upper omphalocele and lower sternal cleft. Skin closure must be achieved to avoid

Table 23.1 Successful repairs of ectopia cordis Author

Year

Cardiac lesion

Method of sternal closure

Koop (Saxena5) Dobell et al.7

1975

None

1982

None

Amato et al.8

1988

None

Lillehei (Hornberger et al 9)

1996

Tetralogy of Fallot

Skin ﬂap closure at 5 hours. Acrylic resin applied to sternal cleft at 7 months Perinatal skin closure in one stage. Second-stage repair with autologous rib grafts Skin ﬂaps mobilized, diaphragm moved inferiorly. Gortex membrane used to close defect with skin ﬂaps over it. Child survived but died of aspiration at 11 months of age Perinatal skin ﬂap closure Blalock-Taussig shunt at 4 days of life and complete repair at 2 years of age. No prosthetic tissue coverage

Biﬁd sternum 241

infection and mediastinitis. Approximation of the abdominal wall is of secondary importance and may require the use of Teﬂon mesh or other prosthetic material (Fig. 23.3a–c). Advances in pediatric cardiac surgery now allow correction of the intrinsic cardiac lesions which were previously fatal. An aggressive approach is required if salvage is to be improved. Patients with intact skin covering the defect, however, have lived years without surgical repair.

BIFID STERNUM Figure 23.2 Newborn male with Cantrell’s pentalogy. Flaring of the lower thoracic cavity is present with a large epigastric omphalocele. The septum transversum and the inferior portion of the pericardium were absent (From Welch,43 by permission of W.B. Saunders Co., Philadelphia)

Costal arch

Liver

Cleft sternum may be complete or incomplete and results from failure of ventral fusion of the sternal bars at or about the eighth week of gestation. In all such cases there is sternal separation and skin coverage of the midline defect, an intact pericardium, intact pleural

Freeing of diaphragmatic leaf

Pericardium closed

Diaphragm sutured to costal arch and to opposite leaf

Left leaf of diaphragm

(b)

(a)

Costal arch

Rectus muscle

Diaphragm

Relaxing incision of rectus sheath

(c)

Figure 23.3 Repair of pentalogy of Cantrell is depicted. (a) The pericardium is closed after appropriate lateral and inferior dissection to the vena cava. The right and left dorsal leaves of the diaphragm which are widely separated are identiﬁed. The liver is retracted inferiorly after division of the falciform ligament. (b) Pedicles of the diaphragm are developed from each side and transposed medially. They are sutured together and to each costal arch. (c) After diaphragmatic closure, the falciform ligament is reconstructed. Closure continues by advancement of the anterior sheath of the rectus muscle to the midline. Lateral relaxing incisions are often required. Parietal repair can be accomplished at the time of cardiac correction. Prosthetic material may be required to obtain closure of the abdominal component of the repair (From Welch,43 by permission of W.B. Saunders Co., Philadelphia)

242 Congenital thoracic deformities

envelopes, and a normal diaphragm. Omphalocele does not occur in association with this anomaly and the condition causes little difﬁculty other than dramatic increase in the deformity with crying or Valsalva maneuver (Fig. 23.4a,b). The sternal defect involved an upper cleft in 46 patients, an upper cleft to the xiphoid in 33 patients, and a complete cleft in 23 patients. The cleft involved the lower sternum in only ﬁve reported cases. A total of 69 repairs have been reported, 25 with primary closure.1 None had intrinsic congenital heart disease. Most authors now recommend surgical treatment in the newborn period when all such malformations can be dealt with by simple direct closure without the use of prosthetic materials.15,16 Cleft sternum has been associated with capillary hemangioma in a cervicofacial distribution and 15 such cases have been identifed.17 Two patients had major airway involvement and one multiple areas of involvement of the small bowel.17,18 All others lacked involvement of viscera. Operation in the perinatal period is recommended in all cases, since direct approximation and suture closure is

possible at that time without compression of the heart (Fig. 23.5a–d). No reports of recurrence or delayed healing have been encountered. Direct approximation and suture closure can be achieved, and partial transverse division of sternal bands is rarely necessary. Reconstruction of the anterior chest wall using multiple oblique sliding chondrotomies leaving the perichondrium intact was reported by Sabiston and subsequently by others.19 This technique is still useful in older infants with a less ﬂexible chest wall and wide defect. Closure employing composite cartilage grafts from the costal arch or prosthetic materials such as Marlex or Teﬂon mesh have also been reported, but these methods can be avoided with repair of the infants in a timely fashion. Recently, Shamberger and Welch1 reviewed their experience with sternal defects at the Children’s Hospital, Boston, MA, USA. A total of 16 patients with sternal defects were identiﬁed, ﬁve with thoracic ectopia cordis, eight with thoraco-abdominal ectopia cordis and

Clavicle

Pericardium and endothoracic fascia Midline incision

Sternal bar

1 2 3 4 5 6 7 (a)

Bifid sternum

(b) Tevdek or PDS sutures

Undermine

(a)

+ – wedge

(c)

(b) Figure 23.4 Newborn infant with a biﬁd sternum. (a) Vigorous crying produces retraction at the defect with inspiration (left) and protrusion with exhalation or Valsalva maneuver (right). (b) Following repair, normal conﬁguration of the sternum is present

(d)

Figure 23.5 (a) Repair of biﬁd sternum is best performed through a longitudinal incision extending the length of the defect. (b) Directly beneath the subcutaneous tissues the sternal bars are encountered with pectoral muscles present lateral to the bars. The endothoracic fascia and pericardium are just below these structures. (c) The endothoracic fascia is mobilized off the sternal bars posteriorly with blunt dissection to allow safe placement of the sutures. Approximation of the sternal bars may be facilitated by excising a wedge of cartilage inferiorly. Repair is best accomplished in the neonatal period because of the ﬂexibility of the chest wall. (d) Closure of the defect is achieved with 2-0 Tevdek or PDS sutures (From Shamberger and Welch,1 by permission of Springer-Verlag, Heidelberg, Germany)

Poland’s syndrome 243

three with cleft sternum.1 Thoracic ectopia cordis was uniformly fatal in our series; thoraco-abdominal ectopia cordis was fatal in ﬁve of eight cases and biﬁd sternum was successfully repaired in all three cases in infancy.

PECTUS EXCAVATUM Pectus excavatum (funnel chest or trichterbrust) is a depression of the sternum and lower costal cartilages. It is generally identiﬁed within the ﬁrst year of life (in 86% of patients) and in many infants it is noted at birth.20 The extent of sternal and cartilaginous deformity is quite variable, but generally consists of posterior displacement of the sternum below the insertion of the second costal cartilage. The ﬁrst and second costal cartilages are generally normal in contour, whereas the third to seventh are curved posteriorly to join the sternum. The ossiﬁed portion of the rib is normal in conﬁguration in infancy. In infants the extreme ﬂexibility of the costal cartilages results in remarkable changes in the deformity with vigorous respiration or crying. Self-limited deformities are either gone or vastly improved by 3 years of age. Hence, I avoid repair in all infants younger than 2 years of age, or later if they have continued sternal ﬂexibility. Pectus excavatum may occur as frequently as one in 300–400 live births.21 The etiology of pectus excavatum is unknown. A family history of some type of anterior thoracic deformity is present in 37% of patients.20 Scoliosis is identiﬁed in up to 15% of patients with pectus excavatum, usually in children with an asymmetric thoracic deformity, but it is generally not seen in infancy. Patients with Marfan’s syndrome have a high incidence of associated chest wall deformities, often in the most severe form and usually accompanied by scoliosis.

PECTUS CARINATUM Pectus carinatum is the anterior protrusion deformity of the chest. It is much less frequent than the depression deformity, comprising 16% of our combined series.22 A spectrum of protrusion deformities exists and these are often divided into four types. The most frequent type consists of anterior displacement of the sternum with symmetric concavity of the costal cartilages laterally. Asymmetric deformities with anterior displacement of the costal cartilages on one side and a normally positioned or oblique sternum and normal cartilages on the contralateral side are less common. ‘Mixed’ lesions have a carinate deformity on one side and a depression or excavatum deformity on the contralateral side, often with sternal obliquity. Most unusual are the upper ‘pouter pigeon’ deformities, with protrusion of the

manubrium and second and third costal cartilages and relative depression of the body of the sternum. The etiology of pectus carinatum is unknown. There is overgrowth of the costal cartilages, with forward buckling and anterior displacement of the sternum. As with pectus excavatum, there is a clear-cut increased family incidence, suggesting a genetic basis. In a recent review, 26% of patients had a family history of chest wall deformity and 12% had a family history of scoliosis.22 It is much more frequent in boys than girls, with a ratio of 4:1. Only the upper ‘pouter pigeon’ deformity is associated with congenital heart disease in 18% of cases.23 In contrast to pectus excavatum, patients with pectus carinatum have a much later appearance of the deformity. In a recent review, only one-sixth of the patients were noted to have a carinate deformity within the ﬁrst year of life and in almost half it was noted after the onset of the pubertal growth spurt at 11 years of age.22 The deformity, which may be mild at birth, often worsens rapidly during the growth period at puberty. Because of mild deformity at birth and ﬂexible costal cartilages, this deformity is rarely repaired during the ﬁrst 2 years of life and is probably best repaired in the early teenage years.

POLAND’S SYNDROME Poland in 1841 described congenital absence of the pectoralis major and minor muscles, associated with syndactyly.24 This entity is a spectrum, often involving chest wall and breast deformity as well as ipsilateral limb anomalies. 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 fourth ribs and cartilages, often called the second to fourth rib syndrome. Breast involvement is signiﬁcant in females, ranging from varying degrees of breast hypoplasia to complete absence of the breast (amastia) and nipple (athelia). Hand deformities are frequent and occurred in the patient described by Poland. They may include hypoplasia (brachydactyly), fused ﬁngers (syndactyly) and mitten or claw deformity (ectromelia). This condition is present from birth and has an estimated incidence of 1 in 30 000 to 1 in 32 000.25 The etiology of this deformity is unknown, but it clearly affects the developing somatic tissue for the entire limb bud and chest wall. Abnormalities in the breast can be recognized at birth by the absence of the underlying breast bud and the hypoplastic, often superiorly displaced nipple. Chest wall deformities are identiﬁed at birth, including absence of ribs or posterior displacement of ribs on the involved side. The etiology of this deformity is unknown, but it clearly affects the develop-

244 Congenital thoracic deformities

ing somatic tissue for the entire limb bud and chest wall. In our experience, the deformity occurs equally in boys and girls. Chest wall correction was required in ten out of 41 cases but again never in infancy.26

THORACIC DEFORMITIES IN DIFFUSE SKELETAL DISORDERS Asphyxiating thoracic dystrophy (Jeune’s disease) Jeune in 1954 ﬁrst described a newborn with a narrow rigid chest and multiple cartilage anomalies.27 The patient died early in the perinatal period because of respiratory insufﬁciency. Subsequent authors have further characterized this form of osteochondrodystrophy which has variable skeletal involvement. It is inherited in an autosomal recessive pattern and is not associated with chromosome abnormalities.28 Its most prominent feature is a narrow ‘bell-shaped’ thorax and protuberant abdomen. The thorax is narrow in both the transverse and sagittal axis and has little respiratory motion due to the horizontal direction of the ribs (Fig. 23.6a–c). The ribs are short and wide and the splayed costochondral junctions barely reach the anterior axillary line. The costal cartilage is abundant and irregular like a rachitic rosary. Microscopic examination of the costochondral junction reveals disordered and poorly progressing endochondral ossiﬁcation, resulting in decreased rib length. Associated skeletal abnormalities which occur with this syndrome include short and stubby extremities with relatively short and wide bones. The clavicles are in a ﬁxed and elevated position, and the pelvis is small and hypoplastic with small, square iliac bones.

(b)

(c)

(a)

Figure 23.6 Infant with asphyxiating thoracic dystrophy (Jeune’s syndrome). (a) Clinical photograph demonstrates small size of thorax relative to infant. (b) Radiograph shows the short horizontal ribs and narrow thorax with limited lung volumes. (c) Lateral radiograph demonstrates the endings of the bony ribs at the mid-axillary line and the abnormal costochondral junctions (arrow)

References 245

The syndrome has variable expression and degrees of pulmonary impairment. While the initial cases reported resulted in neonatal deaths, subsequent reports have documented a wide range of survival of patients with this syndrome.29 The pathological ﬁndings in autopsy cases are variable as well showing a range of abnormal pulmonary development, although in most cases the bronchial development is normal and there is a variable decrease in alveolar divisions.30 Early surgical interventions were reported by Barnes and colleagues, Karjoo and co-workers , and Mustard.31–33 In 1971 Barnes and colleagues31 reported Waterson’s attempts at thoracic enlargement by splitting the sternum in a 4-month-old infant who had required ventilation since birth. The horizontally split sternum was held apart by the eighth rib, but it subsequently became dislodged, resulting in a ﬂail sternum. She needed continued ventilation, however, and at the age of 20 months she had two additional rib grafts added and a Dacron patch to stabilize her sternum. She was eventually weaned entirely from the ventilator. Karjoo and co-workers operated on a 10-month-old infant with failure to thrive and progressive tachypnea and repeated pulmonary infections.32 They also split the sternum and maintained its separation with a stainless steel wire strut and a sheet of Marlex mesh. Ventilation was reported to have improved after surgery. Mustard split the sternum of a 6-month-old child with progressive respiratory distress and cyanotic spells, and placed an iliac crest bone graft between the sternal halves, reinforced with a Vitallium plate.33 The child required long-term ventilation and died of progressive respiratory failure 1 year after surgery. Todd and associates have recently described a method of expanding the thoracic diameter by inserting a methylmethacrylate prosthesis between the sternum split longitudinally and spread 2.5 cm.34 This child was extubated following the surgery and was reported to have improved exercise tolerance. The report of Aronson describes early success of a tibial interposition graft placed between a longitudinally split sternum, but subsequent growth failure of the chest resulted in recurrent respiratory distress.35 Recent reports by Davis et al. describe ‘staggered’ divisions of the ribs laterally to expand the chest.36 Addition to this technique of distraction devices to lengthen the separation between rib segments may achieve some degree of continued growth of the thorax, but complete reports are anxiously awaited. The ultimate results of surgical attempts will depend on the degree of underlying pulmonary parenchymal impairment of the infants.

Spondylothoracic dysplasia (Jarcho-Levin syndrome) Spondylothoracic dysplasia is an autosomal recessive deformity in which there are multiple vertebral and rib

malformations. The ribs have a crab-like appearance. Death occurs in early infancy from respiratory failure and pneumonia.37 Patients have multiple alternating hemi-vertebrae which affect most if not all of the thoracic and lumbar spine. The ossiﬁcation centers rarely cross the midline. Multiple posterior fusions of the ribs as well as remarkable shortening of the thoracic spine result in a ‘crab-like’ radiographic appearance of the chest (Fig. 23.7). One-third of patients with this syndrome have associated malformations including congenital heart disease and renal anomalies. Its occurrence has been reported primarily in Puerto Rican families (15 out of 18 cases).38 Bone formation is normal in these patients. Successful prenatal diagnosis can be established by sonographic examination.39 Thoracic deformity in this entity is really secondary to the spinal anomaly which results in close posterior approximation of the origin of the ribs. Although most infants with this entity succumb before 15 months of age, no surgical efforts have been proposed or attempted.40 Some long-term survivors who did not receive intervention are reported.41,42

Figure 23.7 Radiograph of infant with spondylothoracic dysplasia (Jarcho-Levin syndrome). Severe abnormality of the spine is apparent with multiple hemivertebrae and the ‘crablike’ ribs with close approximation posteriorly and splaying out anteriorly

REFERENCES 1. Shamberger RC, Welch KJ. Sternal defects. Pediatr Surg Int 1990; 5:156–64. 2. Bagnani V, Quartuccio A, Quartuccio A. First-trimester sonographic diagnosis of Cantrell’s pentalogy with exencephaly. J Clin Ultrasound 1999; 27:276–8. 3. Tongson T, Wanapirak C, Sirivatanapa P et al. Prenatal sonographic diagnosis of ectopia cordis. J Clin Ultrasound 1999; 27:440–5. 4. Humpl T, Huggan P, Hornberger LK et al. Presentation and outcomes of ectopia cordis. Can J Cardiol 1999; 15:1353–7.

246 Congenital thoracic deformities 5. Saxena NC. Ectopia cordis child surviving; prosthesis fails. Pediatr News 1976; 10:3. 6. Van Praagh R, Weinberg PM, Smith SD et al. Malpositions of the heart. In: Adams FH, Emmanouilides GC, Riemenschneider TA, eds. Moss’s Heart Disease in Infants, Children, and Adolescents. 4th edn. Baltimore: Williams and Wilkins, 1989: 530–80. 7. Dobell ARC, Williams HB, Long RW. Staged repair of ectopia cordis. J Pediatr Surg 1982; 17:353–8. 8. Amato JJ, Zelen J, Talwalkar NG. Single-stage repair of thoracic ectopia cordis. Ann Thorac Surg 1995; 59:518–20. 9. Hornberger LK, Colan SD, Lock JE et al. Outcome of patients with ectopia cordis and signiﬁcant intracardiac defects. Circulation 1996; 94(Suppl II):32–7. 10. Wilson J. A description of a very unusual formation of the human heart. Phil Trans Roy Soc Lond. Part II, 1798, 346–56. 11. Arndt C. Nabelschnurbruch mit Herzhernie. Operation durch Laparotomie mit tödlichem Ausgang. Centralbl Gynakol 1896; 20:632–3. 12. Weiting K. Eine operative behandelte Hermissbildung. Dtsch Z Chir 1912; 114:293–5. 13. Major JW. Thoracoabdominal ectopia cordis. J Thorac Surg 1953; 26:309–17. 14. Cantrell JR, Haller, JA, Ravitch MM. A syndrome of congenital defects involving the abdominal wall, sternum, diaphragm, pericardium, and heart. Surg Gynecol Obstet 1958; 10:602–14. 15. Daum R, Zachariou Z. Total and superior sternal clefts in newborns: A simple technique for surgical correction. J Pediatr Surg 1999; 34:408–11. 16. Dòmini M, Cupaioli M, Rossi F et al. Biﬁd sternum: Neonatal surgical treatment. Ann Thorac Surg 2000; 69:267–9. 17. Hersh JH, Waterﬁll D, Rutledge J et al. Sternal malformation/vascular dysplasia association. Am J Med Genet 1985; 21:177–86. 18. Ingelrans P, Debeugny P. Observation de biﬁdité du sternum associée à une angiomatose trachéale. Ann Chir Infantile 1965; 6:123–8. 19. Sabiston DC. The surgical management of congenital biﬁd sternum with partial ectopia cordis. J Thorac Surg 1958; 35:118–22. 20. Shamberger RC, Welch KJ. Surgical repair of pectus excavatum. J Pediatr Surg 1988; 23:615–22. 21. Ravitch MM. Pectus excavatum. In: Ravitch MM, ed. Congenital Deformities of the Chest Wall and their Operative Correction. Philadelphia: W.B. Saunders, 1977: 78–205. 22. Shamberger RC, Welch KJ. Surgical correction of pectus carinatum. J Pediatr Surg 1987; 22:48–53. 23. Lees RF, Caldicott WJH. Sternal anomalies and congenital heart disease. Am J Roentgenol 1975; 124:423–7. 24. Poland A. Deﬁciency of the pectoral muscles. Guy’s Hosp Rep 1841; 6:191–3. 25. McGillivray BC, Lowry RB. Poland syndrome in British

26.

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31. 32.

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38. 39.

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43.

Columbia: incidence and reproductive experience of affected persons. Am J Med Genet 1977; 1:65–74. Shamberger RC, Welch KJ, Upton J, III. Surgical treatment of thoracic deformity in Poland’s syndrome. J Pediatr Surg 1989; 24:760–6. Jeune M, Carron R, Beraud C et al. Polychondrodystrophie avec blocage thoracique d’evolution fatale. Pediatrie 1954; 9:390–2. Tahernia AC, Stamps P. ‘Jeune syndrome’ (asphyxiating thoracic dystrophy): report of a case, a review of the literature, and an editor’s commentary. Clin Pediatr 1977; 16:903–8. Kozlowski K, Masel J. Asphyxiating thoracic dystrophy without respiratory disease: report of two cases of the latent form. Pediatr Radiol 1976; 5:30–33. Williams AJ, Vawter G, Reid LM. Lung structure in asphyxiating thoracic dystrophy. Arch Pathol Lab Med 1984; 108:658–61. Barnes ND, Hull D, Milner AD et al. Chest reconstruction in thoracic dystrophy. Arch Dis Childh 1971; 46:833–7. Karjoo M, Koop CE, Cornfeld D et al. Pancreatic exocrine enzyme deﬁciency associated with asphyxiating thoracic dystrophy. Arch Dis Childh 1973; 48:143–6. Ravitch MM. Rib deformities in diffuse skeletal disorders. In: Ravitch MM, ed. Congenital Deformities of the Chest Wall and their Operative Correction. Philadelphia: W.B. Saunders, 1977: 272–84. Todd DW, Tinguely SJ, Norberg WJ. A thoracic expansion technique for Jeune’s asphyxiating thoracic dystrophy. J Pediatr Surg 1986; 21:161–3. Aronson DC, VanNierop JC, Taminiau A et al. Homologous bone graft for expansion thoracoplasty in Jeune’s asphyxiating thoracic dystrophy. J Pediatr Surg 1999; 34:500–3. Davis JT, Ruberg RL, Leppink DM et al. Lateral thoracic expansion for Jeune’s asphyxiating dystrophy: A new approach. Ann Thorac Surg 1995; 60:694–6. Jarcho S, Levin PM. Hereditary malformation of the vertebral bodies. Bull Johns Hopkins Hosp 1938; 62:216–26. Heilbronner DM, Renshaw TS. Spondylothoracic dysplasia. J Bone Joint Surg 1984; 66A:302–3. Wong G, Levine D. Jarcho-Levin syndrome: Two consecutive pregnancies in a Puerto Rican couple. Ultrasound Obstet Gynecol 1998; 12:70–73. Roberts AP, Conner AN, Tolmie JL et al. Spondylothoracic and spondylocostal dysostosis: hereditary forms of spinal deformity. J Bone Joint Surg 1988; 70B:123–6. Lawson ME, Share J, Benacerraf B et al. Jarcho-Levin syndrome: Prenatal diagnosis, perinatal care, and followup of siblings. J Perinatology 1997; 17:407–9. Hayek S, Burke SW, Boachie-Adjei O et al. Jarcho-Levin syndrome: Report on a long-term follow-up of an untreated patient. J Pediatr Ortho Part B, 1999; 8:150–3. Welch KJ. Chest wall deformities. In: Holder TM, Ashcraft KW, eds. Pediatric Surgery. Philadelphia: W.B. Saunders, 1980: 162–82.

24 Mediastinal masses in the newborn STEVEN J. SHOCHAT

Mediastinal masses in the newborn represent a wide variety of congenital and neoplastic lesions which can present interesting diagnostic and therapeutic challenges. However, despite the heterogeneous make-up of this group of lesions, an accurate preoperative diagnosis can usually be established on the basis of the location of the mass. While the subject of this chapter deals with the treatment of masses in the newborn, it is helpful to discuss differences between various age groups when dealing with mediastinal masses in the childhood population.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of mediastinal masses in infants and children is simpliﬁed if the mediastinum is arbitrarily separated into three compartments (Fig. 24.1). For the purpose of this discussion the mediastinum will be partitioned as follows: the anterior mediastinum lies anterior to the heart and lung roots and contains the thymus, anterior mediastinal lymph nodes and rarely a substernal extension of the thyroid and parathyroid. The middle mediastinum contains the trachea, bronchi, mediastinal lymph nodes, heart and Posterior mediastinum Anterior mediastinum

Middle mediastinum

Figure 24.1 Compartments of the mediastinum

great vessels. The posterior mediastinum lies behind the heart and lung roots and contains the esophagus and intercostal sympathetic nerves. Anterior mediastinal masses include teratomas; thymic cysts, hyperplasia or tumors; cystic hygromas and lymphomas. Masses within the middle mediastinum include the lymphomas, bronchogenic cysts and granulomatous infections within the mediastinal lymph nodes. Posterior mediastinal lesions include the tumors of neurogenic origin, enterogenous cysts, and the undifferentiated sarcomas. The age of the patient at the time of diagnosis is extremely important, since certain masses have a predilection for younger infants and others are predominantly seen in older children and adolescents.1–4 In newborns and children under 2 years of age, the most common mediastinal mass is the neuroblastoma within the posterior mediastinum.4 In addition, thymic hyperplasia and bronchogenic cysts are seen predominantly in children less than 2 years of age. The various lymphomas are the most common mediastinal masses seen in children greater than 2 years. The mean age of children with mediastinal Hodgkin’s disease is approximately 13 years of age and the mean age of children who present with non-Hodgkin’s lymphoma is 11 years of age.3 The presenting signs and symptoms in infants and children with mediastinal masses vary depending upon age: • • • • • • • •

acute respiratory distress fever cough shortness of breath cervical adenopathy superior vena caval syndrome Horner’s syndrome asymptomatic

Infants under 2 years of age frequently present with signs of tracheal compression and acute respiratory distress. This is due to the smaller, softer, more pliable tracheobronchial tree in infants as well as the fact that they do not have a ﬁxed mediastinum so that large mediastinal

248 Mediastinal masses in the newborn

masses can cause a signiﬁcant shift of the mediastinum with compromise of the contralateral hemithorax. Older children will present with symptoms of fever, cough and shortness of breath. Approximately half the children with mediastinal lymphomas will present with cervical adenopathy. Superior vena caval obstruction is rare in children, but is occasionally seen. Horner’s syndrome may be the presenting ﬁnding in infants with neuroblastomas or neurogenic tumors of the posterior mediastinum. Asymptomatic mediastinal masses are seen in children of all ages and are frequently noted on a chest X-ray performed for a mild upper respiratory infection or are discovered incidentally following imaging studies for symptoms unrelated to the mediastinal mass.

mediastinal masses in order to detect intraspinous extension of tumor (dumb-bell tumors). Cervical lymph node biopsy should be considered in children with middle mediastinal lesions and suspected lymphoma. A bone marrow aspiration and biopsy should also be performed prior to other invasive studies in children suspected of having non-Hodgkin’s lymphoma. Skin testing and complement ﬁxation titers should be considered in infants with middle mediastinal masses to rule out granulomatous infections. Alpha fetoprotein determination and HCT titers should be performed in children with anterior mediastinal masses if malignant teratomas are suspected. Urinary catecholamine metabolites should be evaluated in infants with posterior mediastinal masses both for diagnosis and for postoperative follow-up in children with suspected neuroblastomas.

DIAGNOSIS ANTERIOR MEDIASTINUM A systematic approach to the diagnosis of a mediastinal mass in the newborn is imperative:5 • • • • • • • • •

posteroanterior–lateral chest X-ray barium swallow ultrasonography CT scan MRI bone marrow–lymph node biopsy skin test – complement ﬁxation serum markers – AFP, HCG urinary catecholamines

The most helpful diagnostic technique in this age group is still the chest X-ray in the posteroanterior and lateral projections, in order to localize the position of the mass. Vertebral anomalies associated with a mediastinal mass in an infant should raise the suspicion of the so-called neuroenteric variety of enterogenous cyst which communicates with the meninges. Calciﬁcation within a posterior mediastinal mass suggests the presence of a neuroblastoma and anterior mediastinal teratomas frequently contain calciﬁcation. In cases of suspected enterogenous and brochogenic cysts, the esophagogram may be of value. Ultrasonography of the chest can be quite helpful in deﬁning complicated mediastinal lesions and has been especially helpful in infants with suspected thymic hyperplasia. Echocardiography should be performed to delineate the heart and great vessels if lesions of these structures are suspected. A computed tomography scan should be reserved for difﬁcult diagnostic dilemmas and for delineating anatomic boundaries in preparation for tumor resection. Magnetic resonance imaging may be of help in differentiating masses of vascular origin from other mediastinal structures and may be helpful in infants with suspected thymic hyperplasia.6 In addition, magnetic resonance imaging should be considered in cases of posterior

Thymic hyperplasia is the most common anterior mediastinal mass seen in infants (Fig. 24.2). This diagnosis is usually not difﬁcult as there is frequently a characteristic ‘sail’ sign on routine chest X-ray. Recently, ultrasonography has been very helpful in differentiating thymic hyperplasia from other mediastinal masses and should be considered in difﬁcult cases. The use of steroids to help with the diagnosis of thymic hyperplasia in infants as listed below is rarely necessary and has not been required in our institution for some time. Benign teratoma is the most frequent anterior mediastinal neoplasm seen in children under 2 years of age (Fig. 24.3). These masses are usually well encapsulated and can be treated by total excision through a posterolateral thoracotomy. Cystic hygromas also are observed in infants, but usually have a cervical or axillary component which makes this diagnosis obvious. Thymic cysts are extremely rare in children and only 20 thymomas have been reported in childhood. Germ cell tumors of the anterior mediastinum are usually seen in older children

< 2 years Benign teratoma Thymic hyperplasia Cystic hygroma

Figure 24.2 Anterior mediastinum

> 2 years Malignant germ cell tumor Thymoma Lymphoma

Middle mediastinum 249

< 2 years Bronchogenic cyst

> 2 years Lymphoma Granuloma

Figure 24.4 Middle mediastinum

Figure 24.3 Cardiac teratoma with anterior mediastinal mass: (a) posteroanterior–lateral chest X-ray; (b) CT scan; (c) MRI scan

and adolescents and many have an endodermal sinus or yolk sac component with an elevated serum alpha fetoprotein.7 AFP and HCG levels should be performed in all older children with anterior mediastinal masses as these markers are helpful not only in diagnosis but in following response to therapy. These tumors are highly malignant lesions and total resection rarely is possible. Evaluation of these patients requires a multidisciplinary approach with consultation between surgeon, pediatric oncologist and radiation therapist. In the rare case where total excision is possible, this should be carried out and followed by multi-agent chemotherapy. However, radical resection is not indicated. When the tumor is non-resectable, a biopsy rather than partial resection is followed by chemotherapy and delayed primary excision. While isolated lymphomas of the thymus do occur, the majority of lymphomas of the anterior mediastinum will also have a major middle mediastinal component which makes diagnosis straightforward.

MIDDLE MEDIASTINUM Bronchogenic cysts may be seen in all age groups, but are the most frequent mass seen within the middle mediastinum in infants and children under 2 years of age (Fig. 24.4). Bronchogenic cysts are located in the subcarinal region and are frequently associated with a characteristic expiratory stridor due to accentuation of the obstruction of the lower trachea during expiration. Bronchogenic cysts are frequently difﬁcult to diagnose on routine chest X-ray, but there is usually a characteristic displacement of the esophagus on barium swallow (Fig. 24.5). Bronchogenic cysts occasionally are

Figure 24.5 Bronchogenic cyst showing displacement of esophagus. Normal appearing chest X-ray

250 Mediastinal masses in the newborn

intimately attached to the membranous trachea and if this is the case a small portion of the cyst should be left attached to the trachea. The most common mediastinal mass in individuals over 2 years of age is Hodgkin’s or non-Hodgkin’s lymphoma. Lymphomas are also the most frequent tumors involving the middle mediastinum. The initial diagnostic work-up in children with suspected lymphoma should include cervical or supraclavicular lymph node biopsy as well as bone marrow biopsy. Mediastinoscopy, anterior mediastinotomy or CT-guided needle biopsy are the procedures of choice to establish a tissue diagnosis in the absence of cervical adenopathy. A normal thoracotomy is rarely indicated for diagnosis or treatment in children with lymphoma. Children who present with a large middle mediastinal mass and respiratory distress and a suspected diagnosis of non-Hodgkin’s lymphoma may be treated initially with steroids prior to biopsy because of the dangers of acute respiratory decompensation on induction of anesthesia. However, every attempt should be made to safely establish a diagnosis prior to the use of steroids since even a brief course of therapy can make subsequent diagnosis difﬁcult.8 A multidisciplinary approach (surgeon, oncologist, radiotherapist) to the child with suspected mediastinal lymphoma is imperative and tissue obtained at the time of biopsy should be placed in saline so that immunologic surface marker studies can be performed. These studies are extremely important in the classiﬁcation and hence therapy of the various nonHodgkin’s lymphomas.9 Granulomatous infections of the paratracheal, subcarinal or hilar lymph nodes are occasionally seen and can usually be diagnosed by appropriate skin tests and complement ﬁxation titers. In the midwest of the USA and other endemic areas, histoplasmosis seems to have a predilection for the azygous node which is characteristically enlarged in children with this infection. Diagnosis is conﬁrmed by mediastinoscopy, mediastinotomy or rarely thoracotomy.

< 2 years Neuroblastoma Enterogenous cyst

> 2 years Ganglioneuroma Sarcoma

Figure 24.6 Posterior mediastinum

extension may present with neurologic symptoms due to spinal cord compression. While the treatment of mediastinal neuroblastomas in children is total excision if at all possible, this does not mean radical chest wall resection. In the rare case of a massive mediastinal neuroblastoma that cannot be resected without a radical operation, a biopsy to establish the diagnosis is followed by chemotherapy and delayed primary excision. While this clinical situation is unusual, we have found that a tissue diagnosis can usually be obtained by a percutaneous core needle biopsy, avoiding formal thoracotomy. In children with disseminated neuroblastoma, thoracotomy and resection should be carried out only after all metastatic sites are controlled with multi-agent chemotherapy. Despite impressive shrinking of tumor following chemotherapy and complete delayed primary excision, the prognosis continues to be discouraging. Children with posterior mediastinal neuroblastoma can also present with unusual symptoms. The case in Fig. 24.7 presented with a 3-month history of diarrhea. The mass turned out to be a large neuroblastoma that extended up

POSTERIOR MEDIASTINUM The most common mass of the posterior mediastinum and in fact the most common mass in newborns is a posterior mediastinal neuroblastoma (Fig. 24.6). Mediastinal neuroblastomas are interesting in that they seem to have a different biological behavior than intraabdominal tumors. The majority of mediastinal neuroblastomas are localized or low-stage disease and have a favorable outcome following resection.10 These tumors are more often occult and are diagnosed on X-ray examination for other complaints. Respiratory distress due to compression or deviation of trachea is a feature in some cases. Thoracic neuroblastomas with dumb-bell

Figure 24.7 Posterior mediastinal neuroblastoma treated by total excision. Note cervical extension (arrow)

References 251

into the cervical region. The tumor contained high concentrations of prostaglandin E which was the etiology of the diarrhea. Vasoactive intestinal polypeptide secreting neuroblastomas have also been described in children with profuse watery diarrhea. Recently, Ratner and Pelton reported an infant who presented with progressively worsening labored respirations and was found to have a neuroblastoma extending from the mediastinum, through the thoracic inlet, and into the neck.11 Enterogenous cysts, while rare, represent an interesting spectrum of lesions.12,13 They may be intimately associated with the esophagus and cause dysphagia or they can contain gastric mucosa which has been associated with peptic ulceration, perforation and bleeding. Large cysts can have abdominal extensions and communicate with an intestinal duplication. An interesting but rare variant is the so-called neurenteric cyst that communicates with the meninges through an intraspinous component. These infants present with a large mediastinal mass, respiratory distress and rarely neurologic symptoms. Characteristic deformities of the lower cervical and upper thoracic spine are always present on routine chest X-ray. During resection of these masses through a posterolateral thoracotomy, the communication between the thoracic and infraspinous component must be identiﬁed and ligated to prevent a spinal ﬂuid leak and meningitis. These patients should be evaluated by MRI scan, as the infraspinous cystic component may require laminectomy and excision.

The most important factor in preventing anesthetic complications in children with a mediastinal mass is a recognition of the above problems and the anticipation of a possible airway problem. A very thorough radiologic evaluation should be performed and CT examination to determine the tracheal cross sectional area may be extremely helpful.15 Pulmonary function studies may be of help as well. Once the preoperative evaluation is completed the anesthetic of choice can be determined depending upon the procedure that will be performed. Preoperative radiation therapy or chemotherapy may be required prior to primary excision or biopsy. Incisional biopsies can be performed under local anesthesia in older children and needle biopsy with local anesthesia can be performed in younger children and infants. In children with benign lesions one lung anesthesia with placement of the endotracheal tube beyond the obstruction has been found to be helpful and occasionally ventilation through a rigid bronchoscope is necessary. While cardiopulmonary bypass or ECMO may be required these techniques are usually not necessary in the majority of patients. A high index of suspicion, meticulous preoperative evaluation, and a multidisciplinary action plan decided upon by surgeons, anesthesiology, radiation therapist, hematology/oncologist, and pathologist can usually avert the potential catastrophe associated with general anesthesia in children with critical mediastinal masses.

OPERATIVE TECHNIQUE FOR REMOVAL OF MEDIASTINAL NEUROBLASTOMA ANESTHETIC MANAGEMENT OF INFANTS WITH A MEDIASTINAL MASS Respiratory compromise on induction of general anesthesia in children with large mediastinal masses is a well recognized complication that must be considered in the preoperative evaluation of any child with a mediastinal mass.14,15 Infants and small children have a small compressible airway, which is associated with a signiﬁcant increased airway resistance with even a modest degree of narrowing. In addition infants do not have a ﬁxed mediastinum and large masses can easily displace the mediastinal structures with compression of the tracheobronchial tree, superior vena cava or right ventricular outﬂow tract. Cardiac output may also be diminished due to pressure on the great vessels. Induction of anesthesia is associated with a decrease in the functional residual capacity, decrease lung capacity, and an increase in lung retractile force. The above alterations are extenuated with the addition of paralysis. Narrowing of the trachea will also become smaller when the patient changes from spontaneous to positive pressure ventilation. All of the above factors lead to the sometime critical condition that is associated with general anesthesia in these patients.

The tumor is usually approached through a standard posterolateral thoracotomy at the approximate level of the tumor. The lung is retracted medially to reveal tumor covered with pleura arising from the sympathetic trunk and an assessment made of it and obvious lymph node involvement in the vicinity. The pleura is incised around the tumor approximately 1 cm from it and the fascia and pleura mobilized towards the tumor. A plane of dissection can usually be developed superﬁcial to endothoracic fascia. The tumor is now mobilized from the ribs by sharp dissection and any intercostal vessels entering the tumor will need division. If the tumor extends far enough anteriorly, the azygos vein on the right side will need division between ties. Care is taken to avoid damage to the ﬁrst thoracic nerve passing laterally across the ﬁrst rib to join the brachial plexus. The superior intercostal artery normally descends between the ﬁrst nerve and the sympathetic trunk. Other intercostal nerves may be sacriﬁced if they are intimate with the tumor. Depending on how far the tumor has extended anteriorly, it will need to be dissected off the main structures in the superior mediastinum. This is most likely to be the esophagus and the closely applied vagus

252 Mediastinal masses in the newborn

nerve, but in a large tumor the trachea may be involved. It may prove useful to have a large size tube in the esophagus to aid dissection. On the left side, the thoracic duct, arch of aorta with subclavian and carotid branches along with the vagus will need protection. It should now prove possible to dissect the tumor off the bodies of the vertebra and any extension into the intravertebral foramen should be carefully dissected out. Titanium clips may prove useful to control hemorrhage in small vessels, and these will not interfere with subsequent CT scanning. They may also be used as markers if all tumor is not excised and radiation therapy is being considered. Any suspiciously involved lymph nodes locally should be taken for biopsy (staging). The chest is closed after leaving a chest drain.

REFERENCES 1. Azarow KS, Pearl RH, Zurcher R et al. Primary mediastinal masses. A comparison of adult and pediatric populations. J Thoracic Cardiovasc Surg 1993; 106:67–72. 2. Grosfeld JL, Skinner MA, Rescorla FJ et al. Mediastinal tumors in children: experience with 196 cases. Ann Surg Oncol 1994; 1:121–7. 3. Glick RD, LaQuaglia MP. Lymphomas of the anterior mediastinum. Sem Ped Surg 1999; 8:69–77. 4. Saenz NC. Posterior mediastinal neurogenic tumors in infants and children. Sem Ped Surg 1999; 8:78–84.

5. Esposito G. Diagnosis of mediastinal masses and principles of surgical tactics and technique for their treatment. Sem Ped Surg 1999; 8:54–60. 6. Siegel MJ, Nadel SN, Glazer HS et al. Lesions in children: comparison of CT and MRI. Radiology 1986; 160:241–4. 7. Billmire DF. Germ cell mesenchymal and thymic tumors of the mediastinum. Sem Ped Surg 1999; 8:85–91. 8. Borenstein SH, Gerstle T, Malkin D et al. The effects of prebiopsy corticosteroid treatment on the diagnosis of mediastinal lymphoma. J Ped Surg 2000; 35:973–6. 9. Warnke RA, Link MP. Identiﬁcation and signiﬁcance of cell markers in leukemia and lymphoma. Am Rev Med 1983; 34:117–31. 10. Adams GA, Shochat SJ, Smith EI et al. Thoracic neuroblastoma: A Pediatric Oncology Group Study. J Pediatr Surg 1993; 28:372. 11. Ratner IA, Pelton JJ. Neuroblastoma of the thoracic inlet. J Pediatr Surg 1990; 25:547–9. 12. Snyder ME, Luck SR, Hernandez R et al. Diagnostic dilemmas of mediastinal cysts. J Pediatr Surg 1985; 20:810–15. 13. Superina RA, Ein SH, Humphreys RR. Cystic duplications of the esophagus and neurenteric cysts. J Pediatr Surg 1984; 19:527–30. 14. Vas L, Naregal F, Naik V. Anesthetic management of an infant with anterior mediastinal mass. Pediatric Anesthesia 1999; 9:439–43. 15. Shamberger RC. Pre-anesthetic evaluation of children with anterior mediastinal masses. Sem Ped Surg 1999; 8:61–8.

25 Subglottic stenosis FELIX SCHIER

INTRODUCTION Artiﬁcial ventilation via endotracheal intubation or tracheostomy represents a main feature of neonatal intensive care. Both techniques have their beneﬁts and complications. Post-intubational complications are mainly restricted to the subglottic area, with subglottic stenosis constituting a major proportion. In these cases, the remedy will generate a disease which outlasts the process which required intubation to begin with. As survival rates increase, more newborns with subsequent subglottic disease will be presented to the pediatric surgeon. From the various techniques on offer, we have formed a preference for three: endoscopic procedures, the anterior cricoid split and the interpositioning of cartilage grafts. In our opinion, they virtually obviate the need for tracheostomies.

DESCRIPTION The term ‘subglottic’ designates the area extending from below the vocal cords down to the pulmonary tree. However, it refers only to the area from immediately below the vocal cords to the most cranial segment of the trachea: the infraglottic cavity and especially the conus (Fig. 25.1). Subglottic, cricoidal and infraglottic are, for all practical purposes, synonyms. Nowhere else is the airway as narrow and as completely outﬂanked by cartilaginous structures as here. A predisposition to mechanical trauma is obvious. Any swelling of the interior soft tissue will have to extend centripetally at the expense of the airway. The normal tracheal diameter at birth is 5–5.55 mm and increases by 0.3 mm/year.1 The radius r enters as r4 into Hagen-Poiseuille’s law (for laminar airﬂow). It is more realistic to assume turbulent airﬂow. Therefore the radius r may well change in the formula to its ﬁfth power r5.2 Given a tracheal diameter of a mere 2.5 mm (i.e. of 50%) would cause a 32fold increase of resistance!

Figure 25.1 The subglottic space, shown by the hatched area

CONGENITAL SUBGLOTTIC STENOSIS Both cartilaginous and soft-tissue malformations are encountered. In roughly 10% of cases they are associated with other laryngotracheal anomalies: pathological ﬁndings outside the larynx or trachea concur in another 10%.3 The lesion can be circumferential or segmental. Surgical correction is seldom required.

ACQUIRED SUBGLOTTIC STENOSIS Intubation is the most common cause for traumatically acquired lesions to the subglottic area:4 it acts both mechanically and as an irritant to the mucosal layer. With delayed mucosal repair, infection will complete the clinical picture. Mucosal damage leads to accumulation of mucus. Bacterial contamination ensues and results in tracheitis. The pathohistological sequence is: mucosal edema, hemorrhage and ulceration, cartilaginous exposure, infection.5 In general, intubation can be considered as the insertion of a foreign body into an infected area, a situation which, according to general medical knowledge, will tend to maintain rather than diminish chronic

254 Subglottic stenosis

inﬂammation. Intermittent suction enhances the mechanical trauma. The healing process, which involves epithelial growth, formation of granulation tissue and thickening of the subepithelial connective tissue, will even persist beyond the period of primary mucosal repair.6 Thus a soft senosis (Fig. 25.2) may develop into a cicatricial ‘hard’ stenosis (Fig. 25.3). The hard stenosis is the one presented to the pediatric surgeon; it results from a concurrence of destructive and reparative processes.5 Apparently, the more immature the baby, the more pronounced the mesenchymal reactions to repeated trauma. There is no correlation

between the duration of the intubation and the later incidence of subglottic stenosis. Finally, although endotracheal intubation is undoubtedly the main cause for subglottic stenosis, a number of other potential causes exist: infections as well as various kinds of chemical, thermal and external physical trauma, and also angioma and cysts.

Clinical features Congenital subglottic stenosis presents itself with inspiratory stridor from birth onwards. The typical clinical picture depends on the severity of the stenosis; in the case of an angioma it may not develop before the fourth to sixth week: dyspnea, inspiratory stridor, sternal or intercostal retractions, a hoarse or bitonal cry, and coughing.6 Air hunger and tachypnea point to intrathoracic stenosis, while stridor and hoarseness are typical clinical symptoms of acquired subglottic stenosis. Apneic attacks may precede stridor, especially in preterm babies.7 Usually, any attempt to extubate will give rise to increasing stridor, hypoxemia, dyspnea on exertion, and mixed acidosis within hours or days. Angiomas, in our experience, develop slowly. On purely clinical grounds there is no speciﬁc difference between congenital and acquired stenosis, except that acquired stenosis is noted only after extubation.

Diagnosis

Figure 25.2 ‘Soft’ stenosis

The history and clinical presentation are indicative. Anteroposterior and lateral neck X-ray will visualize the stenosis. A computed tomography (CT) scan or nuclear magnetic resonance imaging (MRI) will reveal cartilaginous deformities and the extent of the lesion often demonstrates large extrinsic segments of angiomas and lymphangiomas. Finally, tracheoscopy will conﬁrm the diagnosis.

Indication

Figure 25.3 ‘Hard’ stenosis

The previous therapeutic policy was based on a principle adapted from adult surgery: initially bypass the stenosis by tracheostomy and then either wait or ‘launch an attack on the stenotic area’.4,5 However, tracheostomy in children was always a procedure associated with a high rate of morbidity, especially following long-term intubation.3,8 Today, children with localized stenoses, who seem able to tolerate general anesthesia and would otherwise undergo tracheostomy, may initially be submitted to endoscopic laser treatment.9,10 Tracheostomy can thus often be avoided. However, the planning of such interventions must take into account the possibility of redo

Acquired subglottic stenosis 255

procedures under emergency circumstances. The procedure should therefore only be performed in a setting which allows for these follow-up procedures.10,11 During one of these follow-up procedures, inspection of the bronchi is advisable in order to rule out other more distal alterations. Surgically and technically, a distinction needs to be made between congenital and acquired lesions.4

Therapeutic option

ENDOSCOPIC PROCEDURES (LASER, ELECTRORESECTION, CRYOTHERAPY) When technically feasible, endoscopic procedures are preferred. Both Nd: YAG and CO2 lasers are useful tools. However, there are no ﬂexible ﬁbers yet for the CO2 laser and control of bleeding is not as good as with the Hd: YAG laser. Laser treatment avoids some of the risks of open surgery, such as bleeding, scarring and wound infection. It can also obviate tracheostomy and can be repeated several times. In fact, laser therapy usually requires several sessions.10

WAIT AND SEE With ventilation terminated, subglottic stenosis may subside spontaneously. This is rare and can mainly be expected in angiomas and granulations. This was one of the main points made by advocates of tracheostomy: subglottic stenoses may almost disappear after a tracheostomy is performed in the more distal trachea, thus eliminating chronic trauma to the subglottic area.

CONSERVATIVE (STEROIDS, DILATATION, BOUGIENAGE) The recent literature provides no evidence of good results or curative effects with these modalities alone. Balloon dilatation with angioplasty catheters (under radiological control) has been used to treat postoperative restenoses.12 Bougienage may work in case of ﬁbrous and cartilaginous narrowing, but in cases of soft stenosis it may only accelerate the progression to hard stenosis.

STENTING This approach involved other complications and a prolonged duration of treatment. It includes a tracheostomy. We use open and closed stents, which are positioned subglotically.10 In combined stenosis including the larynx, stents are inserted in a glottic or transglottic position and exteriorized through the stoma with a T-like band. In subglottic stenosis, a short open stent is used and the children are supplied with a fenestrated tracheostomy tube for speech training.

ANTERIOR CRICOID SPLIT We prefer the anterior cricoid split in cases with cricoid hypoplasia. The technique is described later.

OPEN SURGERY Open surgery is indicated for more extensive and longdistance stenoses and in all cases of cartilaginous stenosis. We would not consider end-to-end resection in cases of subglottic stenosis. Our chosen techniques are primary tracheoplastic procedures with interposition of cartilage grafts.

TECHNIQUE Endoscopic procedure With the child in the supine position and the head in maximal dorsal ﬂexion, anesthesia is induced via a mask and followed by a short period of hyperoxygenation with 100% oxygen. A topical anesthetic is sprayed into the larynx and trachea. Also, although these instructions are referred to as ‘ventilating’ bronchoscopes (Storz), anesthesiologists would hardly dare to administer relaxants to a child being ventilated with the bronchoscope in place and thus narrowing the available airway.13 Sponges sufﬁce to protect the toothless baby from mechanical trauma. A bronchoscope at room temperature will quickly be blurred by condensation inside the airway. This can be prevented by applying either physiological saline with a few drops of normal household detergent or commercially available anti-clouding solutions to the tip of the bronchoscope. The larynx is exposed by insertion of a laryngoscope blade. With the child’s head extended to a slightly greater degree, the bronchoscope is passed from the corner of the mouth along the base of the tongue until the arytenoid cartilages are visible (Fig. 25.4). The tongue and epiglottis are pushed up, and the tip of the bronchoscope is advanced beyond the epiglottis. The vocal folds then become immediately visible (Fig. 25.5). With the child’s head extended even further, the tracheoscope is advanced through the vocal folds, and the subglottic area becomes fully exposed (Fig. 25.6). A typical postintubation subglottic stenosis will be identiﬁed at once (Fig. 25.7). Now the anesthetic T-piece is attached to the bronchoscope. The surgeon will occlude the child’s nose with his thumb and index ﬁnger. With a moist abdominal pad in the palm of the hand, the surgeon will then try to minimize the escape of anesthetic gases from the mouth. Since the small suction channel tends to become easily occluded by debris, it is advisable to keep physiological saline at hand to facilitate the clearance of the suction.

LASER CO2 laser ﬁbers small enough to be passed through pediatric ventilation bronchoscopes are not yet commercially available. Compared to Nd: YAG laser, they

256 Subglottic stenosis

Figure 25.7 Subglottic stenosis seen from above

Figure 25.4 Advancing of the bronchoscope from the corner of the mouth along the base of the tongue until the arytenoid cartilages are visible

Figure 25.5 The arytenoid cartilages and the vocal cords seen from above

would certainly be better suited for tracheal obstructions because of the limited thermal injury they cause. The ‘bare ﬁber’ of a Nd: YAG laser, however, can easily be passed through the instrument channel of Storz bronchoscopes (a special set is available for laser application in newborns and infants). The Nd: YAG laser has a good penetration and coagulation effect; it is preferable in cases where bleeding is anticipated. Using 15 W and exposure times of 0.2 seconds with intervals of 0.2 seconds, a depth-limited coagulation can be achieved through a contact method. Owing to the simultaneous shrinkage and Hagen-Poiseuille’s law, ventilation is immediately facilitated. Necrotic tissue will be removed with the ﬁber when it adheres to the tip or with suction or forceps. Extreme caution should be exercised as a number of tracheal burns, intratracheal combustions and even explosions have been reported in connection with laser application in airways ventilated with anesthetic gases.14 Ignition of plastic material (whether endotracheal tubes or gastric tubes) may even occur without direct contact to the laser beam. In an experimental setting, tubes burned in 100% O2, 100% N2O or any combination of the two. In air alone, the tubes did not burn. Combustion was weakly supported by 25% O2 and strongly by 30% O2. Additionally, red and latex rubber appeared to be more easily ignitable than plastic vinyl.3 Ignition can be prevented by avoiding the combination of ﬂammable material/anesthetic gases/ laser and by using special tubes.

OPEN SURGERY

Figure 25.6 Exposure of the subglottic area

Anterior cricoid split The anterior cricoid split4,15,16 (Fig. 25.8) consists of a horizontal skin incision and a vertical cartilage incision from just below the notch of the thyroid cartilage through the cricoid ring and the uppermost tracheal cartilage. The cricoid ring then bursts open. The endotracheal tube may become visible. The rationale is to relieve pressure on the cartilaginous ring and to lessen the pressure factors responsible for the subglottic lesion.16 Postoperatively, an endotracheal tube is placed as an internal stent for 10–14 days. An endoscopic

Acquired subglottic stenosis 257

Figure 25.8 The anterior cricoid split. Access is gained by a horizontal skin incision

procedure is not performed at this time. Good results have been reported.15

INTERPOSITIONING OF CARTILAGINOUS GRAFTS In this operation (Fig. 25.9), with the patient in the supine position and after endotracheal intubation, the trachea is exposed through a midline horizontal incision. Rarely, it may prove necessary to divide the cranial part of the sternum. The thymus is divided. The aortic arch and innominate vein are controlled by vessel loops. The trachea is opened by an incision from the cricoid to the third tracheal ring. The endotracheal tube is advanced by

the surgeon into the distal trachea. The posterior segment of the cricoid is dissected. The anterior sternal segment of the second rib is exposed, longitudinally split and slit at the antiperichondrial side in order to achieve greater ﬂexibility of the future interponate.17 The biconcavely shaped interponate is inserted with its perichondrial side to the inner side of the trachea. Interrupted monoﬁlamentous absorbable (PDS) sutures secure it to the cricoidal margins. Fibrin glue seals an occasional small disruption caused by an individual stitch. Postoperatively, our patients are kept intubated for 8–10 days, although others extubate them immediately after the procedure. Dexamethasone 1–1.5 mg/kg, applied intravenously, is believed to reduce postoperative tracheal edema, and high-humidity oxygen or ultrasonic nebulizers may help to reduce eschar formation.9

RESULTS A total of 92 patients with subglottic stenoses were treated, ranging from 680 g to 14 years of age (average 1.4 years; median 5 months). Three types and four stages were distinguished. Type A is a localized lesion: a membrane, or granulations. Type B extends down to the bifurcation, and type C includes the bifurcation and the more distal bronchial tree. According to a classiﬁcation by Cotton, 4, 16 stage I refers to a stenosis of less than 70%, stage II to a stenosis between 70% and 90%, stage III to a stenosis greater than 90%, and stage IV to a complete obstruction (Tables 25.1–3). A total of 62 children suffered from post-intubational scarring, 16 from granulations, 12 from angiomas, and one each from a papilloma and a cyst. The surgical techniques applied and the results obtained were as follows. All 92 children were primarily treated endoscopically with the laser, even when operated on later. As present, 12 children still have a stoma (13%), and two are intubated. All others are well and extubated. Cartilaginous grafts were performed in ten children; six are extubated, three have a stoma and Table 25.1 Types of subglottic stenosis Type

No. of patients

A B C

45 38 9

Table 25.2 Stages of subglottic stenosis Stage Figure 25.9 Cartilaginous graft from the second rib. The rib is split (only one-half is used and the inner side is grooved in order to achieve more ﬂexibility) and inserted into the stenotic tracheal segment. Ventilation is maintained by a tube inserted distally to the incision

I II III IV

No. of patients 6 27 50 9

258 Subglottic stenosis Table 25.3 Types and stages of subglottic stenosis Type

Stage

No. of patients

A

III III III IV

4 20 19 2

B

III III III IV

1 8 24 5

C

III III III IV

– – 7 2

one is still intubated. Anterior cricoid splits were undertaken in four children: they are all well and extubated. The only child with resection is extubated. Bougienage proved effective in 13 out of 14 children. Only two children, in whom stent were applied, are now extubated; ﬁve others either have a stoma or are intubated.

COMMENTARY The most frequent lesions are localized scars, membranes and granulomas. The more the narrowing extends beyond the subglottic region further down into the bronchial tree, the higher the degree of its narrowing effect. Usually, long-distance narrowings are severely stenotic. On average, laser application was necessary three times per patient. In more than 80% of the children, laser application alone was sufﬁcient to allow for subsequent extubation. In 20%, primary laser applications were followed by cricotomy, anterior split, and resection.

REFERENCES 1. Nixon C. Tracheal dimensions in childhood. Am J Roentgenol (letter) 1986; 147:1094–5.

2. Lambertsen CJ. The lung: physical aspects of respiration. In: Mountcastle VB, editor. Medical Physiology. 14th edn. St Louis: Mosby, 1980: 1677–90. 3. Holinger LD. Histopathology of congenital subglottic stenosis. Ann Rhinol Laryngol 1999; 108:101–11. 4. Walner DL, Loewen MS, Kimura RE. Neonatal subglottic stenosis – incidence and trends. Laryngoscope 2001; 111:48–51. 5. Duynstee ML, de Krijger RR, Monnier P, Verwoerd CD, Verwoerd-Verhoef HL. Subglottic stenosis after endolaryngeal intubation in infants and children: result of wound healing processes. Int J Pediatr Otorhinolaryngol 2002; 11:1–9. 6. Minningerode B, Richter HG. Pathophysiology of subglottic tracheal stenosis in childhood. In: Wurnig P, editor. Trachea and Lung Surgery in Childhood. Berlin: Springer-Verlag, 1987, 107. 7. Ratner I, Whitﬁeld J. Acquired subglottic stenosis in the very-low-birth-weight infant. Am J Dis Child 1983; 137:40–3. 8. Rodger BM, Rooks JJ, Talbert JL. Pediatric tracheostomy: long-term evaluation. J Pediatr Surg 1979; 14:258–63. 9. Hollinger PH, Kutnuck SL et al. Subglottic stenosis without tracheotomy. Ann Otol Rhinol Laryngol 1976; 91:407–12. 10. Triglia JM, Nocollas R, Romas S. Management of subglottic stenosis in infancy and childhood. Eur Arch Otorhinolaryngol 2000; 157:382–5. 11. Hollinger PH, Kitnick SL et al. Subglottic stenosis in infants and children. Ann Otol Rhinol Laryngol 1976; 85:591–9. 12. Philippart AI, Long JA, Greenholz K. Balloon dilation of postoperative tracheal stenosis. J Pediatr Surg 1988; 23:1178–9. 13. Hatch DJ, Sumner E. Neonatal anaesthesia and perioperative care. In: Hatch DJ, Sumner E eds. Current Topics in Anaesthesia. 2nd edn. London: Arnold, 1986. 14. Handa KK, Bhalla AP, Arora A. Fire during the use of NdYag laser. Int J Pediatr Otoorhinolaryngol 2001; 60:239–42. 15. Kaschke O, Olze H, Sandmann J. Use of cartilage grafts in treatment of laryngotracheal stenoses and defects in children. Eur J Pediatr Surg 2001; 11:147–53. 16. Silver FM, Myer CM III, Cotton RT. Anterior cricoid split. Update 1991. Am J Orolaryngol 1991; 12:343–6. 17. Kimura K, Mukohara N, Tsugawa C et al. Tracheoplasty for congenital stenosis of the entire trachea. J Pediatr Surg 1982; 17:669–871.

26 Tracheomalacia I. VINOGRAD AND R.M. FILLER

Perhaps more than any other single aspect of care in the acutely ill infant, the management of the airway is the most important determinant of survival or death. The newborn infant has several inherent disadvantages in respiratory mechanics. The diameter of the trachea and bronchi is small; thus the risk of major obstruction is increased. The musculature of the chest wall is relatively weak; thus coughing is less efﬁcient than in older subjects. On the favorable side, however, is the fact that hypoxia is relatively well tolerated. Exchange of gases between the alveolar air sacs and the environment requires an unobstructed tubular passageway, and sufﬁcient intrathoracic negative pressure to draw air into the lungs. Obstruction may occur at several levels and may be congenital or acquired. At the tracheal level, obstruction may result from changes of the tracheal internal lumen, from extrinsic pressure, and as a result of functional tracheal obstruction during the normal respiratory cycle. During normal respiration the diameter of the major airways is determined by the relationship between intrathoracic and intraluminal airway pressures (Fig. 26.1). Intrathoracic airways are narrowed by an increase in intrathoracic pressure during expiration and coughing because pleural pressure rises above the intraluminal airway pressure (atmospheric pressure). The linear movement of air exerts an increased pressure on the forward vector with a corresponding fall in the lateral vector (the Venturi principle). Airway collapse is prevented by the rigidity of the airway wall. With tracheomalacia, airway rigidity is decreased so that the physiologic narrowing that occurs during expiration and coughing can cause airway obstruction. In addition, external pressure from the aorta, innominate artery, or full esophagus, can also compress and narrow an abnormally soft air passage. There are two distinct forms of tracheomalacia – primary and secondary.1 Primary tracheomalacia is caused by a congenital deﬁciency or weakness of the cartilaginous and elastic supporting structure of the trachea. It occurs mainly as an isolated segmental defect,

often found in children born with esophageal atresia and tracheo-esophageal ﬁstula.2 Congenital tracheomalacia was also described in association with the Larsen syndrome3 and polychondritis.4 In primary tracheomalacia the reason for the collapse, weakness and instability of the tracheal wall appears to vary. It may be due to hypoplasia, dysplasia or absence of the normal cartilaginous framework. Histologic study of the trachea by Wailoo and Emery in children with esophageal atresia5 revealed several abnormalities. Cartilage rings were often incomplete, cartilage to muscle ratio was reduced, and there was an increase in the length of the membranous portion of the trachea which is the weakest part of the tracheal wall. The reasons for the association of tracheomalacia and esophageal atresia are

Inspiration (a)

Inspiration (b)

Expiration NORMAL

Expiration

Coughing

TRACHEOMALACIA

Figure 26.1 Physiologic relationship between intrathoracic airway pressure and the diameter of intrathoracic airways. (a) Normally, during expiration, intrathoracic airways are narrowed by the increased intrathoracic pressure. (b) With tracheomalacia, airway rigidity is decreased and the physiologic narrowing which occurs during expiration and coughing is greatly accentuated

260 Tracheomalacia

probably related to the abnormalities in the division of the primitive foregut as it forms the trachea and esophagus. In addition, Davies and Cywes postulated that the chronic compressive force by the dilated and hypertrophied proximal atresic esophageal pouch on the trachea plays a part in retarding the development of the trachea during fetal life.6 The distal tracheo-esophageal ﬁstula may aid in tracheal collapse since it allows a displacement of lung ﬂuid into the distal esophagus during swallowing and hence favors tracheal collapse. Secondary tracheomalacia may be acquired or possibly associated with another congenital anomaly which compresses the airway wall during its development or growth. Frequently the entire tracheobronchial tree is involved. In middle and late life it is most often associated with chronic lung disease, especially emphysema and bronchitis. In infants and children, secondary tracheomalacia may present during the treatment of acquired or congenital severe pulmonary disease such as bronchopulmonary dysplasia,7,8 recurrent bronchitis and cystic ﬁbrosis. A localized area of a soft tracheal cartilaginous wall which develops because of pressure from a vascular ring or a parabronchial tumor or cyst may cause symptoms after the primary lesion is diminished.9

CLINICAL FEATURES Clinical symptoms of tracheomalacia depend on the location, the length of the abnormal airway segment and the severity of the structural abnormality. In mild cases the deﬁciency in the cartilaginous tracheal components is usually small and short; it may interfere with the normal cough mechanism by allowing almost complete tracheal closure when intrapleural pressure increases. This is often clinically recognized as the ‘seal bark’ of the infant who has had repair of esophageal atresia. These infants often have noisy respirations, and may have more frequent episodes of respiratory infection associated with sputum retention than the normal child, especially in the ﬁrst year of life. Improvement occurs with growth. After 1 year of age, mild respiratory symptoms tend to resolve because of an increase in the rigidity of the trachea. In infants with severe tracheomalacia, symptoms may start immediately following birth. The infant may suffer from cyanosis, wheezing and expiratory stridor. Frequent respiratory infections and marked sputum retention are common, and attacks of cyanotic spells (‘dying spells’) may deteriorate to respiratory arrest. The apnoeic spells are usually the most prominent clinical features of the disease because of their life-threatening nature. Although some have suggested that these spells are due to a vagal reﬂex, transcutaneous Po2 measurements have clearly shown signiﬁcant arterial desaturation during feeding, in many cases suggesting that

progressive anoxia develops while eating, presumably because of compression of the soft trachea by the dilated esophagus.10 The affected infant continues to swallow despite the progressive hypoxia and bradycardia, cardiac arrest and respiratory arrest ensue. In some of the most severe cases, endotracheal intubation is necessary to maintain the airway and some of these infants will not be able to be extubated. The casual relationship between tracheomalacia and apnoeic spells can be elusive, especially in children following repair of esophageal atresia because neurologic, cardiac and esophageal problems can cause similar symptoms. Evaluation of all suspected cases should consider these other possible causes.

DIAGNOSIS In evaluating infants for the possibility of tracheomalacia, examination should start with lateral ﬂuoroscopic views of the trachea. This study is helpful to assess the caliber of the air-ﬁlled trachea at the different phases of respiration. A mild degree of airway narrowing during expiration is common in all children, but may be somewhat more notable in an infant who has had repair of esophageal atresia. However, severe narrowing or collapse is usually very signiﬁcant. Barium swallow will rule out recurrent tracheo-esophageal ﬁstula, anastomotic stricture or gastro-esophageal reﬂux, all of which could be present and responsible for symptoms. At the same time, the effect of swallow on the tracheal diameter can be estimated. Gastro-esophageal reﬂux is common in children following surgery after esophageal atresia.11 When found in association with tracheal collapse, it may be difﬁcult to determine which mechanism is responsible for the clinical symptoms. In fact, the reﬂux of gastric contents into the esophagus may in itself cause tracheal collapse if the upper esophagus enlarges during regurgitation. When gastro-esophageal reﬂux is present in association with tracheomalacia, the severity of tracheomalacia is best deﬁned by bronchoscopy. We rely on endoscopic ﬁndings to determine whether aortopexy or fundoplication should be performed in these cases. Bronchoscopy is the most accurate means to evaluate a patient with suspected tracheomalacia. During bronchoscopy, the infant must be breathing spontaneously so that the effect of respiratory phases and coughing can be properly assessed. Marked collapse of the trachea is seen only on forced expiration or during coughing. Endoscopy is best done using a small, rigid ventilating bronchoscope with a ﬁberoptic telescope. Currently available ﬂexible ﬁberoptic bronchoscopes may distort the dynamics of ventilation since much of the lumen of the small trachea is taken up by these solid instruments.

Treatment 261

Computed tomography (CT) and magnetic resonance imaging (MRI) techniques are new modalities which have an established role in the evaluation of ﬁxed airway obstruction. Yet, for dynamic lesions such as tracheomalacia, standard studies have not proved to be useful. Cine CT-ultrafast is a new method of imaging which was recently introduced by the Imatron L-100 scanner which can image up to eighth level in 0.224 seconds and repeat these scans at short time intervals.12,13 The potential for acquiring serial 0.05 s images of the trachea is unique to the ultrafast CT and facilitates the identiﬁcation of functional abnormalities of the trachea in infants and children.14 The experience with MRI for tracheal functional obstruction is more limited. Magnetic resonance images in sagittal and axial sections can clearly demonstrate tracheal compression due to vascular ring, but again do not appear to evaluate second-to-second changes in airway caliber.15

vascular compression of the trachea.20 The concept that this procedure could be used to alleviate the symptoms of tracheomalacia was, however, new. The aim of aortopexy is to change the cross-sectional proﬁle of the trachea from an elipse to a circle so that its walls will not appose during ventilation and coughing, and at the same time move the trachea away from the esophagus so that when full it cannot compress the airway. The suspension of the aorta vascular structure from the under-surface of the sternum is done without disrupting the fascia between it and the adjacent trachea which acts as a suspension ligament to change the conﬁguration of the trachea. The operative procedure of aortopexy now in use was adapted by Schwartz and Filler21 and from the technique originally described by Gross.

TREATMENT

After the initial bronchoscopy to conﬁrm the diagnosis, anesthesia is maintained through the ventilating bronchoscope. This allows continuous intraoperative monitoring of the corrective procedure. Thoracotomy is carried out through the left anterior third interspace. The left lobe of the thymus is resected and the anterior aspect of the aortic arch and great vessels is exposed. Interrupted non-absorbable sutures are placed through the adventitia and wall of the ascending aorta and the origin of the innominate vessel. The sutures are then passed through the sternum to a subcutaneous plane along the anterior surface of the sternum and tied in sequence (Fig. 26.2a). Traction is applied evenly to all sutures to bring the aorta to the sternum, while the degree of correction is assessed bronchoscopically (Fig. 26.2b). After the thoracotomy is closed and the child recovers from anesthesia, bronchoscopy should conﬁrm that aortopexy prevents tracheal collapse during spontaneous breathing and coughing (Fig. 26.2c). A chest drain is inserted in the left pleural cavity. An alternative method of aortopexy was described by Keily and colleagues.22 They sew a small patch of woven Dacron® to the proximal aortic arch with ﬁne suture material. The patch is then attached to the sternum with heavier sutures. This method would be most suitable for the smallest babies in whom the aorta was extremely thin.

Treatment of tracheomalacia depends in large part on the severity of the disease. In children with a minor degree of collapse and mild or moderate symptoms, surgery is not necessary. Usually by 1 year of age, mild respiratory symptoms will resolve because of an increase in the size and rigidity of the trachea. Medical management is directed to the treatment of respiratory infection. Respiratory physiotherapy, bronchodilators and in-hospital observation may be useful. A surgical approach is required for patients with severe tracheomalacia. In 21 infants and children treated by Filler for tracheomalacia and 4 for tracheobronchomalacia,10 life-threatening ‘dying spells’ was the most common surgical indication. Others were recurrent pneumonia, intermittent respiratory obstruction associated with cyanosis, and inability to extubate the airway (Table 26.1). Aortopexy has proved to be a safe, expedient method of treating tracheomalacia in most patients with severe tracheomalacia.10,16–18 In 1976 two articles in the surgical literature by Filler and colleagues19 and Cohen and colleagues2 alerted pediatric surgeons to the problems and treatment of tracheomalacia. The operation had been previously used by Gross and Neuhauser for

Surgical procedure of aortopexy

Table 26.1 Indications for aortopexy in 25 patients with tracheomalacia Indications for surgery

‘Drying spells’ Recurrent pneumonia Intermittent respiratory obstruction Inability to extubate airway

No. of patients Tracheomalacia

Tracheobronchomalacia

12 4 3 2

– – – 4

262 Tracheomalacia

iv v

(b) pa s p aa

(a)

(c)

Figure 26.2 Surgical procedure of aortopexy. (a) A thoracotomy is carried out through the third left anterior interspace. The left lobe of the thymus is removed and the pericardium is opened transversely just below its reﬂection on the arch of the aorta. Following the exposure of the aorta, sutures are placed through the adventitia and wall of the ascending aorta (aa) and the origin of the innominate vessel (iv). (b) The sutures are then passed through the sternum. (c) Traction is applied evenly to all sutures to bring the aorta to the sternum. The degree of correction is assessed bronchoscopically. In (b) and (c), photography of the tracheal lumen: (b) preoperative tracheal lumen appearance; (c) post-aortopexy tracheal lumen during expiration (p, pericardium; pa, pulmonary artery; s, sternum; v, vagus)

Aortic suspension has proved to be effective, safe and a relatively simple method of treatment of most patients with severe tracheomalacia. In patients with tracheobronchomalacia, aortopexy may also be effective by relieving the element of tracheal collapse and decreasing airway resistance during expiration. Lessened intrathoracic pressure during expiration in turn may tend to decrease the bronchial collapse.10 However, our experience has been limited in this group of infants. If bronchoscopy proves that aortopexy fails to improve tracheal collapse, an external splint may be applied on the trachea during the same anesthetic.

splint is determined by the site and extent of airway collapse. The prosthetic splint we use is fabricated from Marlex® mesh that is shaped into the desired semi-rigid form by cementing Silastic ribs or Silastic rings to its surface (Fig. 26.3). The prosthesis is cut and its shape modiﬁed to the same degree at the time of surgery to

Surgical technique of external tracheal stenting External stenting of the airway has been developed to treat tracheal and bronchomalacia which has not responded to aortopexy or in cases in which a long segment of trachea has collapsed and correction by aortopexy is unlikely.23 The surgical approach depends on the size and extent of airway collapse. A left or right main stem bronchus can be approached through a lateral thoracotomy incision. The intrathoracic trachea is exposed through a lower transverse neck incision and upper sternotomy or right posterolateral thoracotomy. The selection of the size and shape of the prosthetic

Figure 26.3 An airway splint made of Marlex® mesh. The splint is shaped into the desired semi-rigid form by cementing Silastic rings to its surface

Postoperative complications 263

conform to the airway to be splinted. The prosthesis is cut so that it overlaps and can be anchored to the normal airway at either end of its defective segment. The prosthesis is placed to encircle 75% of the circumference of the airway. It is sutured to its wall with interrupted non-absorbable sutures (Fig. 26.4). As with aortopexy, anesthesia for these operations is planned to permit intraoperative endoscopic examination of the affected portion of the airway and intraoperative assessment of the adequacy of repair. The use of prophylactic antibiotic therapy is recommended to minimize the possibility of infection associated with the implantation of a foreign body. The technique of implantation of an airway splint is relatively simple and we have had no postoperative complications from the procedure. Long-term follow-up study has revealed that airway growth was not affected and respiratory difﬁculties were effectively treated,24 although in 1 child the prosthesis was removed 1 year later because it had shifted. Other surgical techniques for external tracheal stenting have been described by Johnston and colleagues using a free rib autologous graft in 2 children,25 and by Vinograd and colleagues in an experimental model of tracheomalacia by application of autologous periosteal tibial graft, which becomes incorporated into weakened tracheal wall.26 Both operations have limited clinical experience, and further study is required to establish the effectiveness of these surgical techniques. In infants with diffuse tracheobronchomalacia associated with bronchopulmonary dysplasia, continuous positive airway pressure has been advocated as a successful mode of therapy.27 However, this method would apply to a limited group of patients with tracheomalacia, since signiﬁcant spontaneous improvement in tracheomalacia is unlikely to occur before 1 year of age.

RESULTS OF SURGICAL TREATMENT It is generally agreed that the chief objective in the surgical treatment of tracheomalacia is to relieve serious symptoms and to allow discontinuation of airway intubation in those who require it. As experience with the surgical treatment of tracheomalacia has accumulated, aortopexy has proved to be an effective and reliable method of treatment. In 15 infants of 19 with tracheomalacia treated by Filler,10 aortopexy alone eliminated airway collapse, relieving all symptoms of airway obstruction. In this group, airway decannulation was acquired in 5 patients who required either intermittent or continuous airway intubation. Among the four failures of aortopexy was an infant with unrecognized vascular ring. In the other three, intraoperative bronchoscopy at the completion of aortopexy showed that the tracheal collapse persisted. However, the application of prosthetic splints, as part of the same operation, was successful in eliminating airway collapse. A more recent study by Filler and colleagues reviews the experience of the surgical treatment of 32 children with severe tracheomalacia associated with esophageal atresia.28 Aortopexy was performed in 31 of 32 children, and a splint without aortopexy was used in 1 older girl. Splinting was also necessary in 2 of the 31 at the initial operation, when aortopexy failed to prevent tracheal collapse. There were 4 initial failures. Currently, 29 children are well (median follow-up, 6.6 years), 2 have a tracheostomy in place, and 1 died at home of unknown cause. In a smaller group of 7 patients treated by Rode and colleagues, substantial relief of symptoms was achieved following aortopexy over a period of 14–30 months follow-up.18 The infants were thriving, feeding normally, and only 1 child had residual problems with pneumonia. Postoperative ultrasound evaluation showed ﬁxation of the aortic arch to the under-surface of the sternum, with no evidence of widening or dislodgement.

POSTOPERATIVE COMPLICATIONS

Figure 26.4 Trachea with prosthetic airway splint. The splint is sutured around 75% of the circumference of the tracheomalacic airway

Postoperative complications are usually few and insigniﬁcant.10 Kiely and colleagues reported 8 infants with postoperative minor problems, in a group of 17 infants who had excellent results with immediate and permanent absence of symptoms.22 Thymic hematoma with chest infection appeared in 2 and hemothorax in 1 infant. In both, the left lobe of the thymus had been reﬂected and not excised. Two others developed minor postoperative chest infections and 1 infant showed signs of cardiac failure requiring short-term treatment. Chylopericardium has been reported as an unusual complication after aortopexy for tracheomalacia.29

264 Tracheomalacia Table 26.2 Surgical options in the treatment of functional airway obstruction

A. Tracheomalacia → B. Bronchomalacia →

Primary choice

Other options

Secondary choice

Aortopexy → Internal stent (Palmaz) →

Custom made Tracheostomy → Internal stenting (Palmaz) Segmental resection → External stenting

The indications and preferred operation procedure will vary with the functional status of the patient, the anamotic location and extent of the airway malacia, and the ability of the surgical team. Primary choice is the author’s preferred operative approach to a speciﬁc airway lesion. Secondary choice is recommended if the ﬁrst operation is unsuccessful.

Results of aortopexy in infants with tracheobronchomalacia are less promising. In a limited group of 4 infants reported by Blair and colleagues, 2 patients failed attempts at extubation and have since died.10 Another infant who failed postoperative extubation was treated by aortopexy and placement of a prosthetic splint on the left bronchus. Only 1 infant was extubated and is doing well 9 months following the aortopexy. In view of the experience with the surgical treatment of tracheomalacia, aortopexy has proved itself to be a safe, expedient way to relieve the problem of tracheomalacia in most infants. It may not be sufﬁcient to eliminate airway collapse when the entire length of intrathoracic trachea is involved or in patients with tracheobronchomalacia.

INTERNAL AIRWAY STENTING Stents inserted into the airway lumen have been found to be useful in the management of tracheo or bronchomalacia.30–31,32 The balloon expandable Palmaz stent has been designed and used for vascular stents. Its use in the airway is relatively new. The Palmaz stent is not self expanding but requires a balloon to expand it. Choice of length of stent and diameter of the balloon is critical. A balloon that is too small will not expand the stent to reach the wall of the trachea and will lead to stent displacement. A balloon diameter that is too large may expand the stent and apply excessive pressure on the wall of the airway and lead to ischemia and stricture, or, other complications like aortobronchial ﬁstula.33 The technique of stent insertion is straightforward. The stent is introduced through a rigid bronchoscope under ﬁberoptic control, after deﬁning the position for the stent, stent inﬂation by the balloon is controlled ﬂuroscopically. The position and expanded size of the stent should be conﬁrmed endoscopically. The disadvantage of the Palmaz stent is that once expanded the position of the stent cannot be adjusted and it is very difﬁcult to be removed. Other major problems associated with these devices is intraluminal overgranulation that can produce a severe airway obstruction. In a search to deﬁne the optional intraluminal stent, Loeff and associates34 proposed the following requirements –

1 2 3 4 5

simplicity of insertion, ﬁxation and removal biocompatibility no obstruction of airway tributaries improved clearance of secretion and accommodation to varying tracheal dimensions.

Until better stents can be developed, their use should be limited to patients with bronchial obstruction that cannot be treated safely with current surgical procedures (Table 26.2). Experimental and clinical use of a new intratracheal stent made from nitinol, an alloy with ‘shape memory effect’35,36 showed this new stent is a promising therapeutic adjustment in the management of children with dynamic airway collapse. It fulﬁlled the basic requirements of an optimal luminal airway stent. This stent would require further clinical trial before it could be considered as an optimal alternative to the Palmaz stent. Despite the acceptable short–medium term results of using the internal airway stent, it remains unclear how long such stents may safely remain in situ. The long term implication of the metallic stents in young children is unknown. Many of the patients would require dilatation of the stents with growth. The maximal internal diameter that can be achieved varies with the size of each stent. Overdilatation may affect the structural integrity required to support the lumen. If necessary another larger stent may be placed within and expanded to provide necessary support. Internal airway stenting plays a signiﬁcant adjunctive role in the treatment of selected cases or severe cases with tracheomalacia and mainly bronchomalacia. At present, their use should be restricted to patients in whom conventional treatment has failed or those who have a life threatening airway obstruction, where there is no other reasonable therapeutic option.

REFERENCES 1. Feist JH, Johnson TH, Wilson RJ. Acquired tracheomalacia; etiology and differential diagnosis. Chest 1975; 68:340–5. 2. Benjamin BB, Cohen D, Glasson M. Tracheomalacia in association with congenital tracheosophageal ﬁstula. Surgery 1976; 79:504–8.

References 265 3. Rock MJ, Grun CG, Pauli RM et al. Tracheomalacia and bronchomalacia associated with Larsen syndrome. Pediatr Pulmon 1988; 5:55–9. 4. Greenholz SK, Hall RJ, Lilly JR et al. Surgical implications of bronchopulmonary dysplasia. J Pediatr Surg 1987; 22:1132–6. 5. Wailoo MP, Emery JL. The trachea in children with tracheo-oesophageal ﬁstula. Histopathol 1979; 3:329–38. 6. Davies MRQ, Cywes S. The ﬂaccid trachea and tracheosophageal congenital anomalies. J Pediatr Surg 1978; 13:363–7. 7. Miller RW, Wood P, Kellman RK et al. Tracheobronchial abnormalities in infants with bronchopulmonary dysplasia. J Pediatr 1987; 111:779–82. 8. Denneny JC. Bronchomalacia in the neonate. Ann Otol Rhinol Laryngol 1985; 94:466–9. 9. Filston HC, Ferguson TB, Oldham HN. Airway obstruction by vascular anomalies. Ann Surg 1987; 205:541–9. 10. Blair GR, Filler RM, Cohen R. Treatment of tracheomalacia: 8 years experiences. J Pediatr Surg 1986; 21:781–5. 11. Christie DL. Pulmonary complications of esophageal disease. Pediatr Clin N Am 1984; 31:835–49. 12. Brash RC. Ultrafast computed tomography for infants and children. Radiol Clin N Am 1988; 26:277–86. 13. Kimura K, Sopu RT, Kao SCS et al. Aortosternopexy for tracheomalacia following repair of esophageal atresia: evaluation by cine-CT and technical reﬁnements. J Pediatr Surg 1990; 25:769–72. 14. Freey EE, Smith WL, Sato Y. Chronic airway obstruction in children: evaluation with cine-CT. Am J Roentgenol 1987; 148:347–52. 15. Fletcher B, Dearbon DF, Mulopulos CP. MR imaging in infants with airway obstruction; preliminary observations. Radiology 1986; 160:245–9. 16. Benjamin B. Tracheomalacia in infants and children. Ann Otol Rhinol Laryngol 1984; 193:438–442. 17. Greenholz SK, Karrer FM, Lilly JR. Contemporary surgery of tracheomalacia. J Pediatr Surg 1986; 21:511–14. 18. Rode H, Miller AJW, Vega M et al. Oesophageal atresia – severe tracheomalacia and its correction by aortopexy. Kinderchir 1985; 40:282–6. 19. Filler RM, Rossello PJ, Lebowitz RL. Life-threatening anoxic spells caused by tracheal compression after repair of esophageal atresia; correction by surgery. J Pediatr Surg 1976; 11:739–48. 20. Gross RE, Neuhauser EBD. Compression of the trachea by an anomalous innominate artery; an operation for its relief. Am J Dis Child 1948; 75:570–74. 21. Schwartz MS, Filler RM. Tracheal compression as a cause

22. 23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

of apnea following repair of tracheooesophageal ﬁstula; treatment of aortopexy. J Pediatr Surg 1983; 15:842–8. Kiely EM, Spitz L, Brereton R. Management of tracheomalacia by aortopexy. Pediatr Surg Int 1987; 2:13–15. Filler RM, Buck JR, Bahric A et al. Treatment of segmental tracheomalacia and bronchomalacia by implantation of an airway splint. J Pediatr Surg 1983; 17:597–603. Vinograd I, Filler RM, Bahoric A. A long term functional result of prosthetic airway splint in tracheo and bronchomalacia. J Pediatr Surg 1987; 22:42–6. Johnston MR, Loeber N, Edmunds LH. External stent for repair of secondary tracheomalacia. Ann Thorac Surg 1980; 30:291–8. Vinograd I, Filler RM, England SJ et al. Tracheomalacia; an experimental animal model for a new surgical approach. J Surg Res 1987; 42:597–604. Wiseman NE, Duncan PG, Cameron CB. Management of tracheobronchomalacia with continuous positive airway pressure. J Pediatr Surg 1983; 20:489–93. Filler RM, Messineo A, Vinograd I. Severe tracheomalacia associated with esophageal atresia: results of surgical treatment. J Pediatr Surg 1992; 27:1136–41. Skarsgard ED, Filler RM, Superina RA. Postpericardiotomy syndrome and chylopericardium: two unusual complications after aortopexy for tracheomalacia. J Pediatr Surg 1994; 29:1534–6. Filler RM, Forte V, Chait P. Tracheobronchial stenting for the treatment of airway obstruction. J Pediatr Surg 1998; 33:304–11. Nicolai I, Huber RM, Mantil K et al. Metal airway stent implantation in children. Follow-up of seven children. Pediatr Pulmonal 2001; 31:289–96. Fueman RH, Backier CL, Hlinger LD. The use of balloonexpandable metallic stents in the treatment of pediatric tracheomalacia and bronchomalacia. Archiv Otolaryngol Head Neck Surg 1999; 125:203–7. Cook CH, Bhattachargya N, King DR. Aortobronchial ﬁstula after expandable metal stent insertion for pediatric bronchomalacia. J Pediatr Surg 1998; 33:1306–8. Loeff DS, Filler RM, Gorenstein A et al. A new tracheobronchial reconstruction, experimental and clinical studies. J Pediatr Surg 1988; 23:1113–17. Vinograd I, Klin B, Nevo R et al. A new intratracheal stent made from nitinol, an alloy with ‘shape memory effect’. J Thorac Cardiovasc Surg 1993; 107:1255–61. Tsugawa C, Nisghijima E, Asamo H et al. A shape memory airway stent for tracheobronchomalacia in children: An experimental and clinical study. J Pediatr Surg 1997; 32:50–53.

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27 Vascular rings EHUD DEVIRI AND MORRIS J. LEVY

INTRODUCTION Vascular rings (even when incomplete) are anomalies of the aorta and its branches, compressing the trachea, esophagus or both. Compression of the trachea and esophagus caused by anomalies of the pulmonary arteries will also be discussed in this chapter. Vascular rings were described for the ﬁrst time by Hommel in 1737.1 Bayford in 1789 described an aberrant right subclavian artery causing dysphagia.2 In 1939, Wolman reported the syndrome of esophageal and tracheal compression caused by a double aortic arch3 and a few years later, in 1945, Gross had successfully repaired this type of lesion, followed by the correction of many other forms of vascular rings.4,5 In 1946, Neuhauser introduced the radiographic basis for the diagnosis of vascular rings.6 The term ‘hypothetic double aortic arch’, which is the basis for the development of aortic arch anomalies, was introduced in 1948 by Edwards.7 This model consists of right and left aortic arches, two ductus arteriosus (in this chapter the term ‘ductus arteriosus’ relates either to patent ductus arteriosus or ligamentum arteriosum) and two upper descending aortas. The normal aortic arch is the result of regression of the right upper descending aorta and the right ductus arteriosus (Fig. 27.1). Most vascular rings are the result of either lack of regression of these segments or abnormal regression of other segments, or both. The seminal report of Stewart et al. classiﬁes these anomalies based on the development of the aortic arch.8 This is the basis for classiﬁcation of the vascular rings in the present chapter (Box 27.1).

(a)

Figure 27.1 (a) Embryological origin of aortic arch and its major branches. The normal aortic arch is the result of the regression of right upper descending aorta and right ductus arteriosis (shaded areas). (b) Normal aortic arch and its major branches

Box 27.1 Classiﬁcation of various types of vascular rings and related anomalies I II

III

MORPHOLOGY Double aortic arch Double aortic arch results from the failure of regression of any dorsal aortic root.8 There are two aortic arches,

(b)

IV V

Double aortic arch Left aortic arch Left upper descending aorta Anomalous innominate artery Anomalous left carotid artery Aberrant origin of the right subclavian artery Right-sided upper descending aorta Right-sided aortic arch Mirror-image branches and left ductus arteriosus connected to the aorta Aberrant origin of the left subclavian artery with a left ductus arteriosus connected to the aorta Aberrant left innominate artery Pulmonary sling Cervical aorta

After Stewart et al.8

268 Vascular rings

each giving rise to a carotid and subclavian artery (Fig. 27.2). The anterior arch is located in front of the trachea, and the posterior arch behind the esophagus. When the descending aorta is on the left side, the left arch is anterior and when the aorta descends on the right side, it is posterior. In 45–77% of cases, the aorta descends on the left side.9,10 In the majority of cases, the right arch is the larger. However, occasionally the left arch is the larger or both arches are of a similar size.7–10 Rarely, there is an atretic arch.7–10 In all reported cases, the ductus arteriosus has been found on the left side.10 Signs of compression of the trachea and the bronchus occur in the majority of cases. However, occasionally the patient may be asymptomatic.9 The degree of tracheal and esophageal compression depends on the size of the arches and that of the ductus arteriosus. When the ductus arteriosus is short, it pulls on the pulmonary artery, leads up to compression of the esophagus from the left and therefore contributes to the vascular ring. About 20% of cases may have associated cardiac anomalies such as tetralogy of Fallot, ventricular septal defect, coarctation of the aorta and transposition of the great arteries.8,10

(a)

(b)

Figure 27.2 Double aortic arch. (a) Most often the smaller arch is to the left or anterior to the main arch. (b) The anterior arch is divided between the left carotid and subclavian arteries

Left aortic arch with left upper descending aorta and anomalous innominate artery In this anomaly the innominate artery arises from the aorta more posteriorly than usual or the artery is too short. The trachea may be compressed from its anterior aspect and signs of compression may develop. The anatomy of the aorta and the other branches is normal. According to Mustard et al., 11 compression of the trachea by the innominate artery may be the commonest of all vascular anomalies.

trachea over the anterior surface. When there is sufﬁcient tension over the trachea, symptoms may develop.12

Left aortic arch with aberrant right subclavian artery Aberrant right subclavian artery is the most common anomaly of the aortic arch,7 appearing in 0.5–0.7% of autopsies.8–10 The right subclavian artery arises from the descending aorta and crosses to the right side, mostly behind the esophagus. This anomaly results in the regression of a segment of the ‘hypothetic double aortic arch’ between the right common carotid artery and the right subclavian artery (Fig. 27.3). In some exceptional cases the right subclavian artery may cross from the left to the right between the esophagus and the trachea, or even in front of the trachea.8 When the ductus arteriosus is on the left side, the vascular ring is incomplete and compression of the trachea and the esophagus is not the rule.7 In the few cases presenting with symptoms of stridor and dysphagia, reasons other than vascular compression should be ruled out.8 It was suggested that symptoms of obstruction may exist when the origins of the left and right carotid arteries are close to one another, so the esophagus may be compressed posteriorly by the aberrant right subclavian artery and anteriorly by the trachea and carotid arteries.13 In the rare cases where the ductus arteriosus is on the right side, the vascular ring is complete and signs of compression are more likely.8 A relatively high incidence (37%) of right ductus arteriosus has been found in children with Down syndrome suffering from congenital cardiac anomalies.14 Other associated anomalies are coarctation of the aorta8 and tetralogy of Fallot.10

Left aortic arch and right-sided upper descending aorta This rare anomaly results from regression of the segment between the right ductus arteriosus and the right subclavian artery, regression of the left ductus arteriosus and persistence of the right ductus arteriosus. The ascending aorta passes upwards, arches on the left of the trachea

Left aortic arch with left upper descending aorta and anomalous left carotid artery This anomaly is similar to the previous one. The aorta and its branches are in normal order. The origin of the left carotid artery is deviated to the right and crosses the

(a)

(b)

Figure 27.3 Aberrant right subclavian artery. (a) Anterior view. (b) After ligation and division

Morphology 269

then crosses to the right behind the esophagus, then descends on the right while a ductus arteriosus connects between the right pulmonary artery and the descending aorta.8,9 In cases where the site of the interruption of the hypothetic double aortic arch is between the right carotid and subclavian arteries, an aberrant right subclavian artery may result.7,10 In the majority of the cases there are associated intracardiac anomalies including tetralogy of Fallot, coarctation of the aorta, aortic valve stenosis and incompetence. In two reported cases the aorta crossed from the left to the right in front of the trachea rather than behind the esophagus.10 In a few cases, true vascular ring has been reported.7,8,10

Right aortic arch, mirror-image branches, left ductus arteriosus connected to the aorta Right aortic arch with mirror-image branching will result from regression of the left upper descending aorta. In cases with this anomaly, 95–98% are associated with congenital cardiac anomalies;15,16 90% have tetralogy of Fallot an the rest truncus arteriosus, and transposition of the great arteries.14 In most cases the left ductus arteriosus arises from the left subclavian artery or there is a right ductus arteriosus so there is no vascular ring. In rare cases where the ductus arteriosus connects the left pulmonary artery to the upper descending aorta (as the result of regression of the segment between the left subclavian artery and left ductus arteriosus), there is a complete vascular ring with signs of stridor and dysphagia.8,17–19

Right aortic arch, aberrant left subclavian artery with a left ductus arteriosus The basis of this anomaly is regression of the segment between the left common carotid artery and the left subclavian artery in the hypothetic double aortic arch. The left subclavian artery arises as the last branch and passes to the left behind the esophagus (Fig. 27.4). In the great majority of cases, the ductus arteriosus is left sided and connects the left pulmonary artery to the aberrant left subclavian artery or even to the descending aorta.

(a)

(b)

Figure 27.4 Right aortic arch with retro-esophageal left subclavian and left ligamentum arteriosum (posterior view). (a) Anterior view. (b) Posterior view

The upper descending aorta may cross to the left and descend on the left side, or may descend on the right side.8 There is a vascular ring in this anomaly. However, symptoms may be present in a minority of cases, and only rarely may patients with this anomaly require surgery.16 In contrast to patients with right aortic arch with mirror-image branches, additional intracardiac anomalies are rare in this instance and appear in 10–12% of cases.8,16,20 The associated anomalies may include tetralogy of Fallot,16 coarctation of the aorta and patent ductus arteriosus.18,20

Right aortic arch, aberrant left subclavian artery, atypical origin of the right subclavian artery, without left ductus arteriosus This is an extremely rare anomaly of which only one case has been reported.21 In this case even though the vascular ring was not complete the esophagus was compressed by the subclavian arteries, which were close to one another.

Aberrant left innominate artery This is a rare anomaly of which only a few cases have been reported;22 it results from regression of the left ascending aorta. The ﬁrst branch arising from the aorta is the right carotid artery, followed by the right subclavian artery; the last branch is the left innominate artery arising from the descending aorta. A vascular ring is formed by the right arch, retro-esophageal left innominate artery and the left ductus arteriosus connecting the innominate artery to the left pulmonary artery.

Cervical aortic arch Cervical aortic arch is a rare anomaly. There is an extension of the aortic arch above the clavicles. The embryonic basis may be an aortic arch derived from the second or third, rather than the fourth, brachial arch.23 There may be either left or right aortic arch in the case of cervical aorta. Frequently there are variations of the branching of the great arteries as absence of the innominate artery or aberrant subclavian artery.23 Symptoms of compression on the trachea or esophagus may appear in about half the cases.20 Associated cardiac anomalies, such as septal defect, double outlet right ventricle, tricuspid atresic patent ductus arteriosus, tetralogy of Fallot and multiple coarctations of the aorta have been reported.24

Pulmonary sling Pulmonary sling is an anomaly of the pulmonary artery where the anterior left sixth arch fails to develop. The left lung bud is supplied by a collateral artery branching from

270 Vascular rings

the pulmonary segment of the right sixth arch. Following separation of the lung bud, the artery elongates and takes the place of the left pulmonary artery. The result is a main pulmonary artery and ductus arteriosus in normal position and a left pulmonary artery crossing to the right in front of the trachea, encircling the trachea from the right and extending to the left lung in between the trachea and esophagus8,10 (Fig. 27.5). Signs of compression are common and limited to the respiratory stridor.8,10 Associated anomalies appear in about half the cases of pulmonary artery sling25,26and include left superior vena cava, patent ductus arteriosus, atrial septal defect, aortic arch anomalies, ventricular septal defect, tricuspid atresia, single ventricle and transposition of the great arteries.

cases there are episodes of apnea with cyanosis and unconsciousness. Recurrent respiratory infections aggravate the condition and are more frequent in vascular rings. In mild tracheal compression, symptoms may be present only at the time of respiratory infections. As a result of esophageal compression, the baby feeds poorly and its growth may be retarded. There is difﬁculty in swallowing liquids and solids. Regurgitation and choking, with aggravation of respiratory symptoms, are common in severe cases, whereas in mild cases of obstruction, dysphagia may be the only symptom.29 In case of cervical aortic arch, a pulsatile cervical mass with a thrill or murmur may be noticed.10,23

IMAGING

(a)

(b)

Figure 27.5 (a) Pulmonary artery sling (anterior view). (b) Completed operative repair

SIGNS AND SYMPTOMS About 75% of patients with vascular rings may be symptomatic.27 The four most important vascular rings of infancy and childhood are the double aortic arch, right aortic arch with an aberrant left subclavian artery, pulmonary artery sling, and anomalous origin of innominate artery. Symptoms and signs may appear in 75% of the patients with double aortic arch,10 90% of those with pulmonary artery sling,25,26 and 15% of those with right aortic arch with an aberrant left subclavian artery.16 In pulmonary artery sling and anomalous origin of the innominate artery, the symptoms and signs are related to tracheal obstruction. Usually, symptoms appear in the ﬁrst 6 months of life.23 Approximately half of the patients who are operated on for vascular rings were symptomatic at birth and 96% were symptomatic before 6 months of age.28 The existence and severity of symptoms are related to the tightness and completeness of the vascular ring.10 Respiratory signs include inspiratory stridor with or without an association with an expiratory wheeze and tachypnea. Various positions, such as lying on the back, may aggravate the stridor, while it may be relieved by extension of the neck. Other signs are noisy breathing, a hoarse cry and persistence of a barking cough. In severe

Radiography is a valuable tool in the diagnosis of vascular rings. X-ray presentations of vascular rings have been documented in the past by Neuhauser,6 Stewart et al.8,16 Klinkhamer13 and others. Plain chest X-ray and barium esophagogram may diagnose vascular rings precisely.8 In young children and infants, plain chest Xrays may be misleading when thymic tissue obscures the upper mediastinum. Although plain chest X-ray and barium meal may diagnose vascular rings, further investigations such as bronchoscopy, angiography, computed tomography (CT) scans, magnetic resonance imaging (MRI) and color Doppler echocardiography are necessary to identify the exact anatomy. It is frequently impossible to distinguish between double aortic arch and right aortic arch with aberrant left subclavian artery9 or a cervical aorta and aneurysm of the right carotid artery30 based on chest X-ray and barium esophagogram.

Chest X-ray A chest radiograph is mandatory in any symptomatic child. A normal chest radiograph is evidence against the presence of a vascular ring in symptomatic children.31 The plain X-ray shows prominence of the mediastinum to the right side in double aortic arch, right aortic arch with aberrant left subclavian artery, right aortic arch with mirror-image branching, and left ductus arteriosus and right aortic arch with aberrant left innominate artery. The aortic knob is on the left side in cases of left aortic arch with aberrant innominate or carotid artery, left aortic arch with aberrant right subclavian artery (in this case the aberrant vessel may be seen above the aortic knob) and in left aortic arch with right upper descending aorta (where there is absence of the descending aorta below the aortic knob). In cases of cervical aorta, there is non-speciﬁc widening of the upper mediastinum and absence of the aortic knob in its normal position.

Preoperative considerations 271

Uneven aeration of the lungs while the right lung shows either obstructive emphysema or atelectasis, low left hilus in a frontal X-ray and anterior bowing of the right bronchus in the lateral X-ray are the three radiographic signs typical of pulmonary artery sling.32

Barium esophagogram Barium esophagogram is the most useful method of investigation and is diagnostic in most cases.29, 33 Frontal barium esophagogram shows impression both on the right and left sides in cases of double aortic arch, right aortic arch with mirror-image branching and left ductus arteriosus. Oblique ﬁlling defect from the right, going upwards to the left, is seen in aberrant left subclavian artery with a right aortic arch, while a ﬁlling defect is in the opposite direction in left aortic arch with a right aberrant subclavian artery. In pulmonary artery sling, the esophagus may be deviated to the left. Lateral esophagogram shows posterior compression in cases of double aortic arch, aberrant left or right subclavian artery, aberrant left innominate artery with right aortic arch, left aortic arch with right-sided upper descending aorta, right aortic arch with mirror-image branching and left ductus arteriosus and cervical aortic arch. In pulmonary aortic sling, the esophagus is compressed from the front. In anomalous origin of right innominate or left carotid artery there is no compression on the esophagus. In cases of cervical aortic arch, the posterior pressure on the esophagus is seen at higher levels than in the other anomalies.

Aortography Aortography is an important and accurate method used to assess the anatomy of vascular rings. It may be considered to be the gold standard in the determination of the exact anatomy of vascular rings.8,25,27,34 Although it is an accurate method, angiography involves a signiﬁcant complication rate, especially in neonates.35 Since there are alternative accurate noninvasive imaging methods such as MRI, CT etc., angiograms should only be carried out in cases of rare anomalies where the noninvasive methods fail to obtain the exact anatomy.36

Magnetic resonance imaging MRI is a very accurate noninvasive method that does not necessitate injection of contrast material or radiation.37,38 MRI can demonstrate accurately both the anatomy of the blood vessels and the trachea. In rare cases MRI has compared favourably with angiogram.39 There is increasing evidence that MRI is the method of choice to evaluate the thoracic aorta, principal vessels, pulmonary arteries, and trachea.40–44

Other techniques The development of new CT imaging techniques, can give good imaging of vascular abnormalities.45,46 Ultrafast CT with three-dimensional volume reconstruction provides great anatomic detail of the vascular anomaly and may obviate the need for angiography.47 However CT necessitates injection of contrast material, which may be difﬁcult in the neonate. Bronchoscopy and esophagoscopy should not be used as a rule in the diagnosis of vascular ring, since there may be risk of aggravating the condition of newborns with respiratory distress.25 However, it is very important in the diagnosis of anomalous origin of the innominate artery10,48 and essential in the diagnosis of pulmonary artery sling, since associated tracheobronchial anomalies are common.49 Ultrasonography by using Doppler color ﬂow in suprasternal frontal sweep can display accurately the encirclement of air-ﬁlled trachea by the various types of vascular ring. However, atretic segments without ﬂow cannot be displayed by this method.50 Ultrasonography can diagnose accurately cardiac malformations and is important as a complementary imaging method when additional cardiac defects are suspected.29 In addition vaginal ultrasound can diagnose fetal vascular ring as early as 14–16 weeks’ gestation.51

Diagnosis The initial step in the diagnosis of vascular ring is a chest X-ray and contrast esophagogram. These are simple methods of investigation which may reveal in most cases accurately the anatomy of vascular ring. Once vascular ring has been diagnosed, possibilities other than vascular ring for the patient’s symptoms should be excluded, and a decision made as to whether the patient is symptomatic enough to warrant surgery. When surgery is considered, the anatomy of the vascular ring can be conﬁrmed either by MRI, or alternatively by CT scan.52 Echocardiography should also be performed in order to exclude associated cardiac anomalies and to complete the diagnosis. Aortography should be preserved only for exceptional cases when the results of MRI or CT are not satisfactory, or if there are associated cardiac lesions necessitating cardiac catheterization. In cases of pulmonary artery sling, anomalous origin of innominate artery or suspected tracheobronchial anomalies, bronchoscopy or bronchogram may be performed.

PREOPERATIVE CONSIDERATIONS Indications for surgery It has been shown by Ekstrom and Sanblom that unoperated neonates with severe symptoms of compression

272 Vascular rings

generally die within the ﬁrst 7 months of life.9 On the other hand children with mild symptoms tend to outgrow their symptoms in early childhood. Godtfredsen et al. found that of 11 children with vascular rings and mild symptoms, nine seemed to outgrow their symptoms within 2 years of diagnosis and before 4 years of age.53 Surgical treatment is indicated in neonates and infants with symptoms of stridor, cyanosis, apneic attacks, recurrent intractable respiratory infections and severe dysphagia. Even though in 96% of operated patients symptoms appeared before 6 months of age,28 some older children require surgical intervention due to recurrent respiratory infections54 and some adults were operated on because of dysphagia.48,55 In patients with anomalous innominate artery, bronchoscopy should reveal more than 50% stenosis before surgery is indicated.48

Preoperative management Once the diagnosis of vascular rings and the indication for surgery has been established, operation should not be delayed since there is a risk of sudden death.3,28,56 Patients with severe distress should be operated on without delay following intubation or tracheostomy.28,56 Thorough examination and echocardiogram are mandatory to exclude other tracheo-esophageal or cardiac anomalies. Since tracheobronchial anomalies are common in patients with pulmonary artery sling, preoperative bronchoscopy is recommended as concomitant tracheoplasty might be indicated.48 Neurological investigation, sleep studies and gastro-esophageal reﬂux should be performed to exclude other causes of apneic spells. When other cardiovascular or tracheo-esophageal anomalies are present, it must be determined whether they should be corrected simultaneously with the repair of the vascular ring or separately.48,56

TECHNIQUES OF OPERATION Double aortic arch The approach of choice is through a left thoracotomy in the fourth intercostal space. The technique of thoracotomy is shown in Chapter 25. The lung is retracted forwards and the mediastinal pleura is opened above the descending aorta upwards to the left subclavian artery. The descending aorta, ligamentum arteriosum and aortic arch are dissected completely, including the part of the right arch, which is behind the esophagus. Care is taken to dissect the components of the obstructing vessels away from the trachea and esophagus to relieve the obstruction as much as possible. During the dissection, the recurrent laryngeal phrenic nerves should be identiﬁed and protected.

When the two arches are of the same size, the right posterior arch should be divided between the subclavian artery and descending aorta to maintain normal anatomy. When the arches are of different sizes but both are patent, the smaller arch is to be divided between the subclavian artery and the descending aorta. When there is an atretic segment it should also be divided. Before division of the aortic arch, carotid and radial pulses should be monitored by the anesthetist after a vascular clamp is applied.28,48 The stumps of the aortic arches are sutured with two rows of 4-0 or 5-0 polypropylene stitches. Following division of the aortic arch, the ligamentum arteriosum is divided and ligated, or in the case of patent ductus arteriosus it should be sutured in two rows of 5-0 polypropylene stitches (Fig. 27.2b). To increase the space around the esophagus and trachea, the distal stump of the arch may be transﬁxed to the posterior chest wall by stitches through the adventitia.57 The pleural cavity is drained and the chest wall should be closed in layers. In the case of associated complex cardiac anomalies necessitating complete repair, a combined approach via mid-sternotomy, total circulatory arrest and hypothermia has been described.58 Another option in cases of cyanotic heart diseases in the neonate, or in cases which are not suitable for complete repair, a systemic pulmonary shunt with 4–5 mm polytetraﬂuoroethylene graft is done through a left thoracotomy. As a rule, esophageal atresia should be treated prior to vascular surgery. However, tracheo-esophageal ﬁstula may be treated simultaneously.56

VIDEO-ASSISTED THORACOSCOPIC SURGERY Video-assisted thoracoscopic surgery is an alternative to open thoracotomy with the advantage of minimal trauma to the chest wall structures (muscles and ribs). This technique is suitable for patients with an atretic aortic arch.59 Under general anesthesia with a single-lumen endotracheal tube the patient is placed in the right lateral decubitus position. Four 3 mm long incisions are made in the posterolateral chest wall to introduce grasping forceps, lung retractor, a 4 mm videoscope and a cautery probe. Exposure is achieved by retracting the left upper lobe of the lung inferomedially. The ring elements are dissected off the esophagus and surrounding tissues. Both the aortic attretic arch and ligamentum arteriosum are divided between vascular clips. Fibrous bands around the esophagus are divided, a 12F intercostal drain is inserted and the wounds are closed with STERYSTRIPS™.59 If a patent blood vessel requires division a limited thoracotomy may improve exposure. Proximal and distal control is achieved with vascular clamps and the vascular structure is divided between vascular clamps.59

Techniques of operation 273

Left aortic arch and anomalous innominate artery Anomalous origin of the innominate artery is usually treated by suspension of the proximal part of the artery and the aorta to the sternum. The innominate artery can be approached via mid-sternotomy,25 right anterior thoracotomy11,48 or left anterior thoracotomy.60

MEDIAN STERNOTOMY The sternum is split at the midline. The left lobe of the thymus is excised or retracted to the left. The pericardium is opened at the midline and retracted with stay stitches. The ascending aorta and the proximal 1 cm of the innominate artery are dissected. The artery should not be dissected above the trachea, so that the connective tissue acts as a suspension to the weak tracheal rings when it is retracted. The innominate vein is retracted upwards. Two or three pledged stitches of 2-0 or 1-0 polypropylene are supported with pledgets and are passed through the adventitia of the base of the innominate artery and adjacent aorta, and through the manubrium. Bronchoscopy is done at this stage to assess the relief of the obstruction.48,57 The pericardium is left open, the mediastinal cavity drained and the sternal incision closed.

LEFT THORACOTOMY With the patient lying with the left side elevated, extrapleural or transpleural left anterior thoracotomy is carried out through the second intercostal space. The thymus is retracted or its left lobe is excised. The pericardium is opened anteriorly to the phrenic nerve. The innominate artery is suspended to the manubrium as previously reported. The pericardium is loosely closed, the chest is closed in layers and the mediastinal or pleural cavity is drained.

RIGHT THORACOTOMY The patient is lying on his back and the right side is slightly elevated. Extra- or transpleural anterior thoracotomy is done through the right second intercostal space. The thymus is retracted to the left and the innominate vein retracted upwards. The pericardium is opened, and the superior vena cava retracted to the right. The innominate artery is suspended to the manubrium. Bronchoscopy is done, then the chest is drained and closed.

REIMPLANTATION OF THE INNOMINATE ARTERY Binet and Langlois routinely used division and reimplantation of the innominate artery to a generous annulus in the ascending aorta.56 This technique is not accepted as routine by many authors and may be used in exceptional cases.

Anomalous origin of the carotid artery This anomaly is rare and the surgical technique is identical to that for anomalous innominate artery.

Left aortic arch and aberrant right subclavian artery The approach is through a left thoracotomy. The distal aortic arch and the proximal aberrant right subclavian artery are dissected in the same way as for double aortic arch. The aberrant subclavian artery is divided and the stumps sutured with 5-0 polypropylene. The distal stump should be retracted to the right (Fig. 27.3b). In neonates and young children, the division of the subclavian artery does not cause major complications.61 In adults, the division of the aberrant right subclavian artery through a left thoracotomy and implantation of the right subclavian artery to the right carotid artery through a cervical approach has been described.62 A simpler approach for implantation of the aberrant subclavian artery and relief of the vascular ring is through the right thoracotomy. In case of concomitant coarctation of the aorta, a simultaneous operation for both lesions can be carried out.63

Left aortic arch and right-sided descending aorta The approach is from the right side through a posterolateral thoracotomy in the fourth intercostal space. The ductus arteriosus (or ligamentum arteriosum) is divided and the trachea and esophagus released from adhesive bands.

Right aortic arch with left ductus arteriosus The approach is the left posterolateral thoracotomy in the fourth intercostal space. The ductus arteriosus and ligamentum arteriosum are divided and the trachea and esophagus dissected from adhesive bands.48 The approach is the same, both for patients with mirrorimage branching and those with an aberrant left subclavian artery.48 In a case of compression caused by an aberrant left subclavian artery with an additional division of the ligamentum arteriosum, the left subclavian artery was divided and reimplanted to the left carotid artery.64 Reimplantation of the left subclavian artery is superior to its division without reimplantation. Steal phenomenon, which necessitated late reoperation for reimplantation of the divided aberrant subclavian artery, 44 years after the original operation has been reported.65 In cases of ligamentum arteriosum without compression caused by an aberrant left subclavian artery, division

274 Vascular rings

of the ligamentum arteriosum can be done by videoassisted thoracoscopic surgical techniques.59

POSTOPERATIVE CONSIDERATIONS Mortality

Cervical aorta In cervical aortic arch, relief of compression can be achieved by division of the ligamentum arteriosum.10,20

Pulmonary sling Repair of pulmonary artery sling can be done through a left thoracotomy66 or median sternotomy with cardiopulmonary bypass.

LEFT THORACOTOMY This is the main method used.25,67 A left posterolateral thoracotomy is done through the fourth intercostal space. The superior part of the pulmonary hilum is dissected to identify the left pulmonary artery. The left pulmonary artery is dissected as far as possible and freed from the adjacent structures while the ligamentum arteriosum is divided. The patient is given a heparin dose of 1.5 mg/kg. The pulmonary artery is divided between clamps and the proximal stump closed with a continuous 5-0 polypropylene stitch. Two incisions are made in the pericardium, one anterior to the phrenic nerve and the other posterior to the phrenic nerve. The distal stump is brought into the pericardial cavity in front of the trachea through the posterior incision. The left pulmonary artery is anastomosed to the main pulmonary artery and to the side by using a side-biting clamp. The posterior part is carried out with a single layer of running 5-0 polypropylene stitches and the anterior one by using interrupted sutures. The pericardium is left open and the chest closed.

MEDIAN STERNOTOMY Through a median sternotomy,25 cardiopulmonary bypass is used with a single venous drain. The temperature is lowered to 25°C. The pleural space is opened and the left main pulmonary artery dissected free. The pulmonary artery is resected and reimplanted anteriorly to the trachea on the main pulmonary artery.

RESECTION AND REANASTOMOSIS OF THE RIGHT BRONCHUS Other methods include tracheoplasty associated with reimplantation of the aberrant pulmonary artery on the main pulmonary artery.56 Another method used consists of transection of the right bronchus and reanastomosis posteriorly to the trachea. This method is not routinely used but is useful in cases of associated tracheal stenosis.26

Operative and early postoperative mortality rates vary between 0% and 5%.28,48,55,63,67 In the past 30 years the mortality rate has been approaching 0%.55,56,66,67 Patients undergoing operation for pulmonary artery sling may have a higher mortality rate (up to 50%).26 However, more recent reports show lower mortality rates.48,56,66 The late mortality rate is about 4%.48,55,67 The majority of deaths are caused by respiratory complications due to tracheomalacia and other tracheobronchial abnormalities.26,48,49,67 Following video-assisted thoracoscopy, the mortality rate is 0%.59,68

Postoperative care and operative results The postoperative care of these children may require special attention, including prolonged intubation, repeated tracheal aspiration toilet and bronchoscopies. Some patients may even need a tracheostomy. Tracheomalacia due to prolonged compression and the young age of patients may increase the rate of postoperative respiratory complications. Between 20% and 50% of patients may need prolonged ventilatory support28,62and 5% may need tracheostomy.28,48 Rates of respiratory complication are higher for patients operated on for pulmonary artery sling – 44% may require tracheostomy.48 Following the procedure, immediate relief of symptoms is expected in 43% of the patients,27 and later on 60–90% of the patients are asymptomatic.28,48 The rest of these patients may have various degrees of mild to moderate respiratory complications including cough, stridor, recurrent respiratory infection and recurrent hospitalizations.28,63,67 In the majority of these cases, the symptoms subside within 1 year.56 In these symptomatic patients, medical follow-up, including esophagogram and endoscopies, is required.69 Exceptional cases may require reoperation, including aortopexy, to relieve tracheal pressure.48 Although most cases show signiﬁcant symptomatic relief, respiratory studies show that there is residual elevated respiratory airway resistance up to 10 weeks following the operation.70 Long-term studies show that although most of the patients are asymptomatic following the operation, 41% show abnormal pulmonary function tests.67 Sade et al. showed that following repair of pulmonary artery sling, and good symptomatic relief, the left pulmonary artery was still frequently occluded.26 However, recent studies have shown that the left pulmonary artery was patent in 83% and left lung perfusion was present in all operated patients.66

References 275

REFERENCES 1. Hommel L. Commercium litterarium morimbergae, p.161. Cited by Ekstrom G, Sanblom P. Double aortic arch. Acta Chir Scand 1952; 102:183–202. 2. Bayford D. An account of a singular case of obstructed deglutition. Mem Med Soc Lond 1789; 2:275–86. 3. Wolman IJ. Syndrome of constricting double aortic arch in infancy. Report of a case. J Pediatr 1939; 14:527–33. 4. Gross RE. Surgical relief for tracheal obstruction from a vascular ring. N Engl J Med 1945; 233:586–90. 5. Gross RE. The surgical signiﬁcance of aortic arch anomalies. Surg Gynecol Obstet 1946; 83:435–48. 6. Neuhauser EBD. Roentgen diagnosis of double aortic arch and other anomalies of great vessels. Am J Roentgenol Rad Ther 1946; 56:1–12. 7. Edwards JE. Anomalies of the derivatives of the aortic arch system. Med Clin N Am 1948; (July):925–49. 8. Stewart JR, Kinkai OW, Edwards JE. An Atlas of Vascular Rings and Related Malformations of the Aortic Arch System. Springﬁeld, Illinois: Thomas, 1964. 9. Ekstrom G, Sanblom P. Double aortic arch. Acta Chir Scand 1951; 102:183–202. 10. Keith JD, Rowe RD, Vlad P. Heart Diseases in Infancy and Childhood, New York: Macmillan, 1978. 11. Mustard WT, Bayliss CE, Fearon B et al. Tracheal compression by the innominate artery in children. Ann Thorac Surg 1969; 81:312–19. 12. Gross RE, Neuhauser EBD. Compression of the trachea and oesophagus by vascular anomalies: surgical therapy in 40 cases. Pediatrics 1951; 7:69–88. 13. Klinkhamer AC. Aberrant right subclavian artery – clinical and roentgenological aspects. Am J Roentgenol Rad Ther Nucl Med 1966; 97:438–46. 14. Goldstein WB. Aberrant right subclavian artery in mongolism. Am J Roent Rad Ther Nucl Med 1965; 97:131–4. 15. Felson B, Palayew MJ. The two types of right aortic arch. Radiology 1963; 84:748–59. 16. Stewart JR, Kinkaid OW, Titus JL. Right aortic arch. Plain ﬁlm diagnosis and signiﬁcance. Am J Roentgenol Rad Ther Nucl Med 1966; 97:377–98. 17. Neuhauser EDB. Tracheoesophageal constriction produced by right aortic arch and left ligamentum arteriosum. Am J Roentgenol Rad Ther 1949; 62:493–9. 18. Otero-Cagide M, Moodie DS, Sterba R et al. Digital subtraction angiography in the diagnosis of vascular rings. Am Heart J 1986; 112:1304–8. 19. Slesinger AE, Mendeloff E, Sharkey AM, Spray TL. MR of right aortic arch with mirror branching and a left ligamentum arteriosum: an unusual case of a vascular ring. Pediatr Radiol 1995; 25:455–7. 20. D’Cruz IA, Cantez T, Neumin E et al. Right-sided aorta. Br Heart J 1966; 28:722–39. 21. Yap J, Hayward PE, Lincoln C. Right aortic arch with aberrant subclavian arteries: a cause of esophageal compression. Ann Thorac Surg 1999; 68:2331–2.

22. Grollman JH, Bedynek JL, Henderson HS et al. Right aortic arch with an aberrant retroesophageal innominate artery: angiographic diagnosis. Radiology 1968; 90:782–3. 23. Hyman RA, Stein HL. The cervical aortic arch anomaly. Angiology 1975; 26:749–58. 24. Kumas S, Mandalam KR, Unni M et al. Left cervical arch and associated abnormalities. Cardiovasc Intervent Radiol 1989; 12:88–91. 25. Kirklin JW, Barrat Boyes BG. Cardiac Surgery. New York: Wiley, 1986. 26. Sade RM, Rosenthal A, Fellows K et al. Pulmonary artery sling. J Thorac Cardiovasc Surg 1975; 69:333–46. 27. Bakker DA, Berger RM, Witsenburg M, Bogers AG. Vascular rings: a rare cause of common respiratory symptoms. Acta Paedatr 1999; 88:947–52. 28. Reosler M, de Leval M, Chrispin A et al. Surgical management of vascular ring. Ann Surg 1983; 197:139–46. 29. Lillehei CW, Colan S. Echocardiography in the preoperative evaluation of vascular rings. J Pediatr Surg 1992; 27:1118–20. 30. Beavan TEM, Fatti L. Ligature of aortic arch in neck. Br J Surg 1947; 34:414–16. 31. Pickhardt PJ, Siegel MJ, Gutierrez FR. Vascular rings in symptomatic children: frequency of chest ﬁndings. Radiology 1997; 203:423–6. 32. Capitanio MA, Ramos R, Kirkpatrick JA. Pulmonary sling – roentgen observations. Am J Roentgenol Rad Ther Nucl Med 1971; 112:28–34. 33. Ledwith MV, Duff DF. A review of vascular rings 1980–1992. Ir Med J 1994; 87:178–9. 34. Garti I, Aygen MM, Levy MJ. Double aortic arch anomalies: diagnosis by counter-current right brachial arteriography. Am J Roentgenol 1979; 133:251–6. 35. Stranger P, Heyman MA, Tarnoff H et al. Complications of catheterization of neonates, infants and children. Circulation 1974; 50:595–600. 36. Singh GK, Greenberg SB, Balsara RK. Diagnostic dilemma: left aortic arch with right descending aorta – a rare vascular ring. Pediatr Cardiol 1997; 18:45–8. 37. Coscina WF, Kressel HY, Gofter W et al. MR imaging of double aortic arch. J Comput Assist Tomog 1986; 10:673–5. 38. Kersting-Sommerhoff BA, Sechtem UP, Fisher MR et al. MR imaging of congenital anomalies of the aortic arch. Am J Roentgenol 1987; 149:9–13. 39. McLeary MS, Frye LL, Young LW. Magnetic resonance imaging of a left circumﬂex aortic arch and aberrant right subclavian artery: the other vascular ring. Pediatr Radiol 1998; 28:263–5. 40. Van Son JAM, Julsrud PR, Hagler DJ et al. Imaging strategies for vascular rings. Ann Thorac Surg 1994; 54:604–10. 41. Soer R, Rodriguez E, Requejo I, Fernandez R, Raposo I. Magnetic resonance imaging of congenital anomalies of the thoracic aorta. Eur Radiol 1998; 8:540–6.

276 Vascular rings 42. Beekman RP, Beek FJ, Hazekamp MG, Meijboom EJ. The value of MRI in diagnosis of vascular abnormalities causing stridor. Eur J Pediatr 1997; 156:516–20. 43. Van Son JA, Julsrud PR, Hagler DJ, Sim EK, Pairolero PC, Puga FJ, Danielson GK. Surgical treatment of vascular rings: the Mayo Clinic experience. Mayo Clin Proc 1993; 68:1056–63. 44. Azarow KS, Pearl RH, Hoffman MA, Zurker R, Edwards FH, Cohen AJ. Vascular ring: does magnetic resonance imaging replace angiography. Ann Thorac Surg 1992; 53:882–5. 45. Webb WR, Gamsu G, Speckman HM et al. CT demonstration of mediastinal aortic arch anomalies. J Comput Assist Tomog 1982; 6:445–51. 46. Baron RL, Gutierrez RF, Sagel SS et al. CT of anomalies at the mediastinal vessels. Am J Roentgenol 1981; 137:571–6. 47. Van Son JA, Starr A. Demonstration of vascular ring anatomy with ultrafast computed tomography. Torac Cardiovasc Surge 1995; 43:120–1. 48. Backer CL, Ibawi MN, Idriss FA et al. Vascular anomalies causing tracheoesophageal compression. J Thorac Cardiovasc Surg 1989; 97:725–31. 49. Campbell DN, Clarke DR, Lilly JR. Pulmonary artery sling (letter). Thorac Cardiovasc Surg 1990; 99:725–31. 50. Murdison KA, Andrews BAA, Chin AJ. Ultrasonographic display of complex vascular rings. J Am Coll Cardiol 1990; 15:1645–53. 51. Bronshtein M, Lorber A, Berant M, Auslander R, Zimmer EZ. Sonographic diagnosis of fetal vascular rings in early pregnancy. Am J Cardiol 1998; 81:101–3. 52. Katz M, Konen E, Rozeman J. Spiral CT and 3D image reconstruction of vascular rings and associated tracheobronchial anomalies. J Comp Assist Tomog 1995; 19:564–8. 53. Godtfredsen J, Wennevold A, Efsen F et al. Natural history of vascular ring with clinical manifestations – a follow-up study of eleven unoperated cases. Scand J Thorac Cardiovasc Surg 1977; 11:75–7. 54. Van Aalderen WMC, Hoekstra MO, Hess J et al. Respiratory infections and vascular rings. Acta Paediatr Scand 1990; 790:477–80. 55. Lam B, Kabbani S, Archiniegas E. Symptomatic anomalies of the aortic arch. Surg Gynecol Obstet 1978; 147:673–81.

56. Binet JP, Langlois J. Aortic arch anomalies in children and infants. J Thorac Cardiovasc Surg 1977; 73:248–52. 57. Filston HC, Ferguson TB, Oldham HN. Airway obstruction by vascular anomalies – importance of telescopic bronchoscopy. Ann Surg 1987; 205:541–9. 58. Virdi IS, Keeton BR, Shore DF et al. Surgical management in tetralogy of Fallot and vascular rings. Pediatr Cardiol 1987; 8:131–4. 59. Burke RP, Rosenfeld HM, Wernovsky G, Jonas RA. Videoassisted thoracoscopic vascular ring division in infants and children. J Am Coll Cardiol 1995; 25:943–7. 60. Stark J, de Leval M. Surgery for Congenital Heart Defects. London: Grune and Stratton, 1983, 227–34. 61. Todd DJ, Dangerﬁeld PH, Hamilton DJ et al. Late effects on left upper limb of subclavian ﬂap aortoplasty. J Thorac Cardiovasc Surg 1983; 85:678–83. 62. Syderys H. New operation for symptomatic aberrant right subclavian artery (dysphagia lusoria). J Thorac Cardiovasc Surg 1969; 57:269–76. 63. Richardson JV, Dety DB, Rossi NP et al. Operation for aortic arch anomalies. Ann Thorac Surg 1981; 31:426–32. 64. Chao LC. Repair of right aortic arch with aberrant left subclavian artery and left ligamentum arteriosum. J Pediatr Surg 1990; 25:795–6. 65. Ciocca RG, Wilkerson DK, Madson DL, Andrew CT, Graham AM. Symptomatic subclavian steal syndrome four decades after operation for dyphagia lusoria. Ann Vasc Surg 1995; 9:204–8. 66. Dunn JM, Gordon I, Chrispin AR et al. Early and late results of surgical correction of pulmonary artery sling. Ann Thorac Surg 1979; 28:230–8. 67. Marmon LM, Bye MR, Haas JM et al. Vascular ring and slings – long term follow-up of pulmonary function. J Pediatr Surg 1984; 19:683–92. 68. Lavoie J, Burrows FE, Hansen DD. Video assisted thoracoscopic surgery for the treatment of congenital cardiac defects in the pediatric population. Anesth Analg 1996; 82:563–7. 69. Kraus DM, Hayes JD, Tucker HM. Vascular ring anomaly. Head Neck Surg 1989; 11:170–3. 70. Thompson AH, Beardsmore CS, Firmin R et al. Airway function in infants with vascular rings: preoperative and postoperative assessment. Arch Dis Childh 1990; 65:171–4.

28 Pulmonary air leaks PREM PURI

INTRODUCTION Pulmonary air leaks include urgent life-threatening neonatal emergencies like pulmonary interstitial emphysema, pneumomediastinum, pneumothorax or pneumopericardium.1 The incidence of pulmonary air leaks in the neonates has increased in recent years, possibly because an increasing number of sick infants with respiratory distress on assisted ventilation are now surviving to develop this complication.2 The sequence of events in the occurrence of pulmonary air leaks is similar regardless of whether it is caused by uneven alveolar ventilation, air trapping and high transpulmonary pressure swings. The rupture of terminal air sacs causes air to escape into the pulmonary interstitium, resulting in pulmonary interstitial emphysema. The air tracks along the sheaths of pulmonary blood vessels to the lung hilum and air may then rupture into mediastinum, pleura or pericardium.3 It has also been suggested that air directly enters the pleural cavity following a rupture of a subpleural bleb.4 Rarely systemic air embolism may be a terminal event of pulmonary air leaks.5,6

Presentation and diagnosis Pulmonary interstitial emphysema may be diffuse or localized. It is a radiological diagnosis found on the chest X-ray of an ill neonate. The radiological features consist of hyperinﬂation and multiple cyst-like lucencies that appear to radiate outward from the hilum of the lung (Fig. 28.1). Suspect neonates should be monitored by daily chest X-ray for an earlier diagnosis of PIE.

PULMONARY INTERSTITIAL EMPHYSEMA Pulmonary interstitial emphysema (PIE) is predominantly seen in preterm infants with respiratory distress syndrome (RDS) who are on assisted ventilation.1 Occasionally it follows vigorous resuscitative efforts. The lesion represents air that has dissected along perivascular sheath within pulmonary interstitium. The compression caused by interstitial ‘airconduits’ interferes with ventilation and reduces pulmonary perfusion leading to CO2 retention and hypoxemia. The incidence of PIE increases with low birth weight and prematurity. In one series, 20 out of 303 ventilated low birth weight (LBW) babies developed PIE,7 but signiﬁcantly high incidences of 32% and 42% have been reported in other series.8,9

Figure 28.1 Diffuse pulmonary interstitial emphysema in a baby weighing 1200 g and requiring prolonged positive pressure ventilation for hyaline membrane disease. The lungs are grossly hyperinﬂated with a diffuse cystic pattern in this ﬁlm at 7 days of life. Note narrow heart shadow due to tamponade effect of the distended lungs. A shallow pneumothorax is present in the left upper zone and a left chest drain has been inserted

278 Pulmonary air leaks

Treatment PIE, diffuse or localized, makes ventilatory management difﬁcult. Ventilatory pressures should be kept at a safe minimum while aiming for acceptable blood gas values of PaO2 > 6–7 kPa, pH > 7.25, and PaCO2 < 8 kPa.10 No speciﬁc treatment is indicated for diffuse PIE apart from various changes suggested in ventilation such as withdrawal of positive end-expiratory pressure (PEEP),11 increasing rates to 100–200/minute,12 and reintroduction of use of continuous negative pressure ventilations.13,14 An aggressive approach of decompressing the lungs and creation of artiﬁcial pneumothorax by scariﬁcation of the lung surface through the chest wall has been described.15 If the disease is unilateral or localized, selective partial or complete atelectasis of the desired segment can be achieved by selective bronchial intubation,16,17 or by placing the infant with his hyperinﬂated lung dependent in the lateral decubitus position at all times.18 Localized pulmonary interstitial emphysema cases have also been successfully treated by resection of the diseased lobes.19,20

retrosternal space (Fig. 28.2b). Ultrasound can be used to diagnose pneumomediastinum as an alternative to a decubitus ﬁlm.25 Retrocardiac pneumomediastinum has a strong association with other manifestations of extraalveolar air leaks such as PIE, pneumothorax, dissection of air into the soft tissues of the neck and pneumoperitoneum.26 Tension pneumomediastinum has also been described to cause isolated left ventricular inﬂow obstruction.27

Prognosis The mortality rate from diffuse PIE has been reported to be from 24% to as high as 60%.21,22 There have been no signiﬁcant differences in neonatal parameters between infants who died or survived. However, the survivors had a signiﬁcantly lower maximal peak inspiratory pressure and FiO2 on the ﬁrst day of ventilation.22 PIE is invariably fatal in the group of neonates with RDS who weigh < 1600 g at birth and who develop bilateral PIE within the ﬁrst 48 hours of life, needing FiO2 above 0.6 on the ﬁrst day. High positive inspiratory pressure on day 1 was found to be the most signiﬁcant parameter associated with fatal pulmonary interstitial emphysema. A cut-off level of 26 cmH2O was found to be discriminant.23 These criteria may be useful in selecting neonates who might beneﬁt best from the new modes of ventilation.

(a)

PNEUMOMEDIASTINUM Pneumomediastinum develops when interstitial air in PIE migrates to the mediastinum. If the collection of air is small, it remains asymptomatic. However, large collections of mediastinal air may produce respiratory distress. Heart sounds are mufﬂed and the sternum may appear bowed. The diagnosis is made on chest X-ray. The anteroposterior views may show the characteristic ‘angel-wing’ sign produced by air elevating the thymus gland (Fig. 28.2a). It has also been described as having a crescentic conﬁguration resembling a ‘spinnaker’ sail.24 Lateral X-ray of the chest shows marked hyperlucency in the superior

(b) Figure 28.2 Pneumomediastinum. (a) Anteroposterior view demonstrates the characteristic ‘angel wing’ sign produced by air elevating the thymus from the heart. (b) Lateral view conﬁrms air in the anterior mediastinum

Treatment 279

Symptomatic pneumomediastinum is managed by needle aspiration of the anterior mediastinal compartment. In asymptomatic cases, air is absorbed spontaneously and no treatment is indicated.

PNEUMOTHORAX Pneumothorax is far more frequent in the newborn period than in any other period of life – the incidence is 1% of all newborns.28–31 It is bilateral in about 15–20% of cases.10 Pneumothorax in the newborn predominantly occurs in patients with hyaline membrane disease, meconium aspiration syndrome, pulmonary hypoplasia, and infants requiring vigorous resuscitation at birth. The overall incidence of pneumothorax in the newborn with respiratory difﬁculties has been reported to be as high as 34% of those who are ventilated.32 Pneumothorax can also be caused by iatrogenic perforation of the bronchus33 and as a complication of deep endotracheal tube suction.34 A rare association of spontaneous tension pneumothorax with congenital cystic adenomatoid malformation35 and early spontaneous pneumothorax with common pulmonary vein atresia36 has been reported. The ‘surgical’ cases of pneumothorax and/or pneumomediastinum at the Liverpool Neonatal Surgical Centre included infants with gross renal anomalies, large exomphalos, a rare type of vascular sling, and spontaneous perforation of esophagus. In half of the cases the etiology was less obvious.37 Pneumothorax should be suspected in infants with respiratory distress who suddenly deteriorate. Tachypnea is a uniform ﬁnding and is often accompanied by grunting, chest retractions and cyanosis. Physical ﬁndings in unilateral pneumothorax include a shift of the cardiac impulse to the unaffected side, diminished or absent breath sounds, and a hyperresonant percussion note on the affected side. In tension pneumothorax, hypotension, apnea and bradycardia are usually the initial signs. A large pneumothorax can be diagnosed by transillumination using a high-intensity light with ﬁberoptic probe.38 The advantage of this method is the rapidity with which large life-threatening pneumothoraces can be diagnosed and treated. The gold standard for diagnosis is radiography of the chest. A large pneumothorax is easily recognizable in infants by identiﬁcation of the visceral pleural line, which is most readily seen over the apex and along the costal surface of the lung (Fig. 28.3). Other important observations in pneumothoraces are a mediastinal shift and absence of lung markings. Small volume pneumothoraces are more difﬁcult to identify and in these cases, lateral decubitus cross-table views are very helpful in showing the rise in pleural air to the lateral or medial side of the hemithorax (Fig. 28.4).

Figure 28.3 Right pneumothorax complicating interstitial emphysema in an infant with hyaline membrane disease. Note air lucency around right lung with absence of lung markings. The mediastinum is shifted to the left, indicating tension

Figure 28.4 Small-volume pneumothorax demonstrated in the lateral decubitus view with the right side raised

TREATMENT Most small pneumothoraces with no symptoms need only close observation and monitoring in a neonatal intensive care unit. The ventilatory management should aim to keep pressures at lower acceptable values, faster rates above 60/minute rather than 30–40/minute and use sedation or paralysis earlier.39–41 A pneumothorax should be drained in the following situations:

280 Pulmonary air leaks

• Tension pneumothorax • When it is symptomatic • In all babies on intermittent positive pressure ventilation (IPPV), even if asymptomatic. The infant should be temporarily disconnected from the ventilator during the introduction of a chest drain or aspiration of a pneumothorax to avoid the risk of lung damage.42 In a desperately ill neonate, a life-saving emergency needle aspiration of a tension pneumothorax can be done before formal insertion of a chest drain. A butterﬂy (18gauge) or i.v. cannula with a three-way tap and a 20 ml syringe can be used for decompression. Aspiration is performed through the second intercostal space in the mid-clavicular line. The insertion of the needle is oblique through the muscle plane to avoid entry of air once the needle is removed. Occasionally a single aspiration may be enough but all these babies must be closely observed and monitored clinically and radiologically as nearly all of them require a tube thoracostomy on follow-up. Tube thoracostomy is required in the majority of cases. A chest drain (10–14 French gauge) is inserted through the second intercostal space in the mid-clavicular line or the sixth space in the mid-axillary line under local anesthesia. A purse-string stitch in the skin around the site of the catheter insertion can be left to be tied later at the time of removal of the catheter.37 The tip of the chest tube should be placed anteriorly retrosternally for better drainage.43 After ﬁxing the catheter ﬁrmly, it is connected to an underwater seal drain with or without a low-grade suction of 5–10 cmH2O. Once the lung is expanded and stable, the tube can then be removed. A chest ﬁlm should be obtained after removal of the tube to ensure that a pneumothorax has not recurred. Use of conventional chest drains is not free from complication as they can cause lung perforation,42 and four cases of phrenic nerve paralysis have been reported related to abnormal location of the medial end of the chest tube.44 There are newly designed pigtail pleural drainage catheters available.45,46 but a properly sized ordinary chest drain should be adequate in the majority of cases, with an underwater seal or with a vacuum-control unit. The Heimlick ﬂutter valve, though useful clinically, adds to the resistance of the system, especially if ﬂuid accumulates in the valve.47

of grades 3 or 4 intraventricular hemorrhage in infants with pneumothoraces associated with hypotension is 89% as compared with neonates with pneumothoraces associated with normal blood pressure, which is only 10%.50 This can have a detrimental effect on the neurological outcome. Ventilatory parameters may be helpful in making a prognostic assessment. The survivor group respond well to a fraction of inspired oxygen of less than 70% and a PEEP of 6 cm or less. A CO2 retention associated with pneumopericardium and PIE is a bad sign.48

Pneumopericardium Pneumopericardium is the least frequent pulmonary air leak. However, recently it has been occurring with increasing frequency as a complication of ventilatory therapy. Pneumopericardium can also develop while the patients are on high-frequency ventilation respiratory support.51 Neonatal pneumopericardium has also been reported in a full-term neonate following a forceps delivery and mild asphyxia.52 The exact etiology of pneumopericardium is not known; it is probably interstitial pulmonary air, secondary to alveolar rupture, which dissects into the mediastinum and then enters the pericardial space at the reﬂection of the pericardium onto the great vessels. The pneumopericardium may be asymptomatic or symptomatic. Asymptomatic infants do well without any treatment. The clinical signs in symptomatic patients are those of cardiac tamponade, i.e. a sudden onset of bradycardia, mufﬂed heart sounds, cyanosis and hypotension. Changes in ECG axis and/or voltage may be observed. The classical radiological ﬁnding is a continuous radiolucent band of air that conforms to the cardiac outline and does not extend beyond the level of the great vessels (Fig. 28.5). Extra ventilatory air (PIE and pneumomediastinum) is present in over 90% of patients.

Prognosis Cases with pneumothoraces without underlying lung disease have a good prognosis. The mortality rate is 31% when it is associated with RDS.10 In one series of infants presenting with pneumothoraces within the ﬁrst 24 hours of life, the overall mortality rate was 52%.48 The mortality rate is inversely proportional to the infant’s birth weight: 53% in infants with birth weights < 1 kg.49 The incidence

Figure 28.5 Pneumopericardium in a 2-day-old full-term infant with complicating meconium aspiration. Note right pneumothorax also

References 281

Simple needle pericardiocentesis is the appropriate therapy for most cases with cardiac tamponade. However, a few babies with pneumopericardium uncontrolled by needle aspiration require placement of a pericardial catheter for continuous drainage of air. The mortality rate in infants with pneumopericardium is high.

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management of pulmonary interstitial emphysema: a preliminary study. J Perinatol 1989; 9(1):26–32. Milligan DWA, Issler H, Massam M, Reynolds EOR. Treatment of neonatal pulmonary interstitial emphysema by lung puncture. Lancet 1984; i:1010–11. Brooks JG, Bustamante SA, Koops BL. Selective bronchial intubation for the treatment of severe localised pulmonary interstitial emphysema in newborn infants. J Pediatr 1977; 91:648–52. Weintraub Z, Oliven A, Weissman D, Sonis Z. A new method for selective left main bronchus intubation in premature infants. J Pediatr Surg 1990; 25(6):604–6. Cohen RS, Smith DW, Stevenson DK, Moskowitz PS, Graham CB. Lateral decubitus position as therapy for persistent pulmonary interstitial emphysema in neonates: a preliminary report. J Pediatr 1984; 104:441–3. Fletcher DB, Outerbridge GE, Youssef S. Pulmonary interstitial emphysema in a newborn infant treated by lobectomy. Pediatrics 1974; 54:808–11. Bauer BR, Brennan MJ, Doyle C. Surgical resection for pulmonary interstitial emphysema in the newborn infant. J Pediatr 1978; 93:656–61. Greenough A, Dixon AD, Roberton NRC. Pulmonary interstitial emphysema. Arch Dis Childh 1984; 59:1046–51. Lerman-Sagie T, Davidson S, Wielunsky E. Pulmonary interstitial emphysema in low birth weight infants: characteristics of survivors. Acta Paediatrica Hungarica 1990; 30:383–9. Morisot C, Kacet N, Bouchez MC, Rouland V, Dobos JP, Gremillet C, Lequien P. Risk factors for fatal pulmonary interstitial emphysema in neonates. Eur J Pediatr 1990; 149(7):493–5. Moseley JE. Loculated pneumomediastinum in the newborn. A thymic ‘spinnaker’ sign. Radiology 1960; 75:788–90. Van Gelderen WF. Ultrasound diagnosis of an atypical pneumomediastinum. Paediatr Radiol 1992; 22(6):469. Rosenfeld DL, Cordell CE, Jadeja N. Retrocardiac pneumomediastinum: radiographic ﬁndings and clinical implication. Pediatrics 1990; 85(1):92–7. Case CL, Oslizlok P, Fyfe D, Gillette PC. Neonatal pneumomediastinum with isolated mitral obstruction. Arch Dis Childh 1990; 65:56–8. Steele RW, Metz JR, Bass JW, Dubois JJ. Pneumothorax and pneumomediastinum in the newborn. Radiology 1971; 98:629–32. Sahn SA, Heffner JE. Spontaneous pneumothorax. N Eng J Med 2000; 342(12):868–74. Wilcox DT, Glick PL, Karamanoukian HL et al. Spontaneous pneumothorax: a single-institution experience in patients under 16 years of age. J Pediatr Surg 1995; 30:1452–4. Alter SJ. Spontaneous pneumothorax in infants: a 10-year review. Pediatr Emerg Care 1997; 13:401–3.

282 Pulmonary air leaks 32. Madansky DL, Lawson EE, Chernick V, Taeusch HW. Pneumothorax and other forms of pulmonary air leaks in the newborn. American Review of Respiratory Disease 1979; 120:729–37. 33. Holcomb GW III, Templeton JM Jr. Iatrogenic perforation of the bronchus intermedius in a 1,100-g neonate. J Pediatr Surg 1989; 24(11):1132–4. 34. Jaw MC, Soong WJ, Chen SJ, Hwang B. Pneumothorax: a complication of deep endotracheal tube suction: report of 3 cases. Chin Med J 1991; 48(4):313–17. 35. Bentur L, Canny G, Thorner P, Superina R, Babyn P, Levison H. Spontaneous pneumothorax in cystic adenomatoid malformation. Unusual clinical and histologic features. Chest 1991; 99(5):1292–3. 36. Sharda JK, Kurlandsky LE, Lacina SJ, Radecki LL. Spontaneous pneumothorax in common pulmonary vein atresia. J Perinatol 1990; 10(1):70–4. 37. Irving IM. Neonatal Surgery. Malformations and acquired lesions of lungs, pleura and mediastinum. In: Lister J, Irving IM, editors. Neonatal Surgery. 3rd edn. London: Butterworths, 1990: 259–78. 38. Kulrus LR, Bednarek FJ, Wyman ML, Roloff DW, Borer RC. Diagnosis of pneumothorax or pneumomediastinum in the neonate by transillumination. Pediatrics 1975; 56:355–60. 39. Heicher DA, Kasting DS, Richards JR. Prospective clinical comparison of two methods of mechanical ventilation of neonates: rapid rate and short inspiratory time versus slow rate and long inspiratory time. J Pediatr 1981; 98:957–61. 40. Octave Study Group. Multicentre randomised controlled trial of high against low frequency positive pressure ventilation. Arch Dis Childh 1991; 66:770–8. 41. Cooke RWI, Rennie JM. Pancuronium and pneumothorax. Lancet 1984; i:286–7.

42. Moessinger AC, Driscoll JM Jr, Wigger HJ. High incidence of lung perforation by chest tube in neonatal pneumothorax. J Pediatr 1978; 92:635–7. 43. Allen RW, Jung AL, Lester PD. Effectiveness of chest tube evacuation of pneumothorax in neonates. J Pediatr 1981; 99:629–34. 44. Odita JC, Khan AS, Dincsoy M, Kayyali M, Masoud A, Ammari A. Neonatal phrenic nerve paralysis resulting from intercostal drainage of pneumothorax. Pediatr Radiol 1992; 22(5):379–81. 45. Lawless S, Orr R, Killian A, Egar M, Fuhrman B. New pigtail catheter for pleural drainage in pediatric patients. Crit Care Med 1989; 17(2):173–5. 46. Jung AL, Nelson J, Jenkins MB, Hodson WA. Clinical evaluation of a new chest tube used in neonates. Clin Pediatr 1991; 30(2):85–7. 47. Bakker JC, Liem M, Wijnands JB, Karsdon J, Berger HM. Neonatal pneumothorax drainage systems: in vitro evaluation. Eur J Pediatr 1989; 149(1):58–61. 48. Mandal AK, Yamini S, Bean X. Arterial blood gas and expiratory pressure monitoring in infants with pneumothorax: prognostic predictability. J Natl Med Assoc 1990; 82(1):33–7. 49. Greenough A, Robertson NRC. Morbidity and survival in neonates ventilated for respiratory distress syndrome. Br Med J 1985; 290:597–600. 50. Mehrabani D, Gowen CW Jr, Kopelman AE. Association of pneumothorax and hypotension with intraventricular haemorrhage. Arch Dis Childh 1991; 66(1 Spec No):48–51. 51. Neal RC, Beck DE, Smith VC, Null DM. Neonatal pneumopericardium with high frequency ventilation. Ann Thorac Surg 1989; 47(2):274–7. 52. Bjorklund L, Lindroth M, Malmgren N, Warner A. Spontaneous pneumopericardium in an otherwise healthy full term newborn. Acta Paediatr Scand 1990; 79(2):234–6.

29 Chylothorax and other pleural effusions in neonates RICHARD G. AZIZKHAN

INTRODUCTION Chylothorax results from the leakage of chyle from the thoracic duct into the pleural cavity. Although it is rare, it is a well-established clinical entity and is the most common cause of pleural effusion encountered in neonates.1–3 Whether congenital or acquired, chylothorax generally resolves with nonoperative measures aimed at optimizing ventilation and maintenance of nutrition. When these measures fail to bring about spontaneous healing, operative management becomes imperative. When resolution does not occur, persistent chylothorax can become a life-threatening disorder with profound respiratory, nutritional, and immunologic consequences.1,3–6 While early diagnosis, aggressive initiation of nonoperative management options, and a number of alternative surgical procedures have signiﬁcantly decreased the mortality rate from 50% before the 1950s7,8 to currently reported estimates ranging from 10–20%,2,9–13 signiﬁcant morbidity continues. In light of these facts, chylothorax will be the primary focus of this chapter. A basic description of the anatomy and embryology of the lymphatic system as well as the pathophysiology of chyle will provide the framework essential to an understanding of this disorder. Other pleural effusions, including empyema and hemothorax will also be brieﬂy discussed. Since malignant effusions rarely occur in neonates, they have been omitted from the discussion.

level of the ﬁfth thoracic vertebra, continues its ascent into the neck on the left of the esophagus, and opens into the venous system at the conﬂuence of the internal jugular and subclavian veins. In the thorax it receives lymph from the parietal pleura of both sides via several collecting trunks. Lymphatic branches from structures in the posterior mediastinum and from the left lung and its pleura join to form the left bronchomediastinal trunk; this trunk opens into the thoracic duct or directly into the great veins. There are also several potential lymphovenous communications that may function when the main duct is traumatized or blocked (Fig. 29.1). The lymphatic system, a diffuse network of endothelial channels, appears during the sixth week of

ANATOMY AND EMBRYOLOGY OF THE LYMPHATIC SYSTEM Lymph is collected in the cisterna chyli and reaches the venous system via the thoracic duct, which ascends in the posterior mediastinum between the azygos vein and the descending aorta. This duct crosses to the left at the

Figure 29.1 Anatomy of the lymphatic system

284 Chylothorax and other pleural effusions in neonates

development. The growth of this system is a phenomenon of consecutive centrifugal budding from original lymph sacs. In the early 1900s Sabin14 demonstrated that these sacs originated from the endothelium of the adjacent veins, establishing venous endothelium as the primordial structure of the lining of the lymphatic system. She further recognized that all lymphatic channels are developed as outgrowths of the venous endothelium in six original lymph spaces: two jugular lymph sacs, two iliac sacs, a single retroperitoneal sac, and the cisterna chyli.14 These sacs invade the tissues by continuous growth and branching. The lymphatic system arises by conﬂuence of perivenous mesenchymal spaces to form larger spaces. These in turn join to form continuous vessels that eventually drain into the venous system. While the thoracic duct is usually a singular structure, its embryology underscores the potential for anatomical variations and congenital anomalies.6,15 It may develop in different anatomical patterns with several lymphaticovenous anastomoses. Variation in lymphatic pathways and the presence of accessory lymphatic channels can account for chylous effusions resulting from surgical procedures that do not expose the main thoracic duct.16 Trauma to the duct in the posterior mediastinum can produce a unilateral or bilateral chylothorax. Increased intraductal tension leads to drainage of chyle into the thorax. A lesion to the thoracic duct below the level of the ﬁfth lumbar vertebra will result in a right-sided chylothorax; a left-sided chylothorax occurs with lesions above this level.

PATHOPHYSIOLOGY OF CHYLE At birth, chyle is clear and straw colored; soon after milk feeding begins, chylomicrons (emulsiﬁed fat globules) render it milky white. Depending on the amount of milk ingested, the fat content of the ﬂuid varies from 0.4–4.0 g/100 mL, with a triglyceride content of > 500 mg/100 mL.17 Although the protein and electrolyte contents of chyle are similar to those in plasma, chyle is rich in T-cell lymphocytes, with a lymphocyte count of 80–100%. The volume of chyle loss per day can exceed 1.7 times the patient’s blood volume, resulting in a serious state of depletion characterized by hyponatremia, hypoproteinemia, metabolic acidosis and lymphocytopenia.3 Untreated chylothorax is associated with severe respiratory compromise due to pulmonary parenchymal compression. The thoracic duct drains most of the body lymph, including the entire intestinal lymph (chyle) into the venous system in the neck. Basal ﬂow of the lymph from the duct averages 1.4 mL/kg/hour and varies with meals. Fatty meals may increase lymph ﬂow up to 10 times the basal rate, while lesser increases in the rate of ﬂow are

effected by the ingestion of proteins, carbohydrates, and even by oral intake of water.18

ETIOLOGY OF CHYLOTHORAX Congenital chylothorax Congenital chylothorax is a common cause of neonatal pleural effusion and is classically a disorder of infants at or near term. Males are affected twice as frequently as females and 60% of cases involve the right side of the chest.19 In view of existing knowledge of the anatomy and embryology of the thoracic duct, the occurrence of chylothorax in the absence of other demonstrable disease suggests the existence of congenital malformations involving the lymphatic system. Congenital atresia of the thoracic duct or congenital ﬁstulas due to failure of peripheral lymphatic channels to communicate with the major lymphatic network have moreover been assumed on the basis of diffuse chyle leakages seen during surgery.2 Congenital defects of the lymphatic system that may reveal themselves in chylothorax are well documented in the literature, presenting clinically as lymphangiomatosis20–26 or congenital pulmonary lymphangiectasis.27–29 Congenital chylothorax is also associated with hydrops fetalis30–34 and various syndromes such as trisomy 21,35–37 Turner syndrome, and Noonan syndrome.38,39 Over the past decade, its occurrence in combination with other uncommon disorders such as autosomal recessive lymphatic anomalies, mediastinal neuroblastoma in a newborn, and neonatal thyrotoxicosis has been documented as well.40–42

Acquired chylothorax Acquired chylothorax results primarily from surgical or traumatic insult to the thoracic duct, and virtually every intrathoracic surgical procedure has been associated with it. Iatrogenic injury can occur during surgery in the region of the aortic arch for conditions such as patent ductus arteriosus, coarctation of the aorta, vascular ring and other congenital cardiovascular anomalies, as well as during esophageal repair or repair of congenital diaphragmatic hernia.43–46 Acquired chylothorax also manifests as a complication of both subclavian and internal jugular venous cannulation and/or obstruction, superior vena caval obstruction secondary to central venous catheters or elevated central venous pressures,30,47–52 chest tube insertion53 and traumatic delivery.54 Additionally, in recent years there have been anecdotal reports of chylothorax resulting from a blunt blow to the abdomen due to child abuse.55 Chylothorax/chylopericardium is a rare complication, occurring primarily following surgery for congenital heart diseases.56

Management of chylothorax 285

CLINICAL FEATURES OF CHYLOTHORAX Presenting symptoms Tachypnea, dyspnea, retraction of chest and cyanosis mark the onset of chylothorax, with dullness and diminution of breath sounds on the affected side and displacement of the heart and mediastinum to the opposite side. In cases of congenital chylothorax, symptoms of respiratory distress may be noted shortly after birth or at any time up to 2 weeks of life. In contrast, the interval between surgery and the occurrence of acquired chylothorax can vary from 1–25 days. The time is shortest when there is a direct injury to the duct (5–7 days) and longest when there is high pressure or thrombosis of the vena cava (10–14 days). Chyle may accumulate in the mediastinum for several days before extravasating into the pleural space.

Consequence of continuous chylous ﬂow

Figure 29.2 Chest radiograph in a term neonate demonstrating bilateral chylothorax

The loss of large quantities of chyle over a period of time produces nutritional failure, sepsis, metabolic acidosis and renal failure. Considerable loss of protein and large numbers of lymphocytes may result in immunodeﬁciencies, including hypogammaglobulinemia and abnormal cell-mediated immune responses.

content of the chylothorax may be quite low and the ﬂuid does not have the characteristic milky appearance. The protein content is somewhat less than that of serum and the electrolytes approximate those of serum.

DIFFERENTIAL DIAGNOSIS

MANAGEMENT OF CHYLOTHORAX

Radiographs of the chest typically show opaciﬁcation of one or both hemithoraces, with compression of lung and displacement of mediastinal structures in unilateral chylothorax (Fig. 29.2). Radiographic diagnosis in premature infants may, however, be difﬁcult. Most of these infants already have signiﬁcant pulmonary disease, and chest radiographs may appear to have areas of increasing consolidation rather than the more typical layering of pleural ﬂuid seen in older children. Sonography is a reliable method of detecting chylothorax in these cases, and its increasing use in obstetric practice as the primary method of imaging the fetal chest has led to the increasing frequency with which fetal chylothorax is being diagnosed33, 57–61 (see section on fetal chylothorax). Diagnosis is conﬁrmed after analysis of the pleural ﬂuid drained by thoracentesis or chest tube placement. Initially, this ﬂuid is serous; it turns chylous only after milk feedings have begun. Chyle is characterized by elevated total protein and albumin levels, a speciﬁc gravity of > 1.012, the presence of white blood cells with a predominance of lymphocytes (80–100%) and elevated triglycerides, cholesterol, and total fat levels if the infant is milk fed.13 In the unfed neonate, the fat

Historical overview and current consensus Since chylothorax is associated with a wide array of disorders and accompanying clinical circumstances, the management of patients with this condition has varied considerably. Historically there has been a diversity of opinion regarding nonoperative and operative treatment approaches. The timing and type of operative intervention have been particularly controversial. Despite the differences, it is generally agreed that initial thoracentesis is diagnostic and may provide immediate relief of respiratory failure. If failure persists, mechanical ventilation may be required. A course of therapy that avoids the serious nutritional, metabolic and immunologic sequelae known to the disease should then be chosen.62 If the infant is able to tolerate enteral feeding, nonoperative management initially consists of enteral feeding with medium-chain triglycerides (MCT). In recalcitrant or severe cases, patients may require total parenteral nutrition (TPN) or a combination of both modalities.9–11,56,63,64 This protocol is generally successful. It was established in view of early studies indicating that the most serious complication of chylothorax was protein–calorie malnutrition.7,8 More than 60% of

286 Chylothorax and other pleural effusions in neonates

ingested fats travel to the bloodstream via the thoracic duct. MCTs, which have a 6- to 10-carbon backbone, are the only fats to be absorbed directly via the portal system, bypassing the lymphatics.65 There is general consensus that if lymphatic drainage does not resolve within a 2-week period with nonoperative management, or if a patient’s nutritional or metabolic status declines measurably during that time, surgical intervention should be undertaken.

General management principles The general principles of management for chylothorax include the following: • Thoracentesis is performed to provide immediate relief of respiratory failure and to conﬁrm the diagnosis through chemical analysis of a pleural ﬂuid specimen. • Supportive ventilation is instituted as required. • Thoracostomy tube drainage is carried out if pleural ﬂuid reaccumulates after one or two thoracenteses. (Repeating this procedure carries a risk of producing pneumothorax and introducing infection; chest tube drainage keeps the lungs fully expanded, which is necessary for sealing chyle leakage). • Nutritional losses are replaced through a high-protein diet, rich in MCTs that are absorbed directly into the portal venous system. • Parenteral feeding is instituted. (When superior vena caval thrombosis is present with chylothorax, TPN may need to be delivered via a peripheral vein).47,66 • The albumin, gammaglobulin and ﬁbrinogen that are contained in chyle, as well as fat-soluble vitamins, are adequately replaced. • Full expansion of the lungs is maintained by continuous chest tube drainage of chyle. (These tubes may become obstructed and require replacement as necessary). • Prophylactic antibiotics are given when chest tubes are in place, since many of these infants have an acquired immune deﬁciency caused by lymphocytopenia. Some infants may also need salt restriction, diuretics and digoxin. • Surgical intervention is warranted when these therapies fail to signiﬁcantly diminish chylous drainage for more than 14 days or if there is obvious deterioration in the patient prior to that period of time (Fig. 29.3).

Nonoperative management As cited earlier, an initial trial of nonoperative management relying on adequate drainage of chyle, coupled with nutritional supplementation via MCT-enriched

diets and/or TPN should be given in order to optimize the chance of recovery without surgery. Using this regimen, the majority of cases of congenital chylothorax and 50% of cases with traumatic chylothorax (postoperative) resolve spontaneously.63,64 Some investigators have observed no difference in MCT or TPN in regard to duration or amount of drainage.56,62,66 Others have found that for patients with superior vena caval obstruction and congenital lymphatic malformation, MCT alone is not as effective; thus they recommend the rapid administration of TPN.66 Positive reports on the use of somatostatin in a case of lymphorrhagia from a ruptured thoracic duct67 and the use of a somatostatin analog in the management of congenital chylous ascites68 lend optimism to the possibility of adding new therapies to the current nonoperative treatment armamentarium. Unpublished cases also indicate that moderately high doses of somatostatin have been successful in closing chylous ﬁstulas; this lends further credibility to the likelihood that this may offer another viable nonsurgical option.55 It is also noteworthy that a recently published case report described the use of nitric oxide for the successful management of refractory postoperative chylothorax in a neonate with pulmonary and central venous hypertension.69 This may offer yet another nonoperative therapeutic tool for this subset of the patient population.

Operative management The percentage of neonates requiring surgery and the timing of surgical intervention varies widely among reported series, and are dependent on the patient population studied and the clinical status of individual patients. Operative management has, however, been the mainstay of treatment for a number of clinical conditions that have a high failure rate with standard nonoperative management; these include postsurgical cases in which there is injury to the thoracic duct and massive lymph leakage, caval obstruction, or elevated central venous pressures.16,56,66,70,71 Congenital chylothorax associated with superior vena caval thrombosis in the premature neonate is also particularly refractory to standard nonoperative therapy.47 Since failure is associated with a high mortality rate, some investigators maintain that surgical intervention should be considered early in the management strategy of such cases.66,72–74 Several surgical options exist and they are often used in combination. They include pleuroperitoneal shunting, thoracic duct ligation (open thoracotomy or thoracoscopy), pleurodesis with different agents, pleurectomy, and intrapleural ﬁbrin glue.

PLEUROPERITONEAL SHUNTS The use of pleuroperitoneal shunts has become the ﬁrst line of surgical treatment at a number of major pediatric

Management of chylothorax 287 Chylorthorax

Progressive effusion Chest tube

Stable effusion

Improvement

Failure

Decreasing output

High output > 7 days

MCT-rich feedings 7–10 days Improvement

Failure

Surgical options

TPN 3 weeks

Failure Success

Failure

MCT-rich feedings 21 days

Success Effusion resolving

Postoperative chylothorax

Bilateral chylothorax, SVC obstruction, Congenital lymphangiectasia

Thoracoscopic Thoracic duct ligation + fibrin glue

Regular diet

Primary approach

Failure Pleuroperitoneal shunt Failure Pleurectomy Direct open ligation Lymphatic leaks

Success Shunt remains until effusions resolve (2–3 months)

Figure 29.3 Algorithm of management principles. SVC: superior vena cava; MCT: medium-chain triglycerides; TPN: total parenteral nutrition

centers across North America. First used by Azizkhan et al 75 in 1983 to treat ﬁve ventilator-dependent infants with persistent chylothorax, this procedure is considered safe, highly effective, and easy to perform. Moreover, it avoids the risks of a more complicated, open surgical procedure.74–77 The ideal shunt should have a pumping chamber that is capable of handling ﬂuid with an increased viscosity. It should contain a one-way valve system that opens at a very low pressure to allow transport of lymph from the pleural space, with a mean negative pressure, to the abdominal cavity, with a mean positive pressure. It should also have a reservoir that allows for percutaneous irrigation of the entire shunting system. At Cincinnati Children’s Hospital Medical Center, we use a pleuroperitoneal shunt system (Denver Biomaterials, Inc, Evergreen, CO) that is specially designed for pediatric

patients. The shunt has two polyester cuffs, a doublevalved pumping chamber, and fenestrated afferent and efferent catheter limbs; it is ﬂexible and can be trimmed to the appropriate length. The chamber has a pumping volume of 1.0–1.5 mL and is usually used for infants younger than 6 months. The valves open at a positive pressure of approximately 1.0 cm H2O and are designed to prevent retrograde movement of the chyle through the system. Manual pumping is used to transport ﬂuid from the pleural space into the peritoneal cavity. The shunting procedure is carried out under general anesthesia. The infant is kept in a supine position, with the affected hemithorax elevated by 25–30° on the operating table. A short transverse incision is made over the affected lower chest at the anterior axillary line, allowing access for the pleural catheter; this catheter is then tunneled 2–3 cm through the subcutaneous tissues

288 Chylothorax and other pleural effusions in neonates

(Fig. 29.4a, b). It is placed into the thorax at approximately the seventh or eighth intercostal space in the posterior axillary line, thereby allowing dependent drainage. A second small incision is made overlying the rectus muscle sheath in the upper abdomen midway between the costal margin and the level of the umbilicus. Prior to placement of the peritoneal catheter, the pumping chamber is compressed repeatedly to verify effective pumping action and proper transport of chyle from the thorax. The efferent catheter is tunneled 2–3 cm and placed into the peritoneal cavity through the rectus incision similar to a Tenckhoff catheter placement. A purse-string suture is used in the posterior rectus fascia to secure the catheter. A postoperative chest radiograph is obtained to make certain that the pleural catheter is properly placed. During the immediate postoperative period the pumping chamber is compressed 50–100 times per hour in order to completely clear the hemithorax of chyle. As the

infant’s clinical status improves, a gradual decrease in the frequency of shunt compression is begun. Non-invasive transcutaneous oxygen saturation monitoring, arterial blood gas determination, and serial chest radiographs are used to assess shunt efﬁcacy (Fig. 29.5). Manual compression of the shunt valve is discontinued when it is clear that chylothorax is resolved. This often occurs within 2–3 weeks. However, some infants require a more prolonged period of manual compression, lasting 6–8 weeks. A high-ﬂow external shunt designed to avoid some of the discomfort and positioning problems associated with a subcutaneous reservoir has recently become available.78 Once the chylous effusion clears, parents are taught the technique of pumping the chamber and the patient is discharged from the hospital. Over the ensuing 2–3 months, the frequency of pumping is further reduced. When the chylous effusion completely resolves, the catheter is removed. This approach offers less interruption of the sleep cycle and may facilitate a shorter hospital stay. It could, nevertheless, theoretically increase the likelihood of infection, but this has yet to be veriﬁed in clinical studies. While there has been some concern that elevated right atrial pressures transmitted to the venous and lymphatic bed of the peritoneal space may impair absorption of shunted pleural ﬂuid,73,79 a recent study has reported the successful use of pleuroperitoneal shunting with this patient population, even in the face of moderate elevations in right atrial pressure.73 Failure to resolve chylous effusions is associated with occlusion of the shunt catheter or signiﬁcant intra-abdominal chylous ascites. When the latter occurs, a pleuroperitoneal shunt

(a)

Reservoir Pumping chamber

(b) Figure 29.4 (a) Pleuroperitoneal shunt. (b) Schematic illustration showing placement of a pleuroperitoneal shunt

Figure 29.5 Chest radiograph showing resolution of a chylothorax after pleuroperitoneal shunt placement

Fetal chylothorax (hydrothorax) 289

and a peritoneovenous shunt combination has been successfully used in anecdotal cases. Encouraged by the success of pleuroperitoneal shunting in the management of refractory chylothorax, investigators have applied the same principle in the management of patients with chylopericardium. Case reports indicate that pericardial–peritoneal shunting provides an easy and effective alternative to prolonged pericardial drainage, thoracotomy, or thoracic duct ligation in patients with chylopericardium of various etiologies.80

OTHER SURGICAL ALTERNATIVES Although thoracic duct ligation has historically been the most common surgical therapy and has indeed been a successful approach in terms of resolving chylous leakage,5,81–83 it requires an already compromised, frail, and often premature neonate to undergo a major surgical procedure. Despite this drawback, it remains an option when pleuroperitoneal shunting fails to resolve the chylous leak or when chylothorax is due to penetrating trauma. The affected hemithorax is opened by a posterolateral thoracotomy through the sixth intercostal space. Giving cream through the nasogastric tube several hours before operation helps to identify the sites of leakage of the milky white ﬂuid. Major leaks from the thoracic ducts can be closed by direct suturing or ligating the duct above and below the leak. Chemical or talc pleurodesis84 and parietal pleurectomy85 have been used when there is generalized weeping of chyle from parietal pleura. However, these are also extensive surgical procedures that may increase the possibility of pulmonary lymphedema, ﬁbrosis, and further pulmonary demise.74 Fibrin glue applied to the leakage site after patent ductus arteriosus ligation has recently been reported to successfully manage chylothorax in both a 3.5-month-old infant,86 and a premature infant weighing 600 g.87 Video-assisted procedures are being used with increasing frequency. Video-assisted thoracoscopy offers the advantage of access to the entire hemithorax, with excellent visualization of the mediastinal structures. It allows application of clips to the thoracic duct at the hiatus or to the thoracic duct injuries or pleural defects. It also allows pleurodesis and application of ﬁbrin glue. However, despite its advantages, its use is limited by the infant’s size and pulmonary status. Also, it may be difﬁcult to correctly visualize leaks in the presence of a massive chylous effusion.

FETAL CHYLOTHORAX (HYDROTHORAX) Diagnosis and outcome Congenital chylothorax is the most common cause of fetal effusions. Moreover, with the growth in sonography

over the past 3 decades, it is being diagnosed with increasing frequency – as early as at 17 weeks’ gestation to an average of 30 weeks.34 For the most part, reviews indicate that congenital chylothorax has a much better prognosis when diagnosed after birth than when discovered in utero.1,12,13,60 In contrast to the relatively low mortality rate of newborns diagnosed at birth, only half of all diagnosed fetuses survive. Survival depends on multiple factors, including the presence of associated anomalies, and the gestational age at which diagnosis is ﬁrst made. The prognosis of small volume, unilateral, isolated fetal pleural effusion is usually good, with spontaneous resolution sometimes observed.60,88–90 Prognosis is poor when effusion is associated with chromosomal aberrations, multiple malformations and fetal hydrops. Since most large pleural effusions discovered in utero lead to hydrops and pulmonary hypoplasia, such effusions have a high mortality rate.60 Furthermore, retrospective studies have shown that the absence of hydrops predicts 100% survival; fetuses that initially presented without hydrops and subsequently developed it, had only a 38% survival.34 From a broad perspective, antenatal diagnosis is signiﬁcant not only in that it can often identify the need for potentially helpful intrauterine intervention and facilitate preparation of appropriate postnatal outcome, but also in that it has been found to be a reliable predictor of fatal outcome.91,92 As such, it facilitates the communication of a more accurate prognosis to parents. The presence of hydrops predicts poor perinatal outcome and indeed suggests a strong indication for therapeutic intervention.

Management The management of fetal chylothorax has been a matter of controversy and the optimal approach to its treatment remains unknown. Dissension is focused primarily on the following issues: (1) whether treatment should be attempted in utero or the infant should be delivered and treated after birth, (2) under what clinical circumstances antenatal intervention should be carried out, and (3) whether thoracentesis or pleuroamniotic shunting should be used for thoracic decompression. In an attempt to propose an overall prenatal management scheme, Weber and Philipson93 recently reviewed 124 cases from 38 reports in the medical literature on fetal pleural effusion. They concluded that the presence of three risk factors indicated the highest probability of poor outcome – delivery at less than 32 weeks’ gestation, presence of hydrops, and absence of antenatal intervention. While both thoracentesis and pleuroamniotic shunting have successfully managed prenatal chylothorax,31,32,60,61,94–98 the paucity of published data prevents generalized conclusions as to which approach is better. Both involve

290 Chylothorax and other pleural effusions in neonates

risks and potential complications. In a relatively recent (1995) case report, the authors suggest that in certain cases (nonimmune hydrops associated with a unilateral pleural effusion), single or serial thoracenteses may forego the need for intrathoracic shunt placement. If chylous effusions are not successfully reduced with two thoracenteses, they recommend the placement of a thoracic shunt. As they nevertheless maintain, in light of the scarcity of data, these recommendations are speculative at best.

OTHER PLEURAL EFFUSIONS Hemothorax Although massive hemothorax is very uncommon, accidental injury to the intercostal artery during thoracentesis or closed intercostal drainage can result in intrapleural bleeding.99 Hemothorax has been reported as a complication of a variety of congenital malformations (e.g. sequestration, patent ductus, and pulmonary arteriovenous malformation) and of subclavian vein catheters.100 It is also an occasional manifestation of intrathoracic neoplasms and blood dyscrasias, and bleeding diatheses.101 Additionally, it can occur spontaneously in neonates, sometimes in association with a pneumothorax. Symptoms reveal respiratory embarrassment similar to that seen in tension pneumothorax. However, the percussion note is dull and chest radiographs show opaciﬁcation. More importantly, the infant may show signs of hypovolemic shock. Blood transfusion and urgent tube thoracostomy generally provide adequate control of bleeding. To avoid sudden circulatory collapse, transfusion should precede intercostal drainage. If massive blood loss continues, urgent thoracotomy and identiﬁcation and securing of the bleeding site is required.99

Empyema Owing primarily to improved antibiotic treatment of chest infections, empyema (purulent effusion) has become a rare condition in infants. The most common cause of empyema is a pneumonia caused by organisms such as Staphylococcus areus, Pneumococcus and Hemophilus inﬂuenzae. It may, however, be incurred through the introduction of skin bacteria during thoracentesis or thoracotomy. Empyema may also be accompanied by anaerobic infection.102 Symptoms include indications of respiratory distress, in addition to abdominal distension, lethargy, and at times, a septicemic state. Diagnosis is suspected by chest radiograph in which the effusion and pneumonic process is identiﬁed. Ultrasonography during diagnostic thoracentesis is helpful in localizing the ﬂuid, if loculated. Prior to beginning a course of

antibiotic therapy, a ﬂuid specimen taken during thoracentesis is sent for a Gram stain and aerobic and anaerobic culture. While most cases resolve with effective intercostal tube drainage and a prolonged period of systemic administration of antibiotics, anaerobic infection tends to be multi-locular and may thus require debridement, and in rare instances, decortication.

REFERENCES 1. Vain NE, Swarner OW, Cha CC. Neonatal chylothorax. A report and discussion of nine consecutive cases. J Pediatr Surg 1980; 15:261–5. 2. Van Aerde J, Campbell AN, Smyth JA et al. Spontaneous chylothorax in newborns. Am J Dis Child 1984; 138:961–4. 3. Curci MR, Debbins AW. Bilateral chylothorax in a newborn. J Pediatr Surg 1980; 15:663–5. 4. Kosloske AM, Martin LW, Schubert WK. Management of chylothorax in children by thoracentesis and medium chain triglyceride feedings. J Pediatr Surg 1974; 9:365–71. 5. Bessone LN, Ferguson TB, Burford TH. Chylothorax: collective review. Ann Thorac Surg 1971; 12:527–50. 6. Randolph JG, Gross RE. Congenital chylothorax. Arch Surg 1957; 74:405–19. 7. Schackelford RT, Fisher AM. Traumatic chylothorax. South Med J 1938; 11:766–75. 8. Lampson RS. Traumatic chylothorax: a review of the literature and report of a case treated by mediastinal ligation of the thoracic duct. J Thorac Surg 1948; 17:778–91. 9. Higgins CB, Reinke RT. Postoperative chylothorax in children with congenital heart disease. Pediatr Radiol 1976; 119:409–13. 10. Verunelli F, Georgini V et al. Chylothorax following cardiac surgery in children. J Cardiovasc Surg 1983; 24:227–30. 11. Decancq HG. The treatment of chylothorax in children. Surg Gynecol Obstet 1965; 121:509–12. 12. Chernick V, Reed MH. Pneumothorax and chylothorax in the neonatal period. J Pediatr 1970; 76:624–32. 13. Brodman RF. Congenital chylothorax, recommendations for treatment. NY J Med 1975; 75:553–7. 14. Sabin FR. The origin and development of the lymphatic system. Johns Hopkins Hosp Rep 1916; 17:347–440. 15. McKendry JBJ, Lindsey WK, Gerstein MC. Congenital defects of the lymphatics in infancy. Pediatrics 1957; 19:21. 16. Bond SJ, Guzzetta PC, Snyder ML et al. Management of pediatric postoperative chylothorax. Ann Thorac Surg 1993; 56:469–73. 17. Strausser JL, Flye MW. Management of nontraumatic chylothorax. Ann Thorac Surg 1981; 31:520–6. 18. Harvey JG, Houlsby W, Sherman K et al. Congenital chylothorax: report of a unique case associated with ‘H’-type tracheo-oesophageal ﬁstula. Br J Surg 1979; 46:485–7.

References 291 19. Yancy WS, Spock A. Spontaneous neonatal pleural effusion. J Pediatr Surg 1967; 2:313–19. 20. Berberich FR, Bernstein ID, Ochs HD et al. J Pediatr 1975; 87:941–3. 21. Morphis IG, Arcinne EL, Krause JR. Generalized lymphangioma in infants with chylothorax. Pediatrics 1970; 46:566–75. 22. Takamato RM, Armstrong RG, Stanford W et al. Chylothorax with multiple lymphangiomatoses of the bone. Chest 1971; 59:681–2. 23. Dunkelman H, Sharief N, Berman L et al. Generalized lymphangiomatosis with chylothorax. Arch Dis Child 1989; 64:1058–60. 24. Moerman P, VanGeet C. Lymphangiomatosis of the body wall. Pediatr Pathol Lab Med 1997; 17:617–24. 25. Thomas HM, Shaw NJ, Weindling AM. Generalized lymphangiomatosis with chylothorax. Arch Dis Child 1990; 65:334. 26. Dutheil P, Leraillez J, Guillemette J et al. Generalized lymphangiomatosis with skin lymphangiomas in a neonate. Pediatr Dermatol 1998; 15:296–8. 27. Noonan J, Walter LR, Reeves JT. Congenital pulmonary lymphangiectasis. Am J Dis Child 1970; 120:314–19. 28. Moerman P, Vandenberghe K, Devlieger H et al. Congenital pulmonary lymphangiectasis with chylothorax: a heterogeneous lymphatic vessel abnormality. Am J Med Genet 1993; 47:54–8. 29. Hunter W, Becroft D. Congenital pulmonary lymphangiectasis associated with pleural effusions. Arch Dis Child 1984; 59:278–9. 30. Adiotomre PNA, Burns JE, McIntosh N. Hydrops foetalis and chylothorax associated with superior caval vein obstruction and resolution following balloon dilatation. Acta Paediatr 1994; 83:983–5. 31. Mussat P, Dommergues M, Parat S et al. Congenital chylothorax with hydrops: postnatal care and outcome following antenatal diagnosis. Acta Pediatr 1995; 84:749–55. 32. Aguirre OA, Finley BE, Ridgway LE III et al. Resolution of unilateral fetal hydrothorax with associated non-immune hydrops after intrauterine thoracentesis. Ultrasound Obstet Gynecol 1995; 5:346–8. 33. Ahmad FK, Sherman SJ, Hagglund KH et al. Isolated unilaterial fetal pleural effusion: the role of sonographic surveillance and in utero therapy. Fetal Diagn Ther 1996; 11:383–9. 34. Laberge JM, Crombleholme TM, Longaker MT. Fetal diseases and their management. In: Harrison MR, Golbus MS, Filly RA, editors. The Unborn Patient. 2nd edn. Philadelphia: W.B. Saunders Co., 1991: 314–19. 35. Yoss BS, Lipsitz PJ. Chylothorax in two mongoloid infants. Clin Genet 1977; 12:357–60. 36. Hamada H, Fujita K, Kubo T et al. Congenital chylothorax in a trisomy 21 newborn. Arch Gynecol Obstet 1992; 252:55–8. 37. Foote KD, Vickers DW. Congenital pleural effusion in Down’s syndrome. Br J Radiol 1986; 59:609.

38. Fisher E, Weiss EB, Michaels K et al. Spontaneous chylothorax in Noonan’s syndrome. Br J Pediatr 1982; 138:282–4. 39. Goens MB, Campbell D, Wiggins JW. Spontaneous chylothorax in Noonan syndrome. AJDC 1992; 146:1453–6. 40. Williams MS, Josephson KD. Unusual autosomal recessive lymphatic anomalies in two unrelated Amish families. Am J Med Genet 1997; 73:286–9. 41. Easa D, Balaraman V, Ash K et al. Congenital chylothorax and mediastinal neuroblastoma. J Pediatr Surg 1991; 26:96–8. 42. Ibrahim H, Asamoah A, Krouskop RW et al. Congenital chylothorax in neonatal thyrotoxicosis. J Perintatol 1999; 19:68–71. 43. Cevese PG, Vecchioni R, D’Amico DF et al. Postoperative chylothorax. J Thorac Cardiovasc Surg 1975; 69:966–71. 44. Naik S, Greenough A, Zhang Y-X et al. Prediction of morbidity during infancy after repair of congenital diaphragmatic hernia. J Pediatr Surg 1996; 31:1651–4. 45. Claris O, Besnier S, Lapillonne A et al. Chylothorax following surgical repair of congenital diaphragmatic hernia in ﬁve neonates. Prenat Neonat Med 1996; 1:94–6. 46. Kavvadia V, Greenough A, Davenport M et al. Chylothorax after repair of congenital diaphragmatic hernia—risk factors and morbidity. J Pediatr Surg 1998; 33:500–2. 47. Dhande V, Kattwinkel J, Alford B. Recurrent bilateral pleural effusion secondary to superior vena cava obstruction as a complication of central venous catheterization. Pediatrics 1983; 72:109–13. 48. Ruggieto RP, Caruso G. Chylothorax – a complication of subclavian vein catheterization. J Parenter Enter Nutr 1985; 9:750–3. 49. Seguin JH. Right-sided hydrothorax and central venous catheters in extremely low birthweight infants. Am J Perinatol 1992; 9:154–8. 50. Kramer SS, Taylor GA, Garﬁnkel DJ et al. Lethal chylothoraces due to superior vena caval thrombosis in infants. AJR 1981; 137:559–63. 51. Blalock A, Cunningham RS, Robinson CS. Experimental production of chylothorax by occlusion of the superior vena cava. Ann Surg 1936; 104:359–63. 52. Liote H, Hamy I, Piganeau N et al. Neonatal bilateral chylothoraces secondary to obstruction of the superior vena cava (as complication of inadvertent placement of an umbilical vein catheter). Radiographics 1990; 10:152–6. 53. Kumar SP, Belik J. Chylothorax—a complication of chest tube placement in a neonate. Crit. Care Med 1984; 12:411–12. 54. Wilson-Storey D, MacKinlay GA. Thoraco-abdominal birth injury—presentation, diagnosis and management in an unusual case. Scot Med J 1987; 32:89–90. 55. Rodgers BM. Verbal communication, 2000. 56. Nguyen DM, Shum-Tim D, Dobell ARC et al. The management of chylothorax/chylopericardium following pediatric cardiac surgery: a 10-year experience. J Card Surg 1995; 10:302–8.

292 Chylothorax and other pleural effusions in neonates 57. May DA, Barth RA, Yeager S et al. Perinatal and postnatal chest sonography. Radiol., Clin North Am 1993; 31:499–516. 58. Petres RE, Redwine FO, Cruikshank DP. Congenital bilateral chylothorax: antepartum diagnosis and successful intrauterine surgical management. JAMA 1982; 28:1360–1. 59. Jaffa AJ, Barak S, Kaysar N et al. Antenatal diagnosis of bilateral congenital chylothorax with pericardial effusion. Acta Obstet Gynecol Scand 1985; 64:455. 60. Longaker MT, Laberge JM, Dansereau J et al. Primary fetal hydrothorax: natural history and management. J Pediatr Surg 1989; 24:573–6. 61. Rodeck CH, Fisk NM, Fraser DI et al. Long-term in-utero drainage of fetal hydrothorax. N Engl J Med 1988; 319:1135–8. 62. Allen EM, VanHeeckeren DW, Spector ML et al. Management of nutritional and infectious complications of postoperative chylothorax in children. J Pediatr Surg 1991; 26:1169–74. 63. Robinson C. The management of chylothorax. Ann Thor Surg 1985; 39:90–5. 64. Rubin JW, Moore HV, Ellison RG. Chylothorax: therapeutic alternatives. Am Surg 1977; 43:292–7. 65. Hashim S, Roholt HB, Babayan VK et al. Treatment of chyluria and chylothorax with medium-chain triglyceride. N Engl J Med 1964; 270:756–61. 66. Le Coultre C, Oberhansli I, Mossaz A et al. Postoperative chylothorax in children: differences between vascular and traumatic origin. J Pediatr Surg 1991; 26:519–23. 67. Ullibarri JI, Saqnz Y, Fuentes C et al. Reduction of lymphorrhagia from ruptured thoracic duct by somatostin. Lancet 1990; 336 (8709):258. 68. Caty MG, Hilﬁker ML, Azizkhan RG et al. Successful treatment of congenital chylous ascites with a somatostatin analogue. Pediatr Surg Int 1996; 11:396–7. 69. Berkenbosh JW, Withington DE. Management of postoperative chylothorax with nitric oxide: a case report. Crit Care Med 1999; 27:1022–4. 70. Higgins CB, Mulder DG. J Thorac Cardiovasc Surg 1971; 61:411–18. 71. Puntis JWL, Roberts KD, Handy D. How should chylothorax be managed? Arch Dis Child 1987; 62:593–6. 72. Stringel G, Mercer S, Bass J. Surgical management of persistent postoperative chylothorax in children. Can J Surg 1984; 27:543–6. 73. Rheuban KS, Kron IL, Carpenter MA et al. Pleuroperitoneal shunt for refractory chylothorax after operation for congenital heart disease. Ann Thorac Surg 1992; 53:85–7. 74. Engum SA, Rescorla FJ, West KW et al. The use of pleuroperitoneal shunts in the management of persistent chylothorax in infants. J Pediatr Surg 1999; 34:286–90. 75. Azizkhan RG, Canﬁeld J, Alford BA et al. Pleuroperitoneal shunts in the management of neonatal chylothorax. J Pediatr Surg 1983; 18:842–8.

76. Murphy MC, Newman BM, Rodgers BM. Pleuroperitoneal shunts in the management of persistent chylothorax. Ann Thorac Surg 1989; 48:195–200. 77. Milsom JW, Kron IL, Rheuban KS et al. Chylothorax: an assessment of current surgical management. J Thorac Cardiovasc Surg 1985; 89:221–7. 78. Cummings SP, Wyatt DA, Baker JW et al. Successful treatment of postoperative chylothorax using an external pleuroperitoneal shunt. Ann Thorac Surg 1992; 54:276–8. 79. Sade RM, Wiles HB. Pleuroperitoneal shunt for persistent pleural drainage after Fontan procedure. J Thorac Cardiovasc Surg 1990; 100:621–3. 80. Chan BBK, Murphy MC, Rodgers BM. Management of chylopericardium. J Pediatr Surg 1990; 25:1185–9. 81. Selle JG, Snyder WH, Schreiber JT. Chylothorax: indications for surgery. Ann Surg 1973; 177:245–9. 82. Patterson GA, Todd TRJ, Delarue NC et al. Supradiaphragmatic ligation of the thoracic duct in intractable chylous ﬁstula. Ann Thorac Surg 1981; 32:44–9. 83. Goorwitch J. Traumatic chylothorax and thoracic duct ligation. Case report and review of the literature. J Thorac Surg 1955; 29:467–79. 84. Adler RH, Levinsky L. Persistent chylothorax: treatment by talc pleurodesis. J Thorac Cardiovasc Surg 1978; 76:859–64. 85. Barret DS, Large SK, Rees GM. Pleurectomy for chylothorax associated with intestinal lymphangiectasia. Thorax 1987; 42:557–8. 86. Stenzl W, Rigler B, Tscheliessnigg KH et al. Thoracic Cardiovasc Surg 1983; 31:35–6. 87. Nguyen D, Tchervenkov CI. Successful management of postoperative chylothorax with ﬁbrin glue in a premature neonate. Can J Surg 1994; 37:158–60. 88. Kerr-Wilson RHJ, Duncan A, Hume R et al. Prenatal pleural effusion associated with congenital pulmonary lymphangiectasia. Prenat Diagn 1985; 5:73–6. 89. Jaffe R, Di Segni E, Altaras M et al. Chylothorax spontanie neontatale. Arch Fr Pediatr 1986; 43:752. 90. Lien JM, Colmorgen GHC, Gehret JF et al. Spontaneous resolution of fetal pleural effusion diagnosed during the second trimester. J Clin Ultrasound 1990; 18:54–6. 91. Thompson PJ, Greenough A, Brooker R et al. Antenatal diagnosis and outcome in hydrops fetalis. J Perinat Med 1993; 21:63–7. 92. Echeverria LJ, Benito A, Arena AJ et al. Congenital chylothorax. An Esp Pediatr 1998; 49:161–4. 93. Weber AM, Philipson EH. Fetal pleural effusion: a review and meta-analysis for prognostic indicators. Obstet Gynecol 1992; 79:281–5. 94. Schmidt W, Harms E, Wolf D. Successful prenatal treatment of non-immune hydrops fetalis due to congenital chylothorax: case report. Br J Obstet Gynecol 1985; 92:685–7. 95. Seeds J, Bowes W. Results of treatment of severe fetal hydrothorax with bilateral pleuroamniotic catheters. Obstet Gynecol 1986; 68:577–80.

References 293 96. Roberts A, Clarkson P, Pattison N et al. Fetal hydrothorax in the second trimester of pregnancy: successful intrauterine treatment at 24 weeks gestation. Fetal Ther 1986; 1:203–6. 97. Blott M, Nicolaides KH, Greenough A. Pleuroamniotic shunting for decompression of fetal pleural effusions. Obstet Gynecol 1988; 71:798–800. 98. Mandelbrot L, Dommergues M, Aubry MC et al. Reversal of fetal distress by emergency in utero decompression of hydrothorax. Am J Obstet Gynecol 1992; 167:1278–83. 99. Haller JA. Thoracic injuries. In: Welch KJ, Randolph JG,

Ravich MM, editors. Pediatric Surgery. 4th edn. Chicago: Year Book Medical Publishers, 1986: 143–54. 100. Feliciano D, Mattox K, Graham J et al. Major complications of percutaneous subclavian vein catheters. Am J Surg 1979; 138:869. 101. Stern RC. Diseases of the pleura. In: Beherman RE, Baughan VC, Nelson WE, editors. Philadelphia: W.B. Saunders, 1987: 936–40. 102. Upadhyaya P. Management of empyema thoracis. In: Spitz L, Nixon H, editors. Rob and Smith’s Operative Surgery (Paediatric Surgery). 4th edn. London: Butterworths, 1988: 166–79.

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30 Congenital malformations of the lung HORACE P. LO AND KEITH T. OLDHAM

INTRODUCTION Congenital lung abnormalities are uncommon and diverse in their presentation. However, all those who care for infants and children must have an appreciation for the diagnosis and treatment of these anomalies because the potential consequences can be life threatening. In order to understand the pathophysiology of these malformations, a basic understanding of the embryology of lung development as well as respiratory physiology and anatomy is required and these are brieﬂy presented later. Classical lesions including congenital lung cysts, cystic adenomatous malformation, pulmonary sequestration and lobar emphysema will be considered in some detail later, as well as a number of the less common anomalies.

EMBRYOLOGY During the third week of gestation, the human embryo develops a diverticulum of the ventral foregut, which forms the primordium of the respiratory system. This is mainly of endodermal origin; however, cartilaginous and muscular elements will be derived from the splanchnic mesoderm that surrounds the primitive foregut. As the respiratory diverticulum grows caudad, it becomes separated from the foregut by the lateral esophagotracheal ridges, which fuse to form a septum at the end of the fourth gestational week. Thus, the dorsal esophagus and the more ventral trachea and lung buds are deﬁned. The larynx, which is formed from the fourth and sixth branchial arches, maintains communication between the pharynx and the trachea. The lung buds penetrate the coelomic cavity by caudal growth, resulting in the formation of pleuroperitoneal canals on either side of the foregut. The expanding lung buds eventually come to nearly ﬁll these canals, with the small residual spaces becoming the primitive pleural cavities. The right lung bud divides into three lobes whereas the left divides into two by the mid-portion of

the embryo’s sixth week. The bronchi continue successive dichotomous division, and by the end of the sixth month of gestation, 17 generations of subdivisions have formed. This period is also the time at which terminal bronchioles and alveoli are forming. An additional six divisions of the terminal airways will occur during early postnatal life, however, lung development probably does not cease until about 8 years of age.1 Thus development of conductive airways is essentially complete by the end of the second trimester, while terminal airways and alveoli, which are the site of gas exchange, continue to develop in late fetal life and indeed during infancy and early childhood. As one considers the various clinical lesions and their therapeutic options this perspective is critical.2,3 The pulmonary vasculature begins to develop in the mesoderm around the primitive lung buds at 7–8 weeks of gestation. By the seventh gestational month, pulmonary blood ﬂow has matured to the point where gas exchange is possible.

ANATOMY A brief discussion of clinically relevant anatomy is appropriate; several excellent references are available for a more detailed review.4,5 As seen in early gestational development of the lungs, the mature right lung is composed of three lobes in contrast to the two lobes of the left. The carina is positioned at the level of the fourth thoracic vertebral body in the term infant. The mainstem bronchus of the right lung follows a straighter, more caudad course and is usually shorter and larger in diameter than that of the left. This accounts for the preference of aspirated material to enter the right lower lobe or the posterior segment of the right upper lobe as well as for right mainstem bronchus intubation during endotracheal tube placement. The vascular supply of the trachea, bronchi, and lung parenchyma is systemic in origin and separate from the pulmonary arterial circulation, which is dedicated to gas

296 Congenital malformations of the lung

exchange. The trachea is supplied by branches of the paired inferior thyroid arteries, which anastomose with the bronchial blood supply derived from the aorta on the left, and the third intercostal artery on the right. Venous drainage is via the azygous and hemiazygous systems. This systemic arterial supply and its accompanying venous drainage generally follow the segmental architecture of the lung and bronchi.4–6

CONGENITAL LOBAR OVERINFLATION OR CONGENITAL LOBAR EMPHYSEMA Congenital lobar overinﬂation (CLO), otherwise known as congenital lobar emphysema, is among the most common of the congenital lung anomalies. It is characterized by air trapping and overdistention of one or more lobes which are otherwise anatomically normal. This distention causes compression of adjacent normal lung parenchyma and can result in mediastinal shift and cardiorespiratory compromise (Fig. 30.1). Although a speciﬁc etiology of this disorder cannot be demonstrated in up to half of reported cases,7 it is believed to result most commonly from structural deﬁciency or absence of supportive cartilage in the affected lobar bronchus, thereby causing expiratory collapse of the conducting airway with impedance to expiratory ﬂow.8 Other reported etiologies include extrinsic compression from anomalous or enlarged blood vessels, congenital heart disease, mediastinal lymphadenopathy, bronchogenic and enteric cysts, and tumors.9 Partial obstruction from a reversible endobronchial source such as mucous plugging, inﬂammation, or aspirated materials is a possible cause and should be ruled out by rapid and judicious bronchoscopic evaluation in order to avoid unnecessary lung resection.

Figure 30.1 Congenital lobar emphysema. Chest radiograph in a 3-day-old infant who presented with respiratory distress, showing marked hyperinﬂation of right upper lobe

Polyalveolar morphology mimics lobar emphysema in its clinical presentation. This is a descriptive histologic term that refers to unusual and abnormal anatomic ﬁndings characterized by an increase in the number of alveoli in a particular lobe, resulting in expiratory air trapping and lobar overdistension with respiratory compromise. This is in contrast to lobar emphysema where alveolar histopathology is normal except for overdistention. The diagnosis and treatment of polyalveolar morphology are not different than for congenital lobar emphysema. Congenital lobar emphysema is most often seen in the Caucasian population with a 2:1 or 3:1 male preponderance. It is most common in the left upper lobe (40–50%), with other sites affected less frequently: right middle lobe (30–40%), right upper lobe (20%), and lower lobes (1%).10,11 In 15% of infants, lobar emphysema is associated with congenital heart disease or abnormalities of the great vessels;12,13 therefore, routine echocardiography is recommended in the screening evaluation of these patients.

Presentation and diagnosis Contrary to its moniker, patients with congenital lobar emphysema do not demonstrate respiratory problems immediately at birth, rather they develop symptoms as lobar distention progresses over time with expiratory air trapping in the course of postnatal air breathing. Severity is usually related to age of presentation; the most threatening presentations typically occur in newborns. Approximately half of patients develop respiratory distress within the newborn period while the remainder present up to 4–6 months of age7 or later. Presenting signs are those of respiratory embarrassment, including dyspnea, tachypnea, agitation, and wheezing. Depending upon the severity of adjacent lung compression, cyanosis and respiratory failure can result. Therefore, the surgeon must be available for emergent decompressive thoracotomy, particularly when positivepressure ventilation is employed at procedures such as anesthesia induction or bronchoscopy. A few older children may present with milder symptoms such as recurrent respiratory infections or cough. On exam, the patient with congenital lobar emphysema will demonstrate signs consistent with a hyperinﬂated lobe, including thoracic and respiratory asymmetry, decreased breath sounds and percussive hyperresonance of the ipsilateral chest. Findings of mediastinal shift such as tracheal deviation, and displacement of the cardiac apical impulse are relatively late clinical signs. Chest roentgenography is the initial diagnostic maneuver of choice (Fig. 30.1). There is increased lucency over the affected side, with accompanying atelectasis of adjacent compressed parenchyma and a ﬂattened ipsi-

Congenital cystic adenomatoid malformations 297

lateral hemidiaphragm. Mediastinal displacement to the contralateral side may also be apparent. The chest radiograph should be inspected closely in order to differentiate between congenital lobar emphysema and tension pneumothorax, which may have similar presentation and appearance, but vastly different management. The latter problem, tension pneumothorax, has no peripheral lung markings visible while lobar emphysema does with careful inspection of the ﬁlms. In the ﬁrst hours after birth, the affected lobe may still be ﬁlled with fetal lung ﬂuid and therefore have the appearance of a ﬂuid-density mass lesion. Some authors advocate ventilation-perfusion radioisotope scanning as a useful adjunct to the chest radiograph.14 Others advise the use of computed tomography (CT) and magnetic resonance imaging (MRI). However, these studies are reserved generally for situations in which the diagnosis is in doubt.15

Treatment If a correctable source of endobronchial obstruction cannot be found and successfully reversed, then the often-progressive nature of this lesion, as well as the risk of respiratory failure, dictate thoracotomy with lobectomy of the affected lobe in infants. For the older child without symptoms, this approach can be reasonably tempered. Reconstructive procedures such as bronchoplasty or segmental bronchial resection are generally not appropriate as the bronchial defects may not be focal or readily localized. In addition, lobectomy in the infant population is very well tolerated16,17 and bronchial reconstruction in the newborn is fraught with technical limitations.

CONGENITAL CYSTIC ADENOMATOID MALFORMATIONS Congenital cystic adenomatoid malformations (CCAMs) are a rare group of cystic lobar hamartomatous lesions, but represent up to 50–70% of the bronchopulmonary foregut malformations in some reports.18,19 The lesions are generally large, ﬁrm, multicystic masses that are composed of terminal respiratory structures, usually bronchiolar in origin. CCAMs are thought to result from developmental arrest in terminal bronchiole maturation, resulting in marked overgrowth of these structures in relation to alveoli. This lesion is characterized by a mass of interconnected and disorganized cysts on gross inspection. Because of the histopathology and associated disorders of organogenesis, it has been proposed that the pathogenic event occurs between 3–7 weeks’ gestation, although the precise pathogenesis is unknown.20 Involvement is usually unilobar, with a slight predilection for the lower lobes; right and left sides are affected equally. Histology demonstrates ciliated cuboidal or columnar cells lining the cysts,

with a lack of organized architecture; usually no cartilage is present (Fig. 30.2). These malformations typically communicate with the normal bronchial tree and have a normal vascular supply, although aberrant systemic vasculature, sometimes derived from the aorta, has been described.21 Stocker et al. classiﬁed CCAM into three distinct pathologic types (Table 30.1),22 which carry both descriptive and prognostic signiﬁcance. Type I CCAM accounts for about 50% of cases. These consist of one or more large (> 2 cm) cysts. Patients usually have a good prognosis. Type II lesions have multiple smaller cysts (< 2 cm), and are frequently associated with other congenital anomalies. Type III lesions are more solid than cystic in nature. Both Types II and III lesions have a poor clinical outcome, presumably because they tend to be relatively large and noncompressible, thus limiting normal maturation and development of unaffected but adjacent lung. Physiologic consequences of CCAM can be seen antepartum and occur secondary to mediastinal shift and compression of normal lung tissue. Large masses, especially those involving Types II or III lesions can result in hydrops fetalis and fetal demise. Postpartum complications result from pulmonary hypoplasia of the remaining lung in newborns or secondary infection in older infants and children. Although the presenting symptoms of respiratory failure may be dramatic, only about one-third of patients present in this fashion.23 Most lesions not discovered prenatally will be discovered because of recurrent pneumonia or lung abscess resulting from inability to effectively clear secretions from the abnormal lobe. Gestational polyhydramnios is common with CCAM and may contribute to prematurity, which does affect outcome as well. Malignant degeneration can occur in all congenital cystic lung lesions including CCAM. Although this is rare, it is clearly a long-term risk to be considered as management decisions are made.24

Figure 30.2 Cystic adenomatoid malformation of lung. Histology specimen of lung showing mucinogenic cells, papillary epithelium and disorganized, irregular alveoli

298 Congenital malformations of the lung Table 30.1 Classiﬁcation of congenital cystic adenomatoid malformation Characteristic

Type 1

Type II

Type III

Distribution Associated anomalies Respiratory distress

19 cases Rare (5%) Day 1 to 4 weeks of life

16 cases Common (56%) Day 1 of life plus symptoms of other congenital anomalies

3 cases None reported Within hours after birth

Gestational age Premature Term Not stated Stillborn

32% 52% 16% 16%

75% 25% – 32%

67% 33% – 33%

Gross and microscopic features Cysts Cystic wall cartilage Smooth muscle and elastic tissue Mucus-producing cells Striated muscle outside the cysts Between the cysts

Prognosis

Single or multiple large (>2 cm) Multiple, small (<2 cm) Absent Absent Prominent bands present Absent

Large non-cystic Absent Absent

Present in 30% Absent

Absent Absent

Absent Occasionally present

Alveolar-like structures 1–10 Distended respiratory No cysts, just masses of times the size of normal alveoli bronchioles and dilated alveoli alveolus-seized structures separating bronchiole-like structures Good

Poor

Poor

From Stocker et al.22 and Shamji et al.,25 by permission.

Presentation and diagnosis Since the advent of routine ultrasound in obstetric practice, the majority of cystic lung lesions are now discovered prenatally in many institutions in the USA. The location of the stomach aids in differentiation between CCAM and congenital diaphragmatic hernia (CDH), although prenatal MRI may be needed for deﬁnitive diagnosis in difﬁcult cases.26 Serial ultrasonographic examinations may demonstrate shrinkage or even spontaneous resolution in up to 40% of fetal CCAMs.19,27 More severe lesions may be associated with polyhydramnios or hydrops in the fetus as noted earlier. Polyhydramnios is thought to result from esophageal compression, preventing fetal swallowing of amniotic ﬂuid; hydrops results from mediastinal shift from the mass effect, diminishing cardiac output by vena caval obstruction.19 Either of these ﬁndings during pregnancy is associated with a poor outcome. After birth, some neonates demonstrate tachypnea, dyspnea, cyanosis, or impending respiratory failure. Of the remainder, most will present within the ﬁrst years of life with recurrent or persistent respiratory infections, pulmonary abscesses, reactive airway disease or failure to thrive. As for all bronchopulmonary foregut malformations, the plain chest radiograph is the best initial diagnostic test in the neonate (Fig. 30.3). Nasogastric tube position

Figure 30.3 Cystic adenomatoid malformation of the left lung with gross expansion of the lung, marked mediastinal shift to the right and downward displacement of the diaphragm. Note surgical emphysema of left axilla and chest wall, indicating rupture of a cyst

Congenital cystic adenomatoid malformations 299

is often helpful to distinguish CCAM from CDH, as an intrathoracic stomach is quite common with left CDH. The radiographic ﬁndings are variable; radiographs taken early in the neonatal period may demonstrate ﬂuid within the lesion, whereas later ﬁlms may show air-ﬁlled cysts. Mediastinal shift, an ipsilateral ﬂattened diaphragm and compressed adjacent normal lung may also be present, depending on the severity of disease. It is advisable to obtain an axial imaging study, either a chest CT scan with i.v. contrast or MRI in all patients with cystic lesions of the chest in order to establish a diagnosis as well as delineate anatomic relationships prior to elective resection (Fig. 30.4). Even those who have had spontaneous intrauterine involution of an apparent CCAM demonstrated by serial prenatal ultrasound should be evaluated with CT imaging following birth, as residual parenchymal abnormalities may be present28 and they may still be at risk for pulmonary infections or malignancy.

Treatment The treatment objective in patients with CCAM is to resect the abnormal tissue. Usually this requires postnatal thoracotomy with lobectomy. Patients with multilobular disease may beneﬁt from segmental resection if possible, and total pneumonectomy may be required occasionally.29 Prenatal diagnosis of CCAM should prompt referral to a tertiary care center, where critical care support and emergent pediatric surgical care is available. Like infants with congenital lobar emphysema, the switch to breathing air or positive pressure ventilation may rapidly precipitate a crisis in these patients if there is progressive distention of the affected lobe. Older children who present with pulmonary infection may be managed acutely with antibiotics; however, long-term expectant medical management is not appropriate due to the frequency and severity of infectious complications and the risk of malignant degeneration. As noted earlier, there are a number of reports of spontaneous shrinkage and/or resolution of fetal CCAMs, therefore serial ultrasounds in the fetus are recommended to document ﬁndings. Although it is a point of some controversy, these infants should undergo axial imaging following delivery with elective resection of residual anomalous parenchyma. Recent reports describe some success with fetal intervention for CCAM. The approaches have included thoracoamniotic shunting in lesions with a single predominant cyst, and resection in those with more complicated Types II and III CCAM. It appears that the learning curve for this approach is extremely steep and the risk of maternal–fetal complications is relatively high. The issue of appropriate prenatal patient selection is also critical since many of these fetuses do well without intervention and a number of the lesions resolve

(a)

(b) Figure 30.4 (a) Plain chest radiograph of a 9-year-old child who presented with fever, pleuritic chest pain, and cough. The lesion is an infected cystic adenomatoid malformation of the right lower lobe. (b) The lesion in a is shown on chest CT scan after treatment with antibiotics and before surgical resection of the right lower lobe (With permission from Coran AG, Oldham KT. The pediatric thorax. In: Greenﬁeld LJ, Mulholland MW, Oldham KT et al. editors. Surgery: Scientiﬁc Principles and Practice. Philadelphia: JB Lippincott, 1993:944)

entirely. However, CCAM associated with fetal hydrops or polyhydramnios carries a high mortality rate and fetal intervention at specialized centers may be an option in some of these cases. The subject remains controversial.30,31

300 Congenital malformations of the lung

PULMONARY SEQUESTRATION Pulmonary sequestrations make up 10–30% of the cystic bronchopulmonary foregut malformations.29,32 They are classiﬁed by whether the sequestration resides within the visceral pleura of the normal lung (intralobar sequestration) or is invested by its own visceral pleura (extralobar sequestration). In both types of pulmonary sequestration however, there is no bronchial communication between the sequestrum and the normal tracheobronchial tree. In addition, the malformation receives its blood supply from aberrant systemic arterial vessels (Table 30.2). Intralobar sequestrations make up about 50–70% of the pulmonary sequestrations and most commonly involve the posterior and basal segments of the left lower lobe.33,34 As mentioned, these intralobar lesions are surrounded by normal lung parenchyma and pleura. The arterial supply is usually derived from aberrant branches of the descending thoracic aorta, although occasionally intercostal, brachiocephalic, or abdominal aortic aberrant vessels are encountered. Venous drainage is usually via the associated pulmonary vein. Although sequestrations are by deﬁnition nonfunctional and sequestered from the respiratory tree via functional bronchioles, intralobar sequestrations may communicate with neighboring alveoli in normal lung via abnormal air spaces, allowing some ventilation and airtrapping within the intralobar lesions. Extralobar sequestrations are completely separated from the normal lung, are invested by an individual pleura and are completely separate from the functional

airways. They are found in the left lower chest most commonly, but may occur anywhere; rarely, subdiaphragmatic locations are reported.34,35 A 3:1 male predominance is reported in most series for extralobar sequestrations. These sequestrations also derive arterial blood supply from the descending aorta, with up to 20% having an aberrant vessel traversing the diaphragm (Figs 30.5 & 30.6).36 Drainage into systemic veins, such as the azygous, hemiazygous, or the portal system is typical for extralobar sequestrations. There is an association of extralobar pulmonary sequestrations with CCAM and CDH37 as well as a variety of other congenital defects.6,29,37 Aberrant air space connections are not present, rather extralobar sequestrations are prone to hemorrhage or arterial-venous shunting and the patients may present with high-output congestive heart failure. The embryologic origin of pulmonary sequestrations is unclear, but they are thought to result from either abnormal budding of the tracheobronchial tree or accessory budding of the foregut, or a combination of the two. The stimulus is not known. Extralobar sequestrations are clearly congenital in origin. This conclusion is drawn by the frequent association with other congenital anomalies, their presence in neonatal autopsies, and the now routine discovery of these lesions on prenatal ultrasound.

Presentation and diagnosis Patients with intralobar sequestration will typically present with pulmonary infections due to abnormal airspace connections with inadequate drainage, or from

Table 30.2 Characteristics of pulmonary sequestrations Characteristic

Intralobar

Extralobar

Incidence Incidence ratio Sex Side Location Age at presentation and symptoms Associated anomalies

Uncommon 3 Equal 60% left Usually in the posterior basal segment Adolescent to young adults, 50% >20 years, recurrent pulmonary infections Uncommon

Rare 1 Male 80% 90% left Above the diaphragm, rarely below Neonate 60%, <1 year, respiratory distress

Diagnosis at neonatal autopsy Arterial supply Venous drainage

None Systemic – from aorta, large vessels, often a single Pulmonary – inferior pulmonary vein

Anatomical relations

Not separate, within and part of normal lobe

Connection with foregut Bronchial communication

Very rare Present, small

From Shamji et al.,25 by permission.

Frequent (>50%), e.g. congenital diaphragmatic hernia (30%) Frequent Systemic – from pulmonary or aorta, usually small vessels Systemic – azygos or hemiazygos vein; rarely portal vein Separate, has its own investment – visceral pleura More common None

Pulmonary sequestration 301

(a)

ultrasound has Doppler capability. If the mass is large, shift of mediastinal structures, fetal hydrops, and fetal demise can occur. Due to the frequency of associated anomalies, extralobar sequestrations are often diagnosed early in infancy during evaluation for these other problems. Plain radiographs of the chest will usually demonstrate an intralobar sequestration as a non-aerated, atelectatic mass, or as a cyst with an air-ﬂuid level (Fig. 30.5). Extralobar sequestrations typically appear as a left posterior mediastinal mass or triangular retrocardiac density on chest radiographs. In most infants and children with pulmonary sequestration, additional imaging beyond the initial radiographs is recommended. Ultrasound with Doppler, CT with contrast, or MRI provide good anatomic detail and demonstrate relationships to neighboring structures. Importantly, all delineate the aberrant arterial vessels for purposes of both diagnosis and preoperative planning. Preoperative upper gastrointestinal contrast study may assist in identifying the 10% of patients who have anomalous foregut communication with their sequestration, but some experienced pediatric surgeons do not do this routinely. Angiography, although considered routine in the past, is no longer necessary given the evolution of other less invasive imaging modalities detailed earlier.

Treatment

(b) Figure 30.5 Pulmonary sequestration. (a) Chest radiograph demonstrates a well-deﬁned mass at base of right lung. (b) Prenatal Doppler ultrasound demonstrating two aberrant arterial vessels to extralobar sequestration (arrow)

compressive atelectasis of adjacent parenchyma. Because of this, infants are rarely diagnosed with this lesion, rather presentation occurs later in childhood or adulthood with complaints of recurrent or refractory pneumonias, lung abscesses, or hemoptysis. Extralobar sequestrations, on the other hand, are frequently seen on prenatal ultrasound. The infants are often asymptomatic at birth, however, as noted, these lesions can be associated with arterial-venous shunting and congestive heart failure. The pathognomonic aberrant blood supply may be identiﬁed prenatally if the

Treatment for pulmonary sequestrations consists of excision of the abnormal tissue. Although extralobar sequestrations may be asymptomatic, the cumulative risks of hemorrhage, infection, arteriovenous shunting and late malignancy have generally been considered indication for resection when diagnosed. In patients with extralobar sequestration, this is a relatively straightforward procedure performed via thoracotomy, or more recently by thoracoscopy in some instances. Intralobar sequestration is treated with thoracotomy and lobectomy, although in selected cases, segmentectomy may be appropriate.38 Segmentectomy may be more feasible in situations where prenatal discovery offers opportunity for resection prior to the onset of infectious complications. An essential requirement for all procedures involving resection of a pulmonary sequestration is the identiﬁcation and control of the anomalous systemic arterial blood supply. Reports of unrecognized or uncontrolled hemorrhage from accidental division of the aberrant arteries emphasize this point;39 this is especially true of vessels with a subdiaphragmatic origin that course through the inferior pulmonary ligament and are prone to retraction into the abdomen when severed or avulsed. With modern imaging and knowledge of this risk however, this problem should be managed routinely in contemporary practice.

302 Congenital malformations of the lung

Other important technical points are that particular care must be taken to identify the phrenic nerve, which may travel adjacent and lateral to an extralobar sequestration. Abnormal foregut communications, whether diagnosed preoperatively or not, must be carefully sought and controlled appropriately intraoperatively. Although controversial, fetal interventions such as thoracoamniotic shunting and drainage may be helpful in certain cases of tension hydrothorax and hydrops fetalis. In contemporary pediatric surgical practice the outcome for affected infants and children should be excellent.40,41

CONGENITAL BRONCHOGENIC LUNG CYSTS Congenital lung cysts comprise up to one-third of bronchopulmonary foregut malformations in some reports.42,43 The most common of these lesions are bronchogenic cysts. Bronchogenic cysts are typically thick-walled, unilocular lesions which are comprised of smooth muscle, cartilage and mucous glands lined by pseudostratiﬁed ciliated columnar epithelium. It is believed that they become separated from the tracheobronchial tree during development but remain adjacent, which is where they are found clinically. Congenital lung cysts may develop at any time between the third and 16th weeks of gestation as the lung buds begin their initial segmental divisions and subsegmental dichotomous divisions progress. Bronchogenic cysts arise from the trachea, bronchus or other conducting airways but have usually lost their connection with the parent structure (Fig. 30.6). They are usually simple, and contain mucus, however, air-ﬂuid levels and infection may be seen if there is continuity with the tracheobronchial tree. Because these lesions result from abnormal development of bronchi, they may contain any of the cellular elements of the respiratory tract. In contrast to sequestrations, bronchogenic cysts have a normal bronchial blood supply. Although bronchogenic cysts may reside anywhere in the respiratory tract, including paravertebral, paraesophageal, subcarinal, and cervical areas, the majority are found in the lung parenchyma or mediastinum.8,29,44,45 More rare than bronchogenic cysts are parenchymal lung cysts, which are thought to arise from abnormal budding of distal airways and other respiratory structures. Some consider these among the spectrum of bronchogenic cysts, however most consider them separate because of a more peripheral location and their origin from pulmonary parenchymal structures rather than a conducting airway. Regardless, the histology is variable but resembles that of the structure of origin. The general features of presentation and principles of management for peripheral lung cysts are similar to those of bronchogenic cysts, unless the anomalous

(a)

(b) Figure 30.6 (a) Chest radiograph showing a large cyst occupying lower half right thorax. (b) Lateral view localized the cyst to lower lobe

structure is lymphatic in origin. In these latter cases, pulmonary lymphangiectasis may be present; this is manifested by diffuse bilateral cystic lung involvement and a poor clinical prognosis.6

Presentation and diagnosis Some patients with bronchogenic cysts are asymptomatic. Of those with symptoms, the most common presentations are wheezing, tachypnea or dyspnea, all related to compression of the adjacent conducting airway

Congenital bronchogenic lung cysts 303

with partial obstruction. If there is a patent connection between the tracheobronchial tree and a bronchogenic cyst, patients may develop infection and present with productive cough, fever, chills, and hemoptysis. Rarely, the cyst may enlarge to the point where the mass effect leads to mediastinal displacement, compression of normal lung, and cardiorespiratory failure. Plain chest radiographs typically demonstrate a smooth, spherical, paratracheal or hilar solid mass without calciﬁcations. If airway communication or infection is present, an air–ﬂuid level may be seen. Displacement of adjacent airway structures is commonly observed. More often than not, these cysts are unilocular, however, a honeycomb appearance is seen with some forms of this lesion. As with other congenital cystic lesions, CT or MRI imaging will allow anatomic relationships to be identiﬁed. Other studies to delineate important relationships include contrast esophogram to identify foregut communications or extrinsic compression, and bronchoscopy for similar reasons.

(a)

Treatment Acute respiratory decompensation from a large tense bronchogenic or lung cyst may necessitate needle or chest tube thoracostomy as a temporizing measure. Preexisting pneumonias should be treated with preoperative antibiotics. Thereafter, or in patients with stable cysts, simple cystectomy should be performed with oversewing of any anomalous bronchial communications (Fig. 30.7). If a bronchogenic cyst cannot be removed in its entirety, remaining portions of cyst wall may be destroyed with electrocautery in this situation. For a parenchymal cyst, lobectomy, segmental or wedge resection may be necessary if simple cystectomy is judged to be inadequate. The principle in this circumstance is to preserve as much normal lung parenchyma as possible. Generally, lateral thoracotomy is employed for management of these lesions, although median sternotomy may be appropriate for certain central lesions. Thoracoscopic resection has been used in selected patients with recent success as well.

(b)

(c)

Figure 30.7 Operative technique of lung cystectomy. (a) Cyst wall exposed after incising lung tissue just above the cyst. (b) Dissection in the plane between the cyst and lung tissue. (c) Showing a small bronchus opening into the cyst – the opening is closed by oversewing it

304 Congenital malformations of the lung

PULMONARY HYPOPLASIA, APLASIA, AND AGENESIS Pulmonary hypoplasia refers to the abnormal development of an entire lung or both lungs, resulting in a diminutive and potentially dysfunctional gas exchange organ. This occurs most commonly as a consequence of extrinsic compression during gestational development, although primary hypoplasia does occur. A number of intrathoracic mass lesions may be responsible, however the most common are congenital diaphragmatic hernia and CCAM. Pulmonary aplasia results from developmental arrest during organogenesis sometime after the sixth gestational week, resulting in a reduction in the number of alveoli; this may be marked. The physiologic consequences of both derangements can be severe and include pulmonary hypertension, persistent fetal circulation and respiratory failure. Extraordinary measures of clinical support are frequently required32,46 including high-frequency oscillation, extracorporeal membrane oxygenation, and the use of inhaled nitric oxide. Pulmonary agenesis is the complete absence of one or both lungs. The speciﬁc cause of this accident of embryogenesis is unknown, however there is apparent failure of organogenesis at about the time the trachea divides into the two lung buds, early in the fourth week of gestation. Bilateral pulmonary agenesis is exceedingly rare and is inevitably incompatible with life. Unilateral pulmonary agenesis may be asymptomatic, however symptomatic patients may pose difﬁcult neonatal management issues, not only from the standpoint of respiratory insufﬁciency, but also because of a high incidence of associated anomalies.47–49 Older children may be asymptomatic or demonstrate nonspeciﬁc respiratory symptoms including a history of failure to thrive, exercise intolerance, recurrent respiratory infections, and chest asymmetry or scoliosis. A shift in the location of heart tones and absent ipsilateral breath sounds are demonstratable on physical examination. Chest roentgenograms will demonstrate hyperinﬂation of the contralateral lung or possibly a ﬂuid-ﬁlled ipsilateral thorax. Either is usually associated with marked displacement of the mediastinum. Absence of the ipsilateral mainstem bronchus or the pulmonary artery are deﬁnitive diagnostic ﬁndings and this can be established by endoscopy, angiography, ECHO or axial imaging techniques.

LUNG SURGERY IN NEWBORNS Although a full discussion of thoracic surgery in children is beyond the scope of this chapter, a brief description of surgical technique in neonates is relevant. A number of comprehensive texts are available.50,51 Lung surgery in neonates is generally similar to that in adults except that

the diminutive size, the associated lesions, and the unique pathologic entities require certain special considerations. Of course, the smaller the child, the more care must be taken in order to avoid technical injury. As with all lung surgery, technical problems may result in serious and irreversible consequences. Collaboration with pediatric anesthesiologists familiar with the unique circumstances of pediatric chest surgery is essential.

Lobectomy The patient is positioned in the lateral decubitus position, with the upper arm extended and placed over the head (Fig. 30.8). Rolled towels and other positioning devices may be placed in order to optimize stabilization and exposure of the operative ﬁeld. As always in pediatric surgery, heat loss is a concern, and coverings should be placed over exposed areas without interference to the surgical site. Convective and radiant warmers should also be employed. Optimal exposure is gained by transverse or oblique incision over the fourth or ﬁfth intercostal space, below and lateral to the nipple to avoid cosmetic and functional damage to the breast tissue. There should be some space between the tip of the scapula and the posterior extent of the incision. This becomes important during closure of the muscle layers, especially if the incision must be extended posterolaterally. Underlying muscle and subcutaneous tissue is divided along the line of incision (Fig. 30.8b) by electrocautery. To limit postoperative morbidity, it is desirable and usually possible to employ a muscle-sparing approach; this affords adequate exposure yet avoids division of the serratus anterior and chest wall musculature other than the latissimus dorsi. The scapula is elevated off the chest wall by retractor to gain exposure, and palpation is used to count the ribs to the correct interspace. In most situations in infants, the highest palpable rib is the second. Generally, the fourth interspace is used for a lobectomy although the ﬁfth can be used effectively as well. The incision is then continued with electrocautery just superior to the lower rib of the selected intercostal space to avoid damage to the neurovascular bundle that runs along the inferior border of each rib (Fig. 30.8c). Care must be taken when entering the pleura to avoid injury to the lung parenchyma beneath. A rib spreader is then placed to facilitate retraction (Fig. 30.8d). The incision may then be continued anteriorly or posteriorly from inside the chest if further exposure is needed. The following technique and illustrations are described for left upper lobectomy, however the principles are the same for any lobe resection. Gentle lateral and inferior traction on the lobe exposes the hilum. The visceral pleura is carefully incised circumferentially, exposing the hilar structures (Fig. 30.9). Meticulous dissection reveals the left main pulmonary

Lung surgery in newborns 305

(a)

(b)

(c)

(d)

Figure 30.8 Operative technique of thoracotomy: (a) Transverse lateral incision. (b) Division of external intercostal muscles. (c) Division of intercostal muscles along the upper border of the lower rib. (d) Retraction of ribs to expose the lung

Aorta

Left main pulmonary artery Left upper lobe bronchus

Left lung

Artery branches of the left upper lobe

Carina Aorta

Left pulmonary artery

Left vein branches of left upper lobe

Left upper lobe bronchus Left lower lobe bronchus

Figure 30.10 The main segmental pulmonary artery branches to the left upper lobe

Figure 30.9 Normal anatomy of the left lung hilum containing the pulmonary artery, veins and bronchus

artery as it courses under the aortic arch (Fig. 30.10) and crosses the left upper lobe bronchus. Nearby structures to be noted are the left phrenic nerve anteriomedially along the mediastinum, and the recurrent laryngeal nerve branching from the vagus under the aortic arch. A review of segmental anatomy of the lung describes four main arterial branches supplying the left upper lobe,

however this can be variable. These are individually encircled, ligated and divided. This is typically done with heavy silk and using double proximal ligatures. The bronchial blood supply traveling with the left upper lobe bronchus is likewise identiﬁed and ligated. Attention is then directed to the left upper lobe venous drainage. Again, individual branches are circumferentially dissected and ligated using the same approach as for the

306 Congenital malformations of the lung

arterial circulation (Fig. 30.11). The bronchus is then clamped or otherwise controlled, and divided. Closure of the bronchial stump with commercial surgical stapling devices is appropriate in older children; however, size and other technical limitations make this undesirable in infants, where a simple sewn closure is best (Fig. 30.12). Air leaks may be identiﬁed for suture repair by ﬁlling the chest with warm saline coincident with inﬂation of the residual lobe by the anesthesiologist. The inferior pulmonary ligament should be divided at this time to facilitate expansion of the left lower lobe, or it may be done early in the dissection to facilitate exposure. A chest tube is placed within the pleura for drainage, and the wound is closed in anatomical layers using absorbable sutures. Postoperatively, drains can be removed early, provided no air leak is demonstrable. Wedge resections and lobectomies are remarkably well tolerated in the pediatric population, although age at resection is a factor. Older children demonstrate less compensatory growth than infants. Even so, most children will have little or no functional deﬁcit after these procedures.16,17,52 The need for pneumonectomy is much more limited in infants and children but functional outcomes are still

Left upper pulmonary vein

Left vein branches of left upper lobe

Left main bronchus Left upper pulmonary vein

Figure 30.11 The segmental vein branches of the left superior pulmonary Stump of the upper lobe bronchus

Left lower lobe bronchus

Figure 30.12 Vascular clamp placed across the left upper bronchus and the bronchus oversewn

generally good. Several techniques have been described to manage the potential problem of marked mediastinal shift in the postoperative period.

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congenital cystic adenomatoid malformation: a followup study. Scand J Thorac Cardiovasc Surg 1982; 16:293–8. Wolf SA, Hertzler JH, Philippart AI. Cystic adenomatoid dysplasia of the lung. J Pediatric Surg 1980; 15:925. Adzick NS, Harrison MR, Crombleholme TM et al. Fetal lung lesions: management and outcome. Am J Obstet Gynecol 1998; 179(4):884–9. Miller RK, Sieber WK, Yunis EJ. Congenital adenomatoid malformation of the lung: a report of 17 cases and review of the literature. Pathol Annu 1980; 15:387–407. Rashad F, Grisoni E, Gaglione S. Aberrant arterial supply in congenital cystic adenomatoid malformation of the lung. J Pediatr Surg 1988; 23:1007–8. Stocker JT, Madewell JE, Drake RM. Congenital cystic adenomatoid malformation of the lung. Hum Pathol 1985; 20:483. Wang NS, Chen MF, Chen FF. The glandular component in congenital cystic adenomatoid malformation of the lung. Respirology 1999; 4(2):147–53. Granata C, Gambini C, Balducci T et al. Bronchioalveolar carcinoma arising in congenital cystic adenomatoid malformation in a child: a case report and review on malignancies originating in congenital cystic adenomatoid malformation. Pediatr Pulmonol 1998; 26(3):230–1. Shamji FM, Sachs HJ, Perkins DG. Cystic disease of the lungs. Surg Clin N Am 1988; 68:581–620. Hubbard AM, Adzick NS, Crombleholme TM et al. Congenital chest lesions: diagnosis and characterization with prenatal MR imaging. Radiol 1999; 212(1):43–8. vanLeeuwen K, Teitelbaum DH, Hirschl RB et al. Prenatal diagnosis of congenital cystic adenomatoid malformation and its postnatal presentation, surgical indications, and natural history. J Pediatr Surg 1999; 34(5):794–8. Winters WD, Effmann EL, Ngheim HV et al. Disappearing fetal lung masses: importance of postnatal imaging studies. Pediatr Radiol 1997; 27:535–9. Ryckman FC, Rosenkrantz JG. Thoracic surgical problems in infancy and childhood. Surg Clin North Am 1985; 65:1423. Kitano Y, Adzick NS. New developments in fetal lung surgery. Curr Opin Pediatr 1999; 11(3):193–9. Dommergues M, Louis-Sylvestre C, Mandelbrot L, Aubry MC et al. Congenital adenomatoid malformation of the lung: When is active fetal therapy indicated? Am J Obstet Gynecol 1997; 177(4):953–8. Schwartz MZ, Ramachandran P. Congenital malformations of the lung and mediastinum – a quarter century of experience from a single institution. J Pediatr Surg 1997; 32(1):44–7. Cilley RE. The pediatric chest. In: Greenﬁeld LJ, Mulholland M, Oldham KT et al. editors. Surgery: Scientiﬁc Principles and Practice. 3rd edn. Philadelphia: Lippincott, Williams and Wilkins, 2001. Frazier AA, Rosado de Christenson ML, Stocker JT et al. Intralobar sequestration: radiologic pathologic correlation. Radiographics 1997; 7(3):725–45.

35. Gross E, Chen MK, Lobe TE et al. Infradiaphragmatic extralobar pulmonary sequestration masquerading as an intraabdominal, suprarenal mass. Pediatr Surg Int 1997; 12(7):529–31. 36. Sade RM, Clouse M, Ellis FH Jr. The spectrum of pulmonary sequestration. Ann Thorac Surg 1974; 18:644. 37. Conran RM, Stocker JT. Extralobar sequestration with frequently associated congenital cystic adenomatoid malformation, type 2: report of 50 cases. Pediatr Dev Pathol 1999; 2(5):454–63. 38. Takeda S, Miyoshi S, Inoue M et al. Clinical spectrum of congenital cystic disease of the lung in children. Eur J Cardio-Thor Surg 1999; 15(1):11–17. 39. Savic B, Birtel FJ, Tholen W et al. Lung sequestration: report of seven cases and a review of 540 published cases. Thorax 1979; 34:96–101. 40. Halkic N, Cuenoud PF, Corthesy ME et al. Pulmonary sequestration: a review of 26 cases. Eur J Cardio-Thor Surg 1998; 14(2):127–33. 41. Lopoo JB, Goldstein RB, Lipshutz GS et al. Fetal pulmonary sequestration: a favorable congenital lung lesion. Obstet Gynecol 1999; 94(4):567–71. 42. Evrard V, Ceulemans J, Coosemans W et al. Congenital parenchymatous malformations of the lung. World J Surg 1999; 23(11):1123–32. 43. Wesley JR, Hiedelberger KP, DiPetro MA et al. Diagnosis and management of congenital cystic disease of the lung in children. J Pediatr Surg 1986; 21:202. 44. Ramenofsky ML, Leape LL, McCauley RGK. Bronchogenic cyst. J Pediatr Surg 1979; 14:219–24. 45. DiLorenzo M, Collin PP, Vaillancourt R et al. Bronchogenic cysts. J Pediatr Surg 1989; 24:988–91. 46. Wasak P, Claris O, Lapillonne A et al. Cystic adenomatoid malformations of the lung: neonatal management of 21 cases. Pediatr Surg Int 1999; 15(5–6):326–31. 47. Booth JB, Berry CL. Unilateral pulmonary agenesis. Arch Dis Child 1967; 42:361. 48. Osborne J, Masel J, McCredie J. A spectrum of skeletal anomalies associated with pulmonary agenesis: possible neural crest injuries. Pediatr Radiol 1989; 19:425. 49. Hoffman MA, Superina R, Wesson DE. Unilateral pulmonary agenesis with esophageal atresia and distal tracheoesophageal ﬁstula: report of two cases. J Pediatr Surg 1989; 10:1084. 50. Ferguson MK. Surgical approach to the chest wall and mediastinum: incision, excisions, and repair of defects. In: Nyhus LM, Baker LJ, Fischer JE, eds. Mastery of Surgery. 3rd edn. Boston: Little, Brown, and Co., 1997: 613. 51. Sugarbaker DJ, DeCamp MM Jr, Liptay MJ. Pulmonary resection. In: Nyhus LM, Baker LJ, Fischer JE, editors. Mastery of Surgery. 3rd edn. Boston: Little, Brown, and Co., 1997: 613. 52. Szots I, Toth T. Long-term results of the surgical treatment for pulmonary malformations and disorders. Prog Pediatr Surg 1977; 10:277.

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31 Congenital diaphragmatic hernia TINA GRANHOLM, CRAIG T. ALBANESE AND MICHAEL R. HARRISON

INTRODUCTION Congenital diaphragmatic hernia (CDH) is a malformation characterized by a defect in the posterolateral diaphragm, the foramen of Bochdalek, through which the abdominal viscera migrate into the chest during fetal life. It is a fairly common malformation, occurring at a reported frequency of 1 in 3500–5000 births in recent population-based studies.1 Approximately 20% are right sided, 1–4% are bilateral, and close to 80% are left sided.1,2 In spite of recent advances in neonatal intensive care, the mortality rate remains high – in some series as high as 60%3 – and the infant with CDH thus presents a challenge to every pediatric surgeon. The mortality and morbidity are usually caused by concomitant pulmonary hypoplasia.

Some evidence now suggests that the pathogenesis of CDH may be more complicated than previously proposed. Iritani suggested that hypoplasia of the lung may precede the diaphragmatic defect,9 and Kluth et al. could show that the pleuroperitoneal canals in rats are too small to result in the diaphragmatic defect seen in CDH.10 Several groups have shown an aberrant expression of different growth factors in experimental models as well as in infants with CDH.11,12 Furthermore, the lungs in experimental models of CDH exhibit a response to growth factors differing from normal lungs.13 CDH has been extensively studied in animal models. Surgically created CDH in fetal lambs has proven a useful model for fetal intervention, as well as providing insight into respiratory and cardiovascular physiology.14,15 The teratogen-induced model of exposing pregnant mouse or rat dams to the herbicide Nitrofen has provided further knowledge in the pathogenesis and the role of different growth factors.9

EMBRYOGENESIS The etiology of CDH is unknown. Most cases occur sporadically, but there are reports of familial cases, including known chromosomal aberrations, as well as autosomal recessive inheritance of unknown chromosomal origin.4,5 The embryogenesis of CDH is usually described as a failure of the pleuroperitoneal canals in the posterolateral aspect of the diaphragm to fuse during gestational week 8. The resulting defect allows the gut as well as the liver and spleen to migrate into the chest when the gut returns into the intraperitoneal cavity during gestational week 10.6 The presence of gut, stomach and in particular the left liver lobe in the chest is thought to cause pulmonary hypoplasia by compression of the growing lungs. The pulmonary hypoplasia extends to all aspects of the lung, resulting in fewer bronchial divisions, a decreased number of alveoli and a hypoplastic and abnormal vascular tree.7,8 The morphology of the CDH lung furthermore has an immature appearance. The ipsilateral lung is the most severely affected, but the changes usually extend to the contralateral lung, as well.

PATHOPHYSIOLOGY Live-born infants with CDH usually present with severe respiratory distress. Although the major cause of this is pulmonary hypoplasia, the resulting hypoxia and hypercarbia will result in pulmonary vasoconstriction and pulmonary hypertension. This in turn will cause reversal to right-to-left shunting through the ductus arteriosus and the foramen ovale, and the infant enters a vicious, self-perpetuating cycle, as described in Figure 31.1. There are several additional factors contributing to the severe pulmonary hypertension in CDH. The pulmonary vascular bed is abnormal, with increased muscularization of arterioles in a manner similar to infants with idiopathic persistent pulmonary hypertension of the newborn (PPHN).8 Increased thickness of the media as well as the adventitia of arteries of all sizes has also been demonstrated.16 Furthermore, vasoactive substances such as endothelin-1 seem to be increased in infants with CDH. Kobayashi and Puri found increased blood levels of

310 Congenital diaphragmatic hernia

degree of pulmonary hypoplasia. Currently, intrauterine lung measurement by MRI is being investigated as a means of estimating lung size.24 Postnatally, CDH should be suspected in infants with severe respiratory distress at birth or within the ﬁrst few hours of life. With left-sided CDH, the heart sounds are shifted to the right, and the breathing sounds are decreased bilaterally. The abdomen may be scaphoid, and the thorax enlarged. The deﬁnitive diagnosis is made by chest radiograph, showing bowel loops in the chest, and mediastinal shift to the contralateral side (Fig. 31.1).

TREATMENT

Figure 31.1 Chest radiograph of a left CDH with viscera visible in the left chest, pulmonary hypoplasia, and signiﬁcant mediastinal shift to the right

endothelin, as well as increased expression of endothelin1 in endothelial cells in the pulmonary vasculature.17 Endothelin-1 causes pulmonary vasoconstriction by binding to the endothelin A (ETA) receptor. The ETA receptor is ubiquitously present in the smooth muscle cells of the pulmonary vasculature,18 and the increased endothelin-1 levels may thus adversely affect pulmonary vasoconstriction. Hypoxia and hypercarbia may be further aggravated by a reported immaturity of the surfactant system in experimental animals and infants with CDH.19 Others could, however, not conﬁrm this deﬁciency,20 and recent studies suggest that the apparent surfactant deﬁciency may in fact be secondary to respiratory failure, rather than to a primary deﬁciency.21

On presentation, the infant with CDH should be intubated, paralyzed and have a nasogastric tube placed to prevent distension of the stomach and bowel. CDH was previously considered a surgical emergency, where prompt surgery with reduction of the abdominal viscera, thereby allowing the lungs to expand, was thought to be the only way to save infants in severe respiratory distress. The increased knowledge of the pathophysiology of CDH has led to a different approach, where prolonged preoperative stabilization has proven useful. Most centers now prefer delayed surgery, with a delay of sometimes several days, waiting for the stabilization of the pulmonary circulation before surgery.25 The treatment should be aimed at the different aspects of the vicious cycle (Fig. 31.2), i.e. hypoxia/hypercarbia, pulmonary vasoconstriction and pulmonary hypertension. To this purpose, aggressive hyperventilation and hypocarbia was previously widely used. However, a different approach, using gentle ventilation and permissive hypercarbia, has proven more useful in decreasing the mortality rate.26,27 Without this approach, a high mortality rate from barotrauma can be expected.28,29 Several centers have shown improved survival as compared to historical controls, using a combination of Pulmonary hypoplasia

DIAGNOSIS CDH can predictably be diagnosed prenatally by ultrasonography at approximately 20 weeks’ gestation. At the time of prenatal diagnosis, it is of vital importance to exclude the presence of other anomalies, including neural tube defects, cardiac malformations and chromosomal aberrations, e.g. trisomy 18 and 21. Furthermore, the degree of pulmonary hypoplasia should be assessed. The presence of liver in the chest in left-sided CDH indicates severe pulmonary hypoplasia.22 The lung-to-head ratio (LHR – the area of the right lung at the level of the four-chamber view divided by the head circumference)23 has been shown to be a predictable estimation of the

Hypoxia hypercarbia

Poor gas exchange Right to left shunting

Pulmonary vasoconstriction

Pulmonary hypertension

Figure 31.2 Pathophysiology of the deterioration seen following the ‘honeymoon period’ in infants with CDH

Operative repair 311

gentle ventilation and delayed surgery.27,30 Highfrequency oscillatory ventilation (HFOV) is a valuable tool in the treatment of infants with respiratory distress, since it provides effective ventilation while decreasing barotrauma. However, in CDH, HFOV has not been shown to alter the mortality or morbidity rates.28,31 Appropriate ﬂuid management, as well as the use of inotropic agents, are crucial in the treatment of CDH. Adequate sedation and pain management should be used, but the use of paralysis is controversial. Surgery should be performed when the infant is stable with minimal ventilator settings, is diuresing well, and the chest radiograph is improving. Since the role of pulmonary vasoconstriction and right-to-left shunting was recognized in the late 1970s, a battery of pharmacological agents has been used in an attempt to decrease pulmonary vascular resistance. None of these have a proven effect on CDH. Initially, inhaled nitric oxide (iNO), which provides selective pulmonary vasodilatation, seemed to be a promising therapy,32 but more recent conclusions seem to be that although selected infants may respond well to iNO, this response seems to be variable or temporary.33,34 In consequence, iNO is usually used as an adjunct to conventional mechanical ventilation and HFOV while preparing for extracorporeal membrane oxygenation (ECMO) cannulation. ECMO is used in the treatment of CDH when conventional mechanical ventilation fails. The evidence supporting the use of ECMO is conﬂicting,28,31,35 although some evidence seems to support the use of ECMO in selected cases.27,30,36 ECMO provides a period of lung rest, while allowing the infant to adapt, and the pulmonary vascular resistance to decrease. The problem, however, is the difﬁculty in assessing the amount of pulmonary hypoplasia before starting ECMO treatment in patients with pulmonary hypoplasia incompatible with life. To that extent, several centers advocate the use of ECMO only in patients with evidence of a ‘honeymoon period’, i.e. patients with adequate gas exchange for a period preceding the deterioration in respiratory status. Others use preductal blood gases, where only patients with a period of normal preductal pO2 and pCO2 will be considered for ECMO.27 Some centers, however, claim that no criteria as yet exist to adequately select the patients who will beneﬁt from ECMO. Since some studies suggest surfactant deﬁciency in CDH infants, surfactant replacement has been tried as an adjunct to conventional mechanical ventilation or ECMO. No beneﬁcial effect has as yet been proven.37 Several novel therapies of ventilation are in evolution, several of which have been tried in CDH infants. Partial liquid ventilation has been beneﬁcial in some cases,38 and some preliminary promising results have been obtained by the use of intratracheal pulmonary ventilation (ITPV).39 Both of these methods provide efﬁcient ventilation, while apparently protecting the lung against baro-

trauma. However, none of these methods can improve the fundamental problem with the CDH lung, i.e. hypoplasia, and therefore share the shortcomings of ECMO treatment.

OPERATIVE REPAIR Repair of the defect is usually the most straightforward part of the management of CDH. Preoperative antibiotics are usually used, and although not generally necessary, blood should be available. The defect is exposed through a left subcostal abdominal incision, and the viscera are reduced from the chest (Fig. 31.3). There is usually a layer of peritoneum running from the retroperitoneum over the lower edge of the defect. Division of this tissue usually allows visualization of the posterior edge of the diaphragm. If a large portion of the liver is herniated into the chest, reduction of this organ is facilitated by division of the umbilical vein and falciform ligament. The diaphragm is then closed using interrupted nonabsorbable sutures. In some cases, the defect is too large for primary closure, and prosthetic material is used. An alternative to this approach is a muscle ﬂap taken from the transversus abdominus, leaving the outer abdominal muscle layers intact. This technique should not be performed on

Figure 31.3 Operative repair of CDH. The herniated viscera are reduced, the diaphragmatic defect is inspected, and the peritoneal layer over the retroperitoneum is divided to enhance visualization of the lower diaphragmatic edge

312 Congenital diaphragmatic hernia

patients on ECMO, or at risk of ECMO treatment, because of the risk of hemorrhagic complications. Prior to closure, the abdomen is manually stretched to make room for the herniated viscera. It is controversial whether a chest tube should be inserted prior to closure. If a chest tube is used, suction should not be applied, since it can too rapidly shift the mediastinum and may increase the transpulmonary pressure gradient, and predispose to pneumothorax. Postoperative care should be performed in the same manner as preoperatively, with a close watch on ﬂuid management, ventilatory support and hemodynamic monitoring. Feeding is begun when bowel function is evident.

PRENATAL TREATMENT In spite of the recent advances in neonatal intensive care, a certain proportion of these babies will die from pulmonary hypoplasia, either pre-, peri- or postnatally. This group should be eligible to prenatal treatment. Fetal surgery, with primary repair of the defect, was shown to be promising as a way of mitigating pulmonary hypoplasia in experimental and initial clinical studies.40 However, the herniated liver proved to be a difﬁcult obstacle. In spite of innovative techniques,41 fetal surgery of ‘liver-up’ CDH proved to be impossible, since reducing the liver caused kinking of the umbilical vein, cutting off blood ﬂow from the placenta and causing fetal demise.42 Although open fetal surgery was felt to be physiologically sound and technically feasible, it should thus be reserved for fetuses without liver herniation. However, the survival rate in these fetuses remains high whether treated pre- or postnatally, and they should thus not be eligible for prenatal intervention.43 An experiment of nature led to the evolution of a novel technique of prenatal intervention. Infants with laryngeal atresia were found to have enlarged lungs at autopsy. Furthermore, laryngeal atresia reversed the profound pulmonary hypoplasia in patients with renal agenesis.44 This led to experimental studies, where pulmonary hypoplasia in fetal lambs caused by fetal nephrectomy as well as surgically created CDH, was alleviated by tracheal ligation.45–48 A fetoscopic technique of temporary tracheal occlusion by placing clips on the human trachea was then developed.49,50 This method has undergone further evolution, and currently a technique using one port, and the endoscopic placement of a tracheal balloon, is used. Fetal tracheal occlusion as a means of improving survival in CDH is currently being investigated in a prospective randomized trial, sponsored by the National Institute of Health (http://commons.cit.nih.gov/crisp/crisp_lib.query) and conducted at the Fetal Treatment Center, University of California, San Francisco.

In order to deliver infants with fetal tracheal occlusion, a special method of delivery had to be developed, the ex utero intrapartum treatment procedure (EXIT). Cesarean section is performed with maximal uterine relaxation, and while keeping the infant on placental support, the upper airway can be instrumented. This method is useful as a means of delivering infants with other conditions affecting the upper airway as well, e.g. cystic hygroma of the neck or laryngeal atresia.51 Although tracheal occlusion is very promising, several complications have been reported. Prolonged tracheal occlusion may lead to hydrops and fetal demise,52 and several reports have shown a decrease in type II pneumocytes and deﬁcient surfactant production after tracheal ligation.53–55 Some results seem to favor late gestation occlusion, demonstrating less effect on surfactant production.56 The effect on lung growth by tracheal occlusion and retention of pulmonary ﬂuid seems to be exerted by pulmonary stretch itself, which in turn causes upregulation of different growth factors. Vascular endothelial growth factor (VEGF) has been shown to be upregulated by pulmonary stretch, and may contribute to pulmonary growth by increasing angiogenesis.57 Insulin-like growth factor-I (IGF-I) gene expression is reduced in the lung parenchyma of lambs with surgically created CDH. IGF-I is, however, restored to normal or increased levels after tracheal ligation or postnatal lung distension.58 A similar method of pulmonary stretch has been tried as a means of inducing postnatal lung growth in CDH infants. The lungs are then continuously distended with perﬂuorocarbon during ECMO treatment. Experimental as well as initial clinical results are promising.59 Prenatal non-invasive treatment is thoroughly being investigated as well. Promising results on outcome and pulmonary maturity have been obtained by prenatal treatment with dexamethasone in experimental models on rats and sheep.60 Prenatal us of dexamethasone is currently being investigated in the clinical setting in a prospective randomized trial. Vitamin E has been shown to induce lung growth in experimentally induced CDH, and may in the future be tried clinically, as well.61

PROGNOSIS Although several centers have reported an increased survival rate using novel therapies, including ECMO,27,30 the fact remains that the hidden mortality rate is very high.62 Since most centers are only aware of the cases that reach their center alive, pre- and perinatal mortality is usually not included. In spite of optimal postnatal care, the mortality in isolated CDH diagnosed before 24 weeks’ gestation and followed prospectively, was as high as 58% in a recent study.3 All of those cases fulﬁlled the criteria for prenatal intervention.

References 313

It is of vital importance to recognize variables that predict pre- and perinatal mortality, since they will inﬂuence the information given to the family, as well as deciding eligibility to prenatal intervention. Firstly, other lethal malformations, as well as chromosomal aberrations, should be excluded. In isolated left-sided CDH, herniation of the liver into the chest has been shown to be a predictor of high mortality, whereas survival is highly likely if the liver is not herniated into the thorax.22,63 Furthermore, the LHR has been shown to adequately predict outcome in left-sided, ‘liver-up’ CDH. In a prospective series, an LHR <1.0 was associated with 100% mortality, whereas all patients with an LHR >1.4 survived.23 Currently, fetal MRI as a means of measuring lung volume and thereby predicting pulmonary hypoplasia, is investigated.24 Postnatal prediction of pulmonary hypoplasia and survival has proven more difﬁcult to ascertain. Bohn et al. correlated preoperative Paco2 with an index of ventilation (VI; mean airway pressure × respiratory rate), and could divide the infants into four groups, where the group with a Paco2 <40 mmHg and a VI <1000 had the best survival rate.64 ECMO was not used in this study, however. Several centers use preductal Pao2 as a predictor of survival.27 Recently, a study of computer-assisted analysis of the postoperative chest radiograph has been shown to predict pulmonary hypoplasia.65 However, accurate preoperative predictors are needed in order to avoid placing patients with lethal pulmonary hypoplasia on ECMO.

LONG-TERM OUTCOME Although long-term outcome, regarding respiratory function, has been shown to be excellent, these series usually do not take into account the more recent therapies, including ECMO, where it can be predicted that patients with marginal lung function may survive. Some evidence supports the fact that a signiﬁcant number of survivors may be impaired by long-term pulmonary hypertension.66 Developmental delay, as well as hearing loss, has been reported in patients with CDH.67,68 These complications are most likely to be due to prolonged hypoxia. A signiﬁcant number of survivors report gastrointestinal symptoms, including gastroesophageal reﬂux, which may be symptomatic and incapacitating well beyond the neonatal period.69,70 Furthermore, recurrence of the hernia may lead to rapid deterioration in respiratory function, as well as gastrointestinal symptoms.70, 71 Recurrence is more common in patients repaired with a prosthetic patch. In conclusion, most survivors beyond the neonatal period are able to lead a normal life, but children with CDH should be followed up and assessed for respiratory status until normal lung function can be ascertained.

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hernia complicated by pulmonary hypertension. J Pediatr Surg 1998; 33:382–7. Kobayashi H, Puri P. Plasma endothelin levels in congenital diaphragmatic hernia. J Pediatr Surg 1994; 29:1258–61. Nobuhara KK, Wilson JM. Pathophysiology of congenital diaphragmatic hernia. Semin Pediatr Surg 1996; 5:234–42. Glick PL, Stannard VA, Leach CL et al. Pathophysiology of congenital diaphragmatic hernia II: The fetal lamb CDH model is surfactant deﬁcient. J Pediatr Surg 1992; 27:382–8. Sullivan KM, Hawgood S, Flake AW et al. Amniotic ﬂuid phospholipid analysis in the fetus with congenital diaphragmatic hernia. J Pediatr Surg 1994; 29:1020–4. IJsselstijn H, Zimmermann LJ, Bunt JE et al. Prospective evaluation of surfactant composition in bronchoalveolar lavage ﬂuid of infants with congenital diaphragmatic hernia and of age-matched controls. Crit Care Med 1998; 26:573–80. Metkus AP, Filly RA, Stringer MD et al. Sonographic predictors of survival in fetal diaphragmatic hernia. J Pediatr Surg 1996; 31:148–52. Lipshutz GS, Albanese CT, Feldstein VA et al. Prospective analysis of lung-to-head ratio predicts survival for patients with prenatally diagnosed congenital diaphragmatic hernia. J Pediatr Surg 1997; 32:1634–6. Coakley FV, Lopoo JB, Lu Y et al. Normal and hypoplastic fetal lungs: volumetric assessment with prenatal singleshot rapid acquisition with relaxation enhancement mr imaging. Radiology 2000; 216:107–11. Langer JC, Filler RM, Bohn DJ et al. Timing of surgery for congenital diaphragmatic hernia: Is emergency operation necessary? J Pediatr Surg 1988; 23:731–4. Wung JT, James LS, Kilchevsky E et al. Management of infants with severe respiratory failure and persistence of the fetal circulation, without hyperventilation. Pediatrics 1985; 76:488–94. Wung JT, Sahni R, Mofﬁtt ST et al. Congenital diaphragmatic hernia: survival treated with very delayed surgery, spontaneous respiration, and no chest tube. J Pediatr Surg 1995; 30:406–9. Wilson JM, Lund DP, Lillehei CW et al. Congenital diaphragmatic hernia – a tale of two cities: the Boston experience. J Pediatr Surg 1997; 32:401–5. Sakurai Y, Azarow K, Cutz E et al. Pulmonary barotrauma in congenital diaphragmatic hernia: a clinicopathological correlation. J Pediatr Surg 1999; 34:1813–17. Frenckner B, Ehrén H, Granholm T et al. Improved results in patients who have congenital diaphragmatic hernia using preoperative stabilization, extracorporeal membrane oxygenation, and delayed surgery. J Pediatr Surg 1997; 32:1185–9. Azarow K, Messineo A, Pearl R et al. Congenital diaphragmatic hernia – a tale of two cities: the Toronto experience. J Pediatr Surg 1997; 32:395–400.

32. Frostell CG, Lonnqvist PA, Sonesson SE et al. Near fatal pulmonary hypertension after surgical repair of congenital diaphragmatic hernia. Successful use of inhaled nitric oxide. Anaesthesia 1993; 48:679–83. 33. Shah N, Jacob T, Exler R et al. Inhaled nitric oxide in congenital diaphragmatic hernia. J Pediatr Surg 1994; 29:1010–15. 34. Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics 1997; 99:838–45. 35. UK Collaborative ECMO Trial Group. UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. Lancet 1996; 348:75–82. 36. Congenital Diaphragmatic Hernia Study Group. Does extracorporeal membrane oxygenation improve survival in neonates with congenital diaphragmatic hernia? J Pediatr Surg 1999; 34:720–5. 37. Lotze A, Knight GR, Anderson KD et al. Surfactant (beractant) therapy for infants with congenital diaphragmatic hernia on ECMO: evidence of persistent surfactant deﬁciency. J Pediatr Surg 1994; 29:407–12. 38. Wilcox DT, Glick PL, Karamanoukian HL et al. Partial liquid ventilation and nitric oxide in congenital diaphragmatic hernia. J Pediatr Surg 1997; 32:1211–15. 39. Schnitzer JJ, Thompson JE, Hedrick HL. A new ventilator improves CO2 removal in newborn lambs with congenital diaphragmatic hernia. Crit Care Med 1999; 27:109–12. 40. Harrison MR, Bressack MA, Churg AM et al. Correction of congenital diaphragmatic hernia in utero. II. Simulated correction permits fetal lung growth with survival at birth. Surgery 1980; 88:260–8. 41. Harrison MR, Adzick NS, Flake AW et al. The CDH two-step: A dance of necessity. J Pediatr Surg 1993; 28:813–16. 42. Harrison MR, Adzick NS, Flake AW et al. Correction of congenital diaphragmatic hernia in utero: VI. Hardearned lessons. J Pediatr Surg 1993; 28:1411–18. 43. Harrison MR, Adzick NS, Bullard KM et al. Correction of congenital diaphragmatic hernia in utero VII: A prospective trial. J Pediatr Surg 1997; 32:1637–42. 44. Wigglesworth JS, Desai R, Hislop AA. Fetal lung growth in congenital laryngeal atresia. Pediatr Pathol 1987; 7:515–25. 45. Wilson JM, DiFiore JW, Peters CA. Experimental fetal tracheal ligation prevents the pulmonary hypoplasia associated with fetal nephrectomy: possible application for congenital diaphragmatic hernia. J Pediatr Surg 1993; 28:1433–40. 46. DiFiore JW, Fauza DO, Slavin R et al. Experimental fetal tracheal ligation reverses the structural and physiological effects of pulmonary hypoplasia in congenital diaphragmatic hernia. J Pediatr Surg 1994; 29:248–57. 47. Hedrick MH, Estes JM, Sullivan KM et al. Plug the lung until it grows (PLUG): a new method to treat congenital diaphragmatic hernia in utero. J Pediatr Surg 1994; 29:612–17.

References 315 48. Luks FI, Gilchrist BF, Jackson BT et al. Endoscopic tracheal obstruction with an expanding device in a fetal lamb model: preliminary considerations. Fetal Diagn Ther 1996; 11:67–71. 49. VanderWall KJ, Skarsgard ED, Filly RA et al. Fetendo-clip: a fetal endoscopic tracheal clip procedure in a human fetus. J Pediatr Surg 1997; 32:970–72. 50. Harrison MR, Mychaliska GB, Albanese CT et al. Correction of congenital diaphragmatic hernia in utero IX: Fetuses with poor prognosis (liver herniation and low lung-tohead ratio) can be saved by fetoscopic temporary tracheal occlusion. J Pediatr Surg 1998; 33:1017–23. 51. Mychaliska GB, Bealer JF, Graf JL et al. Operating on placental support: The ex utero intrapartum treatment procedure. J Pediatr Surg 1997; 32:227–31. 52. Graf JL, Gibbs DL, Adzick NS et al. Fetal hydrops after in utero tracheal occlusion. J Pediatr Surg 1997; 32:214–16. 53. O’Toole SJ, Sharma A, Karamanoukian HL et al. Tracheal ligation does not correct the surfactant deﬁciency associated with congenital diaphragmatic hernia. J Pediatr Surg 1996; 31:546–50. 54. O’Toole SJ, Karamanoukian HL, Irish MS et al. Tracheal ligation: the dark side of in utero congenital diaphragmatic hernia treatment. J Pediatr Surg 1997; 32:407–10. 55. Bullard KM, Sonne J, Hawgood S et al. Tracheal ligation increases cell proliferation but decreases surfactant protein in fetal murine lungs in vitro. J Pediatr Surg 1997; 32:207–13. 56. Liao SL, Luks FI, Piasecki GJ et al. Late-gestation tracheal occlusion in the fetal lamb causes rapid lung growth with type ii cell preservation. J Surg Res 2000; 92:64–70. 57. Muratore CS, Nguyen HT, Ziegler MM et al. Stretchinduced upregulation of vegf gene expression in murine pulmonary culture: a role for angiogenesis in lung development. J Pediatr Surg 2000; 35:906–12. 58. Nobuhara KK, DiFiore JW, Ibla JC et al. Insulin-like growth factor-I gene expression in three models of accelerated lung growth. J Pediatr Surg 1998; 33:1057–61. 59. Nobuhara KK, Fauza DO, DiFiore JW et al. Continuous intrapulmonary distension with perﬂuorocarbon accelerates neonatal (but not adult) lung growth. J Pediatr Surg 1998; 33:292–8. 60. Hedrick HL, Kaban JM, Pacheco BA et al. Prenatal

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glucocorticoids improve pulmonary morphometrics in fetal sheep with congenital diaphragmatic hernia. J Pediatr Surg 1997; 32:217–22. Islam S, Narra V, Cote GM et al. Prenatal vitamin E treatment improves lung growth in fetal rats with congenital diaphragmatic hernia. J Pediatr Surg 1999; 34:172–7. Harrison MR, Bjordal RI, Langmark F et al. Congenital diaphragmatic hernia: The hidden mortality. J Pediatr Surg 1978; 13:227–30. Albanese CT, Lopoo J, Goldstein RB et al. Fetal liver position and perinatal outcome for congenital diaphragmatic hernia. Prenat Diagn 1998; 18:1138–42. Bohn D, Tamura M, Perrin D et al. Ventilatory predictors of pulmonary hypoplasia in congenital diaphragmatic hernia, conﬁrmed by morphological assessment. J Pediatr 1987; 111:423–31. Dimitriou G, Greenough A, Davenport M et al. Prediction of outcome by computer-assisted analysis of lung area on the chest radiograph of infants with congenital diaphragmatic hernia. J Pediatr Surg 2000; 35:489–93. Schwartz IP, Bernbaum JC, Rychik J et al. Pulmonary hypertension in children following extracorporeal membrane oxygenation therapy and repair of congenital diaphragmatic hernia. J Perinatol 1999; 19:220–6. Ahmad A, Gangitano E, Odell RM et al. Survival, intracranial lesions, and neurodevelopmental outcome in infants with congenital diaphragmatic hernia treated with extracorporeal membrane oxygenation. J Perinatol 1999; 19:436–40. Bouman NH, Koot HM, Tibboel D et al. Children with congenital diaphragmatic hernia are at risk for lower levels of cognitive functioning and increased emotional and behavioral problems. Eur J Pediatr Surg 2000; 10:3–7. Nagaya M, Akatsuka H, Kato J. Gastroesophageal reﬂux occurring after repair of congenital diaphragmatic hernia. J Pediatr Surg 1994; 29:1447–51. Van Meurs KP, Robbins ST, Reed VL et al. Congenital diaphragmatic hernia: long-term outcome in neonates treated with extracorporeal membrane oxygenation. J Pediatr 1993; 122:893–9. Nobuhara KK, Lund DP, Mitchell J et al. Long-term outlook for survivors of congenital diaphragmatic hernia. Clin Perinatol 1996; 23:873–87.

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32 Extracorporeal membrane oxygenation for neonatal respiratory failure EUGENE S. KIM AND CHARLES J. H. STOLAR

INTRODUCTION Extracorporeal membrane oxygenation (ECMO) was ﬁrst used in newborns in 1974. Since then, the Extracorporeal Life Support Organization (ELSO) has recorded approximately 15 000 newborns who have been treated with ECMO for a variety of cardiorespiratory disorders. The most common disorders in the newborn treated with ECMO are meconium aspiration syndrome (MAS), persistent pulmonary hypertension of the neonate (PPHN), congenital diaphragmatic hernia (CDH), sepsis and cardiac support. Depending on the indication for ECMO, the outcome has varied, but overall, a survival rate of 76% has been reported for newborns treated in this high (> 80%) mortality group.1 This chapter will discuss the selection criteria for ECMO in neonates and the management of these babies while on ECMO. It will then discuss ECMO for use in difﬁcult, clinical scenarios, such as CDH and preterm infants, and ﬁnally review outcome and follow-up of neonates treated with ECMO.

SELECTION CRITERIA FOR NEONATAL ECMO The selection criteria for newborns are based on historic experience from multiple institutions, patient safety and mechanical limitations related to the equipment.

Gestational age The gestational age should be at least 34 weeks. In the early experience with ECMO, premature infants (<34 weeks’ gestation) who were offered ECMO developed signiﬁcant morbidity and mortality related to intracranial hemorrhage.2 Despite reﬁnement of ECMO techniques in the 1980s, premature infants continue to be at risk for intracranial hemorrhage. This may be due to the

fact that ependymal cells within the brain may not be fully developed in preterm infants, thus making them susceptible to intracranial bleeding. In addition, the systemic heparinization necessary to maintain a thrombus-free ECMO circuit also increases the risk of bleeding complications.

Birth weight The birth weight should be nearly 2000 g. The principle of this criteria is limited to the size of the baby and the limitation of cannula size. The smallest single-lumen ECMO cannula is 8 French (Fr.) gauge. Flow through the tube is related to the radius of the tube by a power of 4. If the vein is small, then the cannula will be small, resulting in ﬂow that will be reduced by a 4th power. From historic experience, if the baby weighs less than 2 kg, then the difﬁculty of the placement of the cannula in conjunction with the inadequate ﬂow from small catheters make ECMO in these small babies challenging.

Bleeding complications The baby should have no active bleeding or major coagulopathy. Patients with uncorrectable coagulopathy, ongoing uncontrollable bleeding, or sepsis and its associated coagulopathy are at high risk of bleeding complications while on ECMO. The need for continuous systemic heparin therapy while on ECMO adds to this risk of bleeding.3 Therefore, prior to initiating ECMO, bleeding should be controlled.

Intracranial hemorrhage The infant should not have an intracranial hemorrhage. ECMO candidates with a pre-existing intracranial hemorrhage may exacerbate the problem secondary to

318 Extracorporeal membrane oxygenation for neonatal respiratory failure

the use of heparin and altered cerebral blood ﬂow while on ECMO. Infants with small interventricular hemorrhages (grade I–II) may be considered for ECMO on an individual case basis, but these cases should be closely monitored for worsening bleeding. Patients with previous intracranial bleeds, cerebral infarcts and other risk factors (prematurity, coagulopathy, ischemic central nervous system injury, or sepsis) are particularly at high risk for intracranial hemorrhage.2,4

Reversible disease process The baby should have a reversible lung disease and be supported by aggressive mechanical ventilation for no longer than 10–14 days prior to ECMO. Babies who have had prolonged exposure to high-concentration oxygen and positive-pressure ventilation develop bronchopulmonary dysplasia (BPD).5 Recovery of this type of irreversible lung injury may take from weeks–months to occur, if at all. ECMO therapy can be a good treatment for reversible lung disease over a relatively short period of time (2–3 weeks). However, even a lengthy ECMO course would not be sufﬁcient to permit recovery of the irreversible ﬁbrotic changes that occur to the lung following sustained barotrauma and/or oxygen toxicity. In addition, with a longer ECMO run, the chance of infection, bleeding complications, thromboembolic events, and mechanical failure increase. In a retrospective case–control study which reviewed the records of ECMO patients over 66 months, patients with oxygen dependency at 1 month of age and radiographic evidence of BPD were compared to patients without these ﬁndings.6 Patients with BPD were placed on ECMO at an older mean age than non-BPD patients (135- vs 50-hours-old). The BPD group had longer mean ECMO courses as well (203 vs 122 hours). The authors suggest that risk of BPD from high levels of ventilatory support occur with as little as 4 days of assisted ventilation.

Coexisting anomalies The baby should have no lethal congenital anomalies. Every effort should be made to establish a clear diagnosis before the initiation of ECMO. If that is not possible, then the diagnosis should be established during the course of ECMO. ECMO is not intended to delay an inevitable death. Many lethal pulmonary conditions, though, may present like reversible diseases such as congenital alveolar proteinosis, alveolar capillary dysplasia and overwhelming pulmonary hypoplasia. Other treatable conditions, such as total anomalous pulmonary venous return and transposition of the great vessels, may initially manifest with respiratory failure. If possible, an echocardiogram should be rapidly obtained to determine the need for ECMO or cardiac surgery.

Failure of medical management The baby must have ﬁrst failed optimal medical management. This is often the most difﬁcult criteria to elucidate. Different institutions have varying specialties, capabilities, and expertise. ‘Optimal’ medical management is a subjective term which may vary widely. Current optimal medical management may include pharmacologic support with vasodilator or vasoconstrictive agents, inotropic agents, sedatives and analgesics. Ventilatory support usually begins with conventional strategies, but may change to include exogenous surfactant administration, achievement of respiratory alkalosis, hyperoxia, high postexpiratory end pressure (PEEP), inverse I:E ratios, or high frequency ventilation. Early use of steroids in the management of respiratory distress syndrome (RDS) has been proposed to decrease pulmonary inﬂammation, and achievement of metabolic alkalosis may be preferred to respiratory alkalosis.7 The merits and demerits of all these treatment strategies are beyond the scope of this paper. Innovations in medical management have been developed, which have prevented ECMO in patients who meet the criteria for ECMO. These innovations in management include high-frequency oscillatory ventilation, permissive hypercapnea with spontaneous ventilation and nitric oxide. In 1985, Wung et al. used a non-traditional approach to the management of patients with persistent pulmonary hypertension.8 Hyperventilation and hyperoxia were not emphasized, and muscle relaxants were not used. Permissive hypercapnea in conjunction with spontaneous ventilation was employed. By tolerating a Paco2 of 50–80 mmHg and a PaO2 of 40 mmHg and by using low-pressure ventilator settings to provide adequate chest wall excursion, the series of 15 patients, who met institutional criteria for ECMO, survived with this medical approach alone. Other, more objective criteria have been established to quantify respiratory failure and aid in determining which infants should be placed on ECMO. High-pressure ventilator settings (PIP > 40 cm H2O, PEEP > 7 cm H2O, IMV > 100 and FiO2 of 1.0) have correlated with mortality. In addition, studies have examined arterial oxygen pressure (Pao2 < 40 mmHg), alveolar-arterial oxygen gradient (A − ado2 > 600 mmHg × 4 hours) and oxygenation index (OI > 40) as predictors of mortality as well.9–12 However, some have argued that the alveolar-arterial oxygenation gradient and oxygenation index should not be heavily weighted because these factors can be manipulated by ventilator settings.

CLINICAL MANAGEMENT OF NEONATES ON ECMO Veno-venous vs veno-arterial ECMO A decision is ﬁrst made whether the infant would best be

Clinical management of neonates on ECMO 319

served with veno-venous (VV) or veno-arterial (VA) support. VV support delivers oxygen for respiratory indications. VV ECMO can be performed through a double-lumen catheter which is placed in the right internal jugular vein. The double-lumen catheter both drains deoxygenated blood and returns oxygenated blood to the right atrium. Double-lumen catheters of 12–14 Fr. gauge are commonly used in the newborn. As opposed to VV ECMO, VA ECMO not only delivers oxygen for respiratory failure but also provides circulatory support in the event of cardiac failure, difﬁculty weaning from cardiopulmonary bypass or occasionally CDH anatomy. In these cases, VA support is provided by venous drainage of the right atrium through a cannula inserted in the internal jugular vein (Fig. 32.1). Oxygenated blood is returned through a cannula in the carotid artery. Patients who present with profound lactic acidosis and hypoxic ischemia often have a component of cardiovascular collapse and may also require the circulatory support of VA as opposed to VV ECMO.

Superior thyroid vein

Carotid sheath

Internal jugular vein

Common carotid artery

(a) Venous cannula

Vessel

Cannula

Cannula management The preferred site for cannula placement is in the vessels of the right neck. The internal jugular vein is accessed via an open procedure. During the open procedure, muscle relaxants are given to prevent the inadvertent aspiration of air into the vein. In the event of VA ECMO, the carotid artery is dissected and identiﬁed for catheter placement. After placement of the catheters and initiation of ECMO ﬂow, the catheters are carefully secured with sutures to the blood vessel and skin (Fig. 32.2a–c). Heat exchanger

O2 Fluids Membrane oxygenator

Heparin

Pump

Figure 32.1 Schematic of completed veno-arterial ECMO circuit. Extrathoracic cannulation of the right atrium and acending aorta allows venous drainage to a servo-controlled valley pump and arterial return directly to the heart and brain. Oxygenation and CO2 removal is provided by a nonporous silicone membrane oxygenator. The blood is rewarmed before returning to the infant. All parenterally administered substances such as heparin, ﬂuids, blood products and drugs are given directly into the circuit

Silastic bumper

Arterial cannula (b)

(c)

Figure 32.2 Details of the cannulation procedure. (a) The carotid sheath is opened with the sternomastoid muscle retracted laterally. This exposes the common carotid artery and internal jugular vein. (b) The infant is anticoagulated after the vessels are dissected and then ligated cephalad. A 10 Fr. arterial cannula is passed into the ascending aorta by an arteriotomy. A 12–14 Fr. venous cannula is passed into the right atrium by the venotomy. (c) The cannulas are ﬁxed in position by ligation over a Silastic bumper to facilitate removal. The two ligatures on each vessel are then tied together. After the incision is closed, the cannulas are also sutured to the mastoid process and connected to the ECMO circuit

The position of the catheter is conﬁrmed in two ways. First, a chest radiograph is performed, which can grossly demonstrate catheter position. The tip of the venous cannula should be located within the right atrium, while the tip of the arterial cannula should be located in the ascending aorta. The second mode of conﬁrming cannula placement is cardiac echocardiography. The double-lumen catheter should be visualized within the right atrium, venting the return oxygenated blood through the tricuspid valve to minimize recirculation. Another mode of determining catheter position is also two-dimensional duplex doppler. If there is persistent difﬁculty maintaining ﬂow due to poor venous withdrawal, the possibility of a catheter problem must be entertained and further imaging should be performed to conﬁrm proper position.

320 Extracorporeal membrane oxygenation for neonatal respiratory failure

Prime management The tubing of the ECMO circuit is initially circulated with carbon dioxide gas. This is followed by the addition of crystalloid and 5% albumin solution. The albumin coats the tubing to decrease its reactivity to circulating blood. The carbon dioxide gas dissolves into the ﬂuid. Approximately 2 units of packed red blood cells are required for initial priming of the pump, which displaces the crystalloid and colloid in the circuit. The initial pH, oxygen content and carbon dioxide content of the circuit are then measured and adjusted to physiologic parameters. If the prime blood is acidotic, this may exacerbate the infant’s condition; or if the primed circuit has a low carbon dioxide content, this may cause metabolic problems for the neonate. Additionally, a heat exchanger warms the prime to normal body temperature. In sum, the primed circuit must be physiologically compatible with life prior to initiating ECMO to maximize support and prevent initial worsening of the child’s condition.

Pump management The goal of ECMO is to maintain adequate pump ﬂow, which will result in good oxygen delivery to the tissues and organs. Oxygen delivery to the infant is dependent on the speed or rotations per minute (r.p.m.) of the roller pump as it non-occlusively propels the volume of blood in the ‘raceway’ (tubing within the roller pump housing). With VA ECMO, adequate perfusion and oxygen delivery can be monitored by the pH and Po2 of a ‘mixed venous’ blood sample (pre-oxygenator blood sample). The ﬂow of the roller pump should be adjusted to maintain a mixed venous Po2 of 37–40 mmHg and saturation of 65–70%. With VV ECMO, the ‘mixed venous’ sample may not be a reliable indicator of perfusion as recirculation may produce a falsely elevated Po2. Therefore, other indicators of poor perfusion should be followed: persistent metabolic acidosis, oliguria, seizures, elevated liver function tests and hypotension. If oxygen delivery is found to be inadequate, then the r.p.m. of the pump may need to be increased to improve perfusion. Roller pumps roll against the tubing to propel the blood towards the oxygenator. This area of contact is at risk for tubing rupture over time. To reduce the risk of rupture, the ‘raceway’ is advanced regularly after temporarily stopping the pump ﬂow. Tubing rupture is a rare event thanks to modern materials such as Supertygon (Norton Performance Plastics Corp., Akron, OH, USA), a chemically altered polyvinyl chloride (PVC).

Oxygenator management The silicone membrane (envelope) oxygenator (Avecor, Inc., Minneapolis, MN, USA) is critical to the success of

ECMO and long-term bypass. The mechanism of gas exchange occurs when blood in the tubing enters a manifold region and is distributed around the envelope of a silicone membrane lung. Oxygen, which is mixed with a small amount of carbon dioxide to prevent hypocapnea (Carbogen 95% O2 + 5% Co2), ﬂows through the inside of the membrane envelope in a countercurrent direction to the ﬂow of blood. Oxygen diffuses across the silicone membrane into the blood as carbon dioxide is eliminated. The oxygenated blood drains into a manifold and is returned to the infant via a heat exchanger. A thrombus may form in the oxygenator over time. As a thrombus extends, the membrane surface area is decreased, resulting in decreased oxygen and carbon dioxide transfer. This can lead to increased resistance to blood ﬂow. The gaseous portion of the oxygenator may also develop obstructions, which may lead to air emboli. Long-term use may wear the silicone membrane, resulting in blood and water in the gas phase. Therefore, the oxygenator should be replaced when the post-oxygenator Po2 decreases to < 200 mmHg or pre-oxygenator circuit pressures increase to > 400 mmHg at ﬂow rates required to support the patient. In addition, a larger oxygenator may also be required if the gas and blood ﬂow rating of the old oxygenator are exceeded in order to maintain adequate perfusion.

Volume management While on ECMO, maintenance ﬂuids for a term newborn under a radiant warmer are estimated to be 100 cc/kg/day. Water loss through the oxygenator may approach 2 cc/m2/hour. For a baby weighing 3 kg, this would be about 13 cc/kg/day. Fluid losses from urine, stool, chest tubes, nasogastric tubes, ostomies, mechanical ventilation, radiant ﬂuid loss and blood draws should be carefully recorded and repleted. Fluid management may become difﬁcult in the baby on ECMO as ﬂuid extravasates into the soft tissues during the early ECMO course. Therefore, meticulous recordings of the net ﬂuid balance on ECMO should be maintained. Classically, the weight increases in the ﬁrst 1–3 days as the patient becomes increasingly edematous. Starting the third day on ECMO, diuresis of the excess edema ﬂuid begins, and can be facilitated with the use of furosemide. This diuretic phase is often the harbinger of recovery. In the event of renal failure on ECMO, hemoﬁltration or hemodialysis can be added to the ECMO circuit for removal of excess ﬂuid and electrolyte correction.

Respiratory management on ECMO Once the desired ﬂow is attained, the ventilator should be promptly weaned to avoid further oxygen toxicity and barotrauma. Such ‘rest settings’ have been studied and debated.13 At the current authors’ institution, the FiO2 is

Clinical management of neonates on ECMO 321

decreased to 0.4, PEEP to 5 cm H2O, PIP to 20–25 cm H2O, a rate of 12 breaths/minute and inspiratory time of 0.5 seconds if the infant’s arterial and venous oxygenation are adequate. If the baby remains hypoxic despite maximal pump ﬂow, then higher ventilator settings may be temporarily required. Alternatively, hypoxic neonates on VV ECMO may need to be converted to VA ECMO for full cardiorespiratory support. On occasion, the chest X-ray will worsen in the ﬁrst 24 hours independent of ventilator settings and improve after diuresis. As the patient improves on ECMO and the pump ﬂow is weaned, ventilator settings are then modestly increased to support the baby off ECMO. In neonates, if the oxygen saturation is greater than 93%, the current authors consider an FiO2 of 0.4, PIP < 28, PEEP of 5, and a rate < 30 as adequate settings for a trial off of ECMO. In addition, during the course of ECMO, pulmonary toilet is essential to respiratory improvement and includes gentle chest percussion and postural drainage. Special attention should be made to the ECMO catheters and keeping the head and body aligned. Endotracheal suctioning is also recommended every 4 hours and as needed based on the amount of pulmonary secretions present.

Medical management After the initiation of ECMO, vasoactive medications should be quickly weaned down if the blood pressure remains stable. In the event of seizures, phenobarbital is usually given and maintained to prevent further seizures. In addition, gastrointestinal prophylaxis with an H2blocker, such as ranitidine, is instituted. Fentanyl and midazolam are usually administered for mild sedation, however the use of paralytics should be avoided. The baby’s muscle activity is not only important for ﬂuid mobilization of edema but also for monitoring neurological activity. Infectious prophylaxis is provided by the use of ampicillin and gentamicin, which covers most common perinatal bacterial infections. With the use of gentamicin, attention should be directed to renal function. For this reason, cefotaxime may be used for Gram-negative coverage instead of gentamicin. Due to the cannula and manipulation of the circuit at stopcocks, the risk of infection is a constant concern; therefore, strict observance to aseptic technique when handling the ECMO circuit should be maintained. Routine blood, urine, and tracheal cultures should be obtained to monitor for infection. The caloric intake on ECMO should be maximized using standard hyperalimentation. For a newborn, total parenteral nutrition (TPN) should be started at 100 kcal/kg/day. Normally, this should be supplied as 60% carbohydrates (14.6 g/kg/day) and 40% fat (4.3 g/kg/day). Intralipid infusions may be used as a

fat source, although there is some controversy with its use in the setting of severe lung disease. As a result, the percentage of fat in the hyperalimentation may be lowered. Amino acids may be added but must be considered in the setting of poor renal function and increasing BUN levels. With normal renal function, approximately 2.5 g protein/kg/day should be provided in the TPN mixture. Electrolytes should be closely monitored with potassium, calcium and magnesium repleted as necessary. Sodium and phosphorus are usually not repleted as they are often provided in blood products and volume expanders.

Coagulation management While on ECMO, the baby’s hemoglobin is maintained at 15 g/dL to maximize the oxygen-carrying capacity of the blood. Platelet destruction during ECMO is anticipated and is secondary to the ﬂow through the oxygenator. The platelet consumption should not exceed one-half to three units/day in neonates. In order to reduce the risk of bleeding during ECMO, the platelet count should be kept above 100 000/mm.14 The current authors recommend using ‘hyperspun’ platelets to avoid the excess administration of ﬂuid, and thus preventing further problems with volume overload and edema. Heparin is initially administered as a bolus (50– 100 mg/kg) followed by a constant heparin infusion (30–60 mg/kg/hour) to maintain a thrombus-free circuit. The level of anticoagulation is monitored by the activated clotting time (ACT). The heparin infusion is adjusted to maintain an ACT of 180–220 seconds. After decannulating, the heparin infusion is stopped and not reversed with protamine sulfate.

Complications on ECMO MECHANICAL COMPLICATIONS While hypovolemia is an important cause for poor venous return to the circuit and subsequent poor pump ﬂow, other causes must be eliminated prior to volume infusion. These may include small venous catheter diameter, excessive catheter length, catheter kinks, improper catheter position, insufﬁcient hydrostatic column length (i.e. patient height), and improper calibration or set-up of the venous control module system. After these causes have been excluded, small amounts of volume (5–20 cc/kg) may then be introduced into the circuit to support higher pump ﬂow rate. However, a large amount of volume infusion in conjunction with long-term muscle relaxants and venodilators can lead to anasarca, which in turn, can lead to poor chest wall compliance, compromised gas exchange and oxygen delivery. In some conditions such as sepsis,

322 Extracorporeal membrane oxygenation for neonatal respiratory failure

there may be endothelial damage and capillary leakage, in which case anasarca may be unavoidable.

NEUROLOGIC COMPLICATIONS The most serious complications of the ECMO patient have been neurologic (e.g. learning disorders, motor dysfunction, cerebral palsy) and appear to be due to hypoxia and acidosis prior to ECMO. During the ECMO course, frequent neurological examinations should be performed, and paralytic agents should be avoided. The exam consists of evaluation of alertness and interaction, fullness of the fontanels, reﬂexes, tone, spontaneous movements, eye ﬁndings, and presence of seizures. Intracranial hemorrhage (ICH) is the most devastating complication on ECMO. Therefore, careful attention must be made to the rate of ECMO ﬂow, rate of exchange of Pco2, ﬂuctuations in the ACT and platelet count. Cranial ultrasounds should be performed at least every other day to monitor ICH and after any major event, such as equipment malfunction, sudden worsening in oxygenation status, and pneumothorax. Electroencephalography (EEG) may also be helpful in the neurologic evaluation of the neonate.

RENAL COMPLICATIONS Infants on ECMO may sustain acute tubular necrosis (ATN) marked by oliguria and increasing BUN and creatinine levels. ATN may extend into the ﬁrst 24–48 hours of ECMO before improvement in urine output is seen. If the renal condition does not improve, poor tissue perfusion should be considered. A combination of inadequate ECMO ﬂow rate, low cardiac output and intravascular volume depletion from diuresis may lead to decreased renal function. If the infant remains in complete anuric renal failure and requires dialysis, a hemoﬁltration module can be added in series to the ECMO circuit to remove excess ﬂuid and stabilize electrolyte abnormalities.

Weaning from ECMO As the patient improves during the ECMO course, the ﬂow of the circuit is weaned, based on improving postductal arterial and venous oxygenation. From starting ﬂows as high as 150 cc/kg/minute, the ﬂow is decreased to 30–50 cc/kg/minute while maintaining adequate perfusion. The ACT should be maintained at a higher level due to the lower ﬂows to prevent thrombosis. If the baby tolerates the low ﬂow, then the ECMO cannula (VV) or cannulas (VA) may be clamped while the ECMO circuit recirculates. The current authors prefer to wean patients on to moderate conventional ventilator settings, i.e. IMV 20, FiO2 0.4, PIP 25, and PEEP 5. Higher ventilator settings, though, may be tolerated if the risks of continuing ECMO outweigh those of discontinuing ECMO. If the recirculation is tolerated, then decannulation is

performed. As with the insertion, decannulation should be performed as a sterile surgical procedure. The patient should be placed in the Trendelenburg position and muscle relaxants should be administered to prevent air aspiration into the vein. Prior to decannulation, vasoactive medication and hyperalimentation should be switched from the ECMO circuit to other vascular access. Once the catheter is removed, the vein is ligated and not repaired. This is also true for the artery in the case of VA ECMO.

ECMO in infants with congenital diaphragmatic hernia Neonates with CDH have abdominal viscera in the thoracic cavity, most commonly on the left side. This often leads to signiﬁcant pulmonary hypoplasia and pulmonary hypertension. Pulmonary insufﬁciency can ensue, leading to hypoxemia, hypercarbia, and acidosis soon after birth; this can then lead to a vicious cycle of pulmonary vasospasm, pulmonary hypertension, right-to-left shunting of blood and worsening hypoxemia, hypercarbia and acidosis. This cycle must be broken, if not medically, then with the assistance of ECMO. Medical management has improved greatly with the use of pulmonary vasodilators such as tolazoline and inhaled nitric oxide. If a fetus is antenatally diagnosed with a CDH, plans should be made for delivery in a medical center with ECMO capabilities in case of potential rescue therapy. There is no surgical indication or beneﬁt to early delivery of cesarian section. In the delivery room, intubation should be performed immediately after birth. The baby should then be transferred to a neonatal intensive care unit and started on mechanical ventilation to stabilize oxygenation and hemodynamics. In the past, newborns with CDH have undergone repair as a surgical emergency. However respiratory mechanics frequently worsen postoperatively, perhaps as a result of early repair.15 In the 1980s, however, surgeons reported improved results with delayed surgery after postnatal medical stabilization.16–21 A strategy of delayed repair in CDH patients after stabilization of respiratory and hemodynamic parameters with or without ECMO is the current standard of care.

OUTCOME AND FOLLOW-UP OF NEONATES TREATED WITH ECMO Mortality Mortality statistics for ECMO-treated patients have remained stable over the past decade according to the ELSO registry. Severe respiratory failure has been a major cause for return hospitalization and late deaths, but mortality has remained speciﬁc to the primary diagnosis prior to ECMO.1 For example, ECMO patients with

Outcome and follow-up of neonates treated with ECMO 323

the diagnosis of CDH or total anomalous pulmonary venous return (TAPVR) have about a 50% mortality rate while the diagnosis of meconium aspiration syndrome has a mortality rate of about 5%.1,22 For all diagnoses, the mortality rate for newborns placed on ECMO is about 20% according to the ELSO registry.1 Of the infants who die on ECMO, about half die from severe bleeding complications. Another risk factor for mortality is a birth weight of < 2 kg. A retrospective study reviewed 300 newborns treated with ECMO, and the infants who weighed < 2.5 kg, although meeting the criteria of 2 kg, had a relative mortality risk of 3.45% compared to ECMO neonates with birth weights > 2.5 kg.23

Feeding and growth sequelae After decannulation from ECMO, an important factor affecting NICU discharge is initiation of successful enteral feeding. Feeding problems have been reported in as many as one-third of ECMO-treated infants and varies in presentation.24–26 These problems are due to a variety of possible causes which include interference from tachypnea, generalized CNS depression, poor hunger drive, soreness in the neck from the surgical procedure, sore throat from intubation, poor oral–motor coordination, and manipulation or compression of the vagus nerve during the cannulation procedure.26,27 Feeding problems also differ according to pre-ECMO diagnosis. For example, infants with CDH have a higher incidence of feeding difﬁculty than infants with MAS and RDS.27–29 The CDH infants often have foregut dysmotility which leads to signiﬁcant reﬂux, delayed gastric emptying and feeding difﬁculties. Respiratory compromise and severe chronic lung disease also interfere with feeding. These babies may require prolonged nasogastric feeding or even a gastrostomy, fundoplication and pyloroplasty to maintain adequate growth. However, ECMO infants generally do not have major long-term feeding complications. Although normal somatic growth is most commonly reported, ECMO-treated children are more likely to experience problems with growth than normal controls. Head circumference below the 5th percentile occurs at a higher rate (10%) in post-ECMO children. Furthermore, poor head growth is associated with a major handicapping condition with a risk greater than 75% at 5 years of age.30 Although controversial, there have also been reports of macrocephaly, which follows a pattern of venous obstruction secondary to internal jugular vein ligation observed on neonatal neuro-imaging.30,31 Growth problems are most commonly associated with ECMO children who had CDH or residual lung disease.28

Respiratory sequelae Signiﬁcant respiratory problems are reported in ECMO survivors during the ﬁrst 2 years of life, with

a high rate of re-hospitalizations for pulmonary conditions.32,33 Approximately 15% of infants treated with ECMO require oxygen at 28 days. By the age of 5 years, ECMO children were twice as likely to have a reported case of pneumonia than control children (25% vs 13%). Approximately half of the ECMO children with pneumonia were hospitalized compared to none of the control cases. Half of the cases of pneumonias in ECMO children occurred before 1 year of life compared to none in the control group. In addition, more than half of the ECMO re-hospitalizations for pneumonia occurred within the ﬁrst 6 months of life. Of the ECMO-treated neonates, the primary diagnosis of CDH, in particular, has been found to be associated with chronic lung disease, deﬁned by the need for bronchodilators, diuretics, or supplemental oxygen for the management of pulmonary symptoms. Speciﬁcally, the use of supplemental oxygen at discharge from the hospital has been reported in 22–80% of CDH patients.29,34–36 This is most likely due to aggressive ventilator management and lung injury prior to initiating ECMO. The age at the time of ECMO, correlating with the amount of time on mechanical ventilation prior to ECMO, is another factor associated with oxygen need past 28 days.6 Neonates with severe respiratory failure had an 11.5-fold increased risk of bronchopulmonary dysplasia if ECMO was initiated at later than 96 hours of age. In addition, ECMO infants with birth weights of 2–2.5 kg have a greater risk for chronic lung disease than larger ECMO infants.23

Neurodevelopmental sequelae Perhaps the most serious of post-ECMO morbidities is sensorineural handicap. Reports of neurodevelopmental outcome after 1 year of age have been published from multiple institutions. Among 540 ECMO survivors from 12 institutions, the total rate of sensorineural handicap (cerebral palsy, blindness, hearing impairment) is 6% on average, ranging from 2–18%.30,37–49 Signiﬁcant developmental delay among ECMO survivors is 9% on average, ranging from 0–21%. This is comparable to other critically ill neonates. For example, newborns with extremely low birth weights (< 750 g) have a 15% rate of having major sensorineural handicap with 21% testing in the mentally retarded range.50 Additionally, newborns with PPHN not treated with ECMO have an average sensorineural handicap rate of 23% (0–37% range) among 162 survivors from eight institutions.51–58 Auditory deﬁcits are reported in more than 25% of ECMO neonates at the time of discharge.59 The majority consists of mild–moderate deﬁcit by brainstem auditory evoked response (BAER) testing which generally resolve over time. These auditory deﬁcits may also be partly iatrogenic due to alkalosis secondary to furosemide

324 Extracorporeal membrane oxygenation for neonatal respiratory failure

administration or gentamicin ototoxicity. As a result, hearing screening is recommended at the time of neonatal intensive care unit (NICU) discharge. Examining data for 313 ECMO children from ﬁve centers shows an overall rate of 9% (range 4–21%).30,42,44,46 This rate is not higher than that reported for non-ECMO PPHN children (23%, range 0–37%).51–54 Visual deﬁcits in ECMO neonates are usually due to the immature retina in premature patients. This is uncommon in ECMO neonates weighing more than 2 kg. Concern about retinopathy of prematurity due to the hyperoxic condition of ECMO has not been borne out. Hanley reported ocular ﬁndings in 16 of 85 ECMO neonates. These ﬁndings included vascular immaturity, vitreous and retinal hemorrhage, and optic nerve atrophy.60 However, not all infants were examined in this study and there may have been additional complications. Long-term sequelae were not reported, and non-ECMO controls were not tested. Seizures, both clinical and electroencephalographic, are widely reported among ECMO neonates, ranging widely from 20–70%.61–64 The timing and type of seizure activity are not consistent. However, in a group of 5-year-olds ECMO children, only 2% had a diagnosis of epilepsy. Seizures in the neonate are associated with neurologic disease and poorer long-term outcome, including cerebral palsy and epilepsy.65 According to one study, the handicap rate following neonatal seizures is 8%.66 A predictive association between abnormal EEG and developmental status has been found, with only 18% of infants having normal EEGs with developmental delays; this is compared to 35% of infants with one abnormal EEG and 58% of ECMO infants with two or more abnormal EEGs.62 Neuromotor deﬁcits range from a continuum of reports of mild hypotonia, gross motor delay, and asymmetry to isolated cases of spastic quadraparesis. Although moderate hypotonia is not uncommon at discharge, it generally improves over the next 4–6 months. However, these neuromotor ﬁndings are also seen in normal control children.33 The incidence of severe non-ambulatory cerebral palsy is less than 5%.30,37,42 These cases are generally accompanied by mental retardation, demonstrating a global insult to the brain. More commonly seen is a mild case of cerebral palsy in up to 20% of ECMO children. ECMO-treated neonates as a group most commonly function within the normal range.30,37,39,42–49 The rate of major handicap appears to be stable across studies with an average of 11%, range 2–18%. By the time of discharge, at approximately 1 month of life, ECMO infants still exhibit signs of general CNS depression, including lethargy, hypotonia and weak primitive reﬂexes, an indication of moderate hypoxic– ischemic encephalopathy. By 4 months of age, ECMO infants typically function in the normal range deﬁned by Bayley mental and motor scales. Residual hypotonia or

mild asymmetry persists in about 25%. Mild motor delay usually accompanies the hypotonia. Signiﬁcant neurological abnormalities and motor deﬁcits (more than two standard deviations below norm) are found in approximately 10–15% of affected individuals. By 3 years of age, the rate of handicap appears to be stable, but more subtle handicaps manifest at this age such as learning disabilities, particularly with language and perceptual functioning.26,67–69 By 5 years of age, a diagnosis of mental retardation (IQ < 70, delay in social adaptive functioning) becomes more certain. In one 5-years old, 11% of individuals studied were diagnosed as mentally retarded, most in the mild range with IQs of 50–70. For ECMO children who had carotid artery cannulation and ligation, controversy remains over reconstruction of the artery. Baumgart et al. reported experience of 84 ECMO children who had carotid ligation and 41 who had right common carotid artery reconstruction.70,71 Failure of the reanastomosis, deﬁned by > 50% occlusion or no ﬂow, occurred in 25% of procedures. No signiﬁcant differences were reported for occurrence of grade 3 and 4 hemorrhages, but 60% of the group reanastomosed had moderate to severe abnormalities on EEG, compared to 35% of the non-reconstructed group. Despite this, no differences were reported in the proportion of signiﬁcant neurodevelopmental delays.

SUMMARY Since the ﬁrst use of ECMO in neonates in 1974, much has been learned about the treatment of infants with cardiac and respiratory disease. New, less invasive medication and techniques have been developed which have kept numerous babies from ECMO cannulation. Over the years, much has also been learned about ECMO; indications have been expanded and selection criteria honed. Currently, the successful treatment of a variety of neonatal respiratory diseases such as meconium aspiration syndrome, persistent pulmonary hypertension of the neonate and severe pneumonia can be achieved. ECMO may also be helpful in neonates with cardiac lesions and difﬁculty weaning from bypass. Difﬁcult clinical scenarios such as congenital diaphragmatic hernia and sepsis have also met with success through the use of ECMO. The criteria for ECMO candidates have been slowly ﬁne-tuned to maximize survival rates and avoid unnecessary ECMO in infants with irreversible disease. Such criteria include early gestational age, low birth weight, coagulopathy, intracranial hemorrhage, lethal anomalies and irreversible lung disease. In summary, any hypoxic infant who has a reversible pulmonary or cardiac condition, who is physically large enough for ECMO, and who has failed maximal medical therapy should be considered for

References 325

ECMO. Meticulous attention and thorough documentation of each ECMO patient have improved knowledge about ECMO through the ELSO Registry. With ECMO as a safety net, new therapies can be developed for this poor surviving group of newborns such that the ultimate success of ECMO, will be its discontinuation.

REFERENCES 1. Extracorporeal Life Support Organization. ECLS Registry Report: International Summary. 1999: July. 2. Cilley RE, Zwischenberger JB, Andrews AF, Bowerman RA, Roloff DW, Bartlett RH. Intracranial hemorrhage during extracorporeal membrane oxygenation in neonates. Pediatrics 1986; 78(4):699–704. 3. Sell LL, Cullen ML, Whittlesey GC, Yedlin ST, Philipart AI, Bedard MP, Klein MD. Hemorrhage complications during extracorporeal membrane oxygenation: Prevention and treatment. J Pediatr Surg 1986; 21(12):1087–91. 4. Allmen D, Babcock D, Matsumoto J, Flake A, Warner BW, Stevenson RJ, Ryckman FC. The predictive value of head ultrasound in the ECMO candidate. J Pediatr Surg 1992; 27(1):36–9. 5. Northway WH, Rosan RC, Porter DY. Pulmonary disease following respiratory therapy of hyaline-membrane disease. N Engl J Med 1967; 276(7):357–8. 6. Kornhauser MS, Cullen JA, Baumgart S, McKee LJ, Gross GW, Spitzer AR. Risk factors for bronchopulmonary dysplasia after extracorporeal membrane oxygenation. Arch Ped Adolesc Med 1994; 148:820–5. 7. Sanders RJ, Cox C, Phelps DL, Sinkin RA. Two doses of early intravenous dexamethasone for the prevention of bronchopulmonary dysplasia in babies with respiratory distress syndrome. Pediatr Res 1994; 36(1):122–8. 8. Wung JT, James LS, Kilchevsky E, James E. Management of infants with severe respiratory failure and persistence of the fetal circulation, without hyperventilation. Pediatrics 1985; 76(4):488–94. 9. Krummel TM, Greenﬁeld LJ, Kirkpatrick BV, Mueller DG, Kerkering KW, Ormazabal M, Napolitano A, Salzberg AM. Alveolar-arterial oxygen gradients versus the neonatal pulmonary insufﬁciency index for prediction of mortality in ECMO candidates. J Pediatr Surg 1984; 19(4):380–4. 10. Beck R, Anderson KD, Pearson GD, Cronin J, Miller MK, Short BL. Criteria for extracorporeal membrane oxygenation in a population of infants with persistent pulmonary hypertension of the newborn. J Pediatr Surg 1986; 21(4):297–302. 11. Marsh TD, Wilkerson SA, Cook LN. Extracorporeal membrane oxygenation selection criteria: Partial pressure of arterial oxygen versus alveolar-arterial oxygen gradient. Pediatrics 1988; 82(2):162–6.

12. Ortiz RM, Cilley RE, Bartlett RH. Extracorporeal membrane oxygenation in pediatric respiratory failure. Pediatr Clin N Am 1987; 34(1):39–46. 13. Keszler M, Subramanian KN, Smith YA et al. Pulmonary management during extracorporeal membrane oxygenation. Crit Care Med 1989; 17:495–500. 14. Raithel SC, Pennington DG, Boegner E, Fiore A, Weber TR. Extracorporeal membrane oxygenation in children after cardiac surgery. Circulation 1992; 86:II305–10. 15. Sakai H, Tamura M, Hosokawa Y, Bryan AC, Barker GA, Bohn DJ. Effect of surgical repair on respiratory mechanics in congenital diaphragmatic hernia. J Pediatr 1987; 111:432–8. 16. Cartlidge PHT, Mann NP, Kapila L. Preoperative stabilization in congenital diaphragmatic hernia. Arch Dis Child 1986; 61:1226–8. 17. Breaux CW Jr, Rouse TM, Cain WS, Georgeson KE. Improvement in survival of patients with congenital diaphragmatic hernia utilizing a strategy of delayed repair after medical and/or extracorporeal membrane oxygenation stabilization. J Pediatr Surg 1991; 26:333–8. 18. West KW, Bengston K, Rescorla FJ, Engel WA, Grosfeld JL. Delayed surgical repair and ECMO improves survival in congenital diaphragmatic hernia. Ann Surg 1992; 216:454–62. 19. Nakayama DK, Motoyama EK, Tagge EM. Effect of preoperative stabilization on respiratory system compliance and outcome in newborn infants with congenital diaphragmatic hernia. J Pediatr 1991; 118:793–9. 20. Wung JT, Sahni R, Mofﬁtt ST, Lipsitz E, Stolar CJ. Congenital diaphragmatic hernia: survival treated with very delayed surgery, spontaneous respiration, and no chest tube. J Pediatr Surg 1995; 30(3):406–9. 21. Lally KP, Paranka MS, Roden J et al. Congenital diaphragmatic hernia: Stabilization and repair on ECMO. Ann Surg 1992; 216:569–73. 22. Stewart D, Mendoza J, Winston S, Cook L. Extracorporeal life support (ECLS) in infants with total anomalous pulmonary venous drainage (TAPVD): a review of the ELSO registry. 1992, CNMC ECMO Symposium 81. 23. Revenis M, Glass P, Short BL. Mortality and morbidity rates among lower birth weight infants (2000–2500 grams) treated with extracorporeal membrane oxygenation. J Pediatr 1992; 121:452–8. 24. Grimm P. Feeding difﬁculties in infants treated with ECMO. CNMC ECMO Symposium 1993: 25. 25. Nield T, Hallaway M, Fodera C et al. Outcome in problem feeders post ECMO. 1990, CNMC ECMO Symposium 79. 26. Glass P. Patient neurodevelopmental outcomes after neonatal ECMO. In: Arensman R, Cornish J, editors. Extracorporeal life support. Boston, MA: Blackwell Scientiﬁc Publications, 1993. 27. Tarby T, Waggoner J. Are the common neurologic problems following ECMO related to jugular bulb thrombosis? 1994, ENMC ECMO Symposium 100.

326 Extracorporeal membrane oxygenation for neonatal respiratory failure 28. Van Meurs K, Robbins S, Reed V, Glass P, O’Brien A, Short BL. Congenital diaphragmatic hernia: long-term outcome of neonates treated with ECMO. 1991, CNMC ECMO Symposium 25. 29. Rajasingham S, Reed V, Glass P, Wagner A, Civitello L, Coffman C, Short BL. Congenital diaphragmatic hernia – outcome post-ECMO at 5 years. 1994, CNMC ECMO Symposium 35. 30. Glass P, Wagner A, Papero P et al. Neurodevelopmental status at age ﬁve years of neonates treated with extracorporeal membrane oxygenation. J Pediatr 1995; 127:447–57. 31. Walsh-Sukys M, Bauer R, Cornell D, Friedman H, Stork E, Hack M. Severe respiratory failure in neonates: mortality and morbidity rates and neurodevelopmental outcomes. J Pediatr 1994; 125:104–10. 32. Gershan L, Gershan W, Day S. Airway anomalies after ECMO: bronchoscopic ﬁndings. 1992, CNMC ECMO Symposium 65. 33. Wagner A, Glass P, Papero P, Coffman C, Kjaer M, Short BL. Neuropsychological outcome of neonatal ECMO survivors at age 5. 1994, CNMC ECMO Symposium 31. 34. D’Agostino J, Bernbaum J, Gerdes M et al. Outcome for infants with congenital diaphragmatic hernia requiring extracorporeal membrane oxygenation: the ﬁrst year. J Pediatr Surg 1995; 30:10–15. 35. Van Meurs K, Robbins S, Reed V et al. Congenital diaphragmatic hernia: long-term outcome in neonates treated with extracorporeal membrane oxygenation. J Pediatr 1993; 122:893–9. 36. Atkinson J, Poon M. ECMO and the management of congenital diaphragmatic hernia with large diaphragmatic defects requiring a prosthetic patch. J Pediatr Surg 1992; 27:754–6. 37. Adolph V, Ekelund C, Smith C, Starrett A, Falterman K, Arensman R. Developmental outcome of neonates treated with ECMO. J Pediatr Surg 1990; 25:43–6. 38. Andrews A, Nixon C, Cilley R, Roloff D, Bartlett R. One-tothree year outcome for 14 neonatal survivors of extracorporeal membrane oxygenation. Pediatrics 1986; 78:692–8. 39. Flusser H, Dodge N, Engle W, Garg B, West K. Neurodevelopmental outcome and respiratory morbidity for ECMO survivors at 1 year of age. J Perinatol 1993; 13:266–71. 40. Glass P, Miller M, Short BL. Morbidity for survivors of extracorporeal membrane oxygenation: neurodevelopmental outcome at 12 years of age. Pediatrics 1989; 83:72–8. 41. Grifﬁn M, Minifee P, Landry S, Allison P, Swischuk L, Zwischenberger J. Neurodevelopmental outcome in neonates after ECMO: cranial magnetic resonance imaging and ultrasonography correlation. J Pediatr Surg 1992; 27:33–5. 42. Hofkosh D, Thompson A, Nozza R, Kemp S, Bowen A, Feldman H. Ten years of ECMO: neurodevelopmental outcome. Pediatrics 1991; 87:549–55.

43. Krummel T, Greenﬁeld L, Kirkpatrick B et al. The early evaluation of survivors after ECMO for neonatal pulmonary failure. J Pediatr Surg 1984; 19:585–90. 44. Schumacher R, Palmer T, Roloff D, LaClaire P, Bartlett R. Follow-up of infants treated with ECMO for newborn respiratory failure. Pediatrics 1991; 87:451–7. 45. Towne B, Lott I, Hicks D, Healey T. Long-term follow-up of infants and children treated with ECMO: a preliminary report. J Pediatr Surg 1985; 20:410–14. 46. Wildin S, Landry S, Zwischenberger J. Prospective, controlled study of developmental outcome in survivors of ECMO: the ﬁrst 24 months. Pediatrics 1994; 93:404–8. 47. Stolar CJ, Crisaﬁ MA, Driscoll YT. Neurocognitive outcome for neonates treated with extracorporeal membrane oxygenation: Are infants with congenital diaphragmatic hernia different? J Pediatr Surg 1995; 30:366–72. 48. Davis D, Wilkerson S, Stewart D. Neurodevelopmental follow-up of ECMO survivors at 7 years. 1995 CNMC ECMO Symposium 34. 49. Stanley C, Brodsky K, McKee L, Gringlas M, Graziani L. Developmental proﬁle of ECMO survivors at early school age and relationship to neonatal EEG status. 1995 CNMC ECMO Symposium 33. 50. Hack M, Taylor H, Klein N, Eiben R, Schatschneider C, Mercuri-Minich N. School-age outcomes in children with birthweights under 750 g. N Engl J Med 1994; 331:753–9. 51. Walton J, Hendricks-Munoz K. Proﬁle and stability of sensorineural hearing loss in persistent pulmonary hypertension of the newborn. J Speech Hear Res 1991; 34:1362–70. 52. Naulty C, Weiss I, Herer G. Progressive sensorineural hearing loss in survivors of persistent fetal circulation. Ear Hear 1986; 7:74–7. 53. Leavitt A, Watchko J, Bennett F, Folson R. Neurodevelopmental outcome following persistent pulmonary hypertension of the neonate. J Perinatol 1987; 7:88–291. 54. Sell E, Gaines J, Gluckman C, Williams E. Persistent fetal circulation: neurodevelopmental outcome. Am J Dis Child 1985; 139:25–8. 55. Marron M, Crisaﬁ M, Driscoll J, Wung J, Driscoll Y, Fay T, James L. Hearing and neurodevelopmental outcome in survivors of persistent pulmonary hypertension of the newborn. Pediatrics 1992; 90:392–6. 56. Bifano E, Pfannenstiel A. Duration of hyperventilation and outcome in infants with persistent pulmonary hypertension. Pediatrics 1988; 81:657–61. 57. Ferrara B, Johnson D, Chang P, Thompson T. Efﬁcacy and neurologic outcome of profound hypocapneic alkalosis for the treatment of persistent pulmonary hypertension in infancy. Pediatrics 1984; 105:457–61. 58. Bernbaum J, Russell P, Sheridan P, Gewitz M, Fox W, Peckham G. Long-term follow-up of newborns with persistent pulmonary hypertension. Crit Care Med 1984; 12:579–83.

References 327 59. Desai S, Stanley C, Graziani L, McKee L, Baumgart S. Brainstem auditory evoked potential screening (BAEP) unreliable for detecting sensorineural hearing loss in ECMO survivors: a comparison of neonatal BAEP and follow-up behavioral audiometry. 1994, CNMC ECMO Symposium 62. 60. Haney B, Thibeault D, Sward-Comunelli S, Grin T, StassIsern M, Grist G. Ocular ﬁndings in infants treated with ECMO. 1994, CNMC ECMO Symposium 63. 61. Hahn J, Baucher Y, Bejar R, Coen R. Electroencephalographic and neuroimaging ﬁndings in neonates undergoing extracorporeal membrane oxygenation. Neuropediatrics 1993; 24:19–24. 62. Graziani L, Streletz L, Baumgart S, Cullen J, McKee L. Predictive value of neonatal electroencephalograms before and during extracorporeal membrane oxygenation. J Pediatr 1994; 125:969–75. 63. Campbell L, Bunyapen C, Gangarosa M, Cohen M, Kanto W. The signiﬁcance of seizures associated with ECMO. 1991, CNMC ECMO Symposium 26. 64. Kumar P, Bedard M, Delaney-Black V, Shankaran S. Post-ECMO electroencephalogram (EEG) as a predictor of neurological outcome. 1994, CNMC ECMO Symposium 65. 65. Scher M, Kosaburo A, Beggerly M, Hamid M, Steppe D,

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Painter M. Electrographic seizures in preterm and full-term neonates: clinical correlates, associated brain lesions, and risk for neurologic sequelae. Pediatrics 1993; 91:128–34. Ittman P, Schumacher R, Vanderkerhove J. Outcome in newborns following pre-ECMO CPR. 1993, CNMC ECMO Symposium 30. Stewart D, Davis D, Reese A, Wilkerson S. Neurodevelopmental outcome of extracorporeal life support (ECLS) patients using the Stanford Binet IV. 1993, CNMC ECMO Symposium 24. Mendoza J, Wilkerson S, Reese A, Vogel R. Outcome of neonates treated with ECMO: longitudinal follow-up from 1 to 3 years of age. 1991, CNMC ECMO Symposium 29. Wilkerson S, Stewart D, Cook L. Developmental outcome of ECMO patients over a four year span. 1990, CNMC ECMO Symposium 23. Baumgart S, Graziani L, Streletz L et al. Right common carotid artery reconstruction following ECMO: structural and vascular imaging electrocephalography and neurodevelopmental correlates to recovery. 1993, CNMC ECMO Symposium 27. Stanley C, Merton D, Desai S et al. Four year follow-up doppler ultrasound studies in children who received right common carotid artery (RCCA) reconstruction following neonatal ECMO. 1995, CNMC ECMO Symposium 104.

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33 Bronchoscopy in the newborn JOHN D. RUSSELL

INTRODUCTION Bronchoscopy in the newborn is an important and diagnostic and therapeutic tool.1 Congenital laryngotracheal malformations and airway complications due to prolonged intubation are two of the main indications for pediatric bronchoscopy.2 Bronchoscopy in children was ﬁrst performed by Killian in 1895.3 It was however associated with a high rate of complication because of poor visibility through small-diameter bronchoscopes and poor lighting. Maintaining ventilation was the main problem. Modern Hopkins lens systems and intense yet ‘cold’ light sources together with modern anesthetic techniques have facilitated safer examination of the airway in the neonate.4 In fact continued advances in instrumentation, anesthesia, endoscopic techniques and pharmacology have facilitated the ongoing evolution in the technique of bronchoscopy of the neonatal airway.5 Pediatric ﬂexible bronchoscopy was initiated in the mid 1970s. Since then newer and smaller instruments with suction channels have enabled pediatricians to visualize the airway of premature infants and neonates without the need for general anesthesia. This enables the pediatrician to examine the airway without signiﬁcantly distorting the anatomy or the normal physiology.6

INSTRUMENTATION Good instrumentation is essential for pediatric bronchoscopy. The systematic assessment of the newborn airway involves laryngoscopy, tracheoscopy and bronchoscopy. One therefore needs a full range of laryngoscopes, bronchoscopes, telescopes and telescopic forceps. The author’s preference is for those obtainable from Karl Storz. The Lindholm–Benjamin laryngoscope is one of the best scopes for examining the neonatal larynx. Suspension of the laryngoscope on a Mayo stand is essential (Fig. 33.1). The modern ventilating bronchoscopes have revolutionized the assessment of the airway,

Figure 33.1 Benjamin–Lindholm laryngoscope attached to a Mayo table. Infant is receiving halothane/oxygen via a nasopharyngeal tube

even in the low birth weight (LBW) premature infant. The components of a modern bronchoscope are (Fig. 33.2): 1 A closed gas system allowing connection to an anesthetic circuit 2 A rigid Hopkins rod telescope to allow distal illumination and vision. 3 A side channel for the passage of suction catheters or ﬂexible forceps. The bronchoscopes range in size from 2.5 (outside diameter 4.0 mm) to 6.0 (outside diameter 8.2 mm). Sizes 2.5–3.0 are the most appropriate for neonates (Table 33.1).

INDICATIONS FOR RIGID BRONCHOSCOPY The list in Box 33.1 is not exhaustive but does provide the main indications. The commonest causes of stridor and airway obstruction in a neonate are: (1) laryngomalacia (2) subglottic stenosis, congenital and acquired, and (3)

330 Bronchoscopy in the newborn

Figure 33.2 Equipment for rigid laryngobronchoscopy 0° telescope (top). 2.5 mm ventilating bronchoscope (middle). Benjamin–Lindholm laryngoscope (bottom)

vocal cord paralysis, unilateral and bilateral. Rarer causes include laryngeal clefts, hemangiomas and papillomas. Rigid bronchoscopy is the diagnostic procedure of choice in the management of airway obstruction. Neonates with stridor can be subdivided into three main groups. In the ﬁrst group is the neonate with severe stridor and signiﬁcant airway obstruction, who will require urgent bronchoscopy and airway support. Secondly a neonate with worsening airway obstruction is another indication for bronchoscopy. Thirdly mild or moderate stridor with poor weight gain or difﬁculty in feeding, apnea or cyanosis would also be an indication for endoscopy. Radiological investigations often raise the suspicion of a diagnosis, e.g. a vascular ring on barium swallow. Endoscopy is needed to conﬁrm this diagnosis. In neonates with recurrent aspiration rigid bronchoscopy is necessary to rule out a laryngotracheal cleft. A complete systematic assessment is necessary as about 70% of bronchoscoped neonates have more than one pathology.4 The presence of stridor and respiratory distress is the most common indication for endoscopy in the neonate and congenital abnormalities are the most common problems encountered.7

TECHNIQUE OF RIGID LARYNGOBRONCHOSCOPY Table 33.1 Diameter of rigid Storz bronchoscopes for newborns Length (cm)

Nominal size (mm)

Internal diameter (mm)

External diameter (mm)

20 20 26 20 26 30

2.5 3.0 3.0 3.5 3.5 3.4

3.2 4.2 4.2 4.9 4.2 4.9

4.0 5.0 5.0 5.7 5.0 5.7

Box 33.1 Small Storz Hopkins telescope diameter, 2.8 mm. Standard Storz Hopkins telescope diameter, 4 mm. Management of severe upper airway obstruction To establish a temporary airway in an emergency Management of massive hemorrhage and blood clots To maintain airway and control bleeding Laser bronchoscopy To remove benign tumors (recurrent respiratory papillomatosis) Endoscopic management of strictures, webs, granulation tissue Open airway surgery Foreign body extraction Evaluation of tracheal pathology, e.g. tracheomalacia, laryngotracheal cleft and subglottis. Re-expansion of consolidated/atelectatic pulmonary lobes

All these examinations are performed under general anesthesia. Modern techniques are versatile, controlled and safe. They allow unhurried, precise and complete examination without stress to the patient, anesthesiologist, the surgeon and the staff.8 A full range of neonatal and pediatric laryngoscopes, bronchoscopes and telescopes are essential. Modern 1 chip and 3 chip cameras allow magniﬁcation and excellent resolution of the image on screen of these tiny airways. A spontaneous respiration technique is the anesthetic method of choice. Halothane is in most anesthesiologists’ opinions, the anesthetic of choice. It allows a deep plane of anesthesia without causing respiratory arrest. The following is an orderly sequence of airway assessment in a neonate that is systematic and complete.

Airway assessment The neonate is anesthetized with a mixture of halothane and oxygen via a face mask. The larynx is then visualized and sprayed with topical lignocaine. An appropriately sized nasopharyngeal airway is inserted and the anesthetic agent is then provided via this route. The baby is also given atropine to prevent bradycardia and to dry up the secretions during the assessment. The topical lignocaine prevents laryngospasm. A baby Lindholm laryngoscope is then inserted, exposing the whole larynx. The scope is suspended on a Mayo table to avoid com-

Indications for ﬂexible bronchoscopy 331

pression of the baby’s chest. The larynx is now examined with the aid of a Zeiss operating microscope. Pathological conditions looked for are: (1) laryngeal cleft, (2) webs, (3) cysts, (4) glottic stenosis, and (5) hemangiomas. The mobility of the arytenoids are then checked. Once the larynx is fully examined a 4 mm 0° telescope is introduced into the subglottis and trachea. This allows a complete atraumatic inspection of the subglottis and trachea. In order to examine the bronchi in detail one has to remove the laryngoscope and introduce an appropriately sized bronchoscope (Fig. 33.3). Turning the baby’s head to the left allows entry through the right main bronchus and turning the head to the right allows entry into the left mainstem bronchus. The ﬁnal part of the assessment is to look at the trachea and vocal cords as the baby is lightening up from the anesthetic. This is the only time when tracheobronchomalacia and vocal cord paralysis can be diagnosed.

Vocal cords Epiglottis Laryngoscopic blade Glottis

Figure 33.3 Under direct visualization of the larynx, the bronchoscope is introduced into the trachea

ADVANTAGES OF RIGID BRONCHOSCOPY The major advantage of rigid instruments is the excellent control of ventilation they provide, which is so important in the neonate. They also excel as therapeutic instruments through which surgery can be performed. General anesthesia allows a magniﬁcent unhurried leisurely view of the larynx and lower airways. Rigid bronchoscopy allows the lower airways to be inspected safely and in great detail while maintaining complete and safe control over ventilation. Flexible bronchoscopy does not allow such control and in a small neonate or infant will cause signiﬁcant, if not total airway obstruction. The image quality obtained by the rigid telescope is also superior to that obtained with the ﬂexible ﬁberoptic bundles.

COMPLICATIONS OF RIGID LARYNGOBRONCHOSCOPY The safety of rigid laryngobronchoscopy depends on the anesthetic technique, monitoring of the patient, the procedures performed during the endoscopy, having adequate equipment, the expertise of the staff, and the

condition of the patient.5 The complication rate of rigid laryngobronchoscopy ranges from 2–4%. The types of complications are: laryngospasm, torn vocal cords, subglottic edema, pneumothorax, pneumonia, hoarseness, hemorrhage, cardiac arrhythmia, and death. In Hoeve et al.’s series in 1993,9 tetralogy of Fallot, biopsy or drainage, foreign body extraction and tracheal stenosis were the main risk factors for complications. Interestingly, fewer complications occurred in the age group < 3 months.

FLEXIBLE BRONCHOSCOPY This technique was initiated in the mid 1970s and since then newer and smaller scopes have enabled pediatricians to visualize the airway of premature infants and neonates without the need for general anesthesia. The advantages of the procedure are: (1) it can be performed on an outpatient basis, and (2) it requires little preparation except for no oral intake 4–6 hours preoperatively. Infants up to 18 months old usually tolerate ﬂexible bronchoscopy utilizing only lignocaine jelly in the nose. The average procedure lasts about 30 seconds. The pediatrician however needs to be able to monitor the baby with pulse oximetry, electrocardiographic and respiratory monitors. A resuscitation cart and a video system are also necessary. All personnel should be trained in resuscitation and i.v. access. Provided ﬂexible bronchoscopy is performed by an experienced operator in a controlled setting, the procedure is very safe. Vauthy6 has performed over 10 000 bronchoscopies with no mortality.

INDICATIONS FOR FLEXIBLE BRONCHOSCOPY Flexible bronchoscopy in neonates is particularly useful in the diagnosis of unexplained mild stridor, unexplained wheezing, hemoptysis, or unexplained cough (Box 33.2). Persistent atelectasis and recurrent or persistent Box 33.2 Diagnostic – Unexplained stridor – Unexplained wheezing – Hemoptysis – Unexplained cough – Persistent atelectasis – Recurrent or persistent pulmonary inﬁltrates To aid intubation Therapeutic bronchoalveolar lavage Brush biopsies Removal of airway secretions Diagnose and monitor after lung transplantation Transbronchial biopsy

332 Bronchoscopy in the newborn

pulmonary inﬁltrates are also indications for its use. Flexible bronchoscopy is also extremely useful in the management of the neonate in the intensive care unit (ICU).10 The advantages are severalfold. Firstly the patients can be assessed in the ICU and no longer need to be transferred to the theater. Secondly the procedure can be performed via a tracheostomy or via the endotracheal tube. This assures maintenance of a safe airway. Sudden episodes of deterioration in a neonate’s respiratory status in the ICU can be due to severe mucous plugging, atelectasis, granuloma formation, tracheitis or tracheobronchomalacia. The technique permits the diagnosis of disease and allows careful direction of suction catheters to improve pulmonary toilet. Full-term infants tolerate ﬂexible bronchoscopy with a 3.4 mm instrument which has suction channels for insufﬂation of oxygen, suction and bronchial brushings or bronchoalveolar lavage. Bronchoalveolar lavage has become a very useful tool for the diagnosis of infection, gastro-esophageal reﬂux and the removal of mucous plugs. The avoidance of a general anesthetic, intubation and mechanical ventilation reduces the cost and possible complications of these interventions.

TECHNIQUE OF FLEXIBLE BRONCHOSCOPY Infants up to 18 months old can easily tolerate ﬂexible bronchoscopy using only lignocaine jelly in the nose. It is important to restate that when the information to be gained is not going to alter the patient’s management, or be of substantial beneﬁt to the patient, then ﬂexible bronchoscopy is probably not indicated. The neonate is placed on the table with the assistant providing oxygen via mask or nasal cannula. The average diagnostic procedure lasts approximately 30 seconds. Post-procedure management includes examination after the procedure and 1.5 hours’ observation. The patient is allowed to feed under supervision after this period.

COMMON PITFALLS FOR THE UNWARY FLEXIBLE BRONCHOSCOPIST

most cases. Wood et al. in 1990 encountered only three patients in whom the transnasal passage of the ﬂexible bronchoscope was not possible.11

Pharyngeal hypotonia Patients with tracheostomies or who have reduced muscle tone because of neurologic disease often have pharyngeal hypotonia. Finding the larynx may be very difﬁcult in these cases.

COMPLICATIONS OF FLEXIBLE BRONCHOSCOPY Obstruction of a large proportion of the airway can lead to hypoxemia. It is also difﬁcult to remove foreign bodies with a ﬂexible scope. The contraindications to ﬂexible bronchoscopy are: (1) hypoxemia, (2) respiratory distress, (3) hemorrhagic diathesis, (4) cardiac arrhythmia, and (5) a foreign body. All these problems increase the risk of complications with ﬂexible bronchoscopy. The complication rate ranges from 2.2–8.0%.12 The nature of complications of ﬂexible endoscopy are laryngospasm, pneumothorax, epistaxis, bradycardia and/or hemorrhage. Generally high-risk patients are more likely to undergo rigid bronchoscopy.

CONCLUSION Modern rigid and ﬂexible bronchoscopy in the newborn carried out by trained personnel is a safe, relatively atraumatic procedure with a very low complication rate. This is due to the advances in anesthesia, pharmacology and instrumentation, camera and video techniques. Rigid and ﬂexible bronchoscopy should be viewed as complimentary and not competing mutually exclusive techniques. Both procedures should be in the armamentarium of the pediatric airway surgeon. There are advantages and disadvantages to each technique. It is to the neonate’s advantage to have both types of endoscopes available so the procedure with the highest beneﬁt-torisk ratio can be employed.

Concurrent lesions Children frequently have multiple airway abnormalities and these can often be missed due to the speed of the ﬂexible assessment.

Difﬁcult nasal passage Nasal septal deviations or turbinate hypertrophy can lead to difﬁculty passing the ﬂexible scopes. The use of a topical vasoconstrictor enables the nose to be entered in

REFERENCES 1. Lockhart CH, Elliot JL. Potential hazards of pediatric rigid bronchoscopy. J Pediatr Surg 1989; 19:239. 2. Lindhall H, Rintala R, Malinen L et al. Bronchoscopy during the ﬁrst month of life. J Pediatr Surg 1992; 27:548–50. 3. Clerf LH. Historical aspects of foreign bodies in the air and food passages. Ann Otol Rhinol Laryngol 1952; 1:5–17.

References 333 4. Ungkanont K, Friedman M, Sulek M. A retrospective analysis of airway endoscopy in patients less than 1 month old. Laryngoscope 1998; 108:1724–8. 5. Holinger LD. Diagnostic endoscopy of the pediatric airway. How I do it. Laryngoscope 1989; 99:346–8. 6. Vauthy P. Evaluation of the pediatric airway by ﬂexible endoscopy in practical pediatric otolaryngology. Lippincott-Raven Ch. 29.B. Philadelphia: New York, 1999, 491–6. 7. Holinger LD. Etiology of stridor in the neonate, infant and child. Ann Otol Rhinol Laryngol 1980; 89:397. 8. Benjamin B. Technique of laryngoscopy. Int J Pediatr Otorhinolaryngol 1987; 13:299–313.

9. Hoeve LJ, Rombout J, Meursing AE. Complications of rigid laryngobronchoscopy in children. Int J Pediatr Otorhinolaryngol 1993; 26:47–56. 10. Myer CM, Thompson RF. Flexible ﬁbreoptic bronchoscopy in the neonatal intensive care unit. Int J Pediatr Otorhinolaryngol 1987; 15:143–7. 11. Wood RE. Pitfalls in the use of the ﬂexible bronchoscope in pediatric patients. Chest 1990; 97:1:199–203. 12. Fan LL, Flynn JW. Laryngoscopy in neonates and infants: experience with the ﬂexible ﬁbreoptic bronchoscope. Laryngoscope 1981; 91:451–6.

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4 Esophagus

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34 Esophageal atresia and tracheo-esophageal ﬁstula PAUL D. LOSTY AND COLIN T. BAILLIE

INTRODUCTION

Box 34.1 Landmarks in the history of esophageal atresia and TEF Durston (1670)

Esophageal atresia (EA) and tracheo-esophageal ﬁstula (TEF) remain a signiﬁcant challenge to modern pediatric surgery. There are many unanswered questions in the clinical and basic science arenas. Improved survival has resulted in a greater emphasis on the complications of EA and TEF, with continuing debate over the management of pure long-gap atresia, gastroesophageal reﬂux (GER), anastomotic stricture, and tracheomalacia. A relatively new body of literature is available concerning long-term outcome and quality of life. The ﬁelds of applied embryology and genetics continue to yield fascinating insights into the etiology of EA and TEF, with signiﬁcant contributions arising out of the development of animal models. The control mechanisms for the fundamental embryological processes that are defective in EA and TEF are now being unravelled at the molecular level.

HISTORY The history of EA and TEF is well described in the literature.1 Some of the important landmarks are highlighted in Box 34.1. The period up to 1935 represents the pre-survival era. As survival improved, prognostic variables became a major focus of attention. In 1962, Waterston’s landmark paper demonstrated that survival was likely in EA and TEF, unless neonates belonged to speciﬁc ‘high-risk’ groups as deﬁned by low birth weight, pneumonia and the presence of associated congenital anomalies.2 Improvements in neonatal intensive care and anesthesia have since contributed to the salvage of many of these ‘high-risk’ infants with EA.

Described isolated EA in one of a pair of conjoined twins3 Gibson (1697) Described the common form of EA and distal TEF4 Lamb (1873) Described H-type TEF5 Hoffman (1899) Attempted cervical repair of EA and TEF, performed ﬁrst gastrostomy6 Richter (1913) Attempted ﬁstula ligation, esophagostomy and gastrostomy7 Donovan (1935) First survivor of isolated EA. Initially neonatal gastrostomy. Esophageal continuity established 16 years later by Humphries1 Lanman (1936) First attempted extra-pleural repair. However, by 1940 no survivors in 30 infants8 Imperatori (1938) First successful repair H-type TEF9 Ladd/Leven First survivors EA and distal TEF using (1939) staged gastrostomy, ligation of ﬁstula and esophagostomy, delayed staged formation of ante-thoracic subcutaneous skin-lined neoesophagus10,11 Haight and First successful primary anastomosis12 Towsley (1943) Waterston et al. ‘At risk groups’ based on weight, (1962) pneumonia and congenital anomaly2 Waterston (1964) Popularized colonic interposition in long-gap EA13 Livaditis (1969) Described circular myotomy in long-gap EA14 Cohen et al. Reversed gastric tube interposition in (1974) long-gap EA15 Gough (1980) Popularized anterior ﬂap in long-gap EA16 Spitz (1984) Popularized gastric interposition in long-gap EA17 Spitz et al. (1994) Revised at-risk groups for the 1990s18

338 Esophageal atresia and tracheo-esophageal ﬁstula

CLASSIFICATION In 1929, Vogt proposed the ﬁrst anatomical classiﬁcation of EA and TEF, based on radiological and post-mortem ﬁndings.19 A variety of surgical classiﬁcations were suggested, as operative treatment became successful, the most frequently employed being that of Gross.20 The most detailed classiﬁcation, however, is attributed to Kluth, and incorporates all described anatomical variations of EA and TEF.21 A working classiﬁcation based on the frequency of each anomaly is of the greatest practical value to the neonatal surgeon (Fig. 34.1).

with signiﬁcant morbidity,25 and probably increased mortality (although statistical conﬁrmation is difﬁcult because of the relative rarity of long-gap EA). Table 34.1 Spitz classiﬁcation system Group

Features

Survival

I

Birth weight >1500 g, no major cardiac disease Birth weight <1500 g, or major cardiac disease Birth weight <1500 g, and major cardiac disease

97%

II III

59% 22%

EPIDEMIOLOGY

82.8%

8.4%

3.4%

3.3%

2.1%

Figure 34.1 Classiﬁcation and frequency of esophageal atresia and tracheo-esophageal ﬁstula. EA and distal TEF – 85%; Isolated EA – 7%; H-type TEF – 4%; EA with proximal and distal ﬁstulas – 3%; EA and proximal ﬁstula –1%

PROGNOSIS Waterston’s seminal paper describing the inﬂuence of pulmonary disease, birth weight and associated congenital anomalies on outcome of infants treated for EA,2 provided a historical basis for comparison of subsequent outcome-based classiﬁcation systems. Advances in medical care have now rendered the Waterston classiﬁcation outdated. Spitz et al. have described a simpliﬁed classiﬁcation system for the modern era (Table 34.1), based on birth weight and the presence or absence of major congenital heart disease.18 A Montreal classiﬁcation system places greater emphasis on preoperative ventilator dependence and associated major anomalies as survival determinants.22 Other studies continue to emphasize the negative inﬂuence of respiratory distress syndrome (RDS) and pneumonia on outcome,23 and the contribution of aspiration episodes and other respiratory morbidity to late death following repair of EA.24 The inﬂuence on outcome of factors directly related to the atresia has received little attention. In this category, ‘long-gap’ EA is associated

In the Liverpool region the incidence of EA and TEF is 1 in 3300 live births.26 The reported range varies from 1 in 2440 in Finland,27 to 1 in 4500 both in Australia28 and the USA.29 The sex ratio has been reported as equal by many authors, but others quote a slight male preponderance.30 EA and TEF are more common in twin pregnancies.30 Exposure to teratogenic drugs during pregnancy has been implicated, including thalidomide, progesterone and estrogen.31

GENETICS The sporadic reports of vertical and transverse familial cases of EA and TEF suggest a polygenic hereditary etiology. The best estimate of risk of recurrence for parents of a single affected child is 0.5–2.0%, rising to 20% if another sibling is born with EA. The vertical transmission risk is 3–4%.32 A 10% incidence of non-speciﬁc chromosomal abnormalities (translocations, deletions and duplications) has been noted. However, only trisomies 18 and 21 show any deﬁnite association with EA and TEF. Recognition of a syndrome suggestive of a major chromosomal abnormality in EA and TEF should prompt the urgent involvement of a clinical geneticist before corrective surgery is undertaken. EA and TEF have been described in association with various syndromes including Holt–Oram syndrome, and DiGeorge sequence, polysplenia, and Pierre Robin sequences.32 Chromosome studies in cases of EA and TEF have occasionally shown deletions or translocations, suggesting possible locations for candidate genes. The most likely of these belongs to the clustered homeobox gene family, HOX. HOXD is implicated in embryonic patterning of the axial skeleton, limbs, and genital and digestive tracts. This fundamental involvement in embryological development may explain the frequent association of vertebral, limb and anorectal anomalies with EA and TEF.

Associated anomalies 339

ANIMAL MODELS Signiﬁcant contributions to our understanding of the embryology and genetic control of foregut development are likely to result from basic laboratory research involving animal models of EA and TEF. The adriamycin rat model in which timed pregnant rats are administered i.p. adriamycin on gestational days 8 and 9, yields EA with distal TEF in two-thirds of fetuses.33,34 These pups also demonstrate associated anomalies belonging to the VACTERL spectrum (denoting vertebral, anorectal, cardiac, tracheo-esophageal, radial/renal and limb anomalies). Recently, a murine model of the VACTERL association has been developed in strains with targeted deletions of the transcription factors Gli-2 and Gli-3 for the Sonic hedgehog (Shh) gene, which is involved in axial organogenesis. Gli-2–/–;Gli-3–/– double mutants demonstrate the full phenotypic spectrum of VACTERL suggesting a pivotal role for Shh in the genetic control of foregut development.35,36 These experimental models may yield insights into the molecular pathogenesis of EA and VACTERL in human infants.

EMBRYOLOGY There is no unifying embryological theory which successfully explains all the anatomical variants of EA and TEF. The complete pathology has been demonstrated in the 5-week-old human embryo; therefore the causative factors must operate before this. In the developing embryo, the ventral aspect of the primitive foregut is destined to become the tracheobronchial tree. A median laryngotracheal groove develops in the ventral aspect of the foregut of the 23-day-old embryo. As the groove elongates with the esophagus, it is postulated that lateral epithelial ridges fuse to bring about septation. Whilst explaining tracheo-esophageal cleft and H-type ﬁstula, caudo-cranial separation of the ventral trachea from the dorsal esophagus by a mesenchymal tracheo-esophageal septum, clearly cannot adequately explain all variants of EA and TEF. The ﬁnding of both an increased number of tracheal rings and a longer trachea in the adriamycin model of EA and TEF, suggests localized abnormal proliferation and elongation of the ventral respiratory component of the common foregut tube. The preferential incorporation of tissue into the trachea may result in esophageal discontinuity.37 The association of 13 pairs of ribs with long-gap TEF has also been used to strengthen the argument that abnormal forces, in this case hypersomatization, result in a relative deﬁciency of tissue which is preferentially absorbed into tracheal development at the expense of the esophagus.38

There is evidence from the adriamycin model that the notochord is implicated in signaling activity to determine the fate of neighboring cell populations. Shh protein, which is expressed in notochordal tissue, is postulated to be pivotal in this signaling process.39 Shh stimulates cell proliferation and inhibits apoptosis, probably via intermediary HOX gene expression. Shh binds to the cell surface protein ‘Patched’ (Ptc), which is upregulated by Shh, and thus limits the inductive capabilities of Shh. Ventral misplacement of the notochord may result in an abnormal diffusion gradient for Shh and a localized imbalance of proliferation and apoptosis in the primitive foregut.

ASSOCIATED ANOMALIES Associated anomalies are seen in over half of all newborns presenting with EA and TEF. Although some of these are relatively insigniﬁcant, a high proportion are life threatening and signiﬁcantly contribute to the morbidity and mortality of this condition. The early management of babies with EA and TEF may have to be tailored to accommodate social, ethical and surgical issues relating to these anomalies. The incidence of associated anomalies appears to be highest in pure EA compared with other variants of EA and TEF.31 Infants with EA and TEF have a higher incidence of prematurity than is seen in the normal population. Congenital heart disease (27%) is the commonest comorbid condition and has the greatest impact upon survival. Recently aortic arch anomalies have been shown to occur frequently in association with long-gap EA and TEF.40 Other common associated abnormalities include urogenital (18%), skeletal (12%), anorectal (12%), and other gastrointestinal conditions (9%), most notably duodenal atresia. The spectrum of associated anomalies encountered in EA patients at Alder Hey Children’s Hospital, over 4 decades is shown in Table 34.2. Several phenotypic variants have been reported in association with EA and TEF. The ﬁrst to be described was the VATER association,42 which is now encompassed by the

Table 34.2 Abnormalities associated with esophageal atresia and TOF (Liverpool series 1953–97) 26,41 Type

1953–97 (581 cases)

Cardiac Urogenital Skeletal Vertebral Anorectal Gastrointestinal Palate/laryngotracheal

154 (27%) 105 (18%) 71 (12%) 64 (11%) 67 (12%) 53 (9%) 44 (8%)

VACTERL41

25 (19%)

340 Esophageal atresia and tracheo-esophageal ﬁstula

VACTERL acronym. The presence of three or more of the features is essential to deﬁne the association.43 In a recent Liverpool series, the incidence of the VACTERL association was 19%.41 The CHARGE association (coloboma, heart disease, atresia choanae, retarded development, genital hypoplasia, and ear deformities with deafness), is another constellation of phenotypes associated with EA and TEF.44,45 EA and TEF are also recognized in the SCHISIS association (exomphalos, neural tube defects, cleft lip and palate, and genital hypoplasia).46 Infants with EA and TEF have a higher than expected incidence of pyloric stenosis.47 The almost universal association of gastro-esophageal reﬂux with EA may lead to delays in diagnosis if gastric outlet obstruction is not considered. A degree of tracheomalacia is invariably present in these infants, but the full spectrum of associated tracheobronchial and pulmonary abnormalities deserves closer scrutiny. Excluding tracheomalacia, signiﬁcant anatomical tracheobronchial anomalies can be seen in 47% of infants undergoing bronchoscopy.48 Pulmonary agenesis, foregut duplication cysts, congenital cystic adenomatoid malformations, and sequestered lobe have all been described in association with EA and TEF. Other rare foregut pathologies such as laryngotracheo-esophageal cleft and congenital esophageal stenosis may coexist with EA and TEF.

ANTENATAL PRESENTATION Fetal diagnosis is now possible in cases of EA and TEF.49 This may be advantageous, as delivery can be planned at or near a specialist center with full neonatal surgical capability. Counselling is essential in these cases, and a careful search for associated chromosomal or cardiac anomalies is important. The identiﬁcation of a chromosomal abnormality may have implications for termination of pregnancy. Antenatal diagnosis of EA should theoretically reduce the likelihood of inadvertent feeding and aspiration pneumonitis. Despite the potential advantages of antenatal diagnosis, it is plausible that fetal ultrasonography selects a group of infants with a worse prognosis. The perinatal mortality (excluding terminations) in a series from Newcastle, UK was 21%.50 The classical ultrasonographic features of EA and TEF in the fetus are absence of the stomach bubble and associated hydramnios.51 However, prenatal detection rates remain low (9–24%), and there is a high false-positive rate, with over half of all cases proven not to have EA after birth.50

CLINICAL PRESENTATION AND DIAGNOSIS A newborn with EA is often noted to have difﬁculty clearing saliva. Episodes of coughing, choking and even

transient cyanosis may be observed shortly after birth. These signs are frequently overlooked and attempts to feed the infant result in immediate respiratory distress. The diagnosis is readily conﬁrmed by the failure of passage of a ﬁrm nasogastric tube. A characteristic resistance is felt at the blind ending upper esophageal pouch, and the tube cannot be introduced into the stomach. A plain X-ray, which should include the chest and abdomen, demonstrates the nasogastric tube coiled in the upper pouch. An associated TEF is conﬁrmed by the presence of gas-ﬁlled intestinal loops below the diaphragm (Fig. 34.2). In isolated or pure EA, a featureless gasless abdominal X-ray is observed (Fig. 34.3). The presence of a double bubble on the abdominal ﬁlm suggests associated duodenal atresia (Fig. 34.4). A careful search for associated abnormalities is mandatory, speciﬁcally checking for patency of the anus. The cardiovascular system should be examined to exclude a major congenital heart defect whose treatment may take priority over correction of the EA. Having established the diagnosis, i.v. ﬂuids are started, and a sump suction (Replogle) catheter introduced into the upper pouch to allow continuous aspiration of secretions. Alternatively, the upper pouch and oropharynx should be cleared of secretions by frequent intermittent suction. The infant is nursed in the supine or lateral position. Vitamin K should be administered intramuscularly after parental consent. Arrangements should be made for transfer of the infant to the nearest neonatal surgical unit. Surgery is ideally performed within the ﬁrst 24 hours in an otherwise healthy

Figure 34.2 Chest X-ray ﬁlm of a neonate with EA and TEF. Note the nasogastric tube coiled in the blind-ending upper esophagus. Air outlining intestinal loops below the diaphragm conﬁrms the existence of a distal TEF

Surgical treatment 341

Figure 34.3 Case of ‘pure’ EA. The nasogastric tube is lying coiled in the upper esophageal pouch. Absence of air-ﬁlled abdominal intestinal loops suggests that there is no distal esophageal ﬁstula

be repeated with gentle downward pressure on the Replogle tube. On rare occasions the current authors have observed that a ﬁne nasogastric tube may coil in an otherwise normal proximal esophagus, and the successful passage of the Replogle tube into the stomach prevents an unnecessary thoracotomy. More commonly, the diagnosis is conﬁrmed, but an estimation of the length of the upper pouch will give some idea as to the ease or difﬁculty of the primary anastomosis. An echocardiogram performed prior to surgery will alert the surgeon and anesthetist to an underlying cardiac defect that may adversely inﬂuence prognosis, and may inﬂuence the operative approach by identifying the side of the aortic arch. Blood should be taken for crossmatching, and a hematological and biochemical proﬁle preoperatively. Broad-spectrum antibiotics should be administered and i.v. ﬂuids continued. Other investigations including whole-spine X-rays, and both renal and cranial ultrasonography can be deferred until after surgery. Contrast studies of the upper pouch to identify the rare upper pouch ﬁstula have been superseded by preoperative bronchoscopy.

SURGICAL TREATMENT

Figure 34.4 EA and TEF with duodenal atresia. Nasogastric tube coiled in upper pouch. ‘Double-bubble’ appearance conﬁrms duodenal atresia

newborn, as pneumonitis is an ever-present risk due to aspiration of saliva and reﬂux of gastric acid through the lower pouch TEF. Following transfer to the neonatal surgical unit for deﬁnitive care, the infant should be carefully reexamined, and the radiology reviewed. The X-rays may

Most surgical units advocate preliminary rigid bronchoscopy after induction of general anesthesia. Depending on the infant’s size, a 2.5–3.5 Fr. neonatal bronchoscope (Storz) is used, as this permits the use of a suction catheter. Bronchoscopy allows conﬁrmation of the diagnosis and in most cases will demonstrate the ﬁstula just proximal to the carina. Occasionally the ﬁstula arises at the level of the carina, or from one of the main bronchi. A careful search should be made to exclude an associated upper pouch ﬁstula. The larynx should also be inspected to exclude a laryngotracheoesophageal cleft. Following bronchoscopy, an endotracheal tube is passed, taking care not to intubate the TEF. The infant is positioned for right thoracotomy in a lateral position, with the right arm raised across the head so that the scapula can be easily manipulated (Fig. 34.5). The surgeon may ﬁnd that the use of a headlamp and optical loupe magniﬁcation facilitate the operation. A curved skin crease incision is made 1 cm below the angle of the scapula, extending from the anterior axillary line to the lateral margin of the erector spini muscles. Bianchi has described a high axillary incision, which gives excellent cosmesis.52 The traditional Dennis Brown vertical incision is least acceptable from an esthetic point of view. The anterior ﬁbers of the latissimus dorsi are divided with electrocautery in the posterior aspect of the incision and the inferior digitations of the serratus anterior are separated from the ribs anteriorly. A retractor is used to lift the scapula off the chest wall, and the ribs are counted

342 Esophageal atresia and tracheo-esophageal ﬁstula

(a)

(b)

(c)

(d)

(e)

(f)

(g)

Figure 34.5 (a) The most frequent tracheo-esophageal anomaly. (b) Infant in lateral position prior to operation. Location of skin incision indicated. (c) Division of lateral thoracic and fourth space intercostal muscles. (d) Commencement of gentle stripping of parietal pleura from chest wall to develop extrapleural space. (e) Operative ﬁeld when pleura and lung have been retracted medially. The azygos vein is easily seen. The other structures, i.e. the blind proximal esophageal pouch and the ﬁstulous distal esophagus, with vagal ﬁbers lying on its surface, will require some dissection, and are not as easily seen as is depicted in the diagram. (f) The ﬁstula ligated and divided ﬂush with trachea (g) Lateral and posterior sutures and transanastomotic tube in place

downwards from the second interspace. The chest is opened through the fourth interspace, dividing the intercostal muscle ﬁbers using bipolar diathermy down to the level of the parietal pleura. The pleura is carefully separated from the ribs to commence an extra-pleural approach towards the ﬁstula. The dissection is usually started with moist pledgets and, having developed the plane, may be continued by inserting a moistened gauze swab into the extra-pleural space, sweeping the pleura away from the chest wall superiorly and inferiorly. Exposure is improved by introducing a Finochettio retractor for rib retraction. Great care is required with the dissection as it is particularly easy to create a pleural tear in the anterior aspect of the incision. If a signiﬁcant pleural tear occurs during the dissection, it is probably

wise to convert to a transpleural approach. The advantages of the extra-pleural over the transpleural approach, include the possibility of avoiding a chest drain, and in the event of an anastomotic leak, the potential containment of contamination within the extra-pleural space. The extra-pleural exposure is completed by retracting the posterior mediastinal pleura forwards with a maleable retractor until the azygos vein is visualized as it enters the superior vena cava in the depths of the wound. The azygos vein is mobilized and controlled with suture slings. The current authors advocate temporary occlusion of the vein before ligation, as venous return to the heart may rarely be critically dependent on the azygos system. Provided this maneuver does not affect cardiac output, the azygos vein is ligated and divided as

Long-gap EA with distal TEF 343

it enters the superior vena cava. Following division of the vein, the site of the ﬁstulous communication between the trachea and the distal esophagus is usually apparent. Having conﬁdently identiﬁed the distal esophagus, a vascular sling is carefully passed around it. Traction on the sling controls the ﬁstula and enables its junction with the trachea to be located precisely. Although it is possible to suture ligate the ﬁstula, it is preferable to divide the ﬁstula in stages and apply interrupted 5-0 or 6-0 prolene sutures to the tracheal component of the ﬁstula. The distal esophagus is secured with a stay suture of the same material. The integrity of the TEF repair is evaluated by instilling saline into the thoracic cavity and asking the anesthetist to exert positive airway pressure to ensure that no bubbles leak from the suture line. Occasionally, difﬁculty is encountered in identifying the distal esophagus, and it is quite possible to mobilize the descending aorta in the erroneous impression that this is the distal esophagus. The inexperienced operator may recognize the distal esophagus by following the vagus nerve as it courses distally, and by observing its rhythmic distension in time with ventilation. Attention is then focused on the upper pouch, which is easily identiﬁed by requesting the anesthetist to push ﬁrmly on the Replogle tube. The upper pouch is usually a thick-walled bulbous structure, with a base readily identiﬁed by this maneuver. The upper pouch may be secured using a transﬁxion suture driven through the Replogle tube, which is used for traction during the mobilization of the upper pouch (H. Lindahl, personal communication). Bipolar diathermy is ideal for this dissection, which should proceed to the thoracic inlet unless the gap is small. Mobilization is relatively easy except where the esophagus is closely applied to the trachea. Separation of this plane often requires sharp dissection, and should be performed with great care to avoid injury to the trachea. An upper pouch ﬁstula may be identiﬁed at this stage, and should be repaired using 5-0 or 6-0 interrupted prolene sutures. The esophageal defect is closed with 5-0 or 6-0 interrupted PDS sutures. Following full mobilization of the upper pouch it is usually possible to gauge whether a primary anastomosis is feasible. In most cases of EA with distal TEF, a primary anastomosis is possible, although occasionally considerable tension is required to complete the repair. The upper pouch is opened at its most distal extremity. The posterior wall of the anastomosis is commenced by placing two 5-0 or 6-0 PDS sutures through all layers of the lateral margins of the distal esophagus, taking great care to avoid handling and trauma with tissue forceps. Sutures are completed by including all layers of the corresponding aspect of the upper pouch, so that the knot comes to lie on the inside. Before tying these sutures, two further posterior wall sutures are inserted. All are individually tied drawing the esophageal ends together. Having completed the posterior wall of the anastomosis, a 6–8 Fr. nasogastric

tube is passed by the anesthetist via the nose to the suture line, where it is grasped by the surgeon and carefully introduced into the lower esophagus and stomach. The anterior layer of the anastomosis is completed by laying the knots on the outside. Occasionally, generous mobilization of the lower pouch is also required to enable an anastomosis to be performed without excessive tension. Even when the gap seems too large to permit a primary anastomosis, this can sometimes be achieved by using either a Livaditis myotomy of the upper pouch, or an upper pouch ﬂap as described by Gough. If the anastomosis is under tension, or has required one of these maneuvers, a chest drain is advisable. Under most circumstances where a satisfactory anastomosis has been completed without undue tension and where the extra-pleural plane has been maintained, the current authors, like others, consider a chest drain unnecessary.53 The ribs are loosely approximated using absorbable pericostal sutures, and an anatomical closure of all muscle layers is performed. The chest drain, if present, should be attached to under-water drainage, and the patient transferred to intensive care for postoperative monitoring and ventilatory support. Should additional surgical pathology be present, such as duodenal atresia or imperforate anus, these should be dealt with accordingly under the same anesthetic in the stable infant.

Long-gap EA with distal TEF Rarely the gap between the upper pouch and the distal esophagus is clearly too long to permit a primary anastomosis after division of the ﬁstula, and full mobilization of both the proximal and distal esophagus. Under such circumstances, it is probably wise to proceed to cervical esophagostomy and feeding gastrostomy, accepting the need for esophageal replacement surgery at a later date.

Right-sided aortic arch Opinion is divided amongst pediatric surgeons regarding the optimum surgical strategy when a right-sided aortic arch is encountered. The overall incidence of right-sided arch in association with EA is 1.8–2.5%.54,55 Preoperative echocardiography is at best 20% accurate in identifying this anomaly.55 If a right-sided arch is identiﬁed preoperatively, experience from specialist centers recommends left thoracotomy. More commonly the surgeon will encounter the anomaly unexpectedly during a standard right thoracotomy. The presence of a right-sided arch does not preclude a successful anastomosis in this situation, but the procedure is signiﬁcantly more challenging as is evidenced by the 42% leak rate

344 Esophageal atresia and tracheo-esophageal ﬁstula

seen at Great Ormond Street.55 A trial dissection, including repair of the ﬁstula, via right thoracotomy is appropriate, with completion of the esophageal anastomosis if this seems technically feasible. Where signiﬁcant difﬁculty is encountered with the dissection in preparation for the esophageal anastomosis, left thoracotomy is advisable following division of the ﬁstula through the right chest. The second thoracotomy may be performed immediately or delayed, depending on the stability of the infant, and the experience of the surgeon.

PREMATURE INFANT WITH RDS In premature babies with lung immaturity, emergency surgical intervention may become imperative if ventilation is compromised by the TEF, resulting in abdominal distension and diaphragmatic splinting. The surgical priority is urgent division of the ﬁstula via a transpleural approach. Should the infant’s condition stabilize sufﬁciently after closure of the ﬁstula, a primary repair of the esophagus is appropriate. Otherwise, a delayed repair is undertaken when the infant is stable. Sudden collapse due to gastric perforation is also a signiﬁcant risk in these neonates. In such situations, needle paracentesis prior to laparotomy and gastrostomy formation may be a life-saving measure.56

Postoperative care The infant should be nursed in intensive care following repair of EA and TEF. I.v. ﬂuids and broad-spectrum antibiotics are continued. Weaning from ventilation need not be unduly prolonged in the stable infant with a satisfactory anastomosis. Where the anastomosis is under considerable tension, elective paralysis and ventilation for a period of 3–5 days is widely practised.57 It must be conceded however, that there is no evidence to support the claim that this technique favorably inﬂuences anastomotic healing.58 There is experimental data indicating that the level of tension in the anastomosis correlates with the severity of GER.59 It is the current authors practice to commence all patients on H2-antagonists (e.g. ranitidine), as prophylaxis against anastomotic stricturing potentiated by GER. A contrast esophagogram is optional after 5–7 days to evaluate the anastomosis, although major anastomotic leaks are clinically evident before this time. Minor (radiological) leaks are often seen on the postoperative contrast study. These are of no clinical signiﬁcance and do not preclude the infant from being offered feeds.60 In most cases, transanastomotic tube feeding can be commenced after 48 hours, and slowly increased as tolerated by the infant. Although some authors recommend prophylactic esophageal dilatation at 3 weeks (Rintala, personal

communication), it is uncertain whether this reduces the rate of symptomatic anastomotic strictures.

SURGICAL MANAGEMENT OF ISOLATED (‘PURE’) ESOPHAGEAL ATRESIA The diagnosis of isolated EA is conﬁrmed by the inability to pass a nasogastric tube, and a featureless gasless abdomen on X-ray evaluation (Fig. 34.3). The absence of intestinal gas below the diaphragm however does not always completely exclude the presence of a distal ﬁstula, as a small proportion of children may have a ﬁbrotic connection between the lower pouch and the trachea, which does not permit the passage of air.61 Surgical management of these neonates is challenging and controversial. The majority of pediatric surgeons consider delayed primary anastomosis of the native esophagus, the optimum approach. This strategy demands meticulous nursing care, physiotherapy, and careful attention to nutrition by supervised gastrostomy feeding. A prolonged period of hospitalization is required to achieve this objective. Delayed primary esophageal anastomosis however, is associated with signiﬁcant morbidity, and further procedures to manage esophageal strictures and signiﬁcant GER are commonly required.62 The desire to preserve the infant’s esophagus must be counterbalanced by the humility of knowing when to accept defeat, and to abandon the esophagus in favor of a replacement procedure. The infant with isolated EA is initially managed by feeding gastrostomy and continuous suctioning of the upper pouch. At operation, bronchoscopy should be performed to exclude an associated upper pouch ﬁstula, and rarely an unsuspected atretic distal ﬁstula. Gastrostomy is performed either through a small midline incision, or an oblique left subcostal incision depending on the preference of the operator for later fundoplication. A Stamm gastrostomy is made using an 8–10 Fr. Malecot or Foley catheter. Caution should be taken when performing gastrostomy as the stomach is small and vulnerable to injury. Signiﬁcant morbidity has been reported with gastrostomy insertion in pure EA patients.63 After a period of approximately 3 weeks, the extent of the gap can be assessed by ﬂuoroscopy (Fig. 34.6). A radiopaque tube is pushed into the upper pouch and either contrast instilled via the gastrostomy, or a metal sound is introduced through the gastrostomy and directed via the esophageal hiatus into the distal esophageal stump. This procedure can be repeated at 2-weekly intervals, to assess whether the ends of the esophagus are sufﬁciently close to attempt delayed primary anastomosis.64 A distance of less than two vertebral bodies separating upper and lower pouches is ideal. In practice however, there is little to be gained by delaying restorative surgery beyond 12 weeks of age.

Surgical management of isolated (‘pure’) esophageal atresia 345

Figure 34.6 Gap assessment in a case of pure EA. The scale bar represents gap length (cm)

The operation of delayed primary anastomosis is essentially the same as has been described earlier for EA and TEF. It is to be expected that the anastomosis will be performed under considerable tension. The upper pouch should be fully mobilized to the thoracic inlet. The distal esophagus may be difﬁcult to visualize, and the surgeon should be prepared to pass sounds or an endoscope via the gastrostomy to aid identiﬁcation of the esophageal stump. The esophagus may be dissected to the diaphragmatic hiatus to reduce tension on the anastomosis.65 A Livaditis myotomy,14 or upper pouch ﬂap16,66 may be required to achieve an anastomosis. The current authors perform Livaditis myotomy over the inﬂated balloon of a Foley catheter, and either one or two myotomies can be created. Extra length can be obtained on the lower pouch if necessary by proceeding to laparotomy and performing either a Scharli lesser curve myotomy,67 or a Collis gastroplasty.68 If a primary anastomosis is still not possible using these techniques, the options are immediate esophageal replacement, or cervical esophagostomy and later substitution surgery. The delay in restoration of esophageal continuity has signiﬁcant drawbacks. Firstly, the ever-present risk of aspiration pneumonitis, and secondly, the inability to feed the infant via the normal oral route. Although the child’s nutritional needs are met by gastrostomy feeding, the inability to establish oral feeds may lead to long-term feeding and speech problems. Spitz recommends formally assessing the length of the gap when the gastrostomy is performed. A gap length > 6 vertebral bodies (6 cm), would prompt him to abandon the esophagus and perform a cervical esophagostomy.69 This approach of early cervical esophagostomy and delayed

esophageal replacement permits early sham feeding, which theoretically promotes neuronal maturation and development of the learning skills needed for feeding and later speech acquisition (Bianchi, personal communication). A number of other innovative approaches to the deﬁnitive operative treatment of long-gap EA have been described. True primary repair has been performed even with gap lengths exceeding 5 cm. The hypothesis tested by Foker was that a well-constructed esophageal anastomosis can withstand considerable tension.70 The value added technique for esophageal reconstruction (VATER) operation involves mobilizing the gastric fundus and performing a limited Thal fundoplication. At thoracotomy the proximal stomach is drawn into the chest and a primary esophageal anastomosis is performed.71 Staged neonatal colon esophagoplasty involves the isolation of a short length of transverse colon based on the ascending branch of the left colic vessels at the time of open gastrostomy. The conduit is positioned transhiatally in the posterior mediastinum to be retrieved at thoracotomy several days later, when continuity is restored.72 Several operations are available to restore gastrointestinal continuity in long-gap EA, where the infant’s own esophagus has been abandoned. Colonic or ileocolonic replacement was originally popularized by Waterston.13 The colonic conduit may be isoperistaltic (left colon based on the left colic vessels), or anteperistaltic (right colon based on the ileocolic vessels). The colon may be routed retrosternally, transmediastinally (via the hiatus), or through right or left chest cavities. Either pyloromyotomy or pyloroplasty is performed to promote gastric emptying. Cervical esophago-colonic anastomosis is prone to leakage. The colonic conduit tends to dilate, and kinking is common due to excessive tortuosity. Respiratory problems are seen due to recurrent aspiration. The stomach may be utilized to create a neoesophagus. A gastric tube esophagoplasty is fashioned from the greater curvature of the stomach, based on the left gastroepiploic (ante-peristaltic) or right gastroepiploic arcades (iso-peristaltic), and retrosternal, mediastinal, or thoracic routes may be used.73 The long suture line both of the tube and new greater curve are prone to bleeding and leaking. Reﬂux is a problem and may predispose to anastomotic narrowing. However, dilatation and kinking are not encountered; reﬂux may be controlled by performing a posterior partial wrap fundoplication.74 Gastric transposition has been advocated by Spitz and has the merit of simplicity. The vascular supply is based on the right gastric and right gastroepiploic vessels, which allows full mobilization of the greater and lesser curvatures. After pyloroplasty, the stomach is passed transmediastinally and the gastro-esophageal anastomosis is competed in the neck. Anastomotic leakage occurs in 12%, and strictures in a similar percentage of infants.75

346 Esophageal atresia and tracheo-esophageal ﬁstula

Jejunal interposition is less commonly employed. The vascular anatomy allows only for replacement of the lower esophagus in standard Roux-en-Y fashion. Isolated jejunal segments may be used to replace the esophagus using microvascular techniques, but this approach carries a high risk of graft necrosis.76

H-TYPE TEF H-type TEF is perhaps more accurately described as an N-type ﬁstula, as the ﬁstula runs obliquely from trachea to esophagus. This is a rare anomaly comprising approximately 4% of all EA and TEF variants. Infants with H-type TEF usually present within the ﬁrst month after birth, with a characteristic history of choking on feeds and cyanotic episodes. Marked abdominal distension mimicking intestinal obstruction is an occasional presenting feature. Older children may have frequent chest infections with recurrent right upper lobe pneumonia due to aspiration. The diagnosis may be established by a prone video esophagogram. In this study, contrast is injected through a nasogastric tube, which is slowly withdrawn from the esophagus. However, H-type ﬁstulas may be missed in approximately half of all contrast studies. Where suspicion remains, bronchoscopy should be performed. At bronchoscopy, a size 4 Fr. ureteric catheter is passed through the ﬁstula into the esophagus to facilitate identiﬁcation during subsequent neck dissection. A nasogastric tube is passed into the stomach, and broad-spectrum antibiotics commenced. A right transverse skin crease incision is marked a ﬁnger’s breadth above the clavicle, before positioning the neck in extension with a sandbag placed under the shoulders. The sternomastoid is retracted laterally and if necessary its sternal head divided. The carotid sheath is mobilized after division of the middle thyroid vein. The ipsilateral recurrent laryngeal nerve should be identiﬁed and carefully preserved. The esophagus is dissected and slung with vascular sloops both above and below the ﬁstula. Care should be taken with this maneuver, as the contralateral recurrent nerve is vulnerable to injury at this point. Traction on the esophagus enables the ﬁstula to be identiﬁed and secured with stay sutures. After withdrawing the ureteric catheter, the ﬁstula is divided and the tracheal component repaired with 5-0 or 6-0 interrupted prolene sutures. The esophagus is closed with 5-0 or 6-0 PDS sutures. Some authors recommend tissue interposition between esophageal and tracheal suture lines to prevent a recurrent ﬁstula. The infant should remain intubated and ventilated in the early postoperative period, as tracheal edema can result in progressive stridor. The vocal cords should be checked on extubation, given the signiﬁcant risk of

recurrent nerve palsy. Nasogastric tube feeding may commence after 48 hours and oral feeds may be slowly introduced thereafter. The Nd:YAG laser has also been successfully used to treat congenital H-type TEF. Repeated short duration pulses of laser light are used to coagulate the ﬁstula.77 Despite some success with this approach, the technique has not gained widespread acceptance, and open repair remains the gold standard. Complications following open surgery include recurrent laryngeal nerve palsy (both unilateral and bilateral), and rarely, recurrent ﬁstula.

COMPLICATIONS AND SPECIAL CONSIDERATIONS Anastomotic leak The incidence of anastomotic leak following repair of EA and TEF ranges from 11–21%.60,78 Major anastomotic disruption is uncommon and is usually manifested by early tension pneumothorax and gross salivary drainage from the chest drain. In these situations, it is rare for the anastomosis to be completely disrupted. Provided a transanastomotic tube is in place, it is usually possible to control the leak with an adequately sized chest drain. With good drainage, broad-spectrum antibiotics and total parenteral nutrition, the esophagus will usually heal, although a prolonged period of chest drainage may be necessary. Some surgeons have used hyoscine patches in an attempt to ‘dry up’ the salivary leak (Upadhyay, personal communication). Others advocate early reexploration (<48 hours), with direct repair of the esophagus if possible, and the establishment of satisfactory drainage.79 This early re-operative approach may prove hazardous and further compromise a tenuous anastomosis.26 Where conservative management of a major leak proves unsatisfactory due to uncontrolled sepsis, the establishment of a cervical esophagostomy and a feeding gastrostomy are essential. This usually commits the child to some form of delayed esophageal replacement after recovery. It has been suggested that a clinical anastomotic leak predisposes to the development of an esophageal stricture.80 While this association may seem logical, others have not been able to conﬁrm such a correlation.78

GER Signiﬁcant GER occurs in 40–50% of children following repair of EA and TEF. GER may cause failure to thrive, can predispose to recurrent aspiration episodes, and may lead to esophagitis and stricture formation. Management of symptomatic GER initially entails aggressive medical therapy. Postural therapy and close attention to feeding

Anastomotic stricture 347

regimes, with calorie supplementation of formula feeds, combined with the selective use of overnight continuous pump feeding by nasogastric tube and frequent small daytime bolus feeds may prove effective management strategies. Feed thickeners (e.g. Carobel), antacid preparations (e.g. Gaviscon), H2-antagonists (e.g. Ranitidine), proton pump inhibitors (e.g. Omeprazole), and pro-kinetic agents (e.g. Domperidone), may be used in various combinations if vomiting is signiﬁcant. However, should such measures fail to control GER, surgical treatment may be the only option. GER may contribute to recurrent aspiration episodes, with frequent symptoms of respiratory distress including tachypnea, apneic episodes, cyanosis, and X-ray evidence of patchy pneumonic changes. The differential diagnosis in this clinical setting also includes swallowing inco-ordination, and respiratory distress due to signiﬁcant tracheomalacia. It is not uncommon to see infants in whom all of these factors are operating to a variable degree. It is important not to overlook the possibility of a recurrent TEF as a cause of repeated episodes of respiratory distress, although the history of choking and cyanotic episodes during feeding is usually much more evident in infants with a recurrent ﬁstula. The selective use of esophageal pH monitoring, contrast meal, bronchoscopy, and assessment of swallowing by video ﬂuoroscopy, may assist in evaluating the contribution of GER and other pathologies to respiratory symptoms. Failure to control GER-related symptoms despite full medical therapy is an indication for fundoplication. Fundoplication rates following surgery for EA vary widely between centers (6–45%), reﬂecting the differing enthusiasm for anti-reﬂux operations in this clinical setting.81 There are several reasons for caution when considering fundoplication in EA patients. Dysphagia may be aggravated as a consequence of underlying esophageal dysmotility. Furthermore, fundoplication following EA has a higher failure rate (15–38%) than is generally seen in otherwise normal patients with isolated GER.81 Some authors recommend a partial wrap (Thal) fundoplication, because of the lower incidence of postoperative dysphagia.81 Despite these concerns, many pediatric surgeons prefer a short (1.5–2.0 cm) 360° ﬂoppy Nissen wrap for its proven effectiveness in reducing GER.82 The high failure rate of fundoplication and the signiﬁcant complications associated with surgical treatment of GER, demand vigilant follow-up in this group of patients.

rarely of a sufﬁcient degree to cause symptoms in the early postoperative period. Parents should be counselled to report symptoms of prolonged feeding, incomplete feeding or associated respiratory difﬁculty. Such symptoms prompt us to arrange a contrast study to assess the calibre of the esophageal anastomosis. Balloon dilatation is our preferred method of treating the symptomatic stricture. The radial dilating forces generated during balloon dilatation are considered to be less traumatic than the longitudinal shearing forces caused by conventional bougienage.83 Balloon dilatation is performed under ﬂuoroscopic control, by passing a guide wire through the stricture, over which a balloon dilator of appropriate size is introduced. Its position is conﬁrmed by partially ﬁlling the balloon with contrast medium, so that ‘waisting’ due to the stricture is centrally located (Fig. 34.7). The balloon is then maximally inﬂated using contrast medium to dilate the stricture. A contrast esophagogram is performed after removing the balloon to ensure there has been no perforation. Balloon dilatation may be performed under endoscopic or radiological control, and should be followed by maximal medical treatment of GER. If a stricture requires repeated dilatations, GER should be fully investigated by a combination of an upper GI contrast study, pH study and endoscopy. Recalcitrant strictures may require repeated dilatations, fundoplication, and rarely formal resection at thoracotomy.

Tracheomalacia Tracheomalacia, like GER, is present to a variable degree in all patients with EA. It is thought to be responsible for

Anastomotic stricture Reported deﬁnitions of esophageal stricture following repair of EA lack consistency. The incidence of symptomatic strictures requiring dilatation varies from 37–55%.60,80 Some degree of anastomotic narrowing is seen in all postoperative contrast studies, but this is

Figure 34.7 ‘Wasting’ due to anastomotic stricture at balloon dilatation

348 Esophageal atresia and tracheo-esophageal ﬁstula

the characteristic barking TEF cough. Infants with tracheomalacia demonstrate expiratory stridor, which may result in episodes of desaturation, apnea, cyanosis and bradycardia (often associated with feeding), and lifethreatening so-called ‘dying episodes’. Severe tracheomalacia may be evident in the early postoperative period, when it proves difﬁcult to wean the infant from the ventilator. Indications of the severity of tracheomalacia include ventilator dependency, respiratory distress characterized by stridor and chronic carbon dioxide retention, and dying episodes. Full investigation of GER is advisable alongside evaluation of tracheomalacia, as aspiration secondary to GER can mimic these symptoms. The extent of tracheomalacia is assessed by bronchoscopy under conditions of spontaneous respiration. The lumen of the trachea is signiﬁcantly compressed anteroposteriorly and assumes a scabbard-like appearance during expiration due to tracheal cartilage deﬁciency. A signiﬁcant contribution is often made by the upper esophagus, which may bulge posteriorly into the airway. Tracheobronchomalacia can extend beyond the carina into the main bronchi. As tracheomalacia can be self-limiting, surgical intervention is reserved for patients with life-threatening symptoms. Treatment options include continuous positive airway pressure (CPAP), aortopexy, tracheostomy, and, more recently, tracheal stenting. CPAP is a useful temporizing measure, but may be required for several weeks. Aortopexy is traditionally performed by anterior left thoracotomy through the third interspace. The left lobe of the thymus is excised to gain access to the root of the aorta taking care not to damage the phrenic nerve. Plegetted sutures incorporating reinforcing dacron squares are placed through the adventia of the aortic root and the ascending aorta. The sutures are passed through the periostium of the manubrium and tied, hitching the aorta forwards, thereby relieving pressure on the trachea. Although this operation cannot resolve distal tracheobronchomalacia, it often provides immediate dramatic symptomatic relief. Failure of aortopexy may be an indication for tracheostomy, although some authors advocate tracheal stenting in this situation.84

Recurrent TEF This complication is thought to occur in 5–15% of cases.85 A recurrent TEF may result from an anastomotic leak, but the possibility of a missed upper pouch ﬁstula should be considered. Symptoms include recurrent chest infections and choking attacks during feeding. A high index of suspicion is required if the diagnosis is not to be overlooked. The initial investigation is prone video esophagography. If this study fails to demonstrate a ﬁstula and the diagnosis remains strongly suspected,

combined esophagoscopy and bronchoscopy should be performed. Rigid bronchoscopy is performed initially, and the site of the original ﬁstula carefully examined. The ﬁstula is gently probed with a ureteric catheter and methylene blue is carefully instilled into the ﬁstula pit. Synchronous ﬂexible esophagoscopy is performed to see if the dye can be seen entering the esophagus. Should this fail to demonstrate the ﬁstula, an ‘air/water test’ is a useful supplementary investigation. The esophagus is ﬁlled with water and positive pressure ventilation applied to the bronchoscope. Occasionally, bubbles of air can be seen emanating from the ﬁstulous opening into the esophagus (Rintala, personal communication). Several strategies have been described to deal with the recurrent TEF. The traditional approach is formal repair via right thoracotomy. At bronchoscopy, an attempt should be made to pass a ﬁne ureteric catheter through the ﬁstula into the distal esophagus. If this maneuver fails, it is necessary to separate the esophagus and trachea over a considerable length to ensure that the ﬁstula has been identiﬁed. Having repaired the ﬁstula as described earlier (see H-type ﬁstula), tissue interposition between suture lines is advisable in an attempt to reduce the chances of further ﬁstula formation. A 10–22% risk of reﬁstulation has been reported.85 Therefore, other less invasive approaches have been employed to treat recurrent TEF including diathermy fulguration of the ﬁstula tract.86 This technique has been reﬁned using the Nd:YAG laser to obliterate the epithelial communication. Sclerosing agents, Histoacryl, and ﬁbrin glues have all been injected subepithelially to occlude the ﬁstula. A recent review of endoscopic treatment reported an overall closure rate of 55% with several treatments required to effect closure. The Oxford study concluded that formal surgical re-exploration remained the treatment of choice, except in high-risk patients.85

Quality of life and long-term outcome The improved survival of babies born with EA and TEF has prompted a more detailed analysis of morbidity, with emphasis on long-term outcome data. Several studies have examined respiratory function in EA children. Symptoms of asthma and bronchitis are frequent, especially in the young child, and may persist into adolescence.87 Almost half of all children require future hospitalization due to ongoing respiratory morbidity.88 In a large Melbourne series comprising 334 EA children, episodes of pneumonia were seen in 31% of children under the age of 5, compared with 5% of those over 15. The prevalence of annual attacks of bronchitis in these two age groups was 74% and 41%, respectively, with asthmatic symptoms reported in 40% of patients from each age range.88 Spirometry studies have demonstrated

References 349

both obstructive and restrictive abnormalities in over half the patients, and a similar proportion had a maximal working capacity below the normal range.89 Tracheo-bronchial inﬂammation and airway narrowing have been demonstrated by bronchoscopy in one-third of patients, with histological evidence of inﬂammation in a further third.90 It is plausible that abnormalities of bronchial anatomy, which are common in EA and TEF, may contribute to respiratory morbidity. Regular clinical assessment by a respiratory physician, with chest physiotherapy and aggressive antibiotic treatment for infective exacerbations is recommended. The contribution of aspiration episodes, whether due to esophageal dysmotility or GER, to respiratory symptoms, should be actively investigated. Recognition of the long-term respiratory morbidity associated with EA patients, has prompted the establishment of a specialist TEF clinic at Alder Hey Children’s Hospital, which is staffed by surgeons, respiratory physicians, physiotherapists and dieticians. This multidisciplinary approach ensures that attention is focused on all aspects of the child’s ongoing welfare. Esophageal dysmotility is a signiﬁcant factor in longterm morbidity. It is clearly implicated in many cases of absolute dysphagia due to bolus impaction, when endoscopy reveals no signiﬁcant anastomotic narrowing. Less severe symptoms of dysphagia have been reported in 20% of adolescents91 and in 48% of adults87 in long-term follow-up studies. Esophageal manometry and ﬂuoroscopy studies will demonstrate dysmotility in virtually all patients.89 The dysmotility associated with EA may reﬂect intrinsic innervation abnormalities of the esophagus.92 This may further contribute to respiratory morbidity through repeated ‘silent’ aspiration episodes. GER may persist into adult life. Reported incidence of symptoms of heartburn and acid brash ranges from 18%90 to 50%89 in some long-term follow-up studies. Clinical symptoms may underestimate the true incidence of GER as demonstrated by esophageal pH monitoring. An 8% incidence of Barrett’s esophagus has been reported,93 but the risk of esophageal adenocarcinoma is uncertain. Endoscopic surveillance has also revealed a twofold increase in the incidence of Helicobacter pylori infection,90 which may also have signiﬁcant implications in adult life. It has been proposed that medical treatment for GER in all EA infants might reduce the incidence of long-term respiratory complications.88,90 However, caution should be exercised when considering anti-reﬂux surgery, as esophageal dysmotility may be exacerbated by surgery, which in turn might aggravate respiratory symptoms. Various quality of life measures have been applied to young adults treated for EA and TEF. Using a global quality of life measure, the Spitzer Index, and a gastrointestinal quality of life index, adults who underwent primary anastomosis as newborns were shown to enjoy an unimpaired quality of life. Quality of life measures

were more favorable in those patients who had a primary anastomosis, compared to those who required colonic interposition.87 Standardized psycho-social assessment scores have demonstrated more learning, emotional, and behavioral problems in EA adults than in the general population. Cognitive performance was signiﬁcantly impaired in a high-risk group characterized by associated major congenital abnormalities or the requirement for prolonged ventilation in the neonatal period.94 A parental support group based in the UK (the TOFS society) provides useful information for families, opportunities for them to share problems and experiences, and raises valuable funds for research.95

REFERENCES 1. Myers NA. The history of oesophageal atresia and tracheo-oesophageal ﬁstula: 1670–1984. In: Rickham PP, editor. Progress in Pediatric Surgery. 20th edn. Heidelberg: Springer-Verlag, 1986:106–57. 2. Waterston DJ, Carter RE, Aberdeen E. Oesophageal atresia: tracheo-oesophageal ﬁstula. Lancet 1962; 1:819–22. 3. Durston W. A narrative of a monstrous birth in Plymouth October 22, 1670, together with the anatomical observations taken thereupon by William Durston, Doctor of Physick, and communication to Dr Tim Clerk. Philosophical Transactions of the Royal Society V: 1670:2096. 4. Gibson T. The Anatomy of Human Bodies Epitomised. 5th edn. London: Awnsham and Churchill, 1697. 5. Lamb DS. A fatal case of congenital tracheo-esophageal ﬁstula. Philad Med Times 1873; 3:705. 6. Hoffman W. Atresia oesophagi congenita et communicatio inter oesophagum et tracheum. Inaugural dissertation. Greifswald: Julius Abel, 1899. 7. Richter HM. Congenital atresia of the esophagus. An operation designed for its cure, with a report of two cases operated upon by the author. Surg Gynec Obstet 1913; 17:397–402. 8. Lanman TH. Congenital atresia of the oesophagus. A study of 32 cases. Arch Surg 1940; 41:1060–83. 9. Imperatori CJ. Congenital tracheoesophageal ﬁstula without atresia of the esophagus – report of a case with plastic closure and cure. Arch Otorhinolaryngol 1939; 30:352–9. 10. Ladd WE. The surgical treatment of esophageal atresia and tracheo-esophageal ﬁstulas. N Engl J Med 1944; 230:625–37. 11. Leven NL. Congenital atresia of the esophagus with tracheoesophageal ﬁstula, report of successful extrapleural ligation of ﬁstulous communication and cervical esophagostomy. J Thorac Surg 1941; 10:648–57. 12. Haight C, Towsley HA. Congenital atresia of the esophagus with tracheo-esophageal ﬁstula: extrapleural ligation of ﬁstula and end to end anastomosis of esophageal segments. Surg Gynec Obstet 1943; 76:672–88.

350 Esophageal atresia and tracheo-esophageal ﬁstula 13. Waterston D. Colonic replacement of the esophagus. Surg Clin North Am 1964; 44:1441–7. 14. Livaditis A. End-to-end anastomosis in esophageal atresia. A clinical and experimental study. Scand J Thorac Cardiovasc Surg 1969; 2 (Suppl 2):7. 15. Cohen DH, Middleton AW, Fletcher J. Gastric tube esophagoplasty. J Pediatr Surg 1974; 9:451–60. 16. Gough MH. Esophageal atresia – use of an anterior ﬂap in the difﬁcult anastomosis. J Pediatr Surg 1980; 15:310–11. 17. Spitz L. Gastric transposition via the mediastinal route for infants with long-gap esophageal atresia. J Pediatr Surg 1984; 19:149–54. 18. Spitz L, Kiely EM, Morecroft JA, Drake DP. Oesophageal atresia: at risk groups for the 1990’s. J Pediatr Surg 1994; 29:723–5. 19. Vogt EC. Congenital esophageal atresia. Am J Roent 1929; 22:463–5. 20. Gross RE. Atresia of the oesophagus. In: Gross RE, editor. Surgery of Infancy and Childhood. 1st edn. Philadelphia: W.B. Saunders, 1953. 21. Kluth D. Atlas of esophageal atresia. J Pediatr Surg 1976; 11:901–19. 22. Teich S, Barton DP, Ginn-Pease ME, King DR. Prognostic classiﬁcation for esophageal atresia and tracheoesophageal ﬁstula: Waterston versus Montreal. J Pediatr Surg 1997; 32:1075–80. 23. Yagyu M, Gitter H, Richter B, Booss D. Esophageal atresia in Bremen, Germany – evaluation of preoperative risk classiﬁcation in esophageal atresia. J Pediatr Surg 2000; 35:584–7. 24. Choudhury SR, Ashcraft KW, Sharp RJ et al. Survival of patients with esophageal atresia: inﬂuence of birth weight, cardiac anomaly, and late respiratory complications. J Pediatr Surg 1999; 34:70–4. 25. Brown AK, Tam PKH. Measurement of gap length in esophageal atresia: a simple predictor of outcome. J Am Coll Surg 1996; 182:41–5. 26. Cudmore RE. Oesophageal atresia and tracheooesophageal ﬁstula. In: Lister J, Irving IM, editors. Neonatal Surgery. 3rd edn. London: Butterworths, 1990:231–58. 27. Kyyronen P, Hemminki K. Gastro-intestinal atresia in Finland in 1970–79, indicating time-place clustering. J Epidemiol Community Health 1988; 42:257–65. 28. Myers NA. Oesophageal atresia: epitome of modern surgery. Ann R Col Surg Engl 1974; 54:227–87. 29. Haight C. Some observations on esophageal atresias and tracheoesophageal ﬁstulas of congenital origin. J Thorac Surg 1957; 34:141–72. 30. Harris J, Kallen B, Robert E. Descriptive epidemiology of alimentary tract atresia. Teratology 1995; 52:15–29. 31. Harmon CM, Coran AG. Congenital anomalies of the esophagus. In: O’Neill JA Jr et al. editors. Pediatric Surgery. 5th edn. St Louis: Mosby, 1998:941–67. 32. Pletcher BA, Friedes JS, Breg WR, Touloukian RJ. Familial occurrence of esophageal atresia with and without tracheoesophageal ﬁstula: report of two unusual kindreds. Am J Med Genet 1991; 39:380–4.

33. Merei J, Kotsios C, Hutson JM, Hasthorpe S. Histopathologic study of esophageal atresia and tracheoesophageal ﬁstula in an animal model. J Pediatr Surg 1997; 32:12–14. 34. Thompson DJ, Molello JA, Strebing RJ et al. Teratogenicity of adriamycin and daunomycin in the rat and rabbit. Teratology 1978; 17:151–8. 35. Motoyama J, Lui J, Mo R et al. Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus. Nat Genet 1998; 20:54–7. 36. Kim PCW, Mo R, Hui C. Murine models of VACTERL syndrome: role of sonic hedgehog signaling pathway. J Pediatr Surg 2001; 36:381–4. 37. Xia H, Otten C, Migliazza L et al. Tracheobronchial malformations in experimental oesophageal atresia. J Pediatr Surg 1999; 34:536–9. 38. Kulkarni B, Rao RJ, Oak S, Upadhyay MA. 13 pairs of ribs – a predictor of long gap atresia in tracheoesophageal ﬁstula. J Pediatr Surg 1997; 32:1453–4. 39. Litingtung Y, Lei L, Westphal H, Chiang C. Sonic hedgehog is essential to foregut development. Nat Genet 1998; 20:58–61. 40. Canty TG Jr, Boyle EM Jr, Linden B et al. Aortic arch anomalies associated with long gap esophageal atresia and tracheoesophageal ﬁstula. J Pediatr Surg 1997; 32:1587–91. 41. Driver CP, Shankar KR, Jones MO et al. Phenotypic presentation and outcome of oesophageal atresia in the era of the Spitz classiﬁcation. J Pediatr Surg 2001; 36:1419–21. 42. Quan L, Smith DW. The Vater association. Birth Def 1972; 8:75–8. 43. Nora AH, Nora JJ. A syndrome of multiple congenital anomalies associated with teratogenic exposure: the VACTERL syndrome. Arch Environ Health 1975; 30:17–21. 44. Lillquist K, Warburg M, Andersen SR. Colobomata of the iris, ciliary body and choroid in an infant with oesophagotracheal ﬁstula and congenital heart defects. An unknown malformation complex. Acta Paediat Scand 1980; 69:427–30. 45. Kutiyanawala M, Wyse RKH, Brereton RJ et al. CHARGE and esophageal atresia. J Pediatr Surg 1992; 27:558–60. 46. Chittmittrapap S, Spitz L, Kiely EM, Brereton RJ. Oesophageal atresia and associated anomalies. Arch Dis Child 1989; 64:364–8. 47. Spitz L, Hitchcock RJ. Oesophageal atresia and tracheooesophageal ﬁstula. In: Freeman NV, editor. Surgery of the Newborn. 1st edn. New York: Churchill Livingstone, 1994:353–73. 48. Usui N, Kamata S, Ishikawa S et al. Anomalies of the tracheobronchial tree in patients with esophageal atresia. J Pediatr Surg 1996; 31:258–62. 49. Farrant P. The antenatal diagnosis of oesophageal atresia by ultrasound. Br J Radiol 1980; 53:1202–3. 50. Sparey C, Jawaheer G, Barrett AM, Robson SC. Esophageal atresia in the Northern Region Congenital Anomaly Survey, 1985–1997: prenatal diagnosis and outcome. Am J Obstet Gynecol 2000; 182:427–31.

References 351 51. Stringer MD, McKenna KM, Goldstein RB et al. Prenatal diagnosis of esophageal atresia. J Pediatr Surg 1995; 30:1258–63. 52. Bianchi A, Sowande O, Alizai NK, Rampersad B. Aesthetics and lateral thoracotomy in the neonate. J Pediatr Surg 1998; 33:1798–1800. 53. Kay S, Shaw K. Revisiting the role of routine retropleural drainage after repair of esophageal atresia with distal tracheoesophageal ﬁstula. J Pediatr Surg 1999; 34:1082–5. 54. Bowkett B, Beasley SW, Myers NA. The frequency, signiﬁcance, and management of a right aortic arch in association with esophageal atresia. Pediatr Surg Int 1999; 15:28–31. 55. Babu R, Pierro A, Spitz L et al. The management of oesophageal atresia in neonates with right-sided aortic arch. J Pediatr Surg 2000; 35:56–8. 56. Maoate K, Myers NA, Beasley SW. Gastric perforation in infants with oesophageal atresia and distal tracheooesophageal ﬁstula. Pediatr Surg Int 1999; 15:24–7. 57. Mackinlay GA, Burtles R. Oesophageal atresia: paralysis and ventilation in management of the wide gap. Pediatr Surg Int 1987; 2:10–12. 58. Beasley SW. Does postoperative ventilation have an effect on the integrity of the anastomosis in repaired oesophageal atresia? J Paediatr Child Health 1999; 35:120–2. 59. Guo W, Fonkalsrud EW, Swaniker F, Kodner A. Relationship of esophageal anastomotic tension to the development of gastroesophageal reﬂux. J Pediatr Surg 1997; 32:1337–40. 60. Nambirajan L, Rintala RJ, Losty PD et al. The value of early postoperative oesophagography following repair of oesophageal atresia. Pediatr Surg Int 1998; 13:76–8. 61. Davison P, Poenaru D, Kamal I. Esophageal atresia: Primary repair of a long gap variant involving distal pouch mobilization. J Pediatr Surg 1999; 34:1881–3. 62. Lindahl H, Rintala R. Long-term complications of isolated esophageal atresia treated with esophageal anastomosis. J Pediatr Surg 1995; 30:1222–3. 63. Kimble RM, Harding JE, Kolbe A. The vulnerable stomach in babies born with pure oesophageal atresia. Pediatr Surg Int 1999; 15:467–9. 64. Rossi C, Domini M, Aquino A et al. A simple and safe method to visualize the inferior pouch in esophageal atresia without ﬁstula. Pediatr Surg Int 1998; 13:535–6. 65. Lessin MS, Wesselhoeft CW, Luks FI, DeLuca FG. Primary repair of long-gap esophageal atresia by mobilization of the distal esophagus. Eur J Pediatr Surg 1999; 9:369–72. 66. Davenport M, Bianchi A. Early experience with oesophageal ﬂap oesophagoplasty for repair of oesophageal atresia. Pediatr Surg Int 1990; 5:332–5. 67. Scharli AF. Esophageal reconstruction in very long atresias by elongation of the lesser curvature. Pediatr Surg Int 1992; 7:101–5. 68. Evans M. Application of Collis gastroplasty to the management of esophageal atresia. J Pediatr Surg 1995; 30:1232–5.

69. Spitz L, Ruangtrakool R. Esophageal substitution. Semin Pediatr Surg 1998; 7:130–3. 70. Foker JE, Linden BC, Boyle EM Jr, Marquardt C. Development of a true primary repair for the full spectrum of esophageal atresia. Ann Surg 1997; 226:533–43. 71. Varjavandi V, Shi E. Early primary repair of long gap esophageal atresia: the VATER operation. J Pediatr Surg 2000; 35:1830–2. 72. Lipshutz GS, Albanese CT, Jennings RW et al. A strategy for primary reconstruction of long gap esophageal atresia using neonatal colon esophagoplasty: a case report. J Pediatr Surg 1999; 34:75–8. 73. Anderson KD, Randolph JG. The gastric tube for esophageal replacement in infants and children. J Thorac Cardiovasc Surg 1973; 66:333–42. 74. Ashcraft KW. The esophagus. In: Ashcraft KW, Holder TM, editors. Pediatric Surgery. 3rd edn. Philadelphia: W.B. Saunders, 1993:325–47. 75. Spitz L. Esophageal atresia: past, present, and future. J Pediatr Surg 1996; 31:19–25. 76. Ring WS, Varco RL, L’Heureux PR, Foker JE. Esophageal replacement with jejunum in children: an 18 to 33 year follow-up. J Thoracic Cardiovasc Surg 1982; 83:918–27. 77. Schmittenbecher PP, Mantel K, Hofmann U, Berlein HP. Treatment of congenital tracheoesophageal ﬁstula by endoscopic laser coagulation: preliminary report of three cases. J Pediatr Surg 1992; 27:26–8. 78. Auldist AW, Beasley SW. Esophageal complications. In: Beasley et al. editors. Oesophageal Atresia. 1st edn. London: Chapman & Hall, 1991:305–22. 79. Chavin K, Field G, Chandler J et al. Save the child’s esophagus: management of major disruption after repair of esophageal atresia. J Pediatr Surg 1996; 31:48–52. 80. Chittmittrapap S, Spitz L, Kiely EM et al. Anastomotic stricture following repair of esophageal atresia. J Pediatr Surg 1990; 25:508–11. 81. Snyder CL, Ramachandran V, Kennedy AP et al. Efﬁcacy of partial wrap fundoplication for gastroesophageal refux after repair of esophageal atresia. J Pediatr Surg 1997; 32:1089–92. 82. Bergmeijer JHLJ, Tibboel D, Hazebroek FWJ. Nissen fundoplication in the management of gastroesophageal reﬂux after repair of esophageal atresia. J Pediatr Surg 2000; 35:573–6. 83. Sandgren K, Malmfors G. Balloon dilatation of oesophageal strictures in children. Eur J Pediatr Surg 1998; 8:9–11. 84. Filler RM, Forte V, Fraga JC, Matute J. The use of expandable metallic airway stents for tracheobronchial obstruction in children. J Pediatr Surg 1995; 30:1050–6. 85. Willetts IE, Dudley NE, Tam PKH. Endoscopic treatment of recurrent tracheo-oesophageal ﬁstulae: long-term results. Pediatr Surg Int 1998; 13:256–8. 86. Rangecroft L, Bush GH, Irving IM. Endoscopic diathermy of recurrent tracheo-esophageal ﬁstula. J Pediatr Surg 1984; 19:41–3.

352 Esophageal atresia and tracheo-esophageal ﬁstula 87. Ure BM, Slaney E, Eypasch EP et al. Quality of life more than 20 years after repair of esophageal atresia. J Pediatr Surg 1998; 33:511–15. 88. Chetcuti P, Phelan PD. Respiratory morbidity after repair of oesophageal atresia and tracheo-oesophageal ﬁstula. Arch Dis Child 1993; 68:167–70. 89. Montgomery M, Frenckner B, Freyschuss U, Mortensson W. Esophageal atresia: long-term-follow-up of respiratory function, maximal working capacity, and esophageal function. Pediatr Surg Int 1995; 10:519–52. 90. Somppi E, Tammela O, Ruuska T et al. Outcome of patients operated on for oesophageal atresia: 30 years experience. J Pediatr Surg 1998; 33:1341–6. 91. Romeo C, Bonanno N, Baldari S et al. Gastric motility disorders in patients operated on for esophageal atresia

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and tracheoesophageal ﬁstula: long-term evaluation. J Pediatr Surg 2000; 35:740–4. Nakazato Y, Landing BH, Wells TR. Abnormal Auerbach plexus in the esophagus and stomach of patients with esophageal atresia and tracheo-esophageal ﬁstula. J Pediatr Surg 1986; 11:831–7. Lindahl H, Rintala R, Sariola H. Chronic esophagitis and gastric metaplasia are frequent late complications of esophageal atresia. J Pediatr Surg 1993; 28:1178–80. Bouman NH, Koot HM, Hazebroek FWJ. Long-term physical, psychological, and social functioning of children with esophageal atresia. J Pediatr Surg 1999; 34:399–404. Martin V. The TOF Child. 1st edn. TOFS, Nottingham, Blueprint Group (UK) Limited.

35 Congenital esophageal stenosis SHINTARO AMAE, MASAKI NIO, YUTAKA HAYASHI, AND RYOJI OHI

INTRODUCTION The difﬁculties in obtaining the differential diagnosis of congenital esophageal stenosis (CES) from achalasia and secondary esophageal stenosis, especially stricture due to reﬂux esophagitis,1 has resulted in various clinical problems in its treatment. CES is deﬁned as an intrinsic stenosis of the esophagus caused by the congenital malformation of the esophageal wall architecture. This malformation may result from: • Tracheobronchial remnants in the esophageal wall2–16 • Fibromuscular thickening of the esophageal wall1,11,17–21 • Membranous mucosal diaphragm or web.8, 11, 22–30 Achalasia, inﬂammatory esophagitis, and stenosis caused by tumor or extrinsic compression of the esophagus should be excluded from this category. The localization of the stenosis varies with the type of pathology. Stenosis due to tracheobronchial remnants is the most common type of pathological anomaly, and is localized to the distal esophagus,12 whereas ﬁbromuscular thickening is generally found in the middle or lower portions of the esophagus.11,21 Membranous webs are normally observed in the upper or middle levels of the esophagus.11,26–30 In general, the stenotic area in cases with tracheobronchial remnants is usually identiﬁed, and that of ﬁbromuscular stenosis varies from one to several centimeters in length with circular thickening of the esophageal wall. In almost all cases of membranous web, a single web is found in children,26,28,30 however plural webs, termed multiple trachea-like rings, are observed in young adults.31–33

PATHOLOGICAL FEATURES In the stenotic segment caused by tracheobronchial remnants, mature or immature cartilage, the seromucous tracheobronchial glands and ciliated epithelium are generally found microscopically. Tracheobronchial

remnants are believed to be the result of failure in the normal separation of the embryonic respiratory tract from the foregut. In ﬁbromuscular cases, circumferential proliferation of smooth muscle ﬁbers with moderate ﬁbrosis was revealed.11,21,34 Singaram et al. reported a signiﬁcant reduction of myenteric nitrinergic neurons and ﬁbers in the muscle layer of two young adults diagnosed with CES.35 Lack of submucosa27 and loose, vascular connective tissue and diffuse lymphocytes26 were observed microscopically in specimens of membranous web.

CLINICAL FEATURES Congenital esophageal stenosis is a rare condition and is found in 1 in 25 000–50 000 live births.1,11 Although the reason is unknown, the incidence of CES is higher in Japan.8,36 There is no sex predisposition. The incidence of other anomalies in association with CES has been reported to be 17–33%.11,36 For instance, the association of CES with congenital esophageal atresia,9–11,18,19,24,37–39 cardiac anomalies,11,24 intestinal atresia,11,23 anorectal malformation,10,36 chromosomal anomalies,7,11,21,23 etc. has been reported in the literature. Surgeons should keep in mind the association of congenital esophageal atresia with distal CES due to tracheobronchial remnants. Symptoms of CES include: vomiting or regurgitation, dysphagia, recurrent respiratory tract infections and growth retardation. The onset of regurgitation coincides characteristically with the introduction of semi-solid and solid foods around the age of 6 months in patients with tracheobronchial remnants.34 However, the development of symptoms rarely occurs in the newborn.25 In some patients, a foreign body in the esophagus may be the ﬁrst symptom noted.1

DIAGNOSIS Patients who develop the symptoms described earlier should undergo a barium swallow. Esophagograms show

354 Congenital esophageal stenosis

a tapered or abrupt narrowing of the esophagus in association with various degrees of dilatation of the suprastenotic portion of the esophagus (Fig. 35.1). Most of the stenosis due to tracheobronchial remnants is observed as demonstrated by an abrupt narrowing on the esophagogram, while ﬁbromuscular stenosis usually shows a tapered narrowing. Following surgery for the treatment of esophageal atresia, an esophagogram should be evaluated with great care without failing to ﬁnd a narrowing at the mid-distal esophagus. Newman et al. carried out a retrospective review of 225 records and radiographs, and reported that 8% of tracheo-esophageal ﬁstula (TEF) cases were associated with CES.40 Esophagoscopy, manometric study and pH monitoring are helpful tools for the differential diagnosis of CES from achalasia and secondary esophageal stricture due to gastro-esophageal reﬂux. Esophageal endoscopy can directly evaluate not only the stenotic area (Fig. 35.2) and the site of the gastro-esophageal junction but also the

presence of esophagitis. The mucosa distal to the stenosis is normal in CES. In cases of CES, preoperative esophageal manometry demonstrates the normal pattern of lower esophageal sphincter and a small high-pressure zone in the resting pressure proﬁle (Fig. 35.3), which corresponds to the stenotic area of the esophagus (this small high-pressure zone disappears after corrective surgery). Moreover, an esophageal motility study reveals aperistalsis corresponding to the stenosis. pH monitoring reveals that signiﬁcant positive reﬂux is not a feature in patients with CES in contrast to that seen in patients with gastro-esophageal reﬂux.

Figure 35.3 Preoperative (a) and postoperative (b) resting pressure proﬁle of the gastro-esophageal junction and the esophagus in a case of CES with tracheobronchial remnants. A small high-pressure zone in the lower esophagus is noted and this disappeared after the corrective operation (a)

(b)

Figure 35.1 Abrupt (a) and tapered (b) narrowing on esophagograms

Figure 35.2 Endoscopic view of the stenotic portion of the esophagus

TREATMENT The principles in the treatment of CES patients are the relief of the symptoms caused by the esophageal stenosis and the maintenance of the anti-reﬂux mechanism of the gastro-esophageal junction. This condition can be treated conservatively or by surgical intervention. Bougienage, as a conservative treatment, is the ﬁrst choice of treatment for CES patients. Bougienage should be tried not only for patients with tapered narrowing but also in patients with abrupt narrowing, when the catheter can be passed safely through the stenotic area. Previously, we have attempted retrograde bougienage through a gastrostomy using Tucker’s bougie. We now use the low-compliance (Rigiﬂex) balloon catheter. The effect of balloon dilatation or bougienage varies with the type of pathology. Recent cases with membranous web of the esophagus and some cases of ﬁbromuscular stenosis can be treated successfully by suitable dilatation or bougienage.11,26,28,29 Surgical resection of the stenosis is necessary for tracheobronchial remnants6,8,10–16,36,39 and several cases with ﬁbromuscular thickening.21,34 As a rule, when patients fail to respond to repeated (4–6 times)

Operative procedure 355

attempts of bougienage, surgical intervention should be considered. Complications of treatment, as reported in the literature, are iatrogenic esophageal perforation by bougienage,10,41 anastomotic stenosis and leakage. In particular, iatrogenic esophageal perforation often requires an emergency operation.

PREOPERATIVE PREPARATION Those patients who are undernourished should have their nutritional status corrected prior to surgery. Such patients may require total parenteral nutrition and/or enteral nutrition via a nasogastric tube or gastrostomy. Prior to the surgical procedure, it is essential that the surgeon know the exact site and extent of the stenosis, and the distance from the gastro-esophageal junction. When the stenosis is situated in the distal portion of the esophagus, the current authors always perform cineradiography and another special ﬂuorographic procedure. In this procedure, ﬁrst, a balloon catheter is inserted through the esophagus across the stenosis, and then barium is orally administered. Immediately following this, the balloon is inﬂated and pulled up. Adequate traction should position the balloon just below the stenosis and give a clear image of the stenotic area (Fig. 35.4).

abdominal esophagus, the abdominal approach may be utilized. In the thoracic approach, right thoracotomy is employed for a stenosis in the middle portion of the esophagus, and left thoracotomy for a stenosis of the lower part of the esophagus. After exposing the esophagus, the current authors insert a balloon catheter beyond the stenotic segment from the mouth. The balloon catheter is inﬂated and pulled up to conﬁrm the distal margin of the stenosis. Following resection of the distal end of the stenosis, a sterile balloon catheter is passed through the stenotic area from the oral stump of the esophagus. The upper margin of the stenosis is decided by pulling down the catheter (Fig. 35.5). Complete removal of the stenotic area should be performed. Anastomosis should be made without tension. The use of single- or double-layer interrupted sutures using absorbable material is justiﬁed. The surgeons should, of course, pay attention to the preservation of the phrenic and vagal nerves during surgery. The possibility of simple excision of cartilaginous remnants and subsequent repair of the esophageal wall is limited.5,11 Therefore, segmental resection with end-toend anastomosis of the esophagus should be a standard procedure for patients with a stenosis in the mid or lower

L

OPERATIVE PROCEDURE D

Most cases of CES can be operated upon via the thoracic approach. However, when the stenosis is localized in the

(a)

Esophagus

L

Stenosis

D

Stomach

(b)

Figure 35.4 A special ﬂuorographic examination for the evaluation of the exact site and extension of the stenosis. Stenosis is located between the dilated pouch of the esophagus and the balloon

Figure 35.5 An intraoperative procedure by the use of a Foley catheter to determine the distal (a) and proximal (b) sites of stenosis (arrow), Resection line (solid line), Diaphragm (D), Lung (L)

356 Congenital esophageal stenosis

esophagus which is not close to the gastro-esophageal junction. However, to prevent postoperative reﬂux, an anti-reﬂux procedure, for example a Nissen’s fundoplication (Fig. 35.6), may be necessary, in addition to segmental resection, when the stenosis is situated close to the gastro-esophageal junction. If the vagal nerve is severed by accident, a pyloroplasty should be performed. Patients with extensive ﬁbromuscular stenosis necessitating resection of the esophagus of more than 3 cm may require esophageal replacement with a colon, jejunum or gastric tube. Complications, such as an iatrogenic esophageal perforation following bougienage10,41 and a leakage after segmental resection and reconstruction of the esophagus,11 have been reported. Perforations and major leakages require surgical drainage, but minor leakages can be treated successfully by maintaining the patient on total parenteral nutrition. When gastro-esophageal reﬂux develops following simple resection and anastomosis, the anti-reﬂux procedure should be carried out.

Tacking of the esophagus to the hiatus Transection and end-to-end anastomosis

Nissen's fundoplication

Figure 35.6 Transection of the distal esophagus with end-toend anastomosis combined with an anti-reﬂux procedure (Nissen’s fundoplication)

REFERENCES 1. Bluestone CD, Kerry R, Sieber WK. Congenital esophageal stenosis. Laryngoscope 1969; 79:1095–1103. 2. Frey EK, Duschl L. Der Kardiospasmus. Erge Chirurg Orthopaed 1936; 29:637–716. 3. Bergmann M, Charnas RM. Tracheobronchial rests in the esophagus. J Thorac Surg 1958; 35:97–104. 4. Kumar R. A case of congenital oesophageal stricture due to a cartilaginous ring. Br J Surg 1962; 69:533–4. 5. Pauline E, Roselli A, Aprigliano F. Congenital esophageal stricture due to tracheobronchial remnants. Surgery 1963; 53:547–50.

6. Ishida M, Tsuchida Y, Saito S et al. Congenital esophageal stenosis due to tracheobronchial remnants. J Pediatr Surg 1969; 4:339–45. 7. Rose JS, Kassner EG, Jurgens KH et al. Congenital esophageal strictures due to cartilaginous rings. Br J Radiol 1975; 48:16–18. 8. Ohkawa H, Takahashi H, Hoshino Y et al. Lower esophageal stenosis in association with tracheobronchial remnants. J Pediatr Surg 1975; 10:453–7. 9. Ibrahim NBN, Sandry RJ. Congenital esophageal stenosis caused by tracheobronchial structures in the esophageal wall. Thorax 1981; 36:465–8. 10. Deiraniya AK. Congenital oesophageal stenosis due to tracheobronchial remnants. Thorax 1974; 29:720–5. 11. Fekete CN, Backer AD, Jacob SL. Congenital esophageal stenosis. A review of 20 cases. Pediatr Surg Int 1987; 2:86–92. 12. Sneed WF, LaGarde MS, Kogutt MS et al. Esophageal stenosis due to cartilagious tracheobronchial remnants. J Pediatr Surg 1979; 14:786–8. 13. Spitz L. Congenital esophageal stenosis distal to associated esophageal atresia. J Pediatr Surg 1973; 8:973–4. 14. Briceno LI, Grases PJ, Gallego S. Tracheobronchial and pancreatic remnants causing esophageal stenosis. J Pediatr Surg 1981; 16:731–2. 15. Tubino P, Marouelli LF, Alves E et al. Choristoma: esophageal stenosis, due to tracheobronchial remnants. Z Kinderchir 1982; 35:14–17. 16. Shoshany G, Bar-Maor JA. Congenital stenosis of the esophagus due to tracheobronchial remnants: A missed diagnosis. J Pediatr Gastroenterol Nutr 1986; 5:977–9. 17. Bonilla KB, Bower WF. Congenital esophageal stenosis; pathologic studies following resection. Am J Surg 1959; 97:772–6. 18. Mahour GH, Jounston PW, Gwinn JL et al. Congenital esophageal stenosis distal to esophageal atresia. Surgery 1971; 69:936–9. 19. Tuqan NA. Annular stricture of the esophagus distal to congenital tracheoesophageal ﬁstula. Surgery 1962; 52:394–5. 20. Vidne B, Levy MJ. Use of pericardium for esophagoplasty in congenital stenosis. Surgery 1970; 68:389–92. 21. Todani T, Watanabe Y, Mizuguchi T. Congenital oesophageal stenosis due to ﬁbromuscular thicking. Z Kinderchir 1984; 39:11–14. 22. Beatty CC. Congenital stenosis of the oesophagus. Br J Child Dis 1928; 25:237–70. 23. Huchzermeyer H, Burdeiski M, Hruby M. Endoscopic therapy of a congenital oesophageal stricture. Endoscopy 1979; 11:259–62. 24. Overton RC, Creech O. Unusual esophageal atresia with distant membranous obstruction of the esophagus. J Thorac Surg 1953; 35:674–7. 25. Schwaetz SI. Congenital membranous obstruction of esophagus. Arch Surg 1962; 85:480–2. 26. Grabowski ST, Andrews DA. Upper esophageal stenosis: two case reports. J Pediatr Surg 1996; 31:1438–9.

References 357 27. Takayanagi K, Ii K, Komi N. Congenital esophageal stenosis with lack of the submucosa. J Pediatr Surg 1975; 10:425–6. 28. Sarihan H, Abes M. Congenital esophageal stenosis. J Cardiovasc Surg 1997; 38:421–3. 29. Komuro H, Makino S, Tsuchiya I et al. Cervical esophageal web in a 13-year-old with growth failure. Pediatr International 1999; 41:568–70. 30. Roy GT, Cohen RC, Willeams SJ. Endoscopic laser division of an esophageal web in a child. J Pediatr Surg 1996; 31:439–40. 31. Younes Z, Johnson DA. Congenital esophageal stenosis: Clinical and endoscopic features in adults. Dig Dis 1999; 17:172–7. 32. Katzka DA, Levine MS, Ginsberg GG et al. Congenital esophageal stenosis in adults. AJG 2000; 95:32–6. 33. Pokieser P, Schima W, Schober E et al. Congenital esophageal stenosis in a 21-year-old man: clinical and radiographic ﬁndings. AJR 1998; 170:147–8. 34. Murphy SG, Yazbeck S, Russo P. Isolated congenital esophageal stenosis. J Pediatr Surg 1995; 30:1238–41.

35. Singaram C, Sweet MA, Gaumnitz EA. Peptidergic and nitrinergic denervation in congenital esophageal stenosis. Gastroenterology 1995; 109:275–81. 36. Nishina T, Tsuchida Y, Saito S. Congenital esophageal stenosis due to tracheobronchial remnants and its associated anomalies. J Pediatr Surg 1981; 16:190–3. 37. Sheridan J, Hyde I. Oesophageal stenosis distal to oesophageal atresia. Clin Radiol 1990; 42:274–6. 38. Yeung CK, Spitz L, Brereton RJ et al. Congenital esophageal stenosis due to tracheobronchial remnants: a rare but important association with esophageal atresia. J Pediatr Surg 1992; 27:852–5. 39. Neilson IR, Croitoru DP, Guttman FK et al. Distal congenital esophageal stenosis associated with esophageal atresia. J Pediatr Surg 1991; 26:478–81. 40. Newman B, Bender TM. Esophageal atresia/tracheoesophageal ﬁstula and associated congenital esophageal stenosis. Pediatr Radiol 1997; 27:530–4. 41. Morger R, Muller M, Sennhauser F et al. Congenital esophagostenosis. Eur J Pediatr Surg 1991; 1:142–4.

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36 Esophageal duplication cysts LEELA KAPILA AND HOWARD W. HOLLIDAY

Esophageal duplication cysts are intrathoracic foregut anomalies which may be classiﬁed into two types – intramural and neurenteric. The former is an intrinsic abnormality of the esophagus, whereas the latter is a separate structure closely adherent to the esophagus, lying in the posterior mediastinum and embryologically distinct.

ANATOMY Intramural cysts share a common wall with the esophagus, but communicate with the lumen in less than 10% of cases. The cysts are usually spherical, but can be tubular and vary in size from a few centimeters in diameter to complete ﬁlling of the hemithorax. Embryologically, esophageal epithelial cells proliferate in the sixth week of gestation, forming a solid core which vacuolates by the tenth week to give a lumen.1 Failure of a vacuole to the incorporated into the lumen leaves a rest of cells in the wall of the esophagus, so producing a cyst. Rarely, more than one intramural cyst may form at different levels in the esophagus.2 The cyst wall contains two layers of muscle and is lined by squamous, gastric or ciliated columnar epithelium. The presence of ciliated mucosa does not infer a bronchogenic cyst, which contains cartilage also. Neurenteric or posterior mediastinal cysts are fused with the esophagus but are not incorporated in the wall (Fig. 36.1). Embryologically, in the third week of gestation the notochord separates from the entoderm. Failure of complete separation or adhesion between ectoderm and entoderm produces a traction diverticulum of entoderm, so forming a cyst which is closely related at one point to the vertebrae and at another to the esophagus. This cyst may be associated with incomplete vertebral fusion and may have attachment to the dura or spinal cord. It never communicates with the lumen or the esophagus. Most neurenteric cysts are intrathoracic, but the length of the duplication depends on the eventual destiny of the entoderm: a cyst associated with

Figure 36.1 Mediastinal cross-section showing a neurenteric duplication cyst, closely related to the esophagus and extending through a biﬁd vertebral body, with attachment to the dura

entoderm of the upper gastrointestinal tract will extend below the diaphragm, via the paravertebral fossa, and may even open into duodenum or jejunum.

INCIDENCE Post-mortem studies give an estimated incidence for esophageal duplication cysts of 1 in 8200.3 Ten to ﬁfteen per cent of all alimentary duplications are of the esophagus and 70% of esophageal duplications present in childhood, with a male preponderance of 2 to 1.4,5 The

360 Esophageal duplication cysts

majority (60%) are of the upper esophagus and the remainder are divided equally between the mid and lower esophagus. Approximately 3% of mediastinal masses in infants are due to esophageal duplication cysts.6 It is unlikely that the pediatric surgeon in routine practice will see more than two or three cases in his working lifetime.7

PRESENTATION Esophageal duplication cysts cause symptoms by virtue of their site or because of their secretory linings and present in three situations – incidental, pressure and hemorrhage.

ASSOCIATED ABNORMALITIES The association of thoracic duplication and vertebral anomalies, ranging from spina biﬁda to vertebral fusion defects, has been well documented. In up to 80% of neurenteric cysts, there are vertebral abnormalities. The presenting symptoms in these children can be neurological. The cyst may communicate with the dura and rarely with the alimentary tract below the diaphragm. In a few cases, separate intra-abdominal duplications also had separate intestinal duplications.10 Esophageal duplication has also been reported in association with esophageal atresia.11

CLINICAL COURSE AND DIAGNOSIS

Incidental Older children in particular may have asymptomatic cysts and the lesion only comes to light on a routine chest X-ray. These cysts are usually in the mid or lower esophagus and tend to follow a benign course. They may present eventually in adult life where malignant change has been recorded.

Pressure All cysts are lined by secretory epithelium and have the potential for expansion and therefore compression. Compression by the duplication causes either respiratory or gastrointestinal symptoms. Respiratory symptoms are more common and the diagnosis should always be considered in a neonate with respiratory distress. The neonate may present with stridor, apneic episodes, dyspnea or cyanosis. These symptoms can vary with the position of the child and are due to a cyst of the upper esophagus compressing the trachea or bronchus. Gastrointestinal symptoms are less common and include a variety of complaints, including dysphagia, epigastric pain, retrosternal pain, vomiting and hematemesis. These symptoms are typical of cysts of the mid and lower esophagus, but more commonly present in older children.8

Hemorrhage Hemorrhage depends on communication of the cyst with the esophageal lumen and is therefore more likely with intramural cysts. However, both types of cyst may contain ectopic gastric mucosa9 (up to 50%) and can ulcerate to cause hemoptysis and hematemesis by direct perforation. The exact origin of this bleeding can be difﬁcult to determine in neonates. Overall, hemorrhage is an infrequent presentation, although major hemorrhage may occur and death has been recorded in this situation.

The neonate with respiratory distress due to an esophageal cyst may have one or more of the above features at presentation and demonstrate signs such as nasal ﬂaring, intercostal recession, tachypnea and cyanosis with reduced or absent breath sounds on auscultation. Signs may be limited to the upper thorax but can apply to the whole hemithorax. Differential diagnosis at this stage includes congenital lobar emphysema. Intermittent stridor may later be associated with dysphagia as compression progresses, suggesting an alimentary tract problem. For either respiratory or alimentary symptoms, a plain chest X-ray, posteroanterior and lateral, usually demonstrates the mass and draws attention to other anomalies, e.g. vertebral (Fig. 36.2a,b). For symptoms related to the esophagus, a barium swallow is useful and will help to determine the length of involved esophagus (Fig. 36.3). In patients with a vertebral anomaly, myelography is worth while, even in the absence of neurologic symptoms (Fig. 36.4). Ultrasound is a simple, non-invasive test that will determine whether a mass seen on plain X-ray is solid or cystic, but more information can be gained from computed tomography (CT) scanning. CT has the advantage over conventional diagnostic procedures because it demonstrates the cystic nature of the mass and its relationship to adjacent structures. It permits simultaneous imaging and evaluation of the spine, pulmonary parenchyma, airway and adjacent structures. CT can be combined with myelography for those lesions with suspected communication to the vertebral column. More recently, nuclear magnetic resonance imaging has been used to achieve similar data while having the advantage of being totally non-invasive.12 The differential diagnosis of esophageal cysts includes neuroblastoma, neuroﬁbroma, ganglioneuroma, schwannoma, lymphoma, ﬁbroma, hemangioma and bronchogenic cysts. Once diagnosed, an esophageal duplication cyst should be excised, even if asymptomatic, because of its potential for compression, bleeding, perforation or infection.

Preoperative management 361

(a) Figure 36.3 Barium swallow, showing marked anterior deviation of the esophagus throughout a considerable length by an extrinsic giant esophageal cyst

(b) Figure 36.2 (a,b) Chest X-ray, posteroanterior and lateral, showing a large esophageal duplication cyst with vertebral anomalies

PREOPERATIVE MANAGEMENT In infants presenting with hemorrhage or severe respiratory distress, emergency surgery may be necessary, otherwise surgery should be arranged as soon as the

Figure 36.4 Myelogram, showing cervical spine anomalies with intraspinal extension of a neurenteric cyst

neonate has been fully resuscitated. A full blood count and electrolytes and urea are measured and blood crossmatched. If the neonate has hemorrhaged, a preoperative transfusion may be necessary, and in neonates with respiratory distress blood gases will determine whether ventilatory support is required prior to surgery. In such a patient, both venous and arterial lines are inserted. No further preparation is required for intramural cysts, but where there is suspicion of a neurenteric cyst, then a two-stage procedure should be planned:

362 Esophageal duplication cysts

● if respiratory distress is the presenting complaint, then thoracic surgery is performed ﬁrst ● if the patient has neurologic symptoms, then spinal surgery is performed ﬁrst.

OPERATION All general measures for neonatal cases are observed. A nasogastric tube is inserted. The child is placed in the right or left lateral thoracotomy position with the ipsilateral arm raised over the head, palm upwards. Duplications in the upper third of the esophagus are best approached from the right side, but lower lesions may be approached through the left chest. Most surgeons use an intercostal incision placed over the level of the cyst. The author prefers the vertical Denis Browne incision (Fig. 36.5) in the mid-axillary line; subcutaneous fat and fascia are divided in the same direction using blended diathermy. Care is taken to avoid the long thoracic nerve, which can be recognized by the accompanying vein, and serratus anterior is divided anterior to this nerve. The scapula is then freed and lifted upwards and posteriorly. Depending on the site of the lesion, the chest is entered through a suitable rib space between the fourth and seventh ribs. In neonates, adequate exposure is usually possible without rib resection. The ribs are held apart with a Denis Browne ring retractor which will also hold the scapula away from the wound. The anesthetist temporarily suspends respiration as the intercostal muscles are divided with diathermy and then the pleura is opened. The lung is retracted medially and the duplication cyst is easily visualized. On the right side, the azygous vein may be ligated and divided to give better access. If the cyst is extra-esophageal, then the entire cyst with all its layers is excised by ligating and dividing the blood supply as each vessel is encountered. For a large cyst occupying the whole hemithorax, it may be necessary to puncture and deﬂate the cyst to make access to these vessels easier and safer. Care must be taken posteriorly where there may be an intraspinal connection and, when

Figure 36.5 Patient in position for right thoracotomy as seen from above, with incision in mid-axillary line

encountered, this is ligated as close as possible to the vertebrae, leaving the ﬁnal excision to the spinal operator. At no point in the dissection is it necessary to enter the esophageal wall. For an intramural cyst it is safer to excise only the mucosal lining of the cyst and leave the muscle layers to cover any defect in the esophageal wall. The cyst wall is incised longitudinally in the line of the esophagus (Fig. 36.6) and the muscle layers gently separated from the cyst lining (Fig. 36.7a). Small moist swabs on an artery forcep are used to free the cyst lining (Fig. 36.7b) and bleeding is best controlled with bipolar diathermy. Any breach of the true esophageal mucosa which occurs during this dissection must be repaired. The success of the procedure depends on the careful removal of all the cyst lining (Fig. 36.7c). The muscle of the cyst wall is then trimmed to the appropriate size of the normal esophagus and is repaired with a continuous absorbable suture (Fig. 36.8). This step may not be absolutely necessary and some surgeons leave the muscle layer open with no apparent sequelae.2 The anesthetist reinﬂates the lung and the chest wall is repaired in layers with a chest drain to an underwater seal. Postoperatively the patient should be extubated as soon as condition allows; infants with respiratory distress will require ventilation until their blood gases are satisfactory. Initially the child is nursed with the operating side lowermost, and in the upright position as soon as possible thereafter. Lung expansion is checked by postoperative chest X-ray on the patient’s return to the ward and the chest drain may be removed the next day if there is little or no drainage. Provided that the esophageal mucosa was not breached the nasogastric tube is also removed and oral ﬂuids commenced. The child may progress rapidly to oral feeding and full recovery may be expected within the week.

Figure 36.6 Diagrammatic appearance of a typical intramural cyst of the esophagus, with a longitudinal incision extending over its length

References 363

Figure 36.8 Esophageal wall reconstituted using a continuous absorbable suture

THORACOSCOPIC TREATMENT OF ESOPHAGEAL CYSTS Recently the development of thoracoscopic surgery has made this approach feasible in the treatment of esophageal cysts in children.13,14 Thoracoscopy would seem to have several potential advantages over open techniques in terms of the attendant postoperative pain and pulmonary complications. Compressive cysts with lung compression and mediastinal shift still remain a contraindication for this type of surgery.

REFERENCES

Figure 36.7 (a–c) The muscle wall is held open with stay sutures and the cyst lining is gently separated from the normal esophageal tissue with a moist swab, leaving the esophageal mucosa intact (see text for details)

1. Scherer LR, Grosfeld JL. Congenital oesophageal stenosis, oesophageal duplication, neurenteric cyst and oesophageal diverticulum. In: Holder TD, Ashcraft KW, editors. Paediatric Oesophageal Surgery. New York: Grune and Stratton, 1986: 53–71. 2. Robinson RL, Pavlina PM, Scherer LR et al. Multiple oesophageal duplication cysts. J Thorac Cardiovasc Surg 1987; 94:144–53. 3. Arbona JL, Figueroa Fazi JG, Mayoral J. Congenital oesophageal cysts: case report and review of literature. Am J Gastroenterol 1984; 97:177–82. 4. Whitaker JA, Deffenbaugh LD, Cooke AR. Oesophageal duplication cyst. Am J Gastroenterol 1980; 73:320–2. 5. Bower RJ, Kieswebber WB. Mediastinal masses in infants and children. Arch Surg 1977; 112:1003–9. 6. Pokorny WJ, Sherman JO. Mediastinal masses in infants and children. J Thorac Cardiovasc Surg 1974; 68:869–75. 7. Mekki M, Belghith M, Krichene M et al. Esophageal duplication in children. Report of 7 cases. Arch Pediatr 2001; 8:55–61.

364 Esophageal duplication cysts 8. Sab JA, Ala-Kulija KV. Congenital oesophageal cysts in adults. Ann Thorac Surg 1987; 44:135–8. 9. Ferguson CC, Young LN, Sutherland JR et al. Intrathoracic gastrogenic cyst – pre-operative diagnosis by technetium pertechnetate scan. J Pediatr Surg 1973; 8:827–8. 10. Holcomb GW, Gheissari A, O’Neill J. Surgical management of alimentary tract duplication. Ann Surg 1989; 209:167–74. 11. Helund GL, Bisset GS. Esophageal duplication cyst and aberrant right subclavian artery mimicking a

symptomatic vascular ring. Pediatr Radiol 1989; 19:543–4. 12. Fabris S, Cavazzana A, Gamba P. Vater syndrome and esophageal foregut duplication. A new association. Pediatr Surg Int 1995; 10:252–4. 13. Michel JL, Revillon Y, Montupet P et al. Thoracoscopic treatment of mediastinal cysts in children. J Pediatr Surg 1998; 33:1745–8. 14. Urschel JD, Horan TA. Mediastinoscopic treatment of mediastinal cysts. Ann Thorac Surg 1994; 58:1698–1700.

37 Esophageal perforation in the newborn HIRIKATI S NAGARAJ

INTRODUCTION Accidental perforation of the esophagus and the hypopharynx occurs rarely in newborn infants despite numerous instrumentation, including intubation of the esophagus, pharynx and airway. Iatrogenic perforation of the esophagus in neonates was ﬁrst reported in the literature in 1969 by Eklof and colleagues.1 In the past decade, perforation of the esophagus in premature infants has been increasingly recognized and reported. Spontaneous perforation of the esophagus in neonates (neonatal Boerhaave’s syndrome) is extremely rare, and Fryfogle reported the ﬁrst successful repair.2 Esophageal perforation may be fatal without early diagnosis, and delayed treatment causes an increase in morbidity and mortality.3,4

CLASSIFICATION AND ETIOLOGY Esophageal perforation in newborns can be classiﬁed as iatrogenic or non-iatrogenic. Non-iatrogenic perforations are extremely rare, and are usually seen in full-term infants when they do occur. The most common site of perforation is the lower end of the esophagus. Etiological hypotheses for spontaneous perforation vary and include increased abdominal pressure at delivery, perinatal hypoxemia, peptic esophagitis and gastro-esophageal reﬂux.5–8 Iatrogenic perforation of the esophagus is more commonly seen in premature, small for gestational age (SGA) infants9 and usually occurs in the cervical esophagus. Pharyngeal suctioning with a stiff catheter, endotracheal intubation, traumatic laryngoscopy and digital manipulation of the infant’s head during breech delivery have all been described as etiological factors.10 Esophageal dilatation, intraoperative technical error and postoperative anastomotic leak are potential iatrogenic surgical causes.11,12 During instrumentation, when the neck is hyperextended, traumatic perforation of the proximal

esophagus may occur at the level of the cricopharyngeus muscle, where the posterior esophageal wall is compressed by the body of the sixth or seventh cervical vertebra. Submucosal injury by a laryngoscope blade or endotracheal tube may be the initial injury to the hypopharynx, resulting in cricopharyngeal spasm.13 Endotracheal intubation, particularly in small premature infants, may further compromise the esophageal introitus. Oropharyngeal suctioning or insertion of the nasogastric tube can extend the submucous injury into a full-thickness perforation. Perforation of the middle esophagus is usually associated with dilatation of a stricture or a postoperative anastomotic leak after an esophageal atresia repair.14,15 An improperly placed postoperative chest tube may inadvertently penetrate a fresh esophageal anastomosis or an upper pouch myotomy site.16 Direct pressure necrosis of a normal esophagus in a premature infant has been associated with esophageal perforation.17 Perforation of the distal esophagus may be associated with dilatation of a stricture secondary to esophagitis, technical error during anti-reﬂux procedure or a misplaced gastrostomy Foley balloon.18

CLINICAL MANIFESTATIONS The newborn with an iatrogenic cervical esophageal perforation demonstrates excessive salivation and mucous secretion due to difﬁculty swallowing; the examiner will ﬁnd it difﬁcult to pass a nasogastric tube and respiratory distress may be apparent. An abnormal position of the nasogastric tube by X-ray of the chest may be the ﬁrst indication of esophageal perforation.9 In premature infants, blood-tinged oral secretions after tracheal intubation warrant frequent and careful X-ray examinations of the chest. The proper diagnosis often will be missed in the absence of such an examination. The symptoms of perforation may not be recognized until the child develops esophageal obstruction, which may be mistaken for esophageal atresia.12,19

366 Esophageal perforation in the newborn

Esophageal perforation can be differentiated from esophageal atresia if there is a history of repeated attempts at intubation, vigorous suctioning, absence of polyhydramnios in the perinatal history, and the position and course of the nasogastric tube. Some perforations of the esophagus into the pleural cavity may create acute respiratory distress secondary to right pneumothorax or hydrothorax. Thoracocentesis or placement of a tube thoracostomy may yield serosanguineous, bloody ﬂuid, or contents of the previous feeding. Anteroposterior and lateral X-rays of the chest and neck should be obtained and studied in all suspected cases of perforation. An unusual course of the nasogastric tube (63% will be in the pleural cavity, pericardial cavity (Fig. 37.1) or right side of the mediastinum or retroperitoneum) may be the ﬁrst indication of this diagnosis. More subtle changes such as widening of the mediastinum and blurring of the mediastinal margin may indicate a mediastinitis secondary to a perforation, but they sometimes are not as evident. These latter clues should prompt careful esophagography. Mollit et al.20 described three types of injuries that are seen in premature infants: (1) a pharyngeal diverticulum created in a local cervical leak; (2) mucosal perforation extending posterior and parallel to the esophagus, and (3) free intrapleural perforation where there is obvious leakage of air and esophageal contents into the pleural cavity. If the sudden onset of respiratory distress leads to a chest X-ray that shows the presence of a nasogastric tube in the pleural cavity, the diagnosis of perforation of the

Figure 37.1 Chest X-ray shows displacement of the nasogastric tube to the pericardial sac

esophagus can be conﬁrmed (Fig. 37.2). In this situation, precise localization of the site of perforation by esophagography may not be necessary unless the patient’s clinical condition deteriorates after removal of the nasogastric tube and treatment of pneumothorax by tube thoracostomy drainage. If the symptoms suggest esophageal obstruction, esophagography should be performed by injecting a small quantity of diatrizoate meglumine (Hypaque), diatrizoate sodium (Renograﬁn) or metrizamide, but Gastrograﬁn and barium should be avoided.21 Cricopharyngeal spasm may be so severe in cases of pharyngo-esophageal perforation that no contrast will enter the native esophagus. In this case, several clues should be looked for to differentiate submucous perforation, pseudodiverticular formation and congenital esophageal atresia. The following three features have been suggested:17 • The distance between the tracheal and opaciﬁed tract of a perforation is greater than that of the pouch in a congenital esophageal atresia, which is usually closely associated with the trachea • The opaciﬁed tract in perforation is elongated and more irregular than in esophageal atresia, and • The trachea is slightly compressed on the lateral X-ray ﬁlm by the upper pouch in esophageal atresia, but this is not so in esophageal perforation. Esophagoscopy is usually not indicated in the diagnosis of esophageal perforation and may, in fact, enlarge the perforation. Neonatal spontaneous perforation of the esophagus usually presents with respiratory distress that may be immediate or delayed for several hours after perforation. There is a greater predilection to right-sided pneumothorax in neonatal Boerhaave’s syndrome13 instead of the left pneumothorax found in adults. This may be explained by the close adherence of the aorta to the left side of the esophagus in a small infant, providing additional support to the left side. If the perforation

Figure 37.2 Anteroposterior view demonstrates coiled nasogastric tube in the right pleural cavity and chest tube placed for tension pneumothorax

Management 367

remains undiagnosed, respiratory distress will worsen with subsequent feedings. Esophagography must be promptly performed in all suspected free perforations to evaluate the extent of damage and to localize it.

MANAGEMENT The management of esophageal perforation in newborns has undergone signiﬁcant change in recent years.22 Esophageal perforation can be a rapidly fatal condition that requires immediate recognition and aggressive management for a successful outcome. The concept of treatment of esophageal perforation must be individualized according to the site, size, systemic response of the neonate, and interval between injury and initiation of treatment. Small submucosal perforations of the hypopharynx and the esophagus, limited to the mediastinum with no systemic symptoms, can be managed by nonoperative methods (Figs 37.3a,b). Actual localization of

(a)

the perforation is not essential in these infants. If the nasogastric tube is noted in the mediastinum or pericardial cavity, the tube can be withdrawn and a new tube can be placed by an experienced radiologist under ﬂuoroscopic control. A broad-spectrum antibiotic must be given for 7–14 days. I.v. ﬂuids and hyperalimentation should be started, since oral feedings must be withheld. Esophagography should be performed 7–10 days after the injury. If the perforation is completely healed, oral feeding may be started, but if the perforation has not healed, conservative treatment for another week will usually allow complete healing. Routine surgical intervention does not appear to improve the rate of survival in these critically ill newborns. Tube thoracostomy must be placed where the chest X-ray indicated pneumomediastinum, pneumothorax or hydrothorax. If purulent drainage or esophageal material continues to drain into the chest tube, further closed chest tube drainage may be pursued (Fig. 37.4). All newborn infants with esophageal perforation must be carefully monitored during treatment, including white blood cell counts, blood gases, platelet counts and chest X-rays. If there is clinical deterioration or respiratory compromise, and closed chest tube drainage does not handle the leak, direct repair of the perforation is indicated. In cases where direct repair of the lesion is not technically feasible because of scarring, inﬂammation and friability of the tissue, cervical esophagostomy, and ligation of the perforated area with concomitant gastrostomy, is indicated. All efforts should be made to avoid future esophageal replacement. Long, linear perforations to the lower end of the esophagus require an immediate thoracotomy, débridement of necrotic edges and primary repair with a ﬂap of normal pleura to cover the defect. A concomitant gastrostomy will minimize the risk of gastric reﬂux postoperatively. If there is a delay of more than 24 hours in the diagnosis of a spontaneous perforation, primary repair cannot be accomplished. After adequate débridement,

(b) Figure 37.3 (a) Anteroposterior view shows the nasogastric tube in the mediastinum. Note the absence of pneumothorax. (b) The presence of the long sinus tract parallel to the esophagus without free spillage of contrast media indicates submucosal perforation

Figure 37.4 Free spillage of contrast material into right pleural cavity indicates a free perforation in this infant. Clinical deterioration warranted direct repair

368 Esophageal perforation in the newborn

the treatment should be local esophagectomy with closure of proximal and distal esophagus, proximal cervical esophagostomy, and a gastrostomy. Critically ill newborns should be treated by chest tube drainage, cervical oesophagostomy (with or without ligation of the cardio-esophageal junction) and gastrostomy.23 Broad-spectrum antibiotic therapy, i.v. ﬂuids and hyperalimentation should be continued until clinical signs of sepsis improve. Gastrostomy feedings may be attempted after 48 hours. Where there is extensive debridement or esophageal substitution is indicated after an interval of at least 6 months and resolution of the mediastinal inﬂammatory reaction.

CONCLUSION Iatrogenic perforation of the esophagus is more common than reported in the literature and may be fatal without early diagnosis. The incidence of recognized pharyngeal or esophageal perforation, however, is low considering the large number of suctions and intubations performed in intensive care units.20 Gentle laryngoscopy, proper visualization of the vocal cords during intubation, careful avoidance of protruding stylets, careful suctioning of the pharynx and avoidance of forceful placement of nasogastric tubes are essential factors in the prevention of this injury. It is generally accepted that most iatrogenic perforations of the esophagus occurring in newborns are cervical and made when inexperienced people try to intubate the trachea. With early diagnosis, most of these perforations can be managed non-operatively with successful outcomes.24 However, small infants should be monitored closely. If they appear to be ill, appropriate operative intervention may be required. Early recognition of an esophageal perforation gives many more treatment options which may include non-operative therapy, drainage, or primary repair. Delayed diagnosis may result in the loss of the esophagus necessitating esophageal replacement. The mortality rate in children with esophageal perforation (4%) is signiﬁcantly less than that for adults (25–50%).25 Surgical consultation is warranted in all esophageal perforations for selective management.

REFERENCES 1. Eklof O, Lohr G, Okmian L. Submucosal perforation of the esophagus in the neonate. Acta Radiol 1969; 8:1987. 2. Fryfogle JD. Discussion of the paper by Anderson RL. Rupture of the esophagus. J Thorac Cardiovasc Surg 1952; 24:369–88. 3. Michael L, Grillo HC, Malt RA. Operative and nonoperative management of esophageal perforations. Ann Surg 1981; 194:57. 4. Van der Zee DC, Slooff MJH, Kingma LM. Management of

5. 6.

7.

8. 9.

10. 11. 12. 13.

14. 15. 16.

17.

18. 19.

20.

21.

22.

23.

24.

25.

esophageal perforations: a tailored approach. Neth J Surg 1966; 38:31. Aaronson IA, Cywess S, Louw JH. Spontaneous esophageal rupture in the newborn. J Pediatr Surg 1975; 10:459. Johnson JF, Wright DR. Chest tube perforation of esophagus following repair of esophageal atresia. J Pediatr Surg 1990; 25:1227. Cairns PA, McClure BG, Halliday HL et al. Unusual site for oesophageal perforation in an extremely low birth weight infant. Eur J Pediatr 1999; 158:152–3. Kenigsberg K, Levenbrown J. Esophageal perforation secondary to gastrostomy. J Pediatr Surg 1986; 21:946. Ducharme JC, Bertrano R, Debie J. Perforation of the pharynx in the newborn: a condition mimicking esophageal atresia. Med Assoc J 1971; 104:785. Astley R, Roberts KD. Intubation perforation of the esophagus in the newborn baby. Br J Radiol 1970; 43:219. Lee SB, Kuhn JP. Esophageal perforation in the neonate. Am J Dis Child 1976; 130:325. Wychulis AR, Fontana RS, Payne WS. Instrumental perforation of the esophagus. Chest 1969; 55:184. Girdany BR, Sieber W, Osman MZ. Pseudodiverticulum of the pharynx in the newborn infants. N Engl J Med 1969; 280:237. Sloan EI, Haight C. Congenital atresia of the esophagus in brothers. J Thorac Surg 1956; 32:200. Eraklis AJ, Gross RE. Esophageal atresia, management following an anastomotic leak. Surgery 1966; 60:919. Johnson JF, Wright DR. Chest tube perforation of esophagus following repair of esophageal atresia. J Pediatr Surg 1990; 25:1227. Cairns PA, McClure BG, Halliday HL et al. Unusual site for oesophageal perforation in an extremely low birth weight infant. Eur J Pediatr 1999; 158:152–3. Kenigsberg K, Levenbrown J. Esophageal perforation secondary to gastrostomy. J Pediatr Surg 1986; 21:946. Ducharme JC, Bertrano R, Debie J. Perforation of the pharynx in the newborn: a condition mimicking esophageal atresia. Med Assoc J 1971; 104:785. Mollit DC, Schullinger JW, Santulli T. Selective management of iatrogenic esophageal perforation in the newborn. J Pediatr Surg 1981; 16:989. Blair GK, Filler RM, Theodorescu D. Neonatal pharyngoesophageal perforation mimicking esophageal atresia: clues to diagnosis. J Pediatr Surg 1987; 22:770. Johnson DE, Foker J, Munson DP et al. Management of esophageal and pharyngeal perforation in the newborn. Pediatrics 1982; 70:592–9. Urschel HC Jr, Razzuk MA, Wood RE et al. Improved management of esophageal perforations: exclusion and diversion of continuity. Ann Surg 1974; 179:587. Krasna IH, Rosenﬁeld D, Benjamin BG et al. Esophageal perforation in the neonate: an emergency problem in the newborn nursery. J Pediatr Surg 1987; 227:784. Engum SA, Grosfeld JL, West KW et al. Improved survival of children with esophageal perforation. Arch Surg 1996; 131:604–11.

38 Gastro-esophageal reﬂux VICTOR E. BOSTON

INTRODUCTION Gastro-esophageal reﬂux (GER) is recognized to occur in the majority, if not all neonates. In most of these children, GER will disappear spontaneously and will cause no signiﬁcant clinical problems. A minority however, will run a less benign course and will develop serious pathological complications of their reﬂux, which will require treatment.1–3 Diagnostically, there are difﬁculties in identifying those children who are most at risk.2–5 On the one hand, this is often caused by a lack of speciﬁcity and sensitivity of the tests which are employed; on the other, it may be difﬁcult to be sure that GER is the cause of the clinical complex from which the child is suffering. Treatment may therefore be inappropriate either because pathological reﬂux has been missed or because the child’s problems are unrelated to GER.

FACTORS WHICH INFLUENCE OCCURRENCE OF GER In the past, the gastro-esophageal junction (GEJ) was simply regarded as a valve. However, it is now realized that a complex dynamic relationship exists between several factors acting at the GEJ to prevent or permit GER. In this respect, the pinchcock action of the diaphragm at the hiatus, the cardio-esophageal angle and local thickening of the esophageal mucosa at the GEJ, probably play a minor role. These have not to date been objectively assessed and will not be discussed further. Generally speaking, the risk of reﬂux is inﬂuenced by factors which control the pressure gradient which exists between the lumen of the stomach and the intrathoracic esophagus. A relative increase in intragastric pressure and/or a decrease in the lumenal pressure of the intrathoracic esophagus, will increase this gradient, while a segment of intra-abdominal esophagus if present will reduce it (vide infra). The single most important

factor in preventing reﬂux however, is the physiological lower esophageal sphincter (LES).

Lower esophageal sphincter A high-pressure zone can be identiﬁed at the lower end of the esophagus whether or not the GEJ is above or below the diaphragm. Therefore, while an anatomical sphincter does not exist, there does appear to be tonic contraction of the circular esophageal muscle which behaves like a sphincter and which can be identiﬁed manometrically.6–9 Basal tone is known to vary with post-conceptual age,10 being lower in premature infants than in those at full term or in older children.9 This may be a reﬂection of the bulk of the smooth muscle at the LES, which is known to vary with age.11 These observations may help to explain the frequency of GER in neonates, particularly in those who are premature.9,12–16 In addition, the LES is under the control of the endocrine, paracrine and neurocrine systems. Basal tone is constantly being modulated by humoral factors released from the endocrine and paracrine systems. Gastrin for example, will induce a prolonged increase in LES activity.4,5 On the other hand, ﬁne adjustments appear to be superimposed upon this background activity and are controlled by locally and centrally mediated neural reﬂex arcs through the enteric nervous or neurocrine system. Swallowing is one of the most common of these reﬂexes, with relaxation of the LES following a distally propagated stripping wave of contraction in the esophagus.4 Transient GER is usually observed to coincide with this event. Less frequently, spontaneous relaxation of the LES (SRLES) is observed, which is not preceded by deglutition.4,8,17 This is also associated with GER. Of the two types of relaxation of the LES, this is probably the most important, because it is often associated with a more protracted and pathological form of reﬂux.4 In many situations the cause of SRLES is not apparent. However, it has been noted in patients who have proven esophagitis7,18,19 and experimentally when

370 Gastro-esophageal reﬂux

acid is instilled into the lower esophagus.5 Thus, the GER which causes esophagitis tends to be self-perpetuating.5,7 Knowledge of these control mechanisms will facilitate pharmacological manipulation of the LES and gastric emptying. It is in this important area that most progress is likely to be made in the control of GER (vide infra).

Intra-abdominal esophagus In normal circumstances the GEJ lies below the diaphragm. This anatomical relationship is thought to be maintained by the attachment of the phreno-esophageal ligament from the lower end of the esophagus to the diaphragm at the hiatus.20 The lumen of this segment of the esophagus is thus exposed to the same variations in intra-abdominal pressure as the stomach and hence the gradient between the latter and the former is minimized.2,6,20 This effectively reduces the risk of GER. On the other hand, if the intra-abdominal esophagus is short or if the GEJ lies above the diaphragm, exposing the lower esophagus to the relatively negative mean intrathoracic pressure, the gradient between the stomach and the esophagus is signiﬁcantly increased and GER is more likely to occur.21 Hiatus hernia1,4 and conditions where shortening of the esophagus is present such as tracheoesophageal ﬁstula and esophageal atresia following repair,22,23 are more likely to be associated with GER than if the GEJ were situated below the diaphragm. The length of the intra-abdominal esophagus is related to post-conceptual age, being shorter in preterm than full-term infants.11 Some years will be necessary for this to increase beyond a few millimeters. In addition, the GEJ is mobile relative to the hiatus and as a consequence, the effective length of the intra-abdominal esophagus will be reduced to a greater extent in small preterm infants than older children. The risk of developing signiﬁcant GER in small babies, will therefore be greater than in more mature neonates.

EFFECT OF INCREASED PRESSURE GRADIENT ACROSS THE GEJ It is well documented that even in the presence of otherwise normal anatomy and tone in the LES at the GEJ, GER can still occur.6 These circumstances are often associated with increased gradients across the GEJ. This can result from either excessive negative pressure being generated above the diaphragm in the lumen of the esophagus, or by an increase over and above normal in intragastric pressure. Respiratory efforts associated with idiopathic respiratory distress syndrome (IRDS) or bronchopulmonary dysplasia (BPD), will cause excessive negative intrathoracic pressure during the respiratory cycle.13,15,24, 25

Conversely, such problems as primary gastric dysmotility,4,6,26–28 hypertrophic pyloric stenosis29 or intestinal malrotation30 can raise intragastric pressure. These conditions are recognized to be associated with an increased risk of GER. In addition, food intolerences such as cows milk protein allergy or certain medications can cause a secondary generalized intestinal dysfunction which can delay gastric emptying and predispose to GER.31,32

COMPLICATIONS OF NEONATAL GER The types of pathological problem caused by GER in neonates are similar to those which occur in older children. However, their relative frequency is different. Aspiration of gastric contents into the tracheo-bronchial tree is more common than failure to thrive (FTT) due to protein–calorie deﬁciency or reﬂux esophagitis.33

Aspiration into tracheo-bronchial tree ASPIRATION PNEUMONITIS Generally, a large volume of aspirate ﬂooding the lungs will be more serious than minor contamination of the larynx. The extent to which this occurs will depend ﬁrstly upon the volume which is reﬂuxing from the stomach into the pharynx,12,15,34,35 and secondly, upon the ability of the child to clear the pharynx and upper esophagus of this reﬂuxed material.36 In the ﬁrst instance, aspiration leads to atelectasis and this is rapidly followed by bacterial colonization and pneumonitis. The gag reﬂex and coordination of swallowing are recognized to be poorly developed in small preterm infants.36–38 In addition, these babies may at the same time have IRDS. If this problem is superimposed upon aspiration pneumonitis, then there will be a signiﬁcant increase in morbidity.

APNEIC ATTACKS These have been demonstrated to occur in babies who have had simultaneous polygraphic monitoring of vital functions and esophageal pH. Most often, episodes of GER appear to coincide with apnea associated with an obstructed airway and this is usually followed by hypoxemia and bradycardia.6,34,39,40 It is thought that aspiration of gastric contents into the lungs has caused reﬂex laryngo-bronchospasm. However, less frequently, apnea has also been shown to occur even in the absence of aspiration,39,41,42 either on the basis of reﬂex inhibition of respiration caused by exposure of the esophagus to low pH or abnormal function of the respiratory center. In preterm infants in particular, apneic attacks may not be related to clinically recognized reﬂux episodes.41–43

Diagnosis of neonatal GER 371

STRIDOR Occasionally laryngo-bronchospasm secondary to reﬂux, may present with stridor instead of apneic attacks.44-48 This must be distinguished from tracheomalacia, which can cause the same symptom.49 In tracheo-esophageal ﬁstula and esophageal atresia for example, there is frequently associated tracheomalacia and GER. The relative contribution of both of these as the cause of stridor, must be assessed, in order to plan rational therapy for the child.

SUDDEN INFANT DEATH SYNDROME There is no doubt that GER can sometimes be shown to be associated with near-death episodes of apnea, cyanosis and bradycardia.50–53 There is some evidence that treating GER in known risk groups will reduce the incidence of sudden infant death syndrome (SIDS).54 On the other hand, there is no direct evidence that children who have died from SIDS, have died from aspiration of gastric contents.55 While the etiology of SIDS remains speculative, it is possible that GER may be a cause in at least some cases. As a consequence, surgical treatment is justiﬁable in those cases where aspiration associated with GER has already been documented.25,56

BRONCHO-PULMONARY DYSPLASIA Some studies report a high incidence of reﬂux-related respiratory symptoms in premature infants and in infants with broncho-pulmonary dysplasia (BPD).15,25 Chronic aspiration pneumonitis will lead to progressive scarring of the lungs.15,57 However, the clinical and radiographic picture in these children may be indistinguishable from pulmonary disease often encountered in the same preterm infant population, who because of IRDS, require chronic ventilatory support. GER may be identiﬁable in these cases but may not necessarily account for the lung disease.12 Treatment of GER will be necessary when either there is positive proof that the respiratory disease is caused by GER, e.g. when lipidladen alveolar macrophages are identiﬁed in tracheal lavage ﬂuid,25 or where there is a reasonable suspicion that GER is the cause of the problem. Otherwise these babies will often fall into a cycle of events which are selfperpetuating. Pulmonary disease will predispose to GER13,15 and this will cause further lung disease,12,58 which will lead to GER and so on.

Failure to thrive (FTT) The association between FTT and GER is well recognized.1,2,5,33,55,59 It occurs when the volume of retained feed after vomiting is insufﬁcient for the baby to grow normally. This of course assumes that the volume and the type of feed given to the baby is satisfactory and that the child is otherwise well. Not infrequently, because of

the complexity of the clinical problems in the preterm neonate, there is difﬁculty in deciding whether GER is the sole cause of the FTT.60,61

Reﬂux esophagitis In most cases, it is well documented that this complication is associated with prolonged periods of low pH in the esophagus.2,4 It is not the number of reﬂux episodes which appear to be important, but the duration for which the pH is low. During esophageal pH monitoring, if the pH is < 4 for more than 5% of the study period, the risk of esophagitis being present is recognized to be high. This level of pH leads to activation of the gastric protease pepsin, which will have reﬂuxed with the acid, into the esophagus. Thus, autodigestion of the esophageal squamous epithelium may occur.4,6 Excessive exposure of the esophagus to activated pepsin can result from either increased acid and pepsin production, or, poor clearance of the reﬂuxate. On the one hand, delayed gastric emptying, as in hypertrophic pyloric stenosis,32 will cause an increase in serum Gastrin, which will lead to increased gastric acid and pepsin production. This condition is often associated with esophagitis.62 On the other hand, esophageal dysmotility 4,19,38,60,63,64 will delay the return of reﬂuxed material to the stomach. It is worth noting that, poorly coordinated esophageal motility is common in preterm infants 36,37 compared to other children and thus esophagitis might be expected to be relatively common in this group of patients who also have GER. Once established, esophagitis will tend to be selfperpetuating because it causes further disruption of coordinated esophageal motility as well as increasing the frequency of episodes of SRLES.19 Stricture formation rarely occurs in neonates following inadequately treated esophagitis. However, this complication can occur in babies treated for esophageal atresia, where esophagitis can cause narrowing at the site of the anastamosis.65

DIAGNOSIS OF NEONATAL GER Clinical signs and symptoms Signiﬁcant non-bile stained vomiting, particularly when it occurs after feeding and dating from birth, is suggestive of, but not speciﬁc for GER.1 As a consequence, it is important to distinguish vomiting due to GER from other causes, for example, hypertrophic pyloric stenosis, urinary tract infection, meningitis or raised intracranial pressure.66 It is unusual not to ﬁnd a history of vomiting.2 Hematemesis when it occurs, is relatively sensitive and speciﬁc for GER associated with esophagitis. However, not all neonates with esophagitis will have hematemesis

372 Gastro-esophageal reﬂux

and some will have a rather nonspeciﬁc history of ‘bringing up mouthfuls’ or ‘poor feeding’, a symptom analagous to dysphagia in older children.33 Cyanotic attacks or apnea whether or not accompanied by vomiting, may point to GER as the cause, but without simultaneous polygraphic recording of vital functions and esophageal pH, these events cannot be related to it with certainty.16,50,51,67,68 Recurrent pneumonitis69,70 and stridor48,50 present similar difﬁculties with diagnosis in as much that even with documented evidence of aspiration using radiographic or radioisotopic techniques, it is often difﬁcult to be certain that GER with aspiration is the sole cause of the problem.5,71 While most complications will be associated with a history which points to GER as the cause, rarely this is not so and delays in diagnosis and appropriate treatment will be inevitable.

INVESTIGATIONS The majority of neonates have GER and this is usually symptomatic. Most will resolve spontaneously without complication. Therefore, during the neonatal period, it is only necessary to investigate those children who have potentially serious or life-threatening complications of the condition. No single test will diagnose GER and its complications, and it is important to employ as many investigations as are available in order to reduce the risk of errors (vide infra).

Figure 38.1 Marked esophageal reﬂux in a 3-week-old infant

RADIOGRAPHY Contrast studies are important in determining the presence of structural abnormalities such as a hiatus hernia, gastric outlet obstruction or malrotation29 as well as identifying GER (Figs 38.1 & 38.2). Real-time observation of coordination of swallowing and gastric emptying will give an indication of esophageal and gastric dysmotility, although radioscintigraphy72 or electrical impedance studies73,74 may be the better methods for detecting these important problems. Aspiration into the lungs can sometimes be identiﬁed but radioscintigraphy is more sensitive in this respect.5,71 However, signiﬁcant GER may be missed, or conversely, it may be induced during the examination by excessive use of abdominal pressure, when in physiological circumstances, it is absent.5,71 Esophagitis is usually not detected,5 because secondary stenosis rarely occurs in neonates except when associated with an anastomotic stricture following repair of tracheoesophageal ﬁstula and esophageal atresia.65 Radiographic screening of the upper GI tract is highly subjective and requires an experienced operator to obtain satisfactory results.5 While the speciﬁcity and sensitivity for GER of a contrast study is not as good as with other investigations, it is still an important part of the work up of any patient suspected of having this condition or its complications.5

Figure 38.2 Coarse gastric mucosal folds extending across the diaphragm in continuity, giving characteristic appearance of hiatus hernia

ENDOSCOPY Modern ﬂexible ﬁberoptic endoscopes make it possible to safely examine all but the smallest of neonates. Esophagitis can be directly observed although a minority will appear normal when a biopsy shows signs of inﬂam-

Management of neonatal GER 373

mation35,75 Biopsy is therefore indicated in all cases. Some limited information can usually be obtained about the LES: it’s tone and position, and whether a hiatus hernia is present. This is the only reliable method of detecting esophagitis.

ESOPHAGEAL PH MONITORING Miniaturization of pH electrodes has permitted prolonged esophageal pH monitoring in even the smallest baby.76 Computerized data collection and analysis is now commonplace and this has aided prolonged study periods, which were not previously possible.77 Extensive investigation of affected and otherwise normal infants has facilitated normal and abnormal ranges for esophageal pH to be generated.78 The parameters measured include the number of reﬂux episodes of a speciﬁc pH or less, their duration and the total time for which this occurred as a percentage of the study period.77 The latter appears to be the most important of these as this not only reﬂects the frequency of reﬂux but also the esophageal clearance of reﬂuxed acid. Results however will be dependent upon gastric contents. If a child has had a recent milk feed then gastric acid will be buffered. The pH will by necessity be higher than if the child had been fed on fruit juice. This problem can to some extent be overcome using electrical impedence measurement in the lumin of the esophagus, which is a new and experimental measure of GER and is independent of pH.73 In addition, it should also be recognized that different types of feed will have an effect on gastric emptying and this will indirectly affect the predisposition to GER.79 In the past it has been assumed that pH monitoring has been reproducible and reliable.77,78,80 However, signiﬁcant day-to-day variation can occur between tests.81 This does not invalidate pH monitoring but suggests that results should be interpreted with caution and if necessary the investigation should be repeated. There appears to be considerable variation in the frequency of reﬂux episodes while the baby is awake as compared to when sleeping. Reﬂux episodes are unusual when the child is asleep and this type of GER is usually pathologically associated with recurrent pneumonia, stridor, sleep apnea, acute life-threatening events and possibly SIDS.54,57,67,68,81,82 For this reason it is important that the study period extends over at least 16 hours. In general, GER is likely to be pathological when the esophageal pH is < 4 for more than 5% of the study period (bearing in mind minor age-related differences).78 While this investigation will not be diagnostic of the complications of GER, it does offer a simple objective test which can be used to monitor the effectiveness of anti-reﬂux therapy in preventing or controlling GER within acceptable limits. This is now usually regarded as the ‘gold standard’ in the diagnosis of reﬂux.77

Other investigations MANOMETRY Using either perfusion catheters or strain gauges passed into the esophagus, it is possible to measure intraluminal pressure. This technique has been used to measure the basal tone7,8 and pressure changes in the LES7 and it’s position relative to the diaphragm.9 The pressure gradient between the stomach and the esophagus can also be easily determined.9 By employing simultaneous recording of pressure at several points, it is possible to plot the progression of a wave of contraction down the esophagus and the response of the LES to it.4 Esophageal dysmotility,36 reduced basal tone in the LES and SRLES8 are now recognized to be important in GER4,8 and the type of treatment employed. Some of this information can be obtained in part from other sources but not with the same accuracy.

RADIOSCINTIGRAPHY Gastro-esophageal scintiscanning using Technetium (100 mTc) sulphur colloid has been shown to be at least as sensitive or better than radiography or pH monitoring in detecting GER providing this is continued for several hours.66,75–77,83 It has the added advantage of facilitating the quantiﬁcation of esophageal and gastric emptying2,66,72 while employing different types of test feed mixed with the isotope.76 Gastric electrical impedence studies provide similar advantages in measuring gastric emptying but without the radiation risk.74 Pulmonary aspiration can be directly observed when this may be missed using other techniques.2,66 The main disadvantages for most units are ﬁrstly, that the availability of scintillation scan time is often limited and secondly, that immobilization of the child is necessary for prolonged periods to yield meaningful results. If radioscintigraphy is not available, aspiration can be implied by detection either of lipid-laden macrophages in tracheal lavage25,56 or impairment of respiratory epithelial ciliary activity.84

MANAGEMENT OF NEONATAL GER GER has a tendency to undergo spontaneous improvement and resolution with increasing age.1,3 This has in the past encouraged clinicians to treat these children conservatively, in anticipation of a cure without recourse to surgery. At the same time, this approach may place these babies at unnecessary risk. Fortunately, it is now possible to predict the outcome of GER with greater certainty, so that the patient can be targeted more precisely for the most appropriate therapy. In general, where GER is not life threatening, conservative management with posturing, thickening of

374 Gastro-esophageal reﬂux

feeds and antacids or acid suppression, should be considered ﬁrst.1,3 This may be supplemented with one of the prokinetic agents designed to improve esophageal and gastric emptying. Of course if GER is secondary to a structural problem such as hypertrophic pyloric stenosis or malrotation, then this should receive speciﬁc attention. Reﬂux associated with a hiatus hernia is less likely to resolve spontaneously than if the GEJ is normal. However, a signiﬁcant proportion of these children will get better without surgery and conservative management is initially justiﬁable in most cases.1 The only accepted indication for immediate surgical intervention in the neonatal period, is where there is a history of aspiration associated with GER, causing either apneic attacks, stridor or recurrent pneumonitis, and where there is clearly an ongoing risk of SIDS.43,48,51,54,57,85,86 Uncontrolled esophagitis or FTT will be an indication for surgery in slightly older infants and most in the ﬁrst instance can safely be treated conservatively.

Conservative management POSTURAL THERAPY This form of treatment originated from the observation that children often resolved their tendency to vomit when they achieved the upright walking position. It was assumed that gravitational forces were assisting in keeping gastric contents in the stomach. This argument was taken further and it was recommended that infants suffering from signiﬁcant GER should be treated in the supine position at 60° horizontally, both by day and night. It was claimed that the patients’ symptoms were subjectively improved, that there was possibly an improvement in the radiographic demonstration of a hiatus hernia (or partial thoracic stomach) and that this form of posturing shortened the natural history of resolution in the majority of cases.1 More recent pH studies appear to demonstrate that the supine position, even with the head elevated, may not as previously thought, result in a reduction in low pH GER. The prone position with the head up seems to be more efﬁcient in controling reﬂux and is probably preferred.87–89 On the other hand, the risk of SIDS is recognized to be increased when the baby is nursed in the prone position91,92 and in any case, in practice, the beneﬁts from appropriate posturing may not be worth the effort.92 To be of value this form of treatment, if employed, must clearly be used both by day and night in those patients who are considered to be at risk from ‘pathological’ GER and who at the same time have no risk factors for SIDS.42–57,82,85,86,90,91 This should be continued until low pH GER can no longer be demonstrated or until approximately 1 year of age, when posturing should only be necessary at night, if at all. Beyond this age, this form of therapy appears to be of little clinical value.1

DIET Children with GER often improve spontaneously at the time of weaning when the consistency of their feed is increased by the introduction of solids. It is also observed that children who vomit will be improved if the volume at each feed is reduced (implying more frequent feeding).1 Thickening agents have been extensively employed, carob seed vegetable preparations of low caloriﬁc value (such as Nestergel or Carobel),1,6 being preferred over cereals,55 which contribute signiﬁcantly to the calorie intake in the diet. While thickening the feed appears to have a beneﬁcial clinical effect,1,6 objective scientiﬁc evidence does not support this form of therapy being applied blindly in every case of GER.93–95 While gastric emptying can be inﬂuenced by different feeds,79 manipulation of the diet to enhance this to reduce the risk of GER has not generally been clinically effective. The exception is where there is a true cow’s milk protein allergy which affects gastrointestinal motility and thus predisposes to GER.30,96 These babies are often dramatically improved when placed on formula feeds which do not contain cow’s milk and the possibility of this diagnosis as the cause of GER should always be borne in mind.

ANTACIDS These agents theoretically neutralize the acid gastric contents. It is known that elevation of gastric pH results in a decrease in peptic activity and an increase in LES tone.97 This should reduce the tendency to reﬂux and the severity of it’s complications. However, objective evidence of the effect of antacids compared to placebo in children with GER has not to date been presented. Where data is available comparing different antacids,98 there appears to be no advantage in using the mixture of magnesium trisilicate, aluminium hydroxide and alginic acid (Gaviscon). The high sodium content of Gaviscon means that there are probably few indications for it’s use in neonates.99 If a reduction in the amount of acid reﬂux is the therapeutic aim, then a more effective group of drugs will be those which suppress gastric acid production.

Agents which suppress gastric acid production Histamine, acting through cell surface H2 receptors, stimulates a proton pump in gastric parietal cells, which is responsible for HCL production in the stomach. Acid secretion can be signiﬁcantly reduced either by inhibiting the proton pump or blockade of the H2 receptors using speciﬁc antagonists. This will result in an improvement in clinical status in most cases. As with antacids, this improvement may not only be related to a reduction in the amount of acid in the esophagus, but also to the degree of GER.97

Management of neonatal GER 375

H2 receptor antagonists Cimetidine, the ﬁrst of this group to be employed therapeutically, is effective in most cases although there are reported cases where an adequate dosage has failed to control acid GER.5,100 Ranitidine, a more effective alternative with fewer side effects, is now usually employed as the ﬁrst choice H2 receptor antagonist.101

PROTON PUMP INHIBITORS Omeprazol was the ﬁrst of this group of drugs. It is generally more effective than the H2 receptor anatagonists. It is not licenced for children but can be given on a named-patient basis and can be administered either intravenously or enterally. Long-term usage of both groups of drugs should only be undertaken with caution in view of the nitroso compound production in the stomach and the possible long-term risk of malignancy.

NEUROCRINE AGONISTS AND ANTAGONISTS While detailed knowledge of the neurocrine system is at present incomplete, understanding of some of the more basic mechanisms has resulted in the development of powerful therapeutic tools to counter such abnormalities as esophageal and gastric dyskinesia and poor LES tone. To date most of these pharmacologic agents at our disposal are too nonspeciﬁc in their action and side effects are therefore common. The future may provide a drug designed to counter a speciﬁc abnormality with fewer unwanted actions. Bethanechol This is a choline ester with a selective action on muscarinic receptors. Double blind cross-over trials appear to have demonstrated a beneﬁcial effect in GER by increasing LES tone and increasing esophageal and gastric emptying.102 However these actions do not appear to be superior to simple antacids and the frequency of side effects preclude its widespread use.103 Metoclopramide This benzamide has a dual action being both a dopamine antagonist and a cholinergic agonist. It is very effective in increasing gastric transit and LES tone14,104,105 and has been shown to signiﬁcantly reduce GER.105,106 Unfortunately, the dopaminergic blockade is not speciﬁc to the GIT and unpleasant extrapyramidal side effects occur relatively frequently.105 In addition, a number of patients will develop methemoglobinemia.107 These side effects have generally restricted its use to older patients. Domperidone This imidazole is predominantly a dopamine-receptor blocker. Compared to metoclopramide, it crosses the blood–brain barrier poorly thus CNS side effects are signiﬁcantly reduced and therapeutic efﬁcacy has been

signiﬁcantly improved. Side effects are generally mild and infrequent.108 However, in very small babies, where the blood–brain barrier may not be completely developed, some extrapyramidal signs may be occasionally encountered.109 Cisapride This substituted benzamide was developed in an effort to avoid some of the nonspeciﬁc effects of the above agents. It’s action is through the release of acetylcholine in the enteric plexus and because of this there appear to be few side effects. Compared to other drugs it has a greatly improved effect upon gastrointestinal transit and because of this action it has been called a prokinetic agent. LES tone and gastric emptying are increased and GER is signiﬁcantly reduced.110–113 However, it is now recognized to be the cause of cardiac arrhythmias in some children who will develop abnormalities of the Q-T interval.114,115 It is advisable therefore to perform a preliminary ECG before commencing this drug and to monitor the child’s ECG while therapy continues. Erythromycin This antibiotic has been shown to have prokinetic properties when given in a sub-antibiotic dose.116,117 This is particulary useful as an alternative to Cisapride in small preterm infants who are at risk of GER. However, not all children will beneﬁt from its use and some may develop hypertrophic pyloric stenosis (HPS) while under treatment.118 This can cause signiﬁcant problems with diagnosis and treatment if it is assumed that the child’s continued vomiting is caused by GER and not HPS.

Operation Anti-reﬂux surgery is not commonly performed in the neonate.1,6 As indicated earlier, aspiration associated with GER is perhaps the only indication for intervention in this age group. The principles of any anti-reﬂux procedure are to ﬁrstly control GER and secondly to avoid as many of the unpleasant complications of surgery as possible. Increasingly, these operations are being performed laparoscopically. However there have been no randomized trials in children to suggest that this approach produces a better long-term result or has any other major beneﬁt. Regardless of the method, most of the operations which are employed use the fundus of the stomach, which is wrapped around the lower esophagus after this has been mobilized from the hiatus.6,83–88 This wrap around or fundoplication, acts as a plug, preventing the abdominal esophagus so created, from escaping back into the chest. This mechanism will only continue to work if the hiatus is relatively small and thus some form of plication of the diaphragmatic opening is usually necessary as well.6,119–122 Fundoplication may also act to prevent GER, by creating a ﬂutter valve at the

376 Gastro-esophageal reﬂux

GEJ, by creating an acute angle between the esophagus and the cardia of the stomach.6 This additional mechanism in preventing GER, may not be active in operations where an incomplete wrap around has been performed. Recurrent GER following fundoplication will occur in less than 10% of cases.6,123–125 As a general statement this happens when the GEJ has moved from its immediate postoperative situation below the diaphragm to a position within the chest. This has been recognized for many years both in adults and in children. Consequently there has been a tendency to perform a type of procedure which will tend to work even though the GEJ has been displaced into the chest. The Nissen operation which employs a 360° wrap around behaves in this way.22,120 However, these children tend to be unable to ‘bring up wind’ and unpleasant, painful abdominal distension can often be a problem.22,126 Others have argued that wrap arounds of <360° are just as satisfactory and avoid the other problems associated with the Nissen operation.3,6,127 These children appear postoperatively to be able to ‘bring up wind’ and to vomit if they wish, and GER is adequately controlled. However, this may recur if the GEJ rises into the chest. ‘Gas bloat syndrome’ is probably a signiﬁcant complication of all procedures, although possibly more frequently associated with the Nissen operation.22,126 It was at one time thought to be related entirely to the competence of the new GEJ and the inability of the individual to eructate.22,128 However, intestinal dysmotility causing delay in gastric emptying129,130 is now thought to contribute to this unpleasant complication which might be helped by one of the prokinetic agents described earlier. Pyloroplasty has in the past been employed as an alternative, however, ‘dumping’ may follow such a procedure and there is little evidence to suggest that it improves gastric emptying.25,129 Adhesive obstruction occurs in up to 10% of cases and is an important source of morbitity.123,131 This does not appear to be inﬂuenced by the type of operation employed. Unfortunately, no controlled data exists comparing one type of operation to another in terms of long-term success in controling GER and the incidence of postoperative complications. It would appear that 85% or more of children will have long-term control of GER following fundoplication and less than 10% will have signiﬁcant postoperative complications of their surgery.6,88,123–131

SUMMARY GER is a common disorder in the neonatal period affecting the GEJ. Multiple inter-related factors will inﬂuence the occurrence of GER but the most important of these are the LES and the intra-abdominal esophagus.

In most units, diagnosis will depend on an adequate history, radiographic and endoscopic assessment of the esophagus and stomach and prolonged esophageal pH studies. Radioscintigraphy, esophageal manometry and other investigations, such as measurement of electrical impedance, are unavailable in most units, however the data obtainable from these should in future, make them an important part of the general work up of all patients. GER usually runs a benign course and is more common in premature infants than in those born at term or in older children. As a consequence, most children can be managed conservatively using posturing in the headup position and thickening of feeds, which are given more frequently and in smaller volume. Some in addition will require the use of either antacids or drugs which suppress gastric acid production or one of the prokinetic agents to improve LES tone or gastric emptying. Aspiration of gastric contents into the tracheobronchial tree, associated with GER and the complications which this causes, is the main indication for operation. The best procedure has yet to be determined, but most surgeons favor a type of operation which will allow the patient to ‘bring up wind’ or vomit and this implies a fundoplication with an incomplete type of wrap around.

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124. Turnage RH, Oldham KT, Coran AG et al. Late results of fundoplication for gastroesophageal reﬂux in infants and children. Surgery 1989; 105:457–64. 125. Caniano DA, Ginn-Pease ME, King DR et al. The failed antireﬂux procedure: Analysis of risk factors and morbidity. J Pediatr Surg 1990; 25:1022–6. 126. Shirazi SS, Schulze K, Soper RT. Long-term follow-up for treatment of complicated chronic reﬂux esophagitis. Arch Surg 1987; 122:548–52. 127. Scarli AF. To Nissen or not to Nissen. Prog Pediatr Surg 1985; 18:96–100. 128. Leape LL, Ramenofsky ML. Surgical treatment of gastroesophageal reﬂux in children. Am J Dis Child 1980; 134:935–8. 129. Mulvihill SJ, Fonkalsrud EW. Pyloroplasty in infancy and childhood. J Pediatr Surg 1983; 18:930–6. 130. Papaila JG, Wilmot D, Grosfeld JL, Rescorla FJ, West KW, Vane DW. Increased incidence of delayed gastric emptying in children with gastroesophageal reﬂux. A prospective evaluation. Arch Surg 1989; 124(8):933–6. 131. Wilkins BM, Spitz L. Adhesion obstruction following Nissen fundoplication in children. Br J Surg 1987; 74:777–9.

5 Gastrointestinal

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39 Pyloric atresia and prepyloric antral diaphragm VINCENZO JASONNI

INTRODUCTION Gastric outlet obstruction in the newborn may be due to pyloric atresia, antral web or hypertrophic pyloric stenosis. The most common cause of gastric outlet obstruction is hypertrophic pyloric stenosis.

PYLORIC ATRESIA Pyloric atresia is a rare congenital malformation representing less than 1% of all atresias and diaphragms of the gastrointestinal tract.1–3 About 30% of these patients have associated abnormalities, of which epidermolysis bullosa is the most common.1,4,5 Familial occurrence of pyloric atresia has been reported.5,6 Puri et al. have encountered pyloric atresia in three consecutive siblings in a family.7 Bar-Maor et al. and El Shaﬁe et al. concluded that there is strong evidence to support a genetic determination in an autosomal recessive mode.8,9 Junctional epidermolysis bullosa associated with pyloric atresia (EB-PA; (congenital disorders and malformations) OMIN ≠ 226730) is a rare autosomal recessive inherited disease in which mucocutaneous fragility is associated with this type of gastrointestinal atresia.10 This association is usually fatal during the ﬁrst few weeks or months of life, even following surgical correction of intestinal obstruction. Recently, mutations in the genes encoding the subunit polypeptides alpha 6 beta 4 of integrin (ITGA6 and ITGB4) have been identiﬁed in several patients with peidermolysis bullosa and pyloric atresia.10–12 Prenatal diagnosis of pyloric atresia can be suspected when polyhydramnios is present (this occurs in about half of the cases) associated with dilated stomach. Prenatal diagnosis of pyloric atresia and epidermolysis bullosa was performed in pregnancies at risk for recurrence of this severe syndrome. However, some sonographic signs suggest the possibility of signiﬁcant cutaneous desquamation and blister formation in a fetus, especially when there is positive amniotic acetylcholinesterase coupled with elevated alphafetoprotein.13

The sex distribution is equal and there are a high proportion of infants with low birth weight.14, 15

Clinical presentation and diagnosis The newborn with complete pyloric obstruction presents shortly after birth with persistent non-bilious vomiting and often with epigastric distension.16 Respiratory problems are common, and dyspnea, tachypnea, cyanosis and excessive salivation may be mistaken for esophageal atresia.17 Very rarely, congenital gastric outlet obstruction is associated with esophageal atresia.18 Late diagnosis of pyloric atresia can cause rupture of stomach, although this complication has been reported as early as 12 hours postdelivery.19 A plain X-ray of the abdomen will usually conﬁrm the clinical diagnosis. The typical X-ray (Fig. 39.1) will show gas in the dilated stomach and no gas beyond the pylorus. Contrast study, although unnecessary, can conﬁrm complete obstruction at the pyloric region. The radiological diagnosis is based on the identiﬁcation of three radiological signs: the single gas bubble sign, the absence of beak sign (typical of hypertrophic pyloric stenosis), and the presence of the pyloric dimple sign on a contrast study.20 The single gas bubble sign is not speciﬁc for the diagnosis of pyloric atresia, but is an indicator of a gastric outlet obstruction. The ultrasonographic examination is helpful in the diagnosis of pyloric atresia.20 It demonstrated the absence of the normal echo pattern of the pyloric muscle and the pyloric canal; this is speciﬁc for the diagnosis of this entity. Table 39.1 represents the clinical features of pyloric atresia with their incidence.2,3

Pathological anatomy and operative surgery There are three main different types of pyloric obstruction: (1) membranous pyloric obstruction – type A; (2) longitudinal segmental atresia – type B; and (3) pyloric aplasia – type C (Fig. 39.2). In Table 39.2, the incidence of the different types of pyloric obstruction is shown.2,3

384 Pyloric atresia and prepyloric antral diaphragm

Type A

Type B

Type C

Figure 39.2 Anatomical varieties of congenital pyloric obstruction: type A – membranous pyloric obstruction; type B – longitudinal segmental atresia; type C – pyloric aplasia

Figure 39.1 Abdominal X-ray showing absence of air beyond the stomach

the membrane and pyloroplasty according to HeinekeMikulicz or Finney.1–4 Recently, transgastric excision of the pyloric membrane without pyloroplasty has been reported.21 With longitudinal segmental atresia, the operative method depends on the length of the atresia. When the atresia is short, a Finney pyloroplasty can be carried out, but for longer atresia and aplasia, the surgical procedure of choice is an excision and end-to-end gastroduodenostomy.4 Gastrojejunostomy is not recommended, due to the high mortality rate4 and because of the risk of marginal ulcer and blind loop syndrome.

Table 39.1 Clinical features of pyloric atresia (n = 140 patients) Symptoms and signs

Occurence (%)

Bile-free vomiting Single stomach bubble (one bubble) on X-ray Passage of meconium Distended epigastrium Polyhydramnios Birth weight <2500 g Prematurity Jaundice Peristaltic movements in the epigastrium Hemorrhagic vomiting

100 98 69 68 63 53 45 21 18 12

Preoperative preparation Generally newborns are admitted within the ﬁrst 2 days of life and generally in good physical condition, except those cases of pyloric atresia associated with epidermolysis bullosa. Preoperative preparation should consist of relief gastric distension by nasogastric tube, supplemented by lavage with warm normal saline if there is much thick mucus or if feeding has been attempted. An i.v. infusion should be started and correction of dehydration electrolyte imbalance and metabolic alkalosis is required in most cases.

Data from Muller et al.2 and Lorenzet and Morger3

Table 39.2 Incidence of the different pyloric atresia types (n=140) Type of atresia

n

%

Membranous (type A) Atresia (type B) Aplasia (type C) No details

77 cases 46 cases 12 cases 5 cases

57 34 9 3.5

Data from Muller et al.2 and Lorenzet and Morger3

Corresponding to the classiﬁcation of pyloric obstruction, different operative procedures are used. In the literature, the best results from operative treatment of membranous obstruction were obtained by excision of

OPERATIVE TECHNIQUE Incision A transverse abdominal incision is made 2 cm above the umbilicus, starting 2 cm to the left of the midline and running laterally in a skin crease for about 5 cm (Fig. 39.3a). The abdominal cavity is opened in the line of the incision. Careful exploration and search of other intestinal atresias are performed at this site.9 Identiﬁcation of pathology After the operation, it may be difﬁcult to diagnose the pathology and gastrotomy is often helpful in this regard.16 Another way to ﬁnd the exact location of the web and prevent the gastrotomy can be achieved by advancing a ﬁrm 14 Fr. gauge nasogastric catheter by the anesthesiologist, to the region of the obstruction.22

Pyloric atresia 385

(a)

(b)

(c)

(d)

Figure 39.3 Operative technique of pyloroplasty. (a) skin incision. (b) pyloric longitudinal incision. (c) incision of the membrane and suture. (d) longitudinal incision closed transversely

Pyloroplasty This procedure is for membranous pyloric obstruction (type A) and short atresia (type B).4,7,8 After identiﬁcation of the pylorus, a longitudinal incision is made with cutting diathermy or scissors, starting on the gastric side of the pylorus to the duodenum (Fig. 39.3b). A blunt dissecting forceps, which is inserted into the lumen, is useful at this stage. Care must be taken that no inadvertent damage is done to the posterior wall of the stomach or duodenum. The total length of the incision should be 1.5–2 cm, extending approximately 1 cm on the gastric side and 1.5–1 cm on the duodenal side of the pylorus; it should be midway between the greater and lesser curvatures of the stomach and superior and inferior borders of the duodenum. The greater length on the gastric side is to allow for greater thickness of the gastric wall in making the alignment for closure of the pyloroplasty incision in the transverse direction. The membrane is excised circumferentially and the mucosa approximately with 5-0 Vicryl sutures (Fig. 39.3c). The interior of the duodenum is inspected and a catheter is inserted down the duodenum to ensure that there is no distal atresia. The longitudinal incision is then closed transversely in two layers after meticulous hemostasis (Fig. 39.3d). The

inner layer is done by the Connell suture technique with Vicryl 4-0 sutures. The outer layer is divided by Lambert sutures. Closure of abdomen Gastrostomy is generally not necessary. The abdomen is closed in two layers and the nasogastric tube is left in the stomach for decompression.

Postoperative outcome Early diagnosis and surgical intervention with current neonatal supportive care have improved the survival of pure pyloric atresia. Mortality has been associated with delayed diagnosis8,9 and is mainly due to the associated malformation. The overall mortality rate is about 45% and the majority of these fatal cases are those with epidermolysis bullosa and other multiple intestinal atresias.23 Prenatal diagnosis of epidermolysis bullosa lethalis can be made by fetoscopic skin biopsy, and the parent should undergo genetic counselling due to the familial occurrence and suspicion of transmission by the autosomal recessive mode. Rosenbloom and Ranter suggested the nonoperative management of pyloric atresia, unless the skin disease is responsive to treatment.24 However, Hayashi et al. have recently reported long-term survival in four out

386 Pyloric atresia and prepyloric antral diaphragm

of ﬁve patients with pyloric atresia and epidermolysis bullosa.6

Prepyloric antral diaphragm Prepyloric antral diaphragm is a rare anomaly involving a submucosal web of gastric tissue covered by gastric mucosa and found in the distal gastric antrum. A total of about 150 cases have been reported, divided between the pediatric and adult age ranges.25 Reports have suggested both acquired and congenital forms, citing epidemiological and histological evidence.26 There are three groups of patients: a neonatal group with complete or partial obstruction, a group presenting later in childhood, and a group not diagnosed until later in life.27 Signiﬁcant associated abnormalities are noted in about 30% of children with antral web, including mainly the gastrointestinal tract and cardiovascular system.26

Clinical presentation and diagnosis In the neonatal group, vomiting, often projectile, is the predominant presenting symptom. The vomiting is usually non-bilious. Other symptoms include apnea, cyanosis and no weight gain.26 The older children complained of abdominal pain, vomiting, fullness after eating and eructation. In the elderly group, the clinical history consists of episodic cramping, epigastric pain or fullness following meals and intermittent vomiting. There is one report describing a case in the eighth decade of life.28 The diagnosis of antral web with a central aperture is made radiologically following a barium meal in 90% of cases.26 The typical appearance of a web in an infant is a thin, membranous septum, projecting into the antral lumen, perpendicular to its longitudinal axis 1–2 cm proximal to the pylorus (Fig. 39.4a). Gastroscopy has recently been noted to be of use in conﬁrming clinical and radiological evidence of the web in older infants and in children.29 Features of the web include: • A small ﬁxed central aperture surrounded by gastric mucosa that is smooth and devoid of folds • No change in the opening size of the web with peristalsis, and • That the gastric wall proximal and distal to the web is seen to contract normally.30

TREATMENT The treatment of partially obstructing antral web consists of surgical excision of the web, combined with pyloroplasty if the web is very close to the pylorus (described previously under ‘Pyloric atresia’). Furthermore, at operation, it is important in these cases to pass a Foley catheter from the stomach as far as possible

(a)

(b)

Figure 39.4 (a) Prepyloric antral web. (b) Windsock antral membrane protruding into the duodenum

distally, and then to inﬂate the balloon and to withdraw the catheter.22 Windsock pyloric and antral membranes protruding into the duodenum have been reported (Fig. 39.4b), and would be missed at laparotomy by simple inspection of the gastric lumen.31 Other methods are reported, most notably a recent report of successful endoscopic transection using a standard papillotome32 and forceful dilatation of antral membrane without pyloroplasty.33 Medical treatment consisting of thickened feed and antispasmodics has been reported to be successful in infants with vomiting and a radiographically demonstrable antral web but without pronounced obstruction.34 While this concept of conservative management is supported by some surgeons, the majority of the literature preferred the surgical correction of this entity, which will reduce and prevent the morbidity and unnecessary psychiatric counselling in this group of babies and children.4,25

REFERENCES 1. Dessanti A, Iannuccelli M, Dore A et al. Pyloric atresia: an attempt at anatomic pyloric sphincter reconstruction. J Pediatr Surg 2000; 35:1372–4. 2. Muller M, Morger R, Engert J. Pyloric atresia: report of four cases and review of the literature. Pediatr Surg Int 1990; 5:276–9. 3. Lorenzet CA, Morger R. Beirgrag zur kongenitalen, Pylorus Atresie. Innauguraldisseration, Universitat Zurich, 1987. 4. Hall WH, Read RC. Gastric acid secretory differences in patients with Heineke–Mikulicz and Finney pyloroplasties. Am J Dig Dis 1975; 20:947–50. 5. Kadowaki J, Takeuchi S, Nakahira M et al. Congenital pyloric atresia: a report of three cases. Am K Gastroenterol 1981; 76:449–52. 6. Hayashi AH, Galliana CA, Gillis DA. Congenital pyloric atresia and junctional epidermolysis bullosa: a report of long-term survival and a review of the literature. J Pediatr Surg 1991; 26:1341–5.

References 387 7. Puri P, Guiney EJ, Carroll R. Multiple gastro-intestinal atresias in three consecutive siblings: observations on pathogenesis. J Pediatr Surg 1985; 20:22–4. 8. Bar-Maor JA, Nissan S, Nevo S. Pyloric atresia. J Pediatr Surg 1972; 20:22–4. 9. El Shaﬁe M, Stidham GL, Klippel CH et al. Pyloric atresia and epidermoylsis bullosa letalis: a lethal combination in two premature newborn siblings. J Pediatr Surg 1979; 14:446–9. 10. Mellerio JE, Pulkkimen L, McMillan JR et al. Pyloric atresia – junctional epidermolysis bullosa syndrome: mutations in the integrin bega4 gene (ITGB4) in two unrelated patients with mild diseases. Br J Dermatol 1998; 139:862–71. 11. Dellambra E, Prislei S, Salvati AL et al. Gene correction of integrin beta 4- dependent pyloric atresia epidermolysis bullosa keratinocytes establishes a role for beta 4 tyrosines 1422 and 1440 in hemidesmosome assembly. JK Biol Chem 2001; 44:41336–42. 12. Nakana A, Pulkkinen L, Murrell D et al. Epidermoylsis bullosas with congenital pyloric atresoa: novel mutations in the beta 4 integrin gene (ITGB4) and genotype/phenotype correlations. Pediatr Res 2001; 49:618–26. 13. Lapinard C, Descampo P, Menegurri G et al. Prenatal diagnosis of pyloric atresia – junctional epidermolysis bullosa syndrome in a fetus not known to be at risk. Prenat Diagn 2000; 20:60–75. 14. Kume K, Ikeda K, Hayashida Y et al. Congenital pyloric atresia: a report of three cases and review of literature. Jpn J Pediatr Surg 1980; 16:259–68. 15. Lloyd JR, Clatworthy HW. Hydramnios as an aid for the early diagnosis of congenital obstruction of the alimentary tract: a study of the maternal and fetal factors. Pediatrics 1958; 21:903–9. 16. Ducharme JC, Benoussan AL. Pyloric atresia. J Pediatr Surg 1975; 10:149–50. 17. Campbell JE. Other conditions of the stomach. In: Welch KJ, Randolp JG, Ravitch MM et al. editors. Pediatric Surgery. 4th edn. Chicago: Year Book, 1986:821–2. 18. Friedman AP, Velcek FT, Ergin MA et al. Oesophageal atresia with pyloric atresia. Br J Radiol 1980; 53:1009–11.

19. Burnett HA, Halpert B. Perforation of the stomach of a newborn infant with pyloric atresia. Arch Pathol 1947; 44:318–20. 20. Grunebaum M, Kornreich L, Ziv N et al. The imaging diagnosis of pyloric atresia. Z Kinderchir 1985; 40:308–11. 21. Narasimhan KL, Road KLN, Mitra SK. Membranous pyloric atresia – local excision by a new technique. Pediatr Surg Int 1991; 6:159–60. 22. Raffensperger JG. Pyloric and duodenal obstruction. In: Swenson’s Pediatric Surgery. 5th edn. Norwalk, CT: Appleton & Lange 1990: 509–16. 23. Chittmittrapap S. Pyloric atresia associated with ileal and rectal atresia. Pediatr Surg Int 1988; 3:426–30. 24. Rosenbloom MS, Ranter M. Congenital pyloric atresia and epidermolysis bullosa letalis in premature siblings. J Pediatr Surg 1987; 22:374–6. 25. Blazek FD, Boeckman CR. Prepyloric antral diaphragm: delays in treatment. J Pediatr Surg 1987; 22:948–9. 26. Bell MJ, Gternberg JL, Keating JP et al. Prepyloric gastric antral web: a puzzling epidemic. J Pediatr Surg 1978; 13:307–13. 27. Patnaik DN, Sun S, Groff DB. Newborn gastric outlet obstruction caused by an antral web. J Med Soc N Jers 1976; 73:736–7. 28. Rona A, Sylvestre J. Prepyloric mucosal diaphragm. J Can Assoc Radiol 1975; 26:291–4. 29. Schwatx SE, Rowden DR, Dudgeon DL. Antral mucosal diaphragm. Gastrointest Endosc 1977; 24:33–4. 30. Banks PA, Waye JD. The gastroscopic appearance of the antral web. Gastrointest Endosc 1969; 15:228–9. 31. Haller JA Jr, Cahill JL. Combined congenital gastric and durodenal obstruction: pitfalls in diagnosis and treatment. Surgery 1968; 63:503–6. 32. Berr F, Rienmueller R, Sauerbruch T. Successful endoscopic transection of a partially obstructing antral diaphragm. Gastroenterology 1985; 89:1147–51. 33. Lugo-Vincent HL. Congenital antral membrane: prenatal diagnosis and treatment. J Pediatr Surg 1994; 29:1589–90. 34. Tunell WP, Smith EI. Antral web in infancy. J Pediatr Surg 1980; 15:152–5.

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40 Hypertrophic pyloric stenosis PREM PURI AND GANAPATHY LAKSHMANADASS

INTRODUCTION

GENETICS

Hypertrophic pyloric stenosis (HPS) is the most common condition requiring surgery in the ﬁrst few months of life. It is characterized by hypertrophy of the circular muscle of the pylorus, causing pyloric channel narrowing and elongation. The incidence of pyloric stenosis varies widely with geographic location, season and ethnic origin.1 The incidence has been reported to be approximately three per 1000 live births.2 There is some evidence that in recent years the incidence of pyloric stenosis has increased signiﬁcantly in some parts of the UK.3–5 Boys are affected four times more often than girls.6 A recent study reported a dramatic rise in incidence among male infants but not for females, so that rates for the two sexes were 6.2 and 0.9 per 1000 infants per year.7

As infantile hypertrophic pyloric stenosis (IHPS) tends to run in families, genetic factors have been implicated in its etiology. IHPS is relatively rare in babies of African, Indian, and Chinese extraction.10,11 Boys are affected four times more often than girls,9 and IHPS has been reported in multiple siblings and multiple births.12–14 Siblings of patients with IHPS are 15 times more likely to suffer the condition than children who have no family history of IHPS.15 In a follow-up study extending over 45 years, Carter and Evans found that 5–20% of the sons and 2.5–7% of the daughters of affected patients developed IHPS.16 Sons and daughters of affected female patients had 3–4 times the incidence of IHPS than sons and daughters of affected male patients.15

ABNORMALITIES OF HORMONAL CONTROL ETIOLOGY Although earlier diagnosis, advances in ﬂuid and electrolyte therapy, and pediatric anesthesia have reduced the mortality to practically zero, the exact etiology of pyloric stenosis is unknown.8 This condition is usually classiﬁed as a congenital disorder. It is almost unknown in stillbirths, associated anomalies are very uncommon and the patient usually presents with vomiting after the second week of life. For these reasons it has been suggested that it may be an acquired condition. Recently, Rollins et al. measured pyloric muscle dimensions on ultrasonography in 1400 consecutive newborn infants.9 Nine of these infants subsequently developed pyloric stenosis and were operated upon. Their pyloric muscle measurements at birth were all within the normal range. This study clearly showed that congenital performed muscular hypertrophy is not present in babies who later develop pyloric stenosis.

The human pylorus is characterized by a zone of elevated pressure that relaxes with antral peristalsis, contracts in response to intraduodenal stimulation, and prevents the retrograde movement of duodenal contents into the stomach.17 The hormonal control of the pyloric sphincter function by mediators such as gastrin, cholecystokinin, and secretin, has been reported to be the same as in other gastrointestinal (GI) sphincters.4 Since Dodge successfully induced pyloric stenosis by prolonged perinatal maternal stimulation with pentagastrin in approximately one-half of a litter,18 together with the ﬁnding of elevated serum gastrin levels in infants with IHPS,19 much attention has been paid to the role of gastrin in the pathogenesis of IHPS. It has been suggested that repeated hyperacid stimulation of the duodenum induced by gastrin evokes repeated pyloric sphincter contractions with work hypertrophy of the pylorus.20 However, Janik et al. failed to induce pyloric stenosis in other species by prenatal administration of pentagastrin.21 Some investigators found signiﬁcantly

390 Hypertrophic pyloric stenosis

high plasma gastrin levels in affected infants compared to healthy controls,19,22 whereas others failed to conﬁrm this ﬁnding.23,24 Since raised serum gastrin levels return to normal following pyloromyotomy, it is believed that they are secondary to antral stasis.24

ABNORMALITIES OF PYLORIC INNERVATION A variety of morphological and molecular studies have suggested that the enteric nervous system plays an important role in normal GI smooth-muscle development. It has been reported that the reciprocal interactions between the developing enteric nervous system and GI smooth muscle play a signiﬁcant role in the normal differentiation, maturation, and function of both of these tissue types.25–27 The innervation of the musculature regulating motility is particularly dense at the level of the smooth-muscle sphincters of the GI tract.28 Relaxation of the sphincter is accomplished by activation of inhibitory motor neurons.29 As a defect in pyloric relaxation has been thought to be responsible for the gastric-outlet obstruction and the development of pyloric muscle hypertrophy, many investigators have sought evidence for a neural abnormality in specimens of IHPS that may explain the failure of pyloric muscle relaxation.8 Earlier studies concentrated on abnormalities in the myenteric plexus,30–37 and more recent studies have focused on the neurotransmitter status in both the myenteric plexus and pyloric muscle layers.37–49

Ganglion cells Many investigators have reported conﬂicting morphologic ﬁndings as regards ganglion cells in the myenteric plexus in IHPS. A number of early authors found decreased numbers of ganglion cells, which were attributed either to degenerative changes related to vagal overstimulation 30–32 or to immaturity.33,34 On the other hand, Rintoul and Kirkman suggested that Dogiel type I ganglion cells (primarily motor) were selectively absent in IHPS.35 Belding and Kernohan30 and Spitz and Kaufmann36 found that the majority of myenteric ganglion cells in the hypertrophic pylorus showed degenerative changes. However, Tam, using immunohistochemical stains for neuronspeciﬁc enolase, stated that neurons were neither immature nor severely degenerated.37 In a recent study using electron microscopy, Langer et al. demonstrated that there were fewer nerve cell bodies in the myenteric plexus in IHPS and the total number of ganglia was lower than that in control samples.50

Peptidergic innervation It has been demonstrated that the relaxation mechanism of pyloric smooth muscle appears to be dependent on

non-adrenergic, non-cholinergic (NANC) inhibitory innervation, which is mediated by some neuropeptides. With the advent of immunohistochemical techniques speciﬁc for GI peptides, a number of investigators have examined the peptidergic nerves in the myenteric plexus and smooth-muscle layer in IHPS.37–41 These studies suggested a reduction of immunoreactivity in peptidergic nerve ﬁbers containing enkephalin, neuropeptide Y, substance P, vasoactive intestinal polypeptide (VIP), and gastrin-releasing peptide supplying the circular muscle.37–41 No such reduction was observed in the nerves or cell bodies within the myenteric plexus. Among these neuropeptides, of particular importance is the absence of the inhibitory peptides (VIP and neuropeptide Y) in the intramuscular nerves. These observations are highly suggestive of a mechanism involving failure of pyloric relaxation owing to depletion of inhibitory peptides, resulting in pyloric smooth-muscle hypertrophy and gastric-outlet obstruction in IHPS.

Nitrergic innervation Nitric oxide (NO) has been recognized as a potent mediator of NANC inhibitory nerves, which regulate smooth-muscle relaxation in the mammalian digestive tract.51 Vanderwinden et al.42 and Kobayashi et al.43 have reported that enzyme NADPH diaphorase, which is identical to NO synthase (NOS), is absent or markedly reduced in hypertrophic pyloric muscle while it is preserved in the myenteric plexus in IHPS. Furthermore, a NOS gene-deleted knockout mouse model is described in which the only abnormality is gastric-outlet obstruction due to pyloric hypertrophy.52 Recently, Kusafuka and Puri, using RT-PCR technique, demonstrated low levels of nNOS mRNA in pyloric muscle of IHPS patients compared to normal controls.44 Since a low level of nNOS mRNA may lead to impaired local production of NO, it is suggested that the excessively contracted hypertrophied circular muscle in IHPS is a result of reduced expression of the nNOS gene at the mRNA level.44

Synapse formation Synapses provide the ﬁnal neuronal control of the GI tract by regulating neurotransmission at the neuromuscular terminals. Recent studies have demonstrated reduction of synaptic vesicles and presynaptic terminals in hypertrophied pyloric muscle layers.47,48 Furthermore, a study from the current authors’ laboratory reported markedly reduced neural-cell adhesion molecule (NCAM) expression on nerve ﬁbers within circular and longitudinal muscles in patients with IHPS compared with normal pylorus.43 NCAM plays an important role in the formation of initial contacts between nerve and muscle cells and affects tissue formation during embryo-

Abnormalities of extracellular matrix proteins 391

genesis.53,54 These reports suggest that there is impairment of neurotransmission between nerves and muscle in IHPS.

Nerve-supporting cells The nerve-supporting cells (NSCs) permit cell bodies and processes of neurons to be ordered and maintained in a proper spatial arrangement, and are essential in the maintenance of basic physiological functions of neurons.55 The NSCs of the intrinsic enteric nervous system are often referred to as enteric glia.8 Enteric glia have been reported to express various markers for both astrocytes and Schwann cells, such as: (1) glial ﬁbrillary acidic protein (GFAP), a speciﬁc marker for astrocytes within the central nervous system; (2) S-100, a marker for astrocytes and Schwann cells; and (3) D7, a marker for Schwann cells. A recent study from the current authors’ laboratory demonstrated that in IHPS cases S-100, D7 and GFAP-immunoreactive ﬁbers were either absent or markedly reduced within the hypertrophied circular and longitudinal muscles.49 There is evidence to suggest that NSCs also act as neurotrophic factors.56,57 The limited availability of neurotrophic factors is thought to control the extent of neuronal survival, and thus (indirectly), the density of innervation. Conversely, the presence of nerve ﬁbers is essential for the existence of NSCs; supporting cells degenerate after proximal transection of the nerve ﬁber. The absence or marked reduction of NSC in IHPS corresponds to the absence or reduction of peptidergic, nitrergic, cholinergic, and adrenergic nerve ﬁbers, and is additional evidence that a defect of intramuscular innervation exists in IHPS.

Neurotrophins Neurotrophins are a family of related, target-derived neuronal growth factors that support neuronal growth, survival and differentiation. It is well established that peripheral sensory and postganglionic sympathetic neurons are under the control of neurotrophins for development and maintenance. A recent study showed reduced levels of nerve growth factor (NGF), neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) in pyloric muscle in IHPS compared with normal controls.58 NT-3 immunoreactivity normally is localized to ganglion cells, enteric glia, and connective tissue rich in extracellular matrix, which forms the framework in which NT-3 accumulates. BDNF and NGF normally are localized to ganglion cells and adjacent glia. In IHPS a selective reduction in intramuscular nervesupporting cells (enteric glia) has been reported.49 It is tempting to speculate that the reduction of mature glia in IHPS may partly be responsible for the diminished production of NT-3, BDNF, and NGF. Recently, the current authors have analyzed the expression of glial-

derived neurotrophic factor (GDNF), which is expressed normally by mature enteric glial cells, and found that in IHPS there is a lack of GDNF-positive nerve ﬁbers.59 In contrast to neurotrophins, however, GDNF is produced very early in gut mesenchyme, and in IHPS the pyloric muscle retains the capacity to produce GDNF perhaps compensating for the lack of mature enteric glia. It also is possible that the reported abnormalities of extracellular matrix proteins8 in IHPS could alter neuronal maturation by providing an insufﬁcient latticework for neurotrophins to attach.

ABNORMALITIES OF THE INTESTINAL PACEMAKER SYSTEM (INTERSTITIAL CELLS OF CAJAL) Interstitial cells of Cajal (ICC) are small fusiform or stellate cells with prominent nuclei and varicose processes that form networks in the GI tissues. Morphologic studies have suggested three major functions of ICC: (1) they are pacemaker cells in GI smooth muscle; (2) they facilitate active propagation of electrical events; and (3) they mediate neurotransmission.60,61 A number of investigators have reported a lack of ICC in hypertrophic pyloric muscle from patients with IHPS using C-KIT antibody and electron microscopy.62,63 The lack of ICC in IHPS suggests the disruption of their network and the interruption of the generation of slow waves may contribute to the motility disturbances of the pyloric sphincter.63

ABNORMALITIES OF EXTRACELLULAR MATRIX PROTEINS Previous studies have reported an increase in connective tissue in IHPS, particularly in the septa that run between the circular muscle bundles.30,32 Recent studies have demonstrated that ECM proteins, particularly collagen, are important microenvironmental factors of the neuronal processing pathway in the early embryonal stage and an important matrix for cell adhesion and movement.8 Cass and Zhang reported an increase in extracellular matrix (ECM) proteins such as chondroitin sulfate, ﬁbronectin, and laminin in specimens of pyloric muscle in IHPS.64 Another study reported abnormal amounts of elastin ﬁbers and elastin in the pyloric muscle in IHPS.65 Using M-57 antibody, which can distinguish newly synthesized type I procollagen from fully processed mature collagen, a recent study from the current author’s laboratory demonstrated that type I procollagen was markedly increased in not only the connective tissue septa between circular muscle bundles, but also among the circular muscle ﬁbers in patients with IHPS, suggesting that the hypertrophied circular muscle in IHPS is

392 Hypertrophic pyloric stenosis

actively synthesizing collagen.65,66 These studies suggested that increased ECM proteins may be responsible for the characteristic ‘ﬁrm’ nature of the pyloric tumor.

ABNORMALITIES OF SMOOTH-MUSCLE CELLS The ongoing contractile tone in the smooth-muscle sphincters is generated by myogenic mechanisms. This implies that the contractile state is an intrinsic property of the muscle and independent of the nervous system. On the other hand, transient relaxation of the sphincter to permit the forward passage of material is accomplished by activation of inhibitory motor neurons.29 Dieler et al. examined 37 pyloric specimens from IHPS patients with electron microscopy, comparing the severity and frequency of degenerative changes in the myenteric plexus and smooth-muscle cells (SMCs), and reported primarily myogenic-type abnormality in some and predominently neurogenic-type abnormality in others.67 In the predominantly myogenic type, they observed degenerative or regressive changes of SMCs in hypertrophied pyloric muscle such as swelling and necrosis, various nuclear abnormalities, glycogen accumulation, increased amounts of connective tissue between SMCs, and in particular, alterations of the endoplasmic reticulum (ER) and the presence of numerous dense granules within the cytoplasm. Langer et al.50 found SMCs in IHPS to be morphologically normal, containing contractile ﬁlaments, intermediate ﬁlaments, dense bodies, and caveolae. They found, however, that SMCs in IHPS were frequently in a proliferative phase, with large amounts of dilated rought ER with a lower proportion of contractile ﬁlaments, and very few gap junctions exhibited between SMCs compared with control specimens. In contrast, they demonstrated signiﬁcant ultrastructural abnormalities of the inhibitory enteric nervous system in IHPS. We performed quantitative evaluation of proliferative activity in pyloric muscle in IHPS and showed that proliferative activity is markedly increased in SMCs in IHPS.68

ABNORMALITIES OF GROWTH FACTORS Although the mechanisms responsible for smooth-muscle hypertrophy are unknown, with progress in molecular biology, there is increasing evidence to suggest that the growth of SMCs is regulated by several growth factors.69–71 IGF-I and PDGF-BB are potent SMC mitogens in vitro and act synergistically to stimulate SMC proliferation. IGF-I mediates the growth-promoting effects of PDGF in mesenchymal cells.72 IGF-I and PDGF have been shown to be produced by SMCs, and their effects are mediated via their receptors.73,74 Transforming growth factor alpha

(TGF-α) is a growth regulatory peptide found in a wide range of embryonic and adult tissues. It has been recognized that TGF-α has a growth-promoting effect on vascular and visceral SMCs.75 EGF is best known as a potent growth stimulator. It appears to play a critical role early in growth of cultured smooth muscle, in which its production is highest and its growth-promoting effects are greatest.75 The studies from our laboratory have reported increased expression of IGF-I, PDGF-BB, TGF and EGF, in hypertrophic pyloric muscle in IHPS,76–79 suggesting that the increased local synthesis of peptide growth factors in SMCs may play a critical role in the development of pyloric muscle hypertrophy in IHPS.

CLINICAL FEATURES The usual onset of symptoms occurs between 3 and 6 weeks of age. It may present earlier and has been rarely reported in premature infants.80 Presentation of HPS in infants older than 12 weeks of age is considered rare and reports in the literature are few and far between.81,82 The current authors reviewed 1481 consecutive cases of pyloric stenosis treated at three children’s hospitals in Dublin between 1969 and 1990. A total of 53 (3.6%) patients presented with pyloric stenosis between 12 and 30 weeks of age. Vomiting is the most common presenting symptom. Initially there is only regurgitation of feeds, but soon it is characteristically projectile and free of bile. In 17–18% of cases the vomitus may contain fresh or altered blood, usually attributed to irritative gastritis or esophagitis.83 Spitz and Batcup examined endoscopically 13 infants presenting with hematemesis and found evidence of esophagitis in all cases.84 Owing to inadequate ﬂuid and calorie intake, dehydration and weight loss soon become apparent. In patients who present late, there is disappearance of subcutaneous fat and wrinkled skin. Stools become infrequent, dry, ﬁrm and scanty. Jaundice occurs in about 2% of cases and has been shown to be related to decrease in glucoronyl transferase, which occurs as a consequence of starvation.85 Associated anomalies are found in 6–20% of patients.6,12 These include: esophageal atresia, malrotation of bowel, Hirschsprung’s disease, anorectal anomalies, cleft lip and palate, and urological anomalies.

DIAGNOSIS It should be possible to diagnose HPS on clinical features alone in 80–90% of infants.86–88 The important diagnostic features of pyloric stenosis are visible gastric peristalsis and a palpable pyloric tumor. Physical examination of the infant is best carried out during a test feed which

Management 393

relaxes the abdominal wall and makes the detection of pyloric tumor easier. The abdomen is completely exposed and observation made for gastric peristalsis, which is often visible in this condition as a bulge appearing in the left upper quadrant and moving slowly to the right across the epigastrium. On palpation of the abdomen, an olive-shaped pyloric tumor is palpable in most cases just above the umbilicus at the lateral border of the rectus muscle below the liver edge. In general, the diagnosis of pyloric stenosis can be made with conﬁdence on the basis of the history and clinical examination alone. When the clinical ﬁndings are equivocal, the diagnosis can be conﬁrmed by sonography or barium meal. In 1977, Teele and Smith reported on the sonographic diagnosis of HPS.89 The diagnosis relies on the measurement of the pyloric diameter, pyloric length and muscle thickness. Of the three parameters, muscular wall thickness is considered to be the most precise on sonography. Blumhagen and Coombs were the ﬁrst to point out that pyloric muscle thickness of the hypoechoic ring is the most important sonographic parameter in the diagnosis of pyloric stenosis (Fig. 40.1).90 They considered a thickness of 4 mm or more to be pathological. Other investigators believe that muscle thickness of 5 mm or more is most reliable for the diagnosis of pyloric stenosis.91 Falsepositive results are rare, but false-negative rates range from 0–19% and largely depend upon the skill of the ultrasonographer.6,91 Barium meal usually conﬁrms the diagnosis in patients in whom the pyloric tumor cannot be palpated. A barium study may also detect gastro-esophageal reﬂux or intestinal malrotation. Before barium study, the stomach should be emptied with a nasogastric tube and 30–60 ml of barium is instilled under ﬂuoroscopic control. The characteristic radiological feature of pyloric stenosis is a narrowed elongated pyloric canal giving a ‘string’ or ‘double track’ sign caused by compressed invaginated folds of mucosa in the pyloric canal (Fig. 40.2).

Figure 40.1 Longitudinal real-time sonogram section reveals hypoechoic ring with echogenic center typical of pyloric tumor

Figure 40.2 Pyloric stenosis. Severe narrowing of pyloric region giving the ‘string sign’ in this 3-week-old infant who presented with projectile vomiting

MANAGEMENT Preoperative management Persistent vomiting in these patients results in chloride depletion and metabolic alkalosis. Estimation of serum electrolyte level, urea, hematocrit and blood gases should be done to determine the state of dehydration and acid–base abnormalities. A nasogastric tube is passed to keep the stomach empty. Saline irrigation through the nasogastric tube may help in removing mucus and milk curd. Nowadays, many babies with pyloric stenosis do not show any clinical evidence of dehydration on admission and their serum electrolyte levels are usually normal. They are given their maintenance requirements of ﬂuid as half-straight saline, and are operated on as soon as feasible. If the infant is mildly dehydrated and has hypochloremic alkalosis, maintenance ﬂuids can be given as 0.45% saline with 5% dextrose containing 10 mmol of potassium chloride per 500 ml, together with adequate volumes of isotonic saline to correct for continuing nasogastric losses. If the infant is more severely dehydrated (>5%), sodium and chloride ions must be replaced with isotonic saline to enable the kidney to excrete bicarbonate, thereby correcting the acid–base status.6,92 The operation for pyloric stenosis is not an emergency and should never be undertaken until serum electrolyte levels have returned to normal.

394 Hypertrophic pyloric stenosis

Operation The Ramstedt’s pyloromyotomy is the universally accepted operation for pyloric stenosis.

INCISION A 3 cm transverse right upper quadrant incision provides excellent exposure and direct access to the pylorus with minimal retraction (Fig. 40.3). Another incision which is commonly used is an umbilical fold incision.93–96

PROCEDURE The transverse incision lateral to the rectus muscle is cut through all layers of muscle and peritoneum. The pyloric tumor is delivered by gentle traction on the stomach (Fig. 40.4). The surgeon applies an index ﬁnger to the duodenal end of the pylorus and stabilizes the pyloric tumor. An incision is then made over the anterosuperior

part of the pylorus, beginning at the clearly demarcated pyloroduodenal junction about 2 mm proximal to the pyloric vein and extending onto the gastric antrum, where muscle is thin (Fig. 40.5). The pyloric muscle is then widely split down to the mucosa using mosquito forceps (Fig. 40.6). Some surgeons prefer a Denis Browne pyloric spreader. When the pyloric muscle has been adequately split, the mucosa can be seen to be bulging (Fig. 40.7). The pylorus is dropped back into the abdomen. The peritoneum is closed with 4-0 polyglactin (Vicryl) and muscles approximated using 3-0 polyglactin (Vicryl). 5-0 Vicryl is used for subcuticular stitches. The supraumbilical skin fold incision for pyloromyotomy has been used by several surgeons.93–96 Although this incision does not offer any advantage as regards postoperative feeding tolerance or duration of hospital stay, it certainly gives a superior cosmetic result. The problem with the supraumbilical incision is that it does not always

Pyloric vein

Figure 40.3 Skin incision for pyloromyotomy Figure 40.5 Incision through the serosa of the pyloric tumor

Mucosa

Figure 40.4 Delivery of pyloric tumor

Figure 40.6 Splitting of pyloric muscle

References 395

was begun in the immediate postoperative period or 2–6 hours postoperatively decreased the length of hospitalization and hospital costs without adverse effects.103

COMPLICATIONS

Figure 40.7 Bulging mucosa seen after complete splitting of pyloric muscle

allow easy access to the hypertrophic pyloric muscle. Delivery of a large pyloric tumor can be fairly difﬁcult and time consuming and may damage the serosa of the stomach or duodenum by tearing. Extending the muscle sheath incision vertically has been described to resolve this problem.95

LAPAROSCOPIC PYLOROMYOTOMY Recently, extramucosal pyloromyotomy has been performed successfully by laparoscopy in infants with HPS.97–99 There are no signiﬁcant advantages as regards overall operating time, postoperative feeding tolerance and duration of hospital stay. The main advantage of laparoscopic pyloromyotomy is the superior cosmetic result. However this must be balanced against the ﬁnancial implications of offering a laparoscopic pyloromyotomy.

Postoperative care Maintenance i.v. ﬂuids are continued postoperatively until the infant is feeding satisfactorily. The timing of reintroduction of feeds continues to be controversial.100–103 Several studies have investigated postoperative feeding regimens for IHPS patients with respect to time of reintroduction of feeding and speed of advancement in an attempt to discover the safest and most cost-effective method. Some surgeons recommend starting oral feeds 4–6 hours after operation and gradually increasing the volume and concentration so as to resume normal feeds by the third or fourth day. Others have shown that postoperative vomiting is reduced if feeds are not started until 24 hours postoperatively. The vomiting following pyloromyotomy is usually self-limiting and independent of the timetable or composition of the postoperative dietary regimen.102 A recent study showed that a postoperative standardized feeding regimen for patients with IHPS where feeding

Duodenal perforation is usually the result of excessive separation of ﬁbers at the distal end of the pylorus. It is not serious provided that it is recognized and closed with one or two sutures. A patch of omentum should be brought up and tied over the wound. Other complications included hemorrhage, wound infection and wound dehiscence. With improvements in techniques, the incidence of complications after pyloromytomy is very low.

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65. Oue T, Puri P. Abnormalities of elastin and elastic ﬁbers in infantile hypertrophic pyloric stenosis. Pediatr Surg Int 1999; 15:540–2. 66. Miyazaki E, Yamatakia T, Ohshiro K et al. Active collagen synthesis in infantile hypertrophic pyloric stenosis. Pediatr Surg Int 1998; 13:237–9. 67. Dieler R, Schroder JM, Skopnik H, Steinau G. Infantile hypertrophic pyloric stenosis: myopathic type. Acta Neuropathol 1990; 80:295–306. 68. Oue T, Puri P. Smooth muscle cell hypertrophy versus hyperplasia in infantile hypertrophic pyloric stenosis. Pediatr Res 1999; 45:853–7. 69. Chen Y, Bornfeldt KE, Arner A, Jennische E, Malmqvist U, Uvelius B, Arnqvist HJ. Increase in insulin-like growth factor-I on hypertrophying smooth muscle. Am J Physiol 1994; 266:E224–9. 70. Yamamoto M, Yamamoto K. Growth regulation in primary culture of rabbit arterial smooth muscle cells by plateletderived growth factor, insulin-like growth factor-I and epidermal growth factor. Exp Cell Res 1994; 212:62–8. 71. Pfeifer TL, Chegini N. Immunohistochemical localization of insulin-like growth factor (IGF-I), IGF-I receptor, and IGF binding proteins in the cardiovascular system. Cardiovasc Res 1994; 30:281–9. 72. Clemmones DR, Van Wyk JJ. Evidence for a functional role of endogenously produced somatomedin like peptides in the regulation of DNA synthesis in cultured human ﬁbroblast and porcine smooth muscle cells. J Clin Invest 1985; 75:1914–18. 73. Libby P, Waener SJC, Salmone RN, Brinyi LK. Production of platelet derived growth factor-like mitogen by smooth muscle cells from atheroma. N Engl J Med 1988; 318:1493–6. 74. Ultlrich A, Gray A, Tam AW, Yang-Feng T, Tsubokawa M, Collins C, Henzel W, LeBon T, Kathuria S, Chen F. Insulin like growth factor I receptor primary structural determinants that deﬁne functional speciﬁcity. EMBO J 1986; 5:2503–12. 75. Kuemmerle JF. Autocrine regulation of growth in cultured human intestinal muscle by growth factors. Gastroenterology 1997; 113:817–24. 76. Ohshiro K, Puri P. Increased insulin-like growth factor-I and platelet-derived growth factor system in pyloric muscle in infantile hypertrophic pyloric stenosis. J Pediatr Surg 1998; 33:378–81. 77. Ohshiro K, Puri P. Increased insulin-like growth factor-I mRNA expression in pyloric muscle in infantile hypertrophic pyloric stenosis. Pediatr Surg Int 1998; 13:253–5. 78. Shima H, Puri P. Increased expression of transforming growth factor-α in infantile hypertrophic pyloric stenosis. Pediatr Surg Int 1999; 15:198–200. 79. Shima H, Ohshiro K, Puri P. Increased local synthesis of epidermal growth factors in infantile hypertrophic pyloric stenosis. Pediatr Res 2000; 47:201–7. 80. Tack ED, Perlman JM, Bower RJ et al. Pyloric stenosis in the sick premature infant. Clinical and radiological ﬁndings. Am J Dis Childh 1988; 142:68–70.

398 Hypertrophic pyloric stenosis 81. Evans AL. Hypertrophic pyloric stenosis presenting in childhood. Postgrad Med J 1987; 63:919. 82. Konvolinka CW, Wermutr CR. Hypertrophic pyloric stenosis in older infants. Am J Dis Child 1971; 122:76–9. 83. Cook RCM. Hypertrophic pyloric stenosis. In: Lister J, Irving IM, editors. Neonatal Surgery. London: Butterworths, 406–20. 84. Spitz L, Batcup G. Haematemesis in infantile hypertrophic pyloric stenosis: the source of bleeding. Br J Surg 1979; 66:827–8. 85. Wooley MM, Felsher BF, Asch J. Jaundice hypertrophic pyloric stenosis and hepatic glucuronyl transferase. J Pediatr Surg 1974; 9:359–63. 86. Zeidan B, Wyatt J, MacKensie A et al. Recent results of treatment of infantile hypertrophic pyloric stenosis. Arch Dis Childh 1988; 63:1060–4. 87. Scharli A, Sieber WK, Kiesewetter WB. Hypertrophic pyloric stenosis at the Children’s Hospital of Pittsburgh from 1912 to 1967. J Pediatr Surg 1969; 4:108–14. 88. Forman HP, Leonidas JC, Kronfeld GD. A rational approach to the diagnosis of hypertrophic pyloric stenosis; do the results match the claims? J Pediatr Surg 1990; 25:262–6. 89. Teele RL, Smith EH. Ultrasound in the diagnosis of iopathic hypertrophic pyloric stenosis. N Engl J Med 1977; 296:1149–50. 90. Blumhagen JD, Coombs JB. Ultrasound in the diagnosis of hypertrophic pyloric stenosis. J Clin Ultrasound 1981; 9:289–92. 91. Gribner R, Pistor G, Abou-Touk B et al. Signiﬁcance of ultrasound for the diagnosis of hypertrophic pykloric stenosis. Pediatr Surg Int 1986; 1:130–4. 92. Spicer RD. Infantile hypertrophic pyloric stenosis: a review. Br J Surg 1982; 69:128–35.

93. Tan KC, Bianchi A. Circumbilical incision for pyloromyotomy. Br J Surg 1986; 73:399. 94. Fitzgerald PG, Lau GY, Langer JC et al. Umbilical fold incision for pyloromyotomy. J Pediatr Surg 1990; 25:1117–18. 95. De Caluwe D, Reding R, de Ville de Goyet J, Otte JB. Intraadominal pyloromyotomy through the umbilical route: a technical improvement. J Pediatr Surg 1998; 33:1806–7. 96. Shankar KR, Losty PD, Jones MO, Turnock RR, Lamont GL, Lloyd DA. Umbilical pyloromyotomy – an alternative to laparoscopy? Eur J Pediatr Surg 2001; 11:8–11. 97. Bufo AJ, Merry C, Shah R, Cyr N, Schropp KP, Lobe TE. Laparoscopic pyloromyotomy: a safer technique. Pediatr Surg Int 1998; 13:240–2. 98. Downey EC Jr. Children’s Surgical Associates, Orange, CA 92668, USA. Semin Pediatr Surg 1998; 7:220–4. 99. Fujimoto T, Lane GJ, Segawa O, Esaki S, Miyano T. Laparoscopic extramucosal pyloromyotomy versus open pyloromyotomy for infantile hypertrophic pyloric stenosis: which is better? J Pediatr Surg 1999; 34:370–2. 100. Leahy A, Fitzgerald FJ. The inﬂuence of delayed feeding on post-operative vomiting in hypertrophic pyloric stenosis. Br J Surg 1982; 69:658–9. 101. Foster ME, Lewis WG. Early postoperative feeding – a continued controversy in pyloric stenosis. J Roy Soc Med 1989; 82:532–3. 102. Wheeler RA, Najamaldin AS, Stoodley N et al. Feeding regimens after pyloromyotomy. Br J Surg 1990; 77:1018–19. 103. Leinward MJ, Shaul DB, Anderson KD. A standardized feeding regimen for hypertrophic pyloric stenosis decreases length of hospitalization and hospital costs. J Pediatr Surg 2000; 35:1063–5.

41 Gastric volvulus MARK D. STRINGER

INTRODUCTION Gastric volvulus is a rare, potentially life-threatening condition ﬁrst described by Berti in 1866.1 A review of the world literature in 1980 identiﬁed only 51 cases in children under 12 years of age.2 Of these, 26 (52%) were infants and half of these were younger than 1 month of age. In recent series, neonates have accounted for an even greater proportion of cases.3,4 In older children, gastric volvulus may be associated with neurodevelopmental handicap but in neonates there is a strong link with diaphragmatic defects. In the last 2 decades, numerous descriptions of acute and chronic gastric volvulus in children have been published, bringing the total number of reported cases to more than 100.3–8

DEFINITION Gastric volvulus may be deﬁned as an abnormal rotation of one part of the stomach around another;9 the degree of twist varies from 180o to 360o and is associated with closed loop obstruction and the risk of strangulation. Lesser degrees of gastric torsion are probably common, frequently asymptomatic, and are not diagnostic of volvulus. Such cases may be associated with transient vomiting in infants but spontaneous resolution is the rule.7,10 Gastric volvulus may be either organoaxial, occurring around an axis joining the esophageal hiatus and the pyloroduodenal junction, or mesenteroaxial, around an axis joining the midpoint of the greater and lesser curves of the stomach (Fig. 41.1). Both types of volvulus occur with similar frequency.4 A mixed picture occurs if the stomach rotates around both axes simultaneously. The usual direction of rotation is anterior, i.e. in organoaxial volvulus the greater curve moves upwards and forwards above the lesser curve, causing the posterior gastric wall to face anteriorly. The gastroesophageal junction and the pylorus may both become obstructed. In anterior mesenteroaxial rotation, the

Axes of rotation in gastric volvulus

Organoaxial volvulus (anterior)

Mesenteroaxial volvulus (anterior)

Figure 41.1 Diagrammatic representation of the main types of gastric volvulus

antrum comes to lie anterosuperior to the fundus and obstruction is usually in the antropyloric region. Acute, complete volvulus is most often seen in infancy in contrast to chronic and partial varieties, which more often occur in older children and adults. More complex patterns of gastric volvulus have been described in neonates and infants with abnormal gastric bands or adhesions (see later), and in older children after gastrostomy11 or Nissen fundoplication.12–14

CLINICAL CASES The following three cases illustrate different aspects of the presentation and management of gastric volvulus in infancy.

400 Gastric volvulus

Case 1

Case 2

A full-term male infant presented soon after birth with cyanotic attacks during feeding. A tracheo-esophageal ﬁstula was initially suspected, but a plain chest radiograph (Fig. 41.2a) showed a gastric shadow lying in front of the heart and a barium swallow (Fig. 41.2b) demonstrated an organoaxial gastric volvulus within the chest. Via a left thoracotomy, the stomach was derotated and reduced into the abdomen with repair of the esophageal hiatus. A gastropexy was not performed and subsequent progress was uneventful.

A full-term male infant presented at 4 days of age with intermittent vomiting. This was initially attributed to a urinary infection, but the vomiting continued and a barium meal showed that there was delayed passage of contrast into the stomach from the esophagus. When the barium was injected via a nasogastric tube, the stomach was seen to lie horizontally and to empty very slowly. At laparotomy, the pylorus was hypertrophied and the stomach was distended. The gastrocolic omentum was deﬁcient along most of the greater curve, allowing free organoaxial rotation of the stomach. A pyloromyotomy and anterior gastropexy were performed, after which the child became symptom-free.

Case 3 A female infant presented at the age of 2 months with a history of loud borborygmi, inability to bring up wind after feeding, and occasional vomiting. On examination, bowel sounds were heard in the chest. Barium meal showed an organoaxially rotated intrathoracic stomach. Via an abdominal approach, a large paraesophageal hernia was reduced, followed by a crural repair and Nissen fundoplication. The child remained asymptomatic 4 years later.

(a)

PATHOGENESIS The stomach is relatively ﬁxed at the esophageal hiatus and at the pyloroduodenal junction and is also stabilized by four ‘ligamentous’ attachments – the gastrohepatic, gastrosplenic, gastrocolic and gastrophrenic ligaments (Fig. 41.3). Despite these attachments, considerable changes in shape and position of the normal stomach are possible. This is highlighted by the gastric rotation that can sometimes be observed during air insufﬂation of the stomach at the time of laparoscopically assisted percuta-

(b) Figure 41.2 (a) Plain chest radiograph showing an air-ﬁlled viscus in the chest (case 1). (b) Barium study showing the stomach lying above the diaphragm with the greater curve uppermost (case 1)

Figure 41.3 Diagrammatic view of the stabilizing gastric ligaments

Clinical features 401

neous endoscopic gastrostomy insertion.15 Absence or attenuation of the normal anatomical anchors results in abnormal gastric mobility, which may be encouraged still further by a coexistent diaphragmatic defect. Most cases of gastric volvulus in the newborn are secondary to diaphragmatic defects with or without deﬁcient ligamentous attachments.2,16–22 The contribution of the gastrocolic and gastrosplenic ligaments to ﬁxation of the stomach is demonstrated by the observation in the cadaver that their division allows 180o rotation of the normal stomach.2,5,23 Eventration or herniation of the diaphragm is present in about two-thirds of all children presenting with gastric volvulus. However, this proportion is as high as 80% in some series of infants.2,17 Diaphragmatic hernias are typically paraesophageal or posterolateral defects but gastric volvulus within a Morgagni hernia is also possible.24 The presumed mechanism of gastric volvulus in this situation is upward displacement of the transverse colon, which pulls up the greater curve of the stomach into the expanded left upper quadrant. Acute gastric volvulus may therefore present as an early complication of diaphragmatic defects. Gastric distension may encourage the development of gastric volvulus.23 Infantile hypertrophic pyloric stenosis may rarely be a predisposing factor, as in the second case described earlier. One similar case has been reported but that infant also had a diaphragmatic defect.25 Air swallowing can also cause gastric distension, and intermittent gastric volvulus has been reported in an aerophagic neurologically handicapped infant.21 Other rare causes of gastric volvulus in the neonate and infant include: abnormal bands or adhesions producing an axis of rotation for the stomach;6,17,21,26 rectal atresia with consequent overdistension of the transverse colon;27 congenital absence or resection of the left lobe of the liver which may promote abnormal gastric mobility;28 and congenital deﬁciency of the gastrocolic omentum.5,29 The asplenic syndrome (asplenia, congenital heart disease, with or without intestinal malrotation and deﬁciency of the gastric ligaments) is increasingly recognized as a predisposing condition.30 Nakada et al. reported gastric volvulus as a complication in three of 25 patients with asplenia, the youngest of whom was 1 month of age.31 Anchoring gastric ligaments were deﬁcient in all cases. Because of the potentially fatal outcome of acute gastric volvulus in this situation, Okoye et al. have recommended prophylactic gastropexy.32 Defective ﬁxation and ligamentous laxity also account for the association between gastric volvulus and a wandering spleen.33,34 Intestinal malrotation is associated with gastric volvulus, even in the absence of asplenia.6,21,26,31,35 Gastric volvulus in children may rarely arise as a postoperative complication. It has been described after Nissen fundoplication, presumably because the stomach has been extensively mobilized by division of gastrosplenic and gastrocolic attachments.12–14,36 There is one recorded case of gastric volvulus developing after repair

of a diaphragmatic hernia17 and another as an iatrogenic complication of gastric transposition in infancy.37

CLINICAL FEATURES The clinical features depend on the degree of rotation and obstruction. In adults, the triad of Borchardt is diagnostic of acute volvulus: (1) unproductive retching; (2) acute localized epigastric distension; and (3) inability to pass a nasogastric tube.38 These features are difﬁcult to assess in the infant and may be absent. Persistent regurgitation and vomiting (sometimes unproductive) are common, although non-speciﬁc, presenting symptoms in the newborn. The vomitus may or may not contain bile, depending on the degree of pyloric obstruction. Hematemesis and anemia are well described and occasionally the vomiting is described as projectile. Failure to thrive and chest infections are sometimes evident.35 Upper abdominal pain and distension may be noted in older infants and children. However, abdominal signs may be minimal if the stomach is intrathoracic, when respiratory distress and tachypnea are the dominant features.2,18,20,39,40 Failure to pass a nasogastric tube may have several causes in the newborn and the successful passage of a tube does not exclude the diagnosis.14,17 In neonates, confusion with esophageal atresia is possible but arrest of the nasogastric tube in the distal esophagus and radiographic abnormalities on routine ﬁlms should raise suspicion and prompt investigation by contrast studies.41 In older children, presenting symptoms may be intermittent, chronic and also non-speciﬁc.14 Plain abdominal and chest radiographs are essential. A distended stomach in an abnormal position should suggest the possibility of gastric volvulus. In mesenteroaxial volvulus, the stomach is spherical on the plain ﬁlm taken with the patient in the supine position, and two ﬂuid levels are often visible on the erect ﬁlm – one in the fundus (the lower) and the other in the antrum (upper) (Fig. 41.4a). Contrast studies clarify the anatomy (Fig. 41.4b) and the site(s) of obstruction, which is usually at the pylorus, giving a so-called ‘beak’ deformity.18 Organoaxial volvulus is more difﬁcult to diagnose on plain ﬁlms (especially if there is no associated diaphragmatic defect) and may indeed be missed during a barium study.21 The distended stomach lies rather horizontally on the plain ﬁlm, with a single ﬂuid level. On contrast examination, the esophagogastric junction is lower than normal, the greater and lesser curves are inverted, and the antrum and duodenum are distorted (Fig. 41.5). Obstruction may be present at both the gastro-esophageal junction and the pylorus. In the presence of a diaphragmatic defect, such as a paraesophageal hernia, the antrum may herniate into the retrocardiac position, producing a ﬂuid level in the chest above the gastric fundus, and thus organoaxial volvulus can also rarely give rise to two ﬂuid levels.42

402 Gastric volvulus

(a)

Figure 41.5 Oblique view of barium meal demonstrating an organoaxial gastric volvulus in a neonate who presented with intermittent vomiting (case 2)

TREATMENT Acute gastric volvulus requires appropriate resuscitation and urgent surgery if ischemic necrosis and gastric perforation are to be avoided. If possible, the stomach should be decompressed preoperatively by nasogastric suction but vigorous attempts to pass a tube must be avoided because of a risk of gastric perforation.17 An abdominal approach is recommended, even when the stomach lies in the chest, since this allows identiﬁcation of any associated gastrointestinal anomalies and accurate diaphragmatic repair if required, and because the esophagus is normal in length. The volvulus should be reduced. Occasionally, preliminary needle aspiration of the stomach may be warranted before manipulating a tensely dilated stomach.43 Any associated diaphragmatic defect should be repaired and the stomach ﬁxed to the anterior abdominal wall (Box 41.1). Box 41.1 Surgical options for gastric volvulus in the neonate/infant (b) Figure 41.4 (a) Plain abdominal radiograph showing a distended stomach but only a single ﬂuid level in this neonate with mesenteroaxial gastric volvulus. (b) Barium study conﬁrming mesenteroaxial gastric volvulus

Repair of diaphragmatic defect, division of congenital bands, etc. and anterior gastrostomy Crural repair (if necessary) and anterior gastropexy Crural repair and fundoplication for cases with severe gastro-esophageal reﬂux

References 403

Gastrostomy alone may be used for gastric ﬁxation in neonates, since it provides adequate ﬁxation, postoperative decompression and a route for postoperative feeding. A Stamm gastrostomy using a 10 or 12 Fr. gauge Malecot catheter secured by a double pursestring suture of 4-0 Vicryl or Polydioxanone is appropriate (Fig. 41.6a). In infants with no predisposing diaphragmatic defect, an anterior gastropexy should be added (Fig. 41.6b). This involves suturing the greater curve of the stomach to the parietal peritoneum of the anterior abdominal wall and the undersurface of the diaphragm by a series of 4-0 nonabsorbable sutures. There are three recorded cases of recurrence following this approach44,45 but the initial gastric ﬁxation in these cases was inadequate. Fundoplication may be necessary if there is evidence of gross gastro-esophageal reﬂux but several authors have achieved good results in such cases with a crural repair alone and a more conservative approach is warranted provided the tendency to volvulus is prevented.35,36 Diaphragmatic crural repair must be performed meticulously – there is often a common hiatus for the esophagus and aorta in these patients.36 There is no justiﬁcation for gastrectomy, gastroenterostomy or the colonic displacement operation described by Tanner9 in

(a)

(b)

Figure 41.6 Operative techniques in neonatal gastric volvulus. (a) Anterior Stamm gastrostomy using a Malecot catheter. (b) Anterior gastropexy

this age group. Adults with gastric volvulus have also fared well with relatively simple surgery.46 In older children with isolated gastric volvulus preliminary nasogastric decompression followed by a laparoscopic anterior gastropexy is an option.29 In gastric volvulus due to a wandering spleen, splenopexy alone may be sufﬁcient.47 The mortality from gastric volvulus is difﬁcult to assess and available ﬁgures are subject to publication bias. Deaths have been reported due to missed or delayed diagnosis, with subsequent gastric necrosis and perforation, or inadequate gastric ﬁxation.4,8,17,19,21,22 Most recent series have reported uncomplicated early outcomes after surgery. One long-term follow-up study of nine infants demonstrated no recurrences or late complications.4

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404 Gastric volvulus 16. McDevitt JB. Intrathoracic volvulus of the stomach in a newborn infant. Ir J Med Sci 1970; 3:131–2. 17. Cole BC, Dickinson SJ. Acute volvulus of the stomach in infants and children. Surgery 1971; 70:707–17. 18. Campbell JB. Neonatal gastric volvulus. Am J Roentgenol 1979; 132:723–5. 19. Talukdar BC. Gastric volvulus with perforation of stomach in congenital diaphragmatic hernia in an infant. J Indian Med Assoc 1979; 73:219–21. 20. Starshak RJ, Sty JR. Diaphragmatic defects with gastric volvulus in the neonate. Wisc Med J 1983; 82:28–31. 21. Ziprkowski MN, Teele RL. Gastric volvulus in childhood. Am J Roentgenol 1989; 132:921–5. 22. El-Gohary MA, Etiaby A. Gastric volvulus in infants and children. Pediatr Surg Int 1994; 9:486–8. 23. Dalgaard JR. Volvulus of the stomach. Acta Chir Scand 1952; 103:131–53. 24. Estevao-Costa J, Soares-Oliveira M, Correia-Pinto J et al. Acute gastric volvulus secondary to a Morgagni hernia. Pediatr Surg Int 2000; 16:107–8. 25. Moreno Torres E. Estenosis per hipertroﬁa de piloro con volvulo gastrico. Bol Soc Valenciana Paediatr 1968; 10:231–2. 26. Iko BO. Volvulus of the stomach: an African series and a review. J Natl Med Assoc 1987; 79:171–6. 27. Mizrahi S, Vinograd I, Schiller M. Neonatal gastric volvulus secondary to rectal atresia. Clin Pediatr 1988; 27:302–4. 28. Chuang JH, Hsieh CS, Hueng SC, Wan Y-L. Gastric volvulus complicating left hepatic lobectomy. Pediatr Surg Int 1993; 8:255–6. 29. Odaka A, Shimomura K, Fujioka M et al. Laparoscopic gastropexy for acute gastric volvulus: a case report. J Pediatr Surg 1999; 34:477–8. 30. Aoyama K, Teteishi K. Gastric volvulus in three children with asplenic syndrome. J Pediatr Surg 1986; 21:307–10. 31. Nakada K, Kawaguchi F, Wakisaka M et al. Digestive tract disorders associated with asplenia/polysplenia syndrome. J Pediatr Surg 1997; 32:91–4. 32. Okoye BO, Bailey DMC, Cusick EL, Spicer RD. Prophylactic gastropexy in the asplenia syndrome. Pediatr Surg Int 1997; 12:28–9.

33. Garcia JA, Garcia-Fernandez M, Romance A, Sanchez JC. Wandering spleen and gastric volvulus. Pediatr Radiol 1994; 24:535–6. 34. Spector JM, Chappell J. Gastric volvulus associated with wandering spleen in a child. J Pediatr Surg 2000; 35:641–2. 35. Samuel M, Burge DM, Grifﬁths DM. Gastric volvulus and associated gastro-oesophageal reﬂux. Arch Dis Child 1995; 73:462–4. 36. Stiefel D, Willi UV, Sacher P, Schwobel MG, Stauffer UG. Pitfalls in therapy of upside-down stomach. Eur J Pediatr Surg 2000; 10:162–6. 37. Chan KL, Saing H. Iatrogenic gastric volvulus during transposition for esophageal atresia: diagnosis and treatment. J Pediatr Surg 1996; 31:229–32. 38. Borchardt M. Zur Pathologie und Therapie des Magen volvulus. Arch Klin Chir 1904; 74:243–60. 39. Beckmann KR, Nozicka CA. Congenital diaphragmatic hernia with gastric volvulus presenting as an acute tension gastrothorax. Am J Emerg Med 1999; 17:35–7. 40. Mutabagani KH, Teich S, Long FR. Primary intrathoracic gastric volvulus in a newborn. J Pediatr Surg 1999; 34:1869–71. 41. Yadav K, Myers NA. Paraesophageal hernia in the neonatal period – another differential diagnosis of oesophageal atresia. Pediatr Surg Int 1997; 12:420–1. 42. Scott RL, Felker R, Winer-Muram H et al. The differential retrocardiac air-ﬂuid level: a sign of intrathoracic gastric volvulus. J Can Assoc Radiol 1986; 37:119–21. 43. Asch MJ, Sherman NJ. Gastric volvulus in children: report of two cases. J Pediatr Surg 1977; 12:1059–62. 44. Stephenson RH, Hopkins WA. Volvulus of the stomach complicating eventration of the diaphragm. Am J Gastroenterol 1964; 41:225–7. 45. Colijn AW, Kneepkens CM, van Amerongen AT, Ekkelkamp S. Gastric volvulus after anterior gastropexy. J Pediatr Gastroenterol Nutr 1993; 17:105–7. 46. Wastell C, Ellis H. Volvulus of the stomach. A review with a report of 8 cases. Br J Surg 1971; 58:557–62. 47. Zivkovic SM. Sutureless ‘button and hole’ splenopexy. Pediatr Surg Int 1998; 13:220–2.

42 Gastric perforation ROBERT K. MINKES

BACKGROUND Gastric perforation in the neonatal period is a rare event, however it continues to be associated with signiﬁcant morbidity and mortality. Spontaneous neonatal gastric perforation is estimated to occur in 1 in 2900 live births1 and accounts for approximately 10–15% of all gastrointestinal perforations in neonates and children (Table 42.1). Gastrointestinal perforations occur more frequently in males, however there appears to be no sex predilection for those occurring in the stomach.2–4 The terminology used to describe neonatal gastric perforation has been inconsistent and its etiology a subject of ongoing debate. Spontaneous gastric perforations refer to those with no identiﬁable underlying cause and account for the majority of gastric perforations in most reported series.1, 3, 5–10 Many pediatric surgeons now believe that a contributing cause can be found in most instances and an underlying etiology should be sought in any neonate with a gastric perforation.11 Siebold, in 1826 provided the ﬁrst description of a gastrointestinal perforation with no demonstrable cause, the so-named spontaneous perforation.12 In 1929, Stern et al.13 reported one of the ﬁrst attempts at surgical repair. Agerty et al. reported the ﬁrst successful repair of a neonatal intestinal (ileum) perforation in 194314 and Leger, in 1950, described the ﬁrst successful repair of a neonatal gastric perforation.15 Survival following a gastric perforation in the 1950s was uncommon. While the overall mortality rate has steadily improved it remains signiﬁcant and ranges from 25% to over 50% in most recent

series.1,2,4,11,16,17 The survival rate in premature neonates remains poor despite advances in intensive care, ventilator management, and operative and anesthetic techniques.

ETIOLOGY Gastric perforation in neonates can be broadly categorized as spontaneous (idiopathic), ischemic, or traumatic, however in many instances the etiology is multifactorial. Box 42.1 lists several causes and associations with gastric perforation in the neonate. Spontaneous gastric perforations occur most commonly on the greater curvature and have no identiﬁable cause.1 Spontaneous perforation occurs in full-term, premature, or small for gestational age neonates. Some infants appear to have been healthy and medically stable prior to the development of the perforation, whereas others have underlying medical conditions. Spontaneous perforation may result from unrecognized overdistention or ischemic insult. Ischemic perforations occur in the setting of physiologic stress such as prematurity, asphyxia, sepsis, and necrotizing enterocolitis. These perforations are associated with ulceration and have surrounding necrosis and ischemic tissue. Traumatic perforation results from pneumatic distention during mask ventilation, positive-pressure ventilation, or iatrogenic injury during gastric intubation. Several speciﬁc underlying causes of neonatal gastric perforation have been reported including intestinal atresias, perinatal stress, trauma, and exposure to cortico-

Table 42.1 Incidence of gastrointestinal perforation Author

Year

Total

Grosfeld et al.17 Tan et al.8 Bell4 Borzitta and Groff39 St-Vil et al.40

1996 1989 1985 1988 1992

179 56 60 29 81

16 9 5 2 10 6 5 1 7 stomach–duodenum

405

43 (10%)

Total

Stomach

Duodenum

18 (5%)

Small bowel

Colon/rectum

Non-designated

105 26 30 12 38

37 23 10 11 32

12 4 (multiple) 6 (multiple) 4

211 (52%)

113 (28%)

(5%)

406 Gastric perforation Box 42.1 Causes and associations of neonatal gastric perforation Idiopathic Perinatal stress • Hypoxia • Asphyxia Prematurity3, 8 Anatomic defect • Distal obstruction – Pyloric atresia41 – Duodenal atresia3 – Midgut volvulus25 • Tracheo-esophageal ﬁstula20, 42-45 • Congenital deﬁciency of gastric muscle Iatrogenic • Nasogastric tube22 • Aggressive bag ventilation with or without tracheoesophageal ﬁstula19, 20 • Cardiopulmonary resuscitation30, 46 • Positive pressure ventilation • Inadvertent perforation during surgery (ventriculoperitoneal shunt)27, 47 • Vaginal delivery18 Medication • Indomethacin29, 48 • Corticosteroids28

steroids and nonsteroidal anti-inﬂammatory agents (Box 42.1). A variety of theories on the etiology of spontaneous perforations have been suggested but no single theory is universally accepted. The theories include congenital absence of gastric muscle,5,6 forces exerted during vaginal delivery,18 and pneumatic distention.19, 20 Studies in dogs and human neonatal cadavers suggest that rupture is caused by overdistention and is in keeping with the law of Laplace.7 With gastric distention the greatest wall tension is exerted on the fundus, the site of most spontaneous perforations. Gastric distention can also produce ischemic changes, a ﬁnding present in 41% of cases in one series.2 A recent theory suggests that idiopathic gastric perforations result from a deﬁciency of C-KIT+, a receptor tyrosine kinase crucial for normal development of mast cells.21 Mice lacking C-KIT+ mast cells develop spontaneous gastric ulceration or perforation. In addition, postmortem examination of neonates who died of spontaneous gastric perforation revealed a lower number of gastric C-KIT+ mast cells when compared with those who died from gastric perforation with an identiﬁable underlying causes such as intestinal atresia. The number of CKIT+ mast cells in neonates with idiopathic perforation was also lower than those found in control neonates who died of other causes with no gastric perforation.21

CLINICAL PRESENTATION The clinical presentation of gastric perforation is variable. The majority of cases present within the ﬁrst 5

days of life.4,8,22 The neonates are often premature or have a history of asphyxia or hypoxia.2,3,8,16 Neonates may present with feeding intolerance and emesis that may contain blood. Typically, the neonates develop an abrupt onset of rapidly progressive abdominal distention. These infants develop respiratory distress, hemodynamic instability and signs of shock such as hypothermia, cyanosis, poor peripheral perfusion, and low urine output. The abdomen rapidly becomes tense and tender with signs of peritoneal irritation. Subcutaneous emphysema may develop in the abdominal wall and several authors have reported pneumoscrotum as a presenting feature.23,24 Infants with posterior perforations into the lesser sac may present with a more insidious course, making the diagnosis difﬁcult. Infants with perforation secondary to an underlying process often have evidence of the predisposing condition such as ﬁndings of tracheo-esophageal ﬁstula, duodenal atresia, malrotation, or diaphragmatic hernia.3,20,25,26 In some instances, a secondary cause is found at the time of operation. In cases of iatrogenic perforation a history of traumatic nasogastric intubation, prior surgery, corticosteroid or nonsteroidal administration, and aggressive ventilation or