.
`
`
`
`Q..«W
`
`

`
`Neonatal respiratory
`disorders
`
`

`
`Neonatal respiratory
`disorders
`
`Second edit ion
`
`Edited by
`
`Anne Greenough MD, FRCP, DCH
`Professor of Clinical Respiratory Physiology and
`Honorary Consultant Paediatrician
`King's College School of Medicine and Dentistry
`London, UK
`
`Anthony D Milner MD, FRCP, DCH
`Professor of Neonatology
`Department of Child Health
`United Medical and Dental School of Guy's and
`StThomas' Hospitals
`London, UK
`
`~ ARNOLD
`
`A member of the Hodder Headline Group
`
`LONDON
`
`

`
`First published in Great Britain 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, NY10016
`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 Totten ham 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 80813 6
`
`12345678910
`
`Commissioning Editor: joanna Koster
`Development Editor: Sarah Burrows
`Project Editor: Anke Ueberberg
`Production Controller: Deborah Smith
`Cover Design: Stewart Larking
`
`Typeset in 10/12 Minion by Charon Tee Pvt Ltd., Chennai, India
`Printed and bound in Italy
`
`What do you think about this book? Or any other Arnold title?
`Please send your comments to feedback.arnold@hodder.co.uk
`
`

`
`To our very much loved daughter Antonia, for her unfailing good humor and
`patience while Mummy and Daddy 'wrote the book:
`
`

`
`Contents
`
`List of contributors
`
`Preface
`
`Acknowledgments
`
`List of abbreviations
`
`PART 1 DEVELOPMENT AND PHYSIOLOGY OF THE RESPIRATORY SYSTEM
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`Fetal and postnatal anatomical lung development
`Alison A Hislop
`
`Surfactant
`Bengt Robertson and jan Johansson
`
`lung liquid
`Dafydd V Walters
`
`Control of breathing
`Anthony D Milner, Hugo Lagercrantz and Ronny Wickstrom
`
`Development of the immune system
`Susan Leech
`
`Adaptation at birth
`Anthony D Milner
`
`PART2 ANTENATAL AND POSTNATAL INVESTIGATION
`
`7
`
`8
`
`9
`
`10
`
`11A
`
`11B
`
`12
`
`Clinical assessment
`Anne Greenough, with contributions from NRC Roberton
`
`Microbiology
`Amanda Fife
`
`Immunology
`Susan Leech
`
`Histopathology
`Dl Rushton, with contributions from S Gould
`
`Antenatal imaging and therapy
`Kypros H Nicolaides, with contributions by Anne Greenough
`
`Neonatal imaging
`john Karani
`
`Neonatal bronchoscopy
`jacques de Blic
`
`xi
`
`xiii
`
`xiv
`
`XV
`
`1
`
`3
`
`12
`
`26
`
`37
`
`50
`
`59
`
`67
`
`69
`
`72
`
`77
`
`83
`
`92
`
`99
`
`106
`
`

`
`viii Contents
`
`13
`
`Measurement of lung function
`Anthony D Milner and Gerrard F Rafferty
`
`PART 3 CLINICAL MANAGEMENT OF THE NEONATE WITH RESPIRATORY PROBLEMS
`
`14
`
`15
`
`16A
`
`16B
`
`17
`
`18
`
`Resuscitation at birth
`Anthony D Milner
`
`Respiratory support
`Anne Greenough, including 'Proportional Assist Ventilation' by Andreas Schulze and,
`'Liquid Ventilation' by Thomas H Shaffer and Marla R Wolfson
`
`Intensive care
`Neena Modi
`
`Feeding
`Sean P Devane
`
`Monitoring
`Andrew Lyon and Ben Stenson
`
`Physiotherapy
`Annette Parker and Anne Greenough
`
`PART 4 NEONATAL RESPIRATORY PROBLEMS
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`26
`
`27
`
`28
`
`29
`
`30
`
`31
`
`Respiratory distress syndrome
`Henry L Halliday
`
`Transient tachypnea of the newborn (TTN)
`Anne Greenough
`
`Pneumonia
`Peter RF Dear, with contributions from Amanda Fife
`
`Air leaks
`Anne Greenough
`
`Aspiration syndromes
`Thomas E Wiswell and Pinchi Srinivasan, with contributions by NRC Roberton
`
`Pleural effusions
`Anne Greenough
`
`Pulmonary hemorrhage
`Grenville F Fox
`
`Persistent pulmonary hypertension of the newborn
`Steven H Abman and john P Kinsella
`
`Respiratory presentation of cardiac disease
`Edward Baker
`
`Acute respiratory distress syndrome
`Anne Greenough
`
`Bronchopulmonary dysplasia
`Ilene RS Sosenko and Eduardo Bancalari, with contributions from Anne Greenough
`
`Apnea and bradycardia of prematurity
`]alai M Abu-Shaweesh, Terry M Baird and Richard J Martin
`
`Neonatal upper airway obstruction
`David Albert
`
`112
`
`131
`
`133
`
`149
`
`205
`
`216
`
`224
`
`236
`
`245
`
`247
`
`272
`
`278
`
`311
`
`334
`
`355
`
`365
`
`373
`
`387
`
`396
`
`399
`
`423
`
`437
`
`

`
`32
`
`33
`
`34
`
`35
`
`36
`
`Pulmonary agenesis and hypoplasia
`Anne Greenough
`
`Abnormalities of lung development
`Anne Greenough and Mark Davenport
`
`Abnormalities of the diaphragm
`Anne Greenough and Mark Davenport
`
`Abnormalities of the skeleton
`Anne Greenough
`
`Respiratory problems of infants with neurological disease
`janet M Rennie
`
`APPENDICES
`
`Appendix 1 Normal data for lung function in term infants during the neonatal period
`Simon Hannam
`
`Appendix 2 Normal blood gas values
`Simon Hannam
`
`Appendix 3 Pharmacopeia
`Simon Hannam
`
`Index
`
`Contents ix
`
`449
`
`463
`
`486
`
`505
`
`519
`
`529
`
`531
`
`532
`
`533
`
`539
`
`

`
`List of contributors
`
`Steven H Abman MD
`Professor of Pulmonary and Critical Care, Director,
`Pediatric Heart Lung Center, Department of Pediatrics,
`University of Colorado School of Medicine and
`The Children's Hospital, Denver, CO, USA
`
`Jalal M Abu-Shaweesh MD
`Assistant Professor of Pediatrics, Case Western Reserve
`University, Cleveland, OH, USA
`
`David Albert
`Consultant Paediatric Otolaryngologist, Portland Hospital
`Consulting Suite, London, UK
`
`Terry M Baird MD
`Assistant Professor of Pediatrics, Case Western Reserve
`University, Cleveland, OH, USA
`
`Edward Baker
`Senior Lecturer and Honorary Consultant, Paediatric
`Cardiology, Department of Congenital Heart Disease,
`Guy's Hospital, London, UK
`
`Eduardo Bancalari MD
`Professor of Pediatrics, Director, Division of Neonatology,
`University of Miami School of Medicine, Miami, FL, USA
`
`jacques de Blic MD
`Service de Pneumologie et d'AIIergologie Pediatriques,
`Necker Enfants Malades Hospital, Paris, France
`
`Mark Davenport
`Consultant Paediatric Surgeon, Paediatric Surgery, King's
`College Hospital, London, UK
`
`Peter RF Dear MD FRCP FRCPCH DCH
`Consultant in Neonatal Medicine, Regional Neonatal
`Intensive Care Unit, StJames's University Hospital,
`Leeds, UK
`
`Sean P Devane
`Consultant Neonatologist, Children Nationwide Regional
`Neonatal Intensive Care Centre, King's College Hospital,
`London, UK
`
`Steven M Donn MD
`Professor of Pediatrics, Director, Neonatal-Perinatal
`Medicine, University of Michigan Health System, Mott
`Children's Hospital, Ann Arbor, Ml, USA
`
`and StThomas' School of Medicine, Department of
`Microbiology, King's College Hospital, London, UK
`
`Grenville F Fox MBChB MRCP FRCPCH
`Consultant Neonatologist, Guy's and StThomas' Hospital
`Trust, Guy's Hospital, London, UK
`
`Anne Greenough
`Professor of Clinical Respiratory Physiology,
`Department of Child Health, King's College Hospital,
`London, UK
`
`Henry L Halliday MD FRCPE FRCP FRCPCH
`Professor, The Nuffield Department of Child Health,
`Queen's University of Belfast, Institute of Clinical Science,
`Belfast, Northern Ireland
`
`Simon Hannam
`Consultant and Honorary Senior Lecturer in Neonatal
`Medicine, Department of Child Health, King's College
`Hospital, London, UK
`
`Alison A Hislop PhD
`Reader in Developmental Vascular Biology, Vascular
`Biology and Pharmacology Unit, Institute of Child Health,
`Great Ormond Street Hospital, London, UK
`
`jan Johansson MD PhD
`Professor, Department of Veterinary Medical Chemistry,
`Swedish University of Agricultural Sciences, Uppsala,
`Sweden, Karolinska lnstitutet, Stockholm, Sweden
`
`John Karani
`Consultant Radiologist, Department of Diagnostic
`Radiology, King's College Hospital, London, UK
`
`John P Kinsella MD
`Professor of Neonatology, Department of Pediatrics,
`University of Colorado School of Medicine and
`The Children's Hospital, Denver, CO, USA
`
`Hugo lagercrantz
`Professor, Karolinska lnstitutet, Astrid Lindgren Children's
`Hospital, Department of Woman and Child Health,
`Neonatal Unit, Karolinska Hospital, Stockholm, Sweden
`
`Susan Leech
`Consultant Paediatrician, Department of Child Health,
`King's College Hospital, London, UK
`
`Amanda Fife
`Consultant Microbiologist, South London Public Health
`Laboratory and Department of Infection, Guy's, King's
`
`Andrew lyon MA MB FRCP FRCPCH
`Consultant Neonatologist, Neonatal Unit, Simpson Centre
`for Reproductive Health, Edinburgh, UK
`
`

`
`xii List of contributors
`
`Richard J Martin MD
`Professor of Pediatrics, Case Western Reserve University;
`and Director, Division of Neonatology, Rainbow Babies
`and Children's Hospital, Cleveland, OH, USA
`Anthony D Milner
`Professor of Neonatology, Department of Child Health,
`United Medical and Dental School of Guy's and StThomas'
`Hospitals, London, UK
`Neena Modi MBChB MD FRCP FRCPCH
`Reader and Consultant in Neonatal Medicine, Division of
`Paediatrics, Obstetrics & Gynaecology, Faculty of
`Medicine, Imperial College, Hammersmith Hospital and
`Chelsea and Westminster Hospital, London, UK
`Kypros H Nicolaides
`Director, Harris Birthright Research Centre for Fetal
`Medicine, King's College Hospital, London, UK
`Annette Parker MCSP
`Superintendent Physiotherapist, Physiotherapy
`Department, Taunton and Somerset Hospital,
`Taunton, Somerset, UK
`Gerrard F Rafferty
`Lecturer in non-Clinical Respiratory Physiology,
`Department of Child Health, Guy's, King's & StThomas'
`School of Medicine, London, UK
`janet M Rennie MA MD FRCP FRCPCH DCH
`Consultant and Honorary Senior Lecturer in
`Neonatal Medicine, King's College Hospital,
`London, UK
`N R Clifford Roberton MA MB FRCP
`Emeritus Consultant Paediatrician, Addenbrooke's
`Hospital, Cambridge, UK
`Bengt Robertson MD PhD
`Professor, Laboratory for Surfactant Research,
`Department of Surgical Sciences, Karolinska Institute,
`Stockholm, Sweden
`David I Rushton MB ChB FRCPCH FRCPath
`Consultant Perinatal and Paediatric Pathologist,
`Birmingham Women's Hospital, UK
`
`Andreas Schulze MD
`Professor of Pediatrics, Head, Division of Neonatology,
`Department of Obstetrics and Gynecology, Division of -
`Neonatology, Klinikum Grosshadern, Mlinchen, Germany
`Thomas H Shaffer
`Director, Nemours Lung Center, Department of Research,
`Alfred I. duPoint Hospital for Children, Wilmington,
`DE, USA; and Professor of Physiology and Pediatrics
`and Director, Respiratory Physiology Section, Temple
`University School of Medicine, Departments of Physiology
`and Pediatrics, Temple University Children's Hospital,
`Philadelphia, PA, USA
`Ilene RS Sosenko MD
`Professor of Pediatrics, Associate Director for Clinical
`Development and Outreach, Division of Neonatology,
`University of Miami School of Medicine, Miami, FL, USA
`Pinchi Srinivasan MD
`Fellow in Neonatology, Department of Pediatrics,
`State University of New York, Stony Brook, NY, USA
`Ben Stenson MB MD FRCP FRCPCH
`Consultant Neonatologist, Simpson Centre for
`Reproductive Health Pavilion, Edinburgh, UK
`Dafydd V Walters
`Professor of Child Health, StGeorge's Hospital Medical
`School, University of London, London, UK
`Ronny Wickstrom
`Karolinska lnstitutet, Astrid Lindgren Children's Hospital,
`Department of Woman and Child Health, Neonatal Unit,
`Karolinska Hospital, Stockholm, Sweden
`Marla R Wolfson
`Associate Professor of Physiology and Pediatrics,
`Temple University School of Medicine, Department of
`Physiology and Pediatrics, Temple University Children's
`Hospital, Philadelphia, PA, USA
`Thomas E Wiswell MD
`Attending Neonatologist and Professor of Pediatrics,
`Health Sciences Center, State University of New York,
`Stony Brook, NY, USA
`
`

`
`Preface
`
`Respiratory disorders remain a major problem in neo(cid:173)
`natal intensive care. As a consequence, this is an area of
`intensive research. In writing the second edition we,
`therefore, felt it important to involve leading researchers
`from all over the world to contribute in their specialist
`areas. Our aim is for this book to provide a comprehensive
`
`and up-to-date statement on the physiology, pathology,
`management and outcome of respiratory problems
`facing neonatal clinicians on a daily basis.
`
`Anne Greenough MD, FRCP, DCH
`Anthony D Milner MD, FRCP, DCH
`
`

`
`Acknowledgments
`
`We would like to acknowledge the enormous debt we
`owe to all who contributed chapters to this book and to
`their secretaries. We are particularly grateful to Sue
`Williams in the Department of Child Health at Guy's,
`King's and StThomas' School of Medicine whose excel(cid:173)
`lent secretarial, administrative and interpersonal rela(cid:173)
`tionship skills, patience and goodwill enabled this second
`edition to be completed. We are enormously grateful to
`Dr Paul Cheeseman who spent many hours meticulously
`
`scanning in all the figures, to Dr John Karani who addi(cid:173)
`tionally provided the legends to all the chest radiographs
`and Dr Johan Smith who provided key imaging pictures.
`We also acknowledge the help received from all Edward
`Arnold staff, particularly Sarah Burrows and Dr Joanna
`Koster.
`
`Anne Greenough MD, FRCP, DCH
`Anthony D Milner MD, FRCP, DCH
`
`

`
`Abbreviations
`
`J-L
`WL
`
`a/A0 2
`A/C
`AaD02
`AC
`AchR
`ACT
`ADH
`AFI
`AHA/AAP
`
`heavy chain of IgM molecule
`surrogate light chain of the
`immunoglobulin molecule, formed
`during B-cell development
`arterial/alveolar oxygen
`assist control
`alveolar-arterial oxygen difference
`alternating current
`acetylcholine receptor
`activated clotting time
`antidiuretic hormone
`amniotic fluid index
`American Heart Association/ American
`Academy of Pediatrics
`acquired lobar emphysema
`acute life-threatening event
`alpha-amino-3-hydroxyl-5-methyl-4-
`isoxazole-propionate
`anteroposterior
`acute respiratory distress syndrome;
`adult respiratory distress syndrome
`assistence respiratoire extracorporelle
`acute renal failure
`asphyxiating thoracic dystrophy
`adenosine triphosphate
`American Thoracic Society
`arginine vasopressin
`abdominal wall defects
`atypical, self-renewing B cells with a
`less diverse receptor repertoire than
`conventional B cells, secreting mainly
`IgM
`bronchoalveolar lavage
`bacille Calmette-Guerin
`basic fibroblast growth factor
`bovine liquid extract surfactant
`bronchopulmonary dysplasia
`beats per minute; breaths per minute
`blood urea nitrogen
`gene segment coding for the constant
`region of the IgM heavy chain
`inhibitor of the classical pathway of
`complement activation
`C3, C4, CS, C9 complement component
`
`ALE
`ALTE
`AMPA
`
`AP
`ARDS
`
`AREC
`ARF
`ATD
`ATP
`ATS
`AVP
`AWD
`B-1 cells
`
`BAL
`BCG
`bFGF
`BLES
`BPD
`bpm
`BUN
`CJ-L
`
`Cl esterase
`
`CD
`
`CDH
`CDR3
`
`CAM
`
`cAMP
`CBFV
`CBS
`CClO
`CCAM
`
`cystic adenomatoid malformation of the
`lung
`cyclic adenosine monophosphate
`cerebral blood flow velocity
`captive bubble system
`Clara celllO kDa protein
`congenital cystic adenomatoid
`malformation of the lung
`clusters of differentiation representing cell
`surface molecules
`congenital diaphragmatic hernia
`complementarity determining region
`3 - hypervariable loop at the end of variable
`domain of antibodies or T-cell receptors
`CFTR
`cystic fibrosis transmembrane regulator
`cGMP
`cyclic guanosine monophosphate
`CHAOS
`congenital high airway obstruction
`CHARGE coloboma of the iris and retina, heart
`disease, atresia choanae, retarded growth,
`genital hypoplasia, ear defects
`confidence interval
`creatine kinase
`chronic lung disease
`conventional mechanical ventilation;
`cytomegalovirus
`continuous negative extrathoracic pressure
`central nervous system
`carbon dioxide
`coagulase-negative staphylococci
`continuous positive airways pressure
`congenital pulmonary lymphangiectasis
`complement receptor 3
`carbohydrate recognition domain
`C-reactive protein
`capillary refill time
`cerebrospinal fluid
`computerized tomography
`central venous pressure
`chorion villus sampling
`chest X-ray
`direct current
`disseminated intravascular coagulation
`deoxyribonucleic acid
`dipalmitoylphosphatidylcholine
`
`CI
`CK
`CLD
`CMV
`CMV
`CNEP
`CNS
`C02
`CoNS
`CPAP
`CPL
`CR3
`CRD
`CRP
`CRT
`CSF
`CT
`CVP
`cvs
`CXR
`DC
`DIC
`DNA
`DPPC
`
`

`
`xvi Abbreviations
`
`DTPA
`EA
`EBV
`ECG
`ECHO
`ECMO
`EDHF
`
`EEG
`EPA
`EGF
`ELBW
`ELSO
`
`EMG
`ENaC
`ENG
`ENT
`EOG
`EPI
`EPIMRI
`EPO
`ERS
`ET
`ET-1
`EXIT
`Factor B
`
`FB
`FBM
`Fe
`
`Fcyreceptor
`
`FDLE
`FEV0.5
`FEV0.75
`
`FG
`Fi02
`FPEFVL
`
`FRC
`FSP
`PVC
`GA
`GABA
`GBS
`G-CSF
`GER
`GI
`GM-CSF
`
`GMP
`HB1R
`
`diethylene triamine pentaacetic acid
`early amniocentesis
`Epstein-Barr virus
`electrocardiograph
`echocardiograph
`extracorporeal membrane oxygenation
`endothelium -derived hyperpolarizing
`factor
`electroencephalograph
`essential fatty acid
`epidermal growth factor
`extremely low birthweight
`Extracorporeal Life Support
`Organization
`electromyograph
`epithelial sodium channel
`electroneurogram
`ear, nose and throat
`electro-oculograph
`echoplanar imaging
`echoplanar magnetic resonance imaging
`erythropoietin
`European Respiratory Society
`endotracheal tube
`endothelin -1
`ex utero intrapartum treatment
`component of the alternative pathway of
`complement activation
`fiberoptic bronchoscope
`fetal breathing movements
`fragment crystallizable- contains the
`majority of the constant regions of the
`IgG molecule
`receptor for the constant arm of the IgG
`molecule
`fetal distal lung epithelial
`forced expiratory volume in half a second
`forced expiratory volume in three-
`quarters of a second
`French gauge
`inspired oxygen concentration
`forced partial expiratory flow-volume
`loop
`functional residual capacity
`familial spontaneous pneumothorax
`forced vital capacity
`gestational age
`gamma-aminobutyric acid
`group B streptococcus
`granulocyte-colony stimulating factor
`gastroesophageal reflux
`gastrointestinal
`granulocyte-macrophage colony-
`stimulating factor
`guanosine 3,5-monophosphate
`Hering-Breuer inflation reflex
`
`HFFI
`HFJV
`HFO
`HFOV
`HFPPV
`
`HIV
`HLA
`
`HMD
`HNF-3!3
`HRCT
`HSV
`I:E
`ICH
`ID
`IFD
`IFN
`Ig
`IL
`ILCOR
`
`IMV
`iNO
`IPPV
`IQ
`IRDS
`ITPV
`IVC
`IVH
`IVIG
`JCT
`KGF
`L:S
`LFT
`LPC
`LPEP/LVET
`
`LIT
`LV
`M3G
`M6G
`MAP
`MAS
`MCT
`MDI
`MHC
`MRA
`MRI
`mRNA
`MRSA
`
`MUPG
`
`MV
`Na+
`
`high-frequency flow interrupter
`high-frequency jet ventilation
`high-frequency oscillation
`high -frequency oscillatory ventilation
`high-frequency positive pressure
`ventilation
`human immunodeficiency virus
`human leukocyte antigen - genetic
`designation for MHC
`hyaline membrane disease
`hepatocyte nuclear factor-3!3
`high-resolution computed tomography
`herpes simplex virus
`inspiratory:expiratory
`intracranial hemorrhage
`internal diameter
`infant flow driver
`interferon
`immunoglobulin
`interleukin
`International Liaison Committee on
`Resuscitation
`intermittent mandatory ventilation
`inhaled nitric oxide
`intermittent positive pressure ventilation
`intelligence quotient
`idiopathic RDS
`intratracheal pulmonary ventilation
`inferior vena cava
`intraventricular hemorrhage
`intravenous immunoglobulin
`J chest tube
`keratinocyte growth factor
`lecithin:sphingomyelin (ratio)
`lung function test
`lysophosphatidylcholine
`left ventricular pre-ejection period to
`ejection time
`lung-thorax
`liquid ventilation
`morphine-3-glucuronide
`morphine-6-glucuronide
`mean airway pressure
`meconium aspiration syndrome
`medium chain triglyceride
`metered drug inhaler
`major histocompatibility complex
`magnetic resonance angiography
`magnetic resonance imaging
`messenger ribonucleic acid
`methicillin-resistant Staphylococcus
`au reus
`3-methoxy -4-hydroxyphenylethylene
`glycol
`mechanical ventilation
`sodium ion
`
`

`
`NADH
`NANCi
`nCPAP
`NEC
`nHFOV
`NICHD
`
`NIH
`niPPV
`
`NK cell
`NMDA
`NO
`N02
`NOS
`nSIMV
`
`nicotinamide adenine dinucleotide
`inhibitory non-adrenergic, non-cholinergic
`nasal continuous positive airways pressure
`necrotizing enterocolitis
`nasal high-frequency oscillatory ventilation
`National Institute of Child Health and
`Human Development
`neonatal intensive care unit
`NICU
`NIDCAP Neonatal Individualized Developmental
`Care and Assessment Program
`National Institutes of Health
`nasal intermittent positive pressure
`ventilation
`natural killer cell
`N-methyl-D-aspartate
`nitric oxide
`nitrogen dioxide
`nitric oxide synthase
`nasal synchronized intermittent mandatory
`ventilation
`nasal synchronized intermittent positive
`pressure ventilation
`necrotizing tracheobronchitis
`outside diameter
`oligohydramnios
`odds ratio
`arterial carbon dioxide tension
`platelet activating factor
`pressure at the airway opening
`arterial oxygen tension
`pulmonary alveolar proteinosis
`proportional assist ventilation
`pulsating bubble surfactometer
`phosphatidylcholine
`postconceptional age
`partial pressure of C02
`polymerase chain reaction
`packed cell volume; patient-controlled
`ventilation
`patent ductus arteriosus
`PDA
`PDE
`phosphodiesterase
`PDGF-AA platelet-derived growth factor
`diaphragmatic pressure
`pdi
`expiratory pressure
`PE
`PEEP
`positive end expiratory pressure
`maximal static expiratory pressure
`PEMAX
`endotracheal carbon dioxide pressure
`PETCOz
`PFC
`perfluorochemical
`PG
`phosphatidylglycerol; prostaglandin
`PHA
`phytohemagglutinin
`inspiratory pressure
`PI
`PIA
`L-N-p henylisopropyladenosine
`PIE
`pulmonary interstitial emphysema
`maximal static inspiratory pressure
`PIMAX
`PIP
`peak inflating pressure; peak inspiratory
`pressure
`
`nSIPPV
`
`NTB
`OD
`OH
`OR
`PaC02
`PAF
`Pao
`Pa02
`PAP
`PAV
`PBS
`PC
`PCA
`PC0 2
`PCR
`PCV
`
`Abbreviations xvii
`
`protein kinase A
`partial liquid ventilation
`postmenstrual age
`partial pressure of oxygen
`persistent pulmonary hypertension of the
`newborn
`parts per million
`preterm premature rupture of the
`membranes; prolonged preterm rupture
`of the membranes
`partial prothrombin time
`premature rupture of the membranes
`pressure support ventilation
`prothrombin time
`patient-triggered ventilation
`periventricular leukomalacia
`pulmonary vascular resistance
`respiratory distress syndrome
`rapid eye movement
`respiratory inductive plethysmography
`respiratory insufficiency syndrome
`respiratory mechanical unloading
`retinopathy of prematurity
`rapid plasma reagent
`respiratory quotient
`relative risk; respiratory rate
`respiratory syncytial virus
`oxygen saturation
`synchronized assisted ventilation for
`infants
`severe combined immunodeficiency
`standard deviation
`smooth muscle guanylate cyclase
`syndrome of inappropriate antidiuretic
`hormone secretion
`sudden infant death syndrome
`secretory immunoglobulin
`synchronized intermittent mandatory
`ventilation
`synchronized intermittent positive
`pressure ventilation
`superior laryngeal nerve
`spinal muscular atrophy
`superoxide dismutase
`substance P
`surfactant proteins A, B, C
`supplemental therapeutic oxygen for
`prethreshold retinopathy of prematurity
`superior vena cava
`spontaneous vaginal delivery
`thyroxine
`transcutaneous C0 2
`transcutaneous oxygen
`expiratory time
`transforming growth factor-beta
`thoracic gas volume
`
`PKA
`PLV
`PMA
`POz
`PPHN
`
`ppm
`PPROM
`
`PPT
`PROM
`PSV
`PT
`PTV
`PVL
`PVR
`RDS
`REM
`RIP
`RIS
`RMU
`ROP
`RPR
`RQ
`RR
`RSV
`Sa02
`SAVI
`
`SCID
`SD
`sGC
`SIADH
`
`SIDS
`slg
`SIMV
`
`SIPPV
`
`SLN
`SMA
`SOD
`SP
`SP-A, B, C
`STOP-ROP
`
`svc
`SVD
`T4
`TcC02
`Tc0 2
`TE
`TGF-[3
`TGV
`
`

`
`xviii Abbreviations
`
`THAM
`TI
`TLC
`TLV
`TNF
`TOF
`trTEF/tE
`
`TRH
`tTdT
`
`TTF
`TTN
`TwPdi
`UAC
`UKOS
`URTI
`us
`uvc
`
`tris(hydroxymethyl)aminomethane
`inspiratory time
`total lung capacity
`total liquid ventilation
`tumour necrosis factor
`tracheoesophageal fistula
`relationship between the time to reach peak
`expiratory flow and total expiratory flow
`time
`thyrotropin-releasing hormone
`Terminal deoxynucleotidyl transferase -
`enzyme inserting nucleotides into the gene
`segments in T-cell receptor and
`immunoglobulin variable regions
`thyroid transcription factor
`transient tachypnea of the newborn
`twitch transdiaphragmatic pressure
`umbilical artery catheter
`United Kingdom Oscillation Study
`unspecific respiratory tract infection
`ultrasound
`umbilical venous catheter(ization)
`
`v
`VA
`vcv
`V-D-J
`
`VDRL
`VEGF
`
`volume
`venoarterial
`volume-controlled ventilation
`Variable-diversity-joining gene segments
`which recombine during development of the
`T-cell receptor and immunoglobulin
`molecule
`Venereal Disease Research Laboratories
`vascular epidermal growth factor; vascular
`endothelial growth factor
`volume guarantee
`VG
`inspiratory volume
`VI
`maximum flow
`Vmax
`ventilator-induced lung injury
`VILI
`very low birthweight
`VLBW
`ventrolateral medulla
`VLM
`ventilation-perfusion
`V/Q
`V-region variable region gene segments of the
`immunoglobulin molecule
`tidal volume
`venovenous
`
`VT
`vv
`
`

`
`PART 1
`
`Development and physiology
`of the respiratory system
`
`Fetal and postnatal anatomical lung development
`Surfactant
`Lung liquid
`Control of breathing
`Development of the immune system
`Adaptation at birth
`
`3
`12
`26
`37
`50
`59
`
`001
`
`

`
`O02
`
`002
`
`

`
`1
`
`Fetal and postnatal anatomical
`lung development
`
`ALISON A HISLOP
`
`Fetal stages of lung development
`Development of alveoli
`Development of the pulmonary vasculature
`
`3
`7
`7
`
`The lung at birth
`Factors affecting lung growth
`References
`
`9
`9
`10
`
`There are major changes in the function of the lung at
`the moment of birth. The lung has to be ready to func(cid:173)
`tion efficiently at this time, although it has grown while
`not fulfilling its postnatal function. The lung at birth is
`not a miniature version of the adult lung, but has grown
`sufficiently to support the respiratory needs of the infant.
`The primary function of the lung is gas exchange and the
`airways and blood vessels are arranged to produce a dis(cid:173)
`tribution system for the air and blood to a large surface
`area within a relatively small chest volume.
`During infancy and childhood, as the body surface
`increases the lung grows in size, increasing the size of air(cid:173)
`ways and the surface area for gas exchange in the alveolar
`region with a concomitant increase in the size of blood
`vessels and number of capillaries. The structure of the com(cid:173)
`ponents also mature.
`
`FETAL STAGES OF LUNG DEVELOPMENT
`
`The classic descriptions of lung growth have divided fetal
`development into four major stages based on the appear(cid:173)
`ance of the lung tissue. These are embryonic, pseudo(cid:173)
`glandular, canalicular and alveolar; the last is sometimes
`divided into an earlier saccular or terminal sac phase and
`a later alveolar stage (Table 1.1, Figure 1.1). The alveolar
`stage continues after birth and in some species is entirely
`postnatal. There is also considerable individual variation
`and one stage gradually merges into the next. Within each
`phase, development of specific structures is of major
`importance. During the embryonic period the main hilar
`
`connections of the airways and the pulmonary circula(cid:173)
`tion are made. During the pseudoglandular phase the
`pre-acinar airways with their accompanying arteries and
`veins develop. During the canalicular phase the blood-gas
`barrier thins and the maturation of the surfactant system
`begins. In the alveolar phase alveoli multiply and by birth
`up to half the adult number are present.
`
`Development of the airways
`
`The lung appears as a ventral diverticulum from the endo(cid:173)
`dermal foregut in the fourth week after ovulation. The
`complete lining epithelium of the lung is derived from the
`endoderm. This bud is formed within the splanchnic meso(cid:173)
`derm surrounding the gut and the dorsal aorta; it is from
`this mesenchyme that the airway walls and blood vessels
`are derived. A division produces the left and right bron(cid:173)
`chi by 26-28 days of gestational age and segmental air(cid:173)
`ways are present by 6 weeks. Further division of airways(cid:173)
`into the surrounding mesenchyme continues until the
`end of the pseudoglandular stage ( 17 weeks of gestation)
`by which time all pre-acinar airways to the level of the ter(cid:173)
`minal bronchiolus are present. The majority of divisions
`occur during the tenth to fourteenth weeks of gestation5
`(Figures 1.1 and 1.2).
`During the canalicular period (16-27 weeks of gesta(cid:173)
`tion) the pre-acinar airways increase in diameter and
`length. The peripheral airways continue to divide to form
`the prospective respiratory bronchioli (two to three
`generations in humans) and beyond these the prospect(cid:173)
`ive alveolar ducts. The mesenchymal region between the
`
`003
`
`

`
`4 Fetal and postnatal anatomical lung development
`
`Table 1.1 Phases of lung development in man
`
`Embryonic
`Pseudoglandular
`Canalicular
`
`0-7 weeks of gestation
`6-17 weeks of gestation
`16-27 weeks of gestation
`
`Alveolar
`Postnatal
`
`27 weeks to term
`Up to 18 months
`
`Lung buds form. Blood vessels connect to the heart
`Pre-acinar airways and blood vessels develop
`Respiratory (intra-acinar) region develops. Thinning of peripheral
`epithelium and mesenchyme. Type I and II pneumonocytes
`Development of saccules and then alveoli
`Alveoli and small blood vessels multiply. All structures increase in size
`
`(a)
`
`(b)
`
`(c)
`
`Figure 1.1 Photomicrographs illustrating the classical stages of fetal lung development: (a) pseudoglandular,
`6-17 weeks of gestation; (b) canalicular, 16-27 weeks of gestation; (c) alveolar, 27 weeks to term.
`
`Stages of lung
`development
`
`Embryonic
`0-7 weeks
`gestation
`
`Pseudoglandular
`7-17 weeks
`gestation
`
`Canalicular
`17-27 weeks
`gestation
`
`Alveolar
`28 weeks gestation
`-2-3 years postnatal
`
`Pleura==========
`
`Lung structure
`Trachea
`24 days
`Extra pulmonary main bronchus
`28 days
`
`Bronchi
`8-13 generations
`
`Bronchioli
`3-10 generations
`
`Terminal bronchiolus
`1 generation
`
`Respiratory bronchioli
`3-5 generations
`
`Alveolar ducts
`2-3 generations
`
`Alveoli
`300-600 million
`10000/acinus
`
`Acinus
`
`Figure 1.2 Diagram representing the
`number of airway generations in the
`human lung and the stage and
`gestational age at which they appear.
`
`004
`
`

`
`airways thins and capillaries come to lie beneath the
`epithelium of the peripheral airways, apparently causing
`the epithelium to become thinner. The larger airways
`(prospective bronchi) are lined by columnar epithelium,
`but the distal bronchioli are lined by cuboidal cells. At the
`level of the prospective respiratory bronchioli, part of the
`wall is lined by flattened cells, as are the prospective alveo(cid:173)
`lar ducts which at this stage are sac shaped (saccules).
`By 20-22 weeks of gestation, type I and II alveolar epi(cid:173)
`thelial cells can be identified lining all saccular air spaces.
`The type I cells are flat and elongated and cover the major(cid:173)
`ity of the surface. The ~e II cells maintain a cuboidal
`shape and develop lamd4!! bS?dies around 24 weeks of
`gestation, which is 4-5 wea~lbefore surfactant can be
`detected in the amniotic fluid. By the end of the canalicular
`stage, the air to blood barrier is thin enough to support
`gas exchange (about 0.6 [LID) but the gas exchange units
`are the large thin-walled saccules. True alveoli develop
`later (p. 7).
`Increase in airway size in the prenatal period is linear
`and continuous with antenatal growth. After the first
`year of life, there is a slowing in growth, there being an
`approximately twofold increase between 22 weeks of ges(cid:173)
`tation and 8 months postnatal age and a two- to three(cid:173)
`fold increase between birth and adulthood.20 A previous
`study, measuring airway length and diameter in children
`from birth to adulthood, had reported symmetrical
`growth throughout the lung. 17 Tracheal size does not dif(cid:173)
`fer between sexes during early life, 12 but adult males have
`a larger trachea than females. Girls have wider and/or
`sho