ers handbook of paediatric respiratory medicine...respiratory unit, department of paediatrics,...

handbook

PaediatricRespiratoryMedicineEditorsErnst EberFabio Midulla

handbook Paediatric Respiratory Medicine

The 18 chapters of the ERS Handbook of Paediatric Respiratory Medicine cover the whole spectrum

of paediatric respiratory medicine, from anatomy and development to disease, rehabilitation and

treatment. The Editors have brought together leading clinicians to produce a thorough and easy-to-read reference tool. The Handbook is structured

to accompany the paediatric HERMES syllabus, making it an essential resource for anyone

interested in this field and an ideal educational training guide.

Ernst Eber is a Professor of Paediatrics and Head of the Respiratory and Allergic Disease Division in

the Department of Paediatrics and Adolescence Medicine at the Medical University of Graz, and is

also Head of the ERS Paediatric Assembly.

Fabio Midulla is an Assistant Professor and Director of the Paediatric Emergency Department,

Policlinico Umberto I. “Sapienza” University of Rome, and is Secretary of the ERS Paediatric

Assembly.

PaediatricRespiratoryMedicine

1st Edition

EditorsErnst Eberand Fabio Midulla

handbook

PUBLISHED BY THE EUROPEAN RESPIRATORY SOCIETY

CHIEF EDITORSErnst Eber (Graz, Austria)

Fabio Midulla (Rome, Italy)

ERS STAFFMatt Broadhead, Alyson Cann, Jonathan Hansen, Sarah Hill,

Elin Reeves, Claire Turner

© 2013 European Respiratory Society

Design by Claire Turner, ERSTypeset in China by Charlesworth GroupPrinted by Charlesworth Press

All material is copyright to the European Respiratory Society. It may not be reproduced in any way including electronically without the express permission of the society.

CONTACT, PERMISSIONS AND SALES REQUESTS: European Respiratory Society, 442 Glossop Road, Sheffield, S10 2PX, UKTel: +44 114 2672860 Fax: +44 114 2665064 e-mail: [email protected]

ISBN 978-1-84984-038-5

Table of contents

Contributors xii Preface xvii Get more from this Handbook xviii List of abbreviations xxix

Chapter 1 – Structure and function of the respiratory system

Anatomy and development of the respiratory system 1 Robert Dinwiddie

Applied respiratory physiology 11Caroline Beardsmore and Monika Gappa

Immunology and defence mechanisms 19Diana Rädler and Bianca Schaub

Environmental determinants of childhood respiratory health 29and diseaseErik Melén and Matthew S. Perzanowski Chapter 2 – Respiratory signs and symptoms

History and physical examination 33 Michael B. Anthracopoulos, Kostas Douros and Kostas N. Priftis

Cough 44Ahmad Kantar, Michael Shields, Fabio Cardinale and Anne B. Chang

Tachypnoea, dyspnoea, respiratory distress and chest pain 50Josef Riedler

Snoring, hoarseness, stridor and wheezing 57Kostas N. Priftis, Kostas Douros and Michael B. Anthracopoulos

Exercise intolerance 65Kai-Håkon Carlsen

Chapter 3 – Pulmonary function testing and other diagnostic tests

Static and dynamic lung volumes 70Oliver Fuchs

Respiratory mechanics 77Oliver Fuchs

Reversibility, bronchial provocation testing and exercise testing 83Kai-Håkon Carlsen

Blood gas assessment and oximetry 93Paola Papoff, Fabio Midulla and Corrado Moretti

Exhaled nitric oxide, induced sputum and exhaled breath analysis 100Johan C. de Jongste

Pulmonary function testing in infants and preschool children 107Enrico Lombardi, Graham L. Hall and Claudia Calogero

Single- and multiple-breath washout techniques 113Sophie Yammine and Philipp Latzin

Forced oscillation techniques 118Shannon J. Simpson and Graham L. Hall

Polysomnography 122Sedat Oktem and Refika Ersu

Chapter 4 – Airway endoscopy

Flexible bronchoscopy 132Jacques de Blic

Bronchoalveolar lavage 140Fabio Midulla, Raffaella Nenna and Ernst Eber

Bronchial brushing and bronchial and transbronchial biopsies 146Petr Pohunek and Tamara Svobodová

Rigid and interventional endoscopy 151Thomas Nicolai

General anaesthesia, conscious sedation and local anaesthesia 156Jacques de Blic and Caroline Telion

Chapter 5 – Lung imaging

Conventional radiography 161Meinrad Beer

Computed tomography 166Harm A.W.M. Tiddens, Marcel van Straten and Pierluigi Ciet

Magnetic resonance imaging 176Lucia Manganaro and Silvia Bernardo

Ultrasonography 183Carolina Casini, Vincenzo Basile, Mariano Manzionna and Roberto Copetti

Isotope imaging methods 189Georg Berding

Interventional radiology 193Efthymia Alexopoulou, Argyro Mazioti and Dimitrios Filippiadis

Chapter 6 – Inhalation therapy

Aerosol therapy 198Hettie M. Janssens

Chapter 7 – Acute and chronic lung infections

Epidemiology 207Steve Turner

Microbiology testing and interpretation 214Elpis Hatziagorou, Emmanuel Roilides and John Tsanakas

Immunisation against respiratory pathogens 221Horst von Bernuth and Philippe Stock

Upper respiratory tract infections 227Rossa Brugha, Chinedu Nwokoro and Jonathan Grigg

Community-acquired pneumonia 233Mark L. Everard, Vanessa Craven and Patricia Fenton

Hospital-acquired pneumonia 242Vanessa Craven, Patricia Fenton and Mark L. Everard

Lung involvement in immunodeficiency disorders 248Rifat Chaudry and Paul Aurora

Non-CF bronchiectasis 253Elif Dagli

Pleural infection, necrotising pneumonia and lung abscess 258Fernando M. de Benedictis, Chiara Azzari and Filippo Bernardi

Bacterial bronchitis with chronic wet lung 266Petr Pohunek and Tamara Svobodová

Chapter 8 – Tuberculosis

Pulmonary TB, latent TB, and in vivo and in vitro tests 270Zorica Zivkovic and James Paton

Extrapulmonary TB and TB in the immunocompromised host 284Toyin Togun, Uzor Egere and Beate Kampmann

Chapter 9 – Bronchial asthma and wheezing disorders

Epidemiology and phenotypes of bronchial asthma and 293wheezing disordersFranca Rusconi, Ben D. Spycher and Claudia E. Kuehni

Genetic and environmental factors in bronchial asthma and 298wheezing disorders Oliver Fuchs and Erika von Mutius

Acute viral bronchiolitis 305Fabio Midulla, Ambra Nicolai and Corrado Moretti

Preschool wheezing 310Paul L.P. Brand, Annemie M. Boehmer, Anja A.P.H. Vaessen-Verberne

Bronchial asthma 316Mariëlle Pijnenburg and Karin C. Lødrup Carlsen

Emerging therapeutic strategies 328Giorgio Piacentini and Laura Tenero

Differential diagnosis of bronchial asthma 334Giorgio Piacentini and Laura Tenero

Chapter 10 – Allergic disorders

Pathophysiology and epidemiology of allergic disorders 339Karin C. Lødrup Carlsen

In vivo and in vitro diagnostic tests in allergic disorders 345Gunilla Hedlin

Anaphylaxis 349 Antonella Muraro

Allergic rhinitis 354Michele Miraglia Del Giudice, Francesca Galdo and Salvatore Leonardi

Atopic dermatitis 363Paolo Meglio, Elena Galli and Nunzia Maiello

Food allergy 370Alessandro Fiocchi, Lamia Dahdah and Luigi Terracciano

Allergic bronchopulmonary aspergillosis 376Andrew Bush

Specific immunotherapy, prevention measures and alternative treatment 383Susanne Halken and Gunilla Hedlin

Chapter 11 – Cystic fibrosis

Genetics, pathophysiology and epidemiology of CF 390Sabina Gallati

Screening and diagnosis of CF 397Jürg Barben and Kevin Southern

CF lung disease 402Nicolas Regamey and Jürg Barben

Extrapulmonary manifestations of CF 410Anne Munck, Manfred Ballmann and Anders Lindblad

Emerging treatment strategies in CF 421Melinda Solomon and Felix Ratjen

Prognosis, management and indications for lung transplantation in CF 427Helen Spencer and Andrew Bush

Chapter 12 – Congenital malformations

Airway malformations 435Ernst Eber and Andreas Pfleger

Thoracic malformations 445Ashok Daya Ram, Jennifer Calvert and Sailesh Kotecha

Vascular malformations 452Oliviero Sacco, Serena Panigada, Nicoletta Solari, Elena Ribera, Chiara Gardella, Silvia Rosina, Michele Ghezzi and Francesca Rizzo

Chapter 13 – Bronchopulmonary dysplasia and chronic lung disease

Aetiology, pathogenesis, prevention and evidence-based 461medical managementRobert I. Ross-Russell

Nutritional care 466Kajsa Bohlin

Neurodevelopmental assessment and outcomes 469Charles C. Roehr, Lex W. Doyle and Peter G. Davis

Long-term respiratory outcomes 472Manuela Fortuna, Marco Filippone and Eugenio Baraldi

Chapter 14 – Pleural, mediastinal and chest wall diseases

Pleural effusion, chylothorax, haemothorax and mediastinitis 477Juan Antón-Pacheco, Carmen Lucas-Paredes and Antonio Martinez-Gimeno

Pneumothorax and pneumomediastinum 485 Nicolaus Schwerk, Folke Brinkmann and Hartmut Grasemann

Neuromuscular disorders 492Anita K. Simonds

Chest wall disorders 497Daniel Trachsel, Carol-Claudius Hasler and Jürg Hammer

Chapter 15 – Sleep-related disorders

Physiology and pathophysiology of sleep 503Sedat Oktem and Refika Ersu

OSAS and upper respiratory airway resistance syndrome 514Maria Pia Villa and Silvia Miano

Central sleep apnoea and hypoventilation syndromes 521Malin Rohdin and Hugo Lagercrantz

Impact of obesity on respiratory function 528Andrea Bon, Martina Tubaro and Mario Canciani

Chapter 16 – Lung injury and respiratory failure

Lung injury 533Andreas Schibler

Acute and chronic respiratory failure 538Robert I. Ross-Russell and Colin Wallis

Home oxygen therapy, invasive ventilation and NIV, and home 545ventilatory supportBrigitte Fauroux, Adriana Ramirez and Sonia Khirani

Chapter 17 – Other respiratory diseases Primary ciliary dyskinesia 551Deborah Snijders, Serena Calgaro, Massimo Pifferi, Giovanni Rossi and Angelo Barbato

Gastro-oesophageal reflux-associated lung disease and 559aspiration syndromeOsvaldo Borelli, Efstratios Saliakellis, Fernanda Cristofori and Keith J. Lindley

Foreign body aspiration 566Iolo Doull

Bronchiolitis obliterans 570Francesca Santamaria, Silvia Montella and Salvatore Cazzato

Plastic bronchitis 577Bruce K. Rubin and William B. Moskowitz

Haemangiomas, lymphangiomas and papillomatosis 582Thomas Nicolai

Interstitial lung diseases 587Annick Clement, Guillaume Thouvenin, Harriet Corvol and Nadia Nathan

Surfactant dysfunction and alveolar proteinosis 596Armin Irnstetter, Carolin Kröner, Ralf Zarbock and Matthias Griese

Pulmonary vascular disorders 601Andrea McKee and Andrew Bush

Eosinophilic lung diseases and hypersensitivity pneumonitis 610Carlo Capristo, Giuseppina Campana, Francesca Galdo, Emilia Alterio and Laura Perrone

Pulmonary haemorrhage 619Robert Dinwiddie

Sickle cell disease 625Tobias Ankermann

Lung and mediastinal tumours 630Amalia Schiavetti

Systemic disorders with lung involvement 636Andrew Bush

Lung transplantation and management of post-lung transplant patients 647Paul Robinson and Paul Aurora

Chapter 18 – Rehabilitation in chronic respiratory diseases

Rehabilitation programmes and nutritional management 656Andreas Jung

Prevention of indoor and outdoor pollution 662Giuliana Ferrante, Velia Malizia, Roberta Antona and Stefania La Grutta

Respiratory physiotherapy 665Beatrice Oberwaldner Fitness-to-fly testing 670Mary J. Sharp and Graham L. Hall

Sports medicine 673Giancarlo Tancredi, Giovanna De Castro and Anna Maria Zicari

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Contributors

Emilia AlterioDepartment of Pediatrics, Second University of Naples, Naples, Italy.

Efthtymia Alexopoulou2nd Department of Radiology, University Hospital ATTIKON, Athens, [email protected]

Tobias Ankermann Klinik für Allgemeine PädiatrieUniversitätsklinikum Schleswig-Holstein (UKSH), Kiel, [email protected]

Michael B. AnthracopoulosRespiratory Unit, Department of Paediatrics, University of Patras, Patras, [email protected]

Roberta AntonaConsiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunolo-gia Molecolare, Palermo, [email protected]

Juan L. Antón-PachecoPediatric Surgery, Hospital Universi-tario 12 de Octubre, Madrid, [email protected]

Paul AuroraGreat Ormond Street Hospital for Children, London, [email protected]

Chiara AzzariDepartment of Pediatrics, University of Florence, Mayer Children’s Hospital, Florence, [email protected]

Manfred BallmannDepartment of Pediatric Pulmonology, Ruhr-University Bochum, Bochum, [email protected]

Eugenio Baraldi Pediatric Pneumonolgy, University of Padova, Padova, [email protected]

Angelo Barbato Department of Pediatrics, University of Padova, Italy. [email protected]

Jürg BarbenDivision of Respiratory Medicine, Children’s Hospital St. Gallen, St Gallen, [email protected]

Chief Editors Ernst EberRespiratory and Allergic Disease Division, Department of Paediatrics and Adolescence, Medical University of Graz, Graz, [email protected]

Authors

Fabio MidullaDepartment of Paediatrics,“Sapienza” University of Rome, Rome, [email protected]

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Vincenzo BasilePediatric Department, Monopoli Hospital, Bari, [email protected]

Caroline BeardsmoreDepartment of Infection, Immunity and Inflammation (Child Health), University of Leicester, Leicester, [email protected]

Meinrad BeerDepartment of Pediatric Radiology, Medical University Graz, Graz, [email protected]

Georg BerdingDepartment of Nuclear Medicine, Hannover Medical School, Hannover, [email protected]

Filippo BernardiDepartment of Pediatrics, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, [email protected]

Silvia BernardoRadiological Oncological and Pathological Sciences, Umberto I Hospital, “Sapienza” University of Rome, Rome, [email protected]

Annemie M. BoehmerDepartment of Paediatrics, Maasstad Hospital, Rotterdam, The [email protected]

Kajsa Bohlin Neonatal intensive Care, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, [email protected]

Andrea BonPediatric Department, University of Udine, Udine, [email protected]

Osvaldo BorrelliDepartment of Paediatric Gastroenterology, Division of Neurogastroenterology and Motility, Great Ormond Street Hospital for Children, ICH University College of London, London, [email protected]

Paul L.P. BrandPrincess Amalia Children’s Clinic, Isala Klinieken, Zwolle, The [email protected]

Folke BrinkmannDepartment of Pediatrics, Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, [email protected]

Rossa BrughaCentre for Paediatrics, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, [email protected]

Andrew BushDepartment of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, [email protected]

Claudia CalogeroRespiratory Medicine, Anna Meyer, University Hospital for Children, Florence, [email protected]

Serena CalgaroDepartment of Pediatrics, University of Padova, Padova, [email protected]

Jennifer CalvertDepartment of Neonatal Medicine, University Hospital of Wales, Cardiff and Vale LHB, Cardiff, UK.

Giuseppina CampanaDepartment of Pediatrics, Second University of Naples, Naples, Italy.

Mario Canciani Pediatric Department, Azienda Ospedaliero, Universitaria di Udine, Udine, [email protected]

Carlo Capristo Department of Pediatrics, Second University of Naples, Naples, [email protected]

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Fabio Cardinale Department of Pediatric Allergy and Pulmonology, Paediatric Hospital Giovanni XXIII, University of Bari, Bari, [email protected]

Kai-Håkon Carlsen Institute of Clinical Medicine, University of Oslo, Oslo, [email protected]

Carolina Casini Pediatric Department, Sant’Andrea Hospital, Rome, [email protected]

Salvatore CazzatoDept of Pediatrics, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, [email protected]

Anne B. ChangRespiratory Medicine, Royal Children’s Hospital, Brisbane, [email protected]

Rifat Chaudry Great Ormond Street Hospital for Children, London, [email protected]

Pierluigi CietRadiology and Pediatric Pulmonology, Erasmus Medical Center, Sophia Children’s Hospital, Rotterdam, The [email protected]

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Annick Clement Paediatric Pulmonary Department, Reference Centre for Rare Lung Diseases, AP-HP, Hôpital Trousseau, INSERM UMR S-938, Université Pierre et Marie Curie, Paris, [email protected]

Roberto Copetti Latisana General Hospital, Latisana, [email protected]

Harriet CorvolPaediatric Pulmonary Department, Reference Centre for Rare Lung Diseases, AP-HP, Hôpital Trousseau, INSERM UMR S-938, Université Pierre et Marie Curie, Paris, [email protected]

Vanessa CravenDepartment of Respiratory Medicine and Microbiology, Sheffield Children’s Hospital, Sheffield, [email protected]

Fernanda CristoforiPediatrics Department, University of Bari, Bari, [email protected]

Elif Dagli Pediatric Pulmonology, Marmara University, Istanbul, [email protected]

Lamia DahdahDivision of Allergy, Department of Pediatrics, Pediatric Hospital Bambino Gesù, Rome, [email protected]

Peter G. DavisDepartment of Newborn Research, The Royal Women’s Hospital, Melbourne, [email protected]

Ashok Daya RamDepartment of Paediatric Surgery, Birmingham Children’s Hospital, Birmingham, [email protected]

Fernando M. de Benedictis Department of Mother and Child Health, Salesi University Children’s Hospital, Ancona, [email protected]

Jacques de BlicUniversité Paris Descartes, Assistance Publique des Hôpitaux de Paris, Hôpital Necker Enfants Malades, Service de Pneumologie et Allergologie Pédiatriques Paris, [email protected]

Giovanna De CastroDepartment of Paediatrics, “Sapienza” University of Rome, Rome, [email protected]

Johan C. de Jongste Dept of Pediatrics/Respiratory Medicine, Erasmus Medical Center, Sophia Childrens’ Hospital, Rotterdam, The [email protected]

Robert Dinwiddie Portex Unit, Institute of Child Health, London, [email protected]

Iolo DoullDepartment of Paediatric Respiratory Medicine, Children’s Hospital for Wales, Cardiff, [email protected]

Kostas DourosRespiratory Unit, 3rd Department of Paediatrics, “Attikon” Hospital, University of Athens, Athens, [email protected]

Lex W. Doyle Department of Obstetrics and Gynaecology, The University of Melbourne, Melbourne, [email protected]

Uzor EgereVaccinology Theme, Medical Research Council (MRC) Unit, The Gambia, [email protected]

Refika Ersu Division of Pediatric Pulmonology, Marmara University, Istanbul, [email protected]

Mark L. EverardSchool of Paediatrics and Child Health, University of Western Australia, Princess Margaret Hospital, Subiaco, [email protected]

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Brigitte Fauroux AP-HP, Hopital Armand Trousseau, Pediatric Pulmonary Department, INSERM U 955, Université Pierre et Marie Curie, Paris, [email protected]

Patricia FentonDepartment of Respiratory Medicine and Microbiology, Sheffield Children’s Hospital, Sheffield, [email protected]

Giuliana Ferrante Consiglio Nazionale delle Ricerche, Dipartimento di Scienze per la Promozione della Salute e Materno Infantile, University of Palermo, Palermo, [email protected]

Dimitrios Filippiadis2nd Deaprtment of Radiology, University Hospital ATTIKON, Athens, [email protected]

Marco FilipponeDepartment of Pediatrics, University of Padova, Padova, [email protected]

Alessandro Fiocchi Division of Allergy, Dept of Pediatrics, Pediatric Hospital Bambino Gesù, Rome, [email protected]

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Manuela FortunaPediatric Pneumonolgy, University of Padova, Padova, [email protected]

Oliver Fuchs Division of Paediatric Allergology, University Children’s Hospital, Ludwig-Maximilians-University, Munich, [email protected]

Francesca GaldoDepartment of Pediatrics, Second University of Naples, Naples, Italy.

Sabina Gallati Division of Human Genetics, Departments of Paediatrics and Clinical Research, Inselspital, University of Bern, Bern, [email protected]

Elena GalliDepartment of Pediatric Allergy, Research Centre, San Pietro Hospital - Fatebenefratelli, Rome, [email protected]

Monica GappaChildren’s Hospital and Research Insitute for the Prevention of Allergies and Respiratory Diseases in Children, Marien-Hospital Wesel GmbH, Wesel, [email protected]

Chiara GardellaDept of Pulmonary Disease, G. Gaslini Institute, Genoa, [email protected]

Michele GhezziPulmonary Disease Department,G. Gaslini Institute, Genoa, Italy.

Hartmut GrasemannDivision of Respiratory Medicine, Department of Pediatrics, The Hospital for Sick Children, Toronto, [email protected]

Matthias Griese Hauner Childrens’ Hospital, University of Munich, Germany. [email protected]

Jonathan Grigg Paediatric Respiratory and Environmental Medicine Blizard Institute, Barts and the London School of Medicine and Dentistry,Queen Mary University of London, London, [email protected]

Susanne HalkenHans Christian Andersen Children’s Hospital, Odense University Hospital, Odense,[email protected]

Graham L. HallPaediatric Respiratory Physiology , Telethon Institute for Child Health Research, Perth, Australia. [email protected]

Jürg HammerPaediatric Intensive Care and Pulmonology, University-Children’s Hospital Basel, Basel, [email protected]

Carol-Claudius HaslerPaediatric Orthopaedics, University Children’s Hospital UKBB, Basel, [email protected]

Elpis HatziagorouPeadiatric Respiratory Unit, 3rd Paediatric Dept, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece. [email protected]

Gunilla HedlinAstrid Lindgren Children’s Hospital, Department of Women’s and Children’s Health and Centre for Allergy Research, Karolinska Institutet, Stockholm, [email protected]

Armin IrnstetterPneumology Dept, University of Munich, Dr. von Haunersches Kinderspital, Munich, [email protected]

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Hettie M. Janssens Department of Paediatric Respiratory Medicine, Erasmus Medical Center, Sophia Children’s Hospital, Rotterdam, The [email protected]

Andreas Jung Children`s University Hospital Zurich, Division of Respiratory Medicine, Zurich, [email protected]

Beate Kampmann Vaccinology Theme, Medical Research Council (MRC) Unit, The Gambia, [email protected]

Ahmad Kantar Department of Paediatrics, Institutes of Bergamo Hospitals, Bergamo, [email protected]

Sonia KhiraniA.A.O. Ospedali Riuniti di Bergamo, U.S.C. Pneumologia, Bergamo, [email protected]

Sailesh KotechaDepartment of Child Health, School of Medicine, Cardiff University, University Hospital of Wales, Cardiff, [email protected]

Carolin KrönerPediatrics Dept, University of Munich, Munich, [email protected]

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Claudia E. KuehniDivision of International and Environmental Health, Institute of Social and Preventive Medicine, University of Bern, Switzerland. [email protected]

Stefania La Grutta Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare, Palermo, [email protected]

Hugo LagercrantzNeonatal Research Unit, Department of Woman and Child Health, Karolinska Institutet, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, [email protected]

Philipp Latzin Division of Respiratory Medicine, Department of Paediatrics, University Children’s Hospital of Bern, Bern, Switzerland. [email protected]

Salvatore Leonardi Department of Pediatrics, University of Catania, Catania, [email protected]

Anders LindbladDept of Pediatrics, Queen Silvias Hospital, Gothenburg University, Gothenburg, [email protected]

Keith J. LindleyGreat Ormond Street Hospital, London, [email protected]

Karin C. Lødrup Carlsen Department of Paediatrics, Women and Children’s Division, Oslo University Hospital, Oslo, [email protected]

Enrico Lombardi Paediatric Pulmonary Unit, Anna Meyer Paediatric University Hospital, Florence, [email protected]

Carmen Luna-ParedesHospital Universitario 12 de Octubre, Madrid, [email protected]

Nunzia MaielloDepartment of Women, Children and General and Specialized Surgery, Second University of Naples, Naples, [email protected]

Velia MaliziaConsiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare, Palermo, Italy. [email protected]

Lucia ManganaroDepartment of Radiological Sciences, Umberto I Hospital, “Sapienza” University of Rome, Rome, Italy. [email protected]

Mariano ManzionnaPediatric Department, Monopoli Hospital, Bari, [email protected]

Antonio Martinez-Gimeno Division of Respiratory Medicine, Hospital Universitario 12 de Octubre, Madrid, [email protected]

Argyro MaziotiDepartment of Radiology, General Hospital of Larissa, Larissa, [email protected]

Andrea MckeePaediatric Respiratory Medicine, Royal Brompton Hospital, London, [email protected]

Paolo MeglioDepartment of Pediatric Allergy, Research Centre, San Pietro Hospital - Fatebenefratelli, Rome, [email protected]

Erik Melén Institute of Environmental Medicine, Karolinska Institutet, Stockholm, [email protected]

Silvia Miano“Sapienza” University of Rome, Rome, [email protected]

Michele Miraglia del Giudice Department of Pediatrics, Second University of Naples, Naples, [email protected]

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Silvia MontellaDepartment of Pediatrics, Federico II University, Naples, [email protected]

Corrado MorettiDepartment of Paediatrics Emer-gency and Intensive Care, “Sapienza” University of Rome, Rome, [email protected]

William B. MoskowitzDepartment of Pediatrics, The Children’s Hospital of Richmond at VCU, Richmond, VA, [email protected]

Anne MunckPaediatric CF Centre Gastrointesti-nal and Pulmonology Department, Robert Debré University Hospital, Paris-Diderot AP-HP, Paris, [email protected]

Antonella Muraro Food Allergy Centre, Department of Women and Child Health, University of Padua, Padua, [email protected]

Nadia NathanPaediatric Pulmonary Department, Reference Centre for Rare Lung Diseases, AP-HP, Hôpital Trousseau, INSERM UMR S-938, Université Pierre et Marie Curie, Paris, [email protected]

Raffaella NennaDepartment of Paediatrics, “Sapienza” University of Rome, Rome, [email protected]

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Ambra NicolaiDepartment of Paediatrics, University of Rome, Rome, [email protected]

Thomas Nicolai University Kinderklinik, Munich, [email protected]

Chinedu NwokoroCentre for Paediatrics, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, [email protected]

Beatrice Oberwaldner Klinische Abteilung für Pulmonologie und Allergologie,Univ. Klinik für Kinder-und Jugendheilkunde, Graz, [email protected]

Sedat OktemIstanbul Medipol University, Division of Pediatric Pulmonology, Istanbul, [email protected]

Serena PanigadaPediatric Pulmonary and Allergy Unit, Istituto Giannina Gaslini, Genoa, [email protected]

Paola PapoffPICU, Policlinico Umberto I, “Sapienza” University of Rome, Rome, [email protected]

James PatonRoyal Hospital for Sick Children, Glasgow, [email protected]

Laura PerroneDepartment of Pediatrics, Second University of Naples, Naples, [email protected]

Matthew S. PerzanowskiDepartment of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, [email protected]

Andreas PflegerRespiratory and Allergic Disease Division, Department of Paediatrics and Adolescence Medicine, Medical University of Graz, Graz, [email protected]

Maria Pia Villa Dept of Pediatrics, University Hospital, Rome, [email protected]

Giorgio Piacentini Department of Pediatrics, University of Verona, Verona, [email protected]

Massimo PifferiDepartment of Pediatrics, University of Pisa, Pisa, [email protected]

Mariëlle Pijnenburg Department of Paediatrics/Paediatric Respiratory Medicine, RotterdamThe [email protected]

Petr Pohunek Paediatric Pulmonology, University Hospital Motol, Prague, Czech [email protected]

Kostas N. Priftis Respiratory Unit, 3rd Department of Paediatrics, “Attikon” Hospital, University of Athens, Athens, [email protected]

Diana RädlerPulmonary Dept, University Children´s Hospital, Munich, [email protected]

Adriana RamirezADEP ASSISTANCE, Suresnes, [email protected]

Felix Ratjen Hospital for Sick Children, Toronto, [email protected]

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Nicolas Regamey Division of Respiratory Medicine, Department of Paediatrics, Inselspital and University of Bern, Bern, [email protected]

Elena RiberaPulmonary Disease Department,G. Galini Institute, Genoa, Italy.

Josef Riedler Children’s Hospital Schwarzach, Salzburg, [email protected]

Francesca RizzoPulmonary Disease Department,G. Galini Institute, Genoa, Italy.

Paul RobinsonDept of Respiratory Medicine, Children’s Hospital at Westmead, Westmead, [email protected]

Charles C. Roehr Dept of Neonatology, Charité Berlin, Berlin, [email protected]

Malin RohdinNeonatal Research Unit, Department of Woman and Child Health, Karolinska Institutet, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, [email protected]

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Emmanuel RoilidesPeadiatric Respiratory Unit, 3rd Paediatric Dept, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece. [email protected] Rosina

Giovanni RossiPulmonary and Allergy Units, Giannina Gaslini Institute, Genova, [email protected]

Robert I. Ross-RussellDepartment of Paediatrics, Addenbrooke’s Hospital, Cambridge, [email protected]

Bruce K. RubinChildren’s Hospital of Richmond at VCU, Richmond, VA, [email protected]

Franca Rusconi Epidemiology Unit, Anna Meyer, Children’s Hospital, Florence, [email protected]

Oliviero SaccoPulmonary Disease Department, G. Gaslini Institute, Genoa, [email protected]

Efstratios Saliakellis Great Ormond Street Hospital, London, [email protected]

Francesca SantamariaDepartment of Paediatrics, Federico II University, Naples, [email protected]

Bianca Schaub University Children’s Hospital Munich, Munich, [email protected]

Amalia SchiavettiDepartment of Paediatrics, “Sapienza” University of Rome, Rome, [email protected]

Andreas Schibler Paediatric Critical Care Research Group, Paediatric Intensive Care Unit, Mater Children’s Hospital, Brisbane, [email protected]

Nicolaus Schwerk Department of Pediatrics , Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, [email protected]

Mary Sharp Neonatology Clinical Care Unit, King Edward Memorial Hospital for Women, Perth, [email protected]

Michael ShieldsDepartment of Child Health, Queen’s University of Belfast, Belfast, [email protected]

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Anita K. Simonds NIHR Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, London [email protected]

Shannon J. SimpsonPaediatric Respiratory Physiology, Telethon Institute for Child Health Research, University of Western Australia, Perth, [email protected]

Deborah SnijdersDepartment of Pediatrics, University of Padova, Padova, Italy. [email protected]

Nicoletta SolariPulmonary Disease Department,G. Gaslini Institute, Genoa, Italy.

Melinda SolomonHospital for Sick Children, Toronto, [email protected]

Kevin SouthernInstitute of Child Health, University of Liverpool, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK. [email protected]

Helen SpencerGreat Ormond Street Hospital, London, [email protected]

Ben D. SpycherDivision of International and Environmental Health, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland. [email protected]

Philippe StockCharité Kinderklinik mit Schwerpunkt Pneumologie und ImmunologieLabor Berlin – Fachbereich Allergologie, Berlin, [email protected]

Tamara SvobodováPaediatric Respiratory Division, University Hospital Motol, Prague, Czech [email protected]

Giancarlo Tancredi Department of Paediatrics, “Sapienza” University of Rome, Rome, [email protected]

Caroline TelionDépartement d’anesthesie, Assistance Publique des Hôpitaux de Paris, Hôpital Universitaire Necker Enfants Malades, Paris, [email protected]

Laura TeneroClinica Pediatrica,Pediatria Verona, Verona, [email protected]

Luigi TerraccianoMelloni Paediatria, Melloni University Hospital, Milan, Italy. [email protected]

xxv

Guillaume ThouveninPaediatric Pulmonary Department, Reference Centre for Rare Lung Diseases, AP-HP, Hôpital Trousseau, INSERM UMR S-938, Université Pierre et Marie Curie, Paris, [email protected]

Harm A.W.M. TiddensPediatric pulmonology, Erasmus Medical Center, Sophia Children’s Hospital, Rotterdam, The [email protected]

Toyin TogunVaccinology Theme, Medical Research Council (MRC) Unit, The Gambia, [email protected]

Daniel Trachsel Paediatric Intensive Care and Pulmonology, University-Children’s Hospital Basel, Basel, [email protected]

JohnTsanakasPeadiatric Respiratory Unit, 3rd Paediatric Dept, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece. [email protected]

Martina Tubaro Pediatric Department, University of Trieste, Trieste, [email protected]

Steve Turner Child Health, Royal Aberdeen Children’s Hospital, Aberdeen, [email protected]

Anja A.P.H. Vaessen-Verberne Department of Paediatrics, Amphia Hospital, Breda, The [email protected]

Horst von BernuthPediatric Pneumology and Immunology, Charité Berlin, Berlin, [email protected]

Marcel van StratenDepartment of Radiology, Erasmus MC, Rotterdam, The [email protected]

Erika von Mutius University Children’s Hospital, Ludwig Maximilians-University, Munich, [email protected]

Colin Wallis Respiratory Unit, Great Ormond Street Hospital, London, [email protected]

Sophie YamminePediatric Pulmonology Dept, University of Bern, Bern, [email protected]

xxvi

Ralf ZarbockPediatrics Dept, University of Munich, Munich, [email protected]

Anna Maria Zicari Department of Paediatrics, “Sapienza” University of Rome, Rome, [email protected]

Zorica ZivkovicMedical Center Dr Dragisa Misovic, Hospital for Lung Diseases andTuberculosis, Belgrade, Serbia. [email protected]

xxvii

Preface

The dissemination of knowledge, and medical and public education constitute a fundamental objective of the ERS mission; and the ERS School aims to provide excellence in respiratory medicine education. In 2005, the ERS School started the very ambitious HERMES (Harmonised Education in Respiratory Medicine for European Specialists) project. Since then, seven HERMES Task Forces have formed to standardise training and education within different specialties of respiratory medicine. To support the implementation of various educational activities, the ERS has produced a series of Handbooks as educational tools, with the ERS Handbook of Respiratory Medicine being the first textbook to be launched in 2010.

Starting in 2007, the Paediatric Respiratory Medicine Task Force, using a formal consensus process and working with numerous experts throughout Europe, developed a HERMES syllabus (description of the competencies required) and a HERMES curriculum (description of how competencies should be taught, learned and assessed), as well as a voluntary European examination in paediatric respiratory medicine. With the paediatric HERMES project now well underway, it is an opportune time to publish an ERS Handbook of Paediatric Respiratory Medicine to provide a comprehensive update for specialists within this field of respiratory medicine. The content of this Handbook follows the HERMES syllabus and curriculum to provide a compact, state-of-the-art textbook, with each of the sections prepared by senior specialists and clinical experts in the field.

We hope that this Handbook will not only inform our trainees but also provide an easily accessible and comprehensive update for colleagues at all levels of seniority across paediatric respiratory medicine. Thus, this educational tool is intended to make a significant contribution to increasing the standards of training in paediatric respiratory medicine throughout Europe and, ultimately, to improving the care of children with respiratory disease.

We are indebted to the ERS School Committee and to the ERS staff who so thoroughly and thoughtfully curated this Handbook, and last, but not least, to all the contributors who have shared their knowledge and experience with the readers.

Ernst Eber and Fabio Midulla

Chief Editors

“Tell me and I forget.Teach me and I remember.

Involve me and I learn.”Benjamin Franklin

xxviii

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European Respiratory Monograph 56: Paediatric Asthma covers all aspects of paediatric asthma from birth through to the start of adulthood. It considers diagnostic problems in relation to the many phenotypes of asthma, covers the treatment of both mild-to-moderate and severe asthma, and discusses asthma exacerbations as well as exercise-induced asthma. The issue provides an update on the pathophysiology of asthma, the role of bacterial and viral infections, and the impact of environmental factors, allergy, genetics and epigenetics.

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xxix

List of abbreviations

(C)HF (Congestive) heart failureAHI Apnoea–hypopnoea indexAIDS Acquired immunodeficiency syndromeBMI Body mass indexCF Cystic fibrosisCOPD Chronic obstructive pulmonary diseaseCPAP Continuous positive airway pressureCT Computed tomographyECG ElectrocardiogramENT Ear, nose and throatFEV1 Forced expiratory volume in 1 sFVC Forced vital capacityHb HaemoglobinHIV Human immunodeficiency virusHRCT High-resolution computed tomographyKCO Transfer coefficient of the lung for carbon monoxideMRI Magnetic resonance imagingNIV Noninvasive ventilationOSA(S) Obstructive sleep apnoea (syndrome)PaCO2 Arterial carbon dioxide tensionPaO2 Arterial oxygen tensionPCR Polymerase chain reactionPtcCO2 Transcutaneous carbon dioxide tensionSaO2 Arterial oxygen saturationSpO2 Arterial oxygen saturation measured by pulse oximetryTB TuberculosisTLC Total lung capacity TLCO Transfer factor for the lung for carbon monoxideV'E Minute ventilation

Anatomy and developmentof the respiratory system

Robert Dinwiddie

Anatomy of the lower respiratory tract

The lower respiratory tract consists of thetrachea, hila of the lungs, large bronchialairways, small airways and alveoli. The larynxlies at the junction of the upper and lowerrespiratory tract and since it is a frequentsource of pathology in children its anatomywill also be described. The mediastinumcontains the heart and its related cardiacstructures:

N thymus,N trachea,N thoracic lymph nodes,N thoracic duct,N vagus nerves,N recurrent laryngeal nerves,N autonomic nerve plexus.

Another important structure which passesthrough the thorax via the mediastinum isthe oesophagus.

Larynx The larynx can be divided into threeareas (fig. 1):

N supraglottis,N glottis,N subglottis.

It extends from the tip of the epiglottis to thelower border of the cricoid cartilage. In theneonatal period it lies at the level of cervicalvertebrae C2–C3 and in adults at the level ofC3–C6. It contains major cartilaginousstructures including the epiglottic, thyroidand cricoid cartilages, and the pairedarytenoid cartilages. The vocal apparatus ismuscular and consists of the false vocalcords (vestibular folds) and the true vocalcords (folds). The true vocal cords are drawntogether by adduction of the arytenoidcartilages. The larynx is bounded on eachside by the aryepiglottic folds. These liebetween the lateral borders of the epiglottisanteriorly and the upper edge of thearytenoid cartilages, which join posteriorlyto form the interarytenoid cartilage. Thelarynx is chiefly innervated by branches ofthe vagus nerves. The subglottic area issupplied by the recurrent laryngeal nerveswhich also arise from the vagal nervoussystem. These supply the vocal cords anddamage to them can result in unilateral orbilateral vocal cord paralysis.

Hila Each hilum forms the root of the lungjoining it to the heart and the trachea.Structures that pass through this area oneach side include the major bronchus,pulmonary artery, superior and inferiorpulmonary veins, bronchial artery and vein,vagus nerves, pulmonary autonomic nervesand lymphatic vessels. Lymph nodes withineach hilum are often directly involved in

Key points

N The anatomy of the thorax can bedivided into the lungs, heart,mediastinum, pleura, diaphragm andchest wall.

N The lungs can be further subdividedinto the trachea, bronchi, hila, lobesand preacinar and acinar regions.

N The mediastinum contains thethymus, the heart and its associatedstructures, thoracic lymphatics,sympathetic and parasympatheticnerves and the oesophagus.

ERS Handbook: Paediatric Respiratory Medicine 1

disease processes spreading systemicallyfrom the lung parenchyme.

Trachea and bronchi The trachea is made upof anterolateral cartilaginous rings and afibro-muscular posterior wall. The tracheadivides into the right and left main bronchi(fig. 2). The right main bronchus is morevertically orientated than the left resulting ina greater percentage of inhaled foreignbodies entering that side. The right mainbronchus gives off the right upper lobebronchus and continues as the bronchusintermedius. This divides into the rightmiddle and lower lobe bronchi. The rightupper lobe bronchus divides into threesegmental bronchi: apical, posterior andanterior. The right middle lobe bronchusdivides into two: the medial and lateralsegments of the middle lobe. The right lowerlobe bronchus gives off a superiorsegmental branch and then medial, lateral,anterior and posterior segments. Segmentalbronchi are particularly important torecognise during bronchoscopy. The leftmain bronchus divides into the left upperand lower lobe bronchi. The left upper lobebronchus gives off the superior divisionsupplying the apical, anterior and posteriorbranches of the left upper lobe. The inferiordivision of the left upper lobe supplies thesuperior and inferior segments of the lingua.The left lower lobe bronchus then descendslaterally to give off a posteriorly locatedapical segment of the left lower lobe andthen the antero-medial, lateral and posteriorbasal segmental bronchi. After dividing intosegmental bronchi the airways furthersubdivide into subsegmental bronchi andthen, from generation seventeen onwards,

become bronchioles before finallybecoming a terminal bronchiole (table 1).The portion of the respiratory tree from thetrachea down to the terminal bronchioles isknown as the preacinar region. The acinarregion comprises the gas exchanging unitsand includes seven further branches of thedistal lung made up of the respiratorybronchioles, alveolar ducts and thealveolar sacs.

The blood supply to the trachea andbronchi is principally via the bronchialarteries and the intercostal arteries, whicharise via the systemic circulation from theaorta. The upper trachea is supplied bybranches of the inferior thyroid arteries.The venous drainage from the tracheareturns via the inferior thyroid venousplexus. The tracheal nerve supply is viathe vagus nerves, the recurrent laryngealnerves, supplying parasympatheticfibres and sympathetic nerves arisingfrom the upper ganglia of thesympathetic trunks.

Vestibular fold(false cord)

Epiglottis

Trachea

Interarytenoidcartilage

Aryepiglottic fold

Vocal cord (fold)

Figure 1. Laryngeal anatomy as seen from above.

Figure 2. The trachea and bronchi. �P.L. Shah.

2 ERS Handbook: Paediatric Respiratory Medicine

Pulmonary vasculature and lymphaticdrainage The pulmonary artery carriesdeoxygenated blood to the lungs, thereaftersubdividing and eventually becomingalveolar capillaries. Oxygenated blood thenreturns via the pulmonary capillary andvenous circulation to the left atrium. Thepulmonary arteries lie anterior to the carinaand main bronchi. Each artery then entersthe lung via the hilum. There are twopulmonary veins on each side (superior andinferior) that pass in front of and below theadjacent pulmonary artery and majorbronchus.

The lymphatic drainage of the lungs, pleuraeand mediastinum is via visceral lymphnodes. These are arranged along thebifurcation of the trachea, major bronchiand peripheral bronchi. Further nodes aresituated in the mediastinum. The output ofmost of these vessels is into abronchomediastinal trunk on each side ofthe trachea. Another major lymphatic vesselin the chest is the thoracic duct. This startsin the abdomen and enters the chest on theright side through the aortic hiatus of thediaphragm. It then ascends close to the

aorta, subsequently crossing to the left sideand runs alongside the oesophagus. It endsin the neck where it enters the left internaljugular vein. The right bronchomediastinallymphatic trunk joins the right lymphaticduct and enters the venous circulation at thejunction of the subclavian and internaljugular veins. Leakage of fluid from thethoracic duct is the primary cause ofchylothorax in the paediatric age group.

Mediastinum The mediastinum is dividedinto superior, anterior, middle and posteriorportions. It contains the thymus, whichdevelops from the third branchial pouch andhas two lobes located in the superior andanterior mediastinum. Its principle functionis the programming of thymocytes.Thymocytes, which originate from bonemarrow, mature into T-lymphocytes andhave major immune functions, especially inrelation to resistance to infection and thedevelopment of atopic status and allergy. T-helper (Th)-1 lymphocytes form part of thecellular immune system and are principallyinvolved in the response to infection. Th-2lymphocytes are part of the humoralimmune system mainly involved in allergic

Table 1. Anatomical subdivisions of the lung

Trachea

Right main bronchus Left main bronchus

Segmental bronchi right Segmental bronchi left

Right upper lobe: Left upper lobe:

Apical Apical

Posterior Posterior

Anterior Anterior

Right middle lobe: Left middle lobe:

Lateral Superior

Medial Inferior

Right lower lobe: Left lower lobe:

Superior (apical) Apical

Medial basal Antero-medial basal

Anterior basal Lateral basal

Lateral basal Posterior basal

Posterior basal


responses resulting in atopy and allergy-related diseases including anaphylaxis,asthma and allergic rhinitis.

The thymus gland is proportionately largestin infancy and early childhood; byadolescence it has begun to atrophy andgreatly decreases in size.

Mediastinal lymph nodes are located in thepre-tracheal, paratracheal and subcarinalareas, as well as adjacent to theoesophagus.

Diaphragm The diaphragm is the principalmuscle of respiration in childhood. Itconsists of a fibro-muscular sheet of tissuethat separates the thorax from the abdomen.It is comprised of a central membranoustendon to which the muscles of thediaphragm are attached. These comprisemuscles arising from the xiphoid process ofthe lower sternum, the lower six costalcartilages and the upper two to three lumbarvertebrae. Diaphragmatic muscles are moreeasily fatigued in infancy because theycontain a smaller proportion of fatigue-resistant muscle fibres than in later life. Thediaphragm is perforated by a number ofhiatal openings through which importantstructures pass from the thorax to theabdomen. These include the oesophagus(oesophageal hiatus), the aorta (aortichiatus) and the inferior vena cava (venacaval hiatus). The diaphragm is supplied bythe right and left phrenic nerves arisingthrough the cervical vertebrae C3, C4 and C5.

Chest wall The chest wall includes the ribsand the intercostal muscles. The ribs initiallydevelop as cartilage. The chest wallfunctions as a pump which performs therespiratory movements driving respirationitself. In the fetus the ribs are almost at rightangles to the vertebral column and themuscles of the diaphragm are arrangedmore horizontally than in later life. Chestmovements are therefore less efficient inearly life than later life when the child adoptsa more upright posture. The cartilaginousnature of the ribs also makes the chest wallless stiff, thus, resulting in the potential forparadoxical movements and indrawing ofthe thoracic cage during inspiration,

especially in preterm infants. Intercostalmuscles are also less active during rapid eyemovement (REM) sleep which lasts twice aslong in infancy as in later life. As the childmatures and spends more time awake andin the vertical position, gravity acts on theribs and intercostal muscles pulling themdownwards. The chest also becomes lesscircular in shape and more ovoid,particularly in the preschool years. The ribcage becomes increasingly calcified with ageand consequently stiffer which improves itsmechanical efficiency.

Development of the lungs

Lung development starts very early in fetallife, just before 28 days of gestation, as anendodermal outgrowth of the fetal gut calledthe ventral diverticulum. Although almost allof the lung structure is in place by the timeof birth the process continues throughoutchildhood into adolescence.

Intrauterine lung development Lungdevelopment in utero is divided into fourperiods.

N Embryonic: 3rd to 7th week of gestation.N Pseudoglandular: 7th to 17th week.N Canalicular: 17th to 27th week.N Alveolar period: from 27th week to term.Embryonic period (3–7 weeks): During thisperiod the initial lung bud develops as anendodermal groove from the fetal foregut(respiratory diverticulum). The lining of thelarynx, trachea, major airways and alveoli isendodermal in origin. The thyroid, cricoidand arytenoid cartilages and their associatedmuscles, originating from the mesoderm ofthe fourth and sixth branchial arches, alsodevelop during this period. The developingtracheobronchial tree then subdivides intothe major bronchi, lobar bronchi andperipheral airways. Other locally developingmesodermal tissues influence thisbranching pattern. At the end of this periodthe major subdivisions of lung anatomyhave already formed and although theassociated blood supply is not fullydeveloped each lung bud is supplied via thepulmonary trunk, which appears at 5 weeksgestation from the sixth bronchial arch anddivides into right and left branches. Each


lung bud is also connected to the evolvingleft atrium by a pulmonary vein. Theassociated capillaries begin theirdevelopment in the adjacent mesenchyme.

Pseudoglandular period (7–17 weeks): Duringthis period there is further rapid branchingof the airways. By 16 weeks the terminalbronchioles have developed and airwaycolumnar and cuboidal lining cells haveappeared. Fetal lung fluid develops and ispropelled through the airways by fetalbreathing movements first seen at around10 weeks of gestation with importantconsequences for volume expansion of thefluid-filled lungs. Other specialised tissuesdevelop including the cilia from 6 weeks,which becomes fully developed, including inthe trachea, by 18 weeks. Cartilage andlymph vessels develop from 10 weeksonwards. These spread peripherally throughthe developing lungs. Goblet cells, mucusglands and airway muscles also first appearat this time and continue their developmentthroughout prenatal and post-natal life. Themain pulmonary arteries and veins developfurther; the right pulmonary artery arisesfrom the proximal part of the sixth rightbranchial arch following which the distalpart degenerates. The left pulmonary arteryarises from the sixth left aortic arch whichgives off the main artery and then continues

as the arterial duct (ductus arteriosus) andremains patent until the early period ofadaptation to post-natal life. Bronchialarteries also develop directly from the aorta.The more distal preacinar arteries developand are fully present by 16 weeks.

Canalicular period (17–27 weeks): At thisstage the lungs develop their distalarchitecture. The peripheral airways elongateand the epithelial lining cells becomecuboidal in shape in the lower airwaygenerations. Mesodermal tissue thins outand the pulmonary microcirculationmatures. Terminal bronchioles, respiratorybronchioles and distal alveolar sacs developrapidly. The acinus, which forms the distalgas exchange unit of the lung, develops itsfinal structure by 24 weeks; immediatelybefore this time thin-walled saccules appearto develop into individual alveoli. The mostperipheral pulmonary vascular structuresdevelop as intimately associated alveolarcapillary units to form a blood–gas barriersufficient to maintain extrauterine life evenat this gestation (fig. 3).

The alveolar lining cells subdivide into twotypes: Type I and Type II. Each ishistologically distinguished by 24 weeksgestation. Type I (gas exchanging) cellsoccupy 95% of the alveolar lining. Primarysurfactant production occurs in Type II cells.

Trachea Majorbronchi

Bronchioli

Terminal Respiratory Ducts SacAlveoli

333bronchi

10–15 8–10Airwaygenerations

Preacinus# Acinus¶

11

Segmental/subsegmental

Figure 3. Anatomy of the tracheobronchial tree. #: this region comprises the conducting portion includingtrachea, bronchi and bronchioli to terminal bronchioles; ": this region comprises a gas exchanging unit(with alveoli) and includes respiratory bronchioli, alveolar ducts and alveolar sacs. Reproduced fromDinwiddie (1997), with permission from the publisher.


Signalling pathways Overall, lungmorphogenesis is under the control of anumber of signalling pathways. These areprimarily controlled by genetic factors,especially for the development of lunglobulation and the first 16 airwaygenerations. These activities are mediatedthrough a number of peptide growth factorsand more distally by similar substancesmodified by local physical factors thatregulate distal airway branching,development of the pulmonary vasculatureand, ultimately, the alveoli. A number ofpolypeptides are known to be involved inthis process including transforming growthfactor (TGF)-b, bone morphogenic protein(BMP)-4, fibroblast growth factors (FGFs),platelet-derived growth factor (PDGF),epidermal growth factors (EGF)/TGFs, sonichedgehog (SHH), vascular endothelialgrowth factor (VEGF), insulin-like growthfactors (IGFs) and granulocyte-macrophagecolony-stimulating factor (GM-CSF), as wellas thyroid transcription factor (TTF)-1protein.

Surfactant

Surfactant is produced in the Type II alveolarlining cells. It has a number of importantfunctions. The primary role of surfactant isto promote and maintain lung volume andprevent alveolar collapse during expiration.Thus, surfactant decreases the mechanicalwork and energy expenditure of breathing,especially at birth. Surfactant also has animportant role in host defence of the lungsagainst infection and in their response totissue insults, such as barotrauma duringtreatment. Genetic defects in surfactantproduction are now known to be majoraetiological factors in several chronic andpotentially lethal lung diseases of infancyand childhood (table 2).

Type II alveolar lining cells are principallyinvolved in the production, storage,secretion and recirculation of surfactantthrough the intracellular lamellar bodies.The principal surface active lipid insurfactant is phosphatidylcholine.

Four surfactant proteins have beenidentified. Surfactant protein (SP)-A is water

soluble and acts mainly by decreasingprotein-related inhibition of surfactantactivity. It also has an important role in lunginflammation where it acts as part of thehost defence mechanism. SP-A levels areresponsive to pre-natal corticosteroidtherapy. SP-B, which is hydrophobic, is animportant component of lamellar bodies. Itfacilitates the reduction of alveolar surfacetension when alveolar volume is reducedduring expiration. SP-C, also hydrophobic, isanother important protein component oflamellar bodies. It appears to functionclosely with SP-B in the spreading ofsurfactant onto the alveolar surface, thus,facilitating its surface tension reducingproperties. SP-D is water soluble and notdirectly associated with the function ofsurfactant phospholipids. Its principal roleappears to be as an innate immune systemprotein that acts as part of the host defenceagainst infections, e.g. with commonrespiratory tract bacteria and viruses.

ABCA3 is another important substancerelated to surfactant function. It is an ATPbinding cassette protein. Its precise functionis not yet fully known but it has been shownto be widely present in Type II alveolarepithelial lining cells. Its most likely action isin the inward transport of lipids forsurfactant production.

Surfactant secretion occurs by a process inwhich lamellar bodies are released fromType II lining cells within the alveoli.Phospholipids combine with SP-A, SP-B andSP-C. Secretion is stimulated by stretchingof the lung parenchyma, as well as byextrinsically administered b-adrenergic

Table 2. Components of surfactant

Phospholipids 78%

Dipalmitoylphosphatidylcholine 66%

Phosphatidylglycerol 4%

Phosphatidylethanol 5%

Sphingomyelin 3%

Cholesterol, glycerides andfatty acids

12%

Surfactant proteins A, B, C and D 10%


agonists. Surfactant lasts for approximately5 h before being broken down.Approximately 50% of active surfactant isrecycled through the lamellar bodies beforebeing reused. When secreted into the alveoliand distal small airways, mature surfactantforms a structure (tubular myelin) that,along with other compounds, lines thealveolar surface. Fully functional surfactantsecreted in normal amounts into the alveoliresults in decreasing surface tension as thealveoli shrink in volume, preventing theircollapse at the end of expiration. Oninspiration surface tension rises.

At birth, even in the presence of surfactant,an initial opening pressure is required toestablish a stable functional residualcapacity (FRC) of ,30 mL?kg-1. This is in theorder of 15 cmH2O. In the surfactant-deficient pre-term infant, pressures twice asgreat may be needed just to initially openthe alveoli with a tendency for recurrentcollapse at end expiration. The presence ofadequate amounts of active surfactant alsoresults in the achievement of significantlygreater lung volumes at full inspiration.

Several potentially severe conditions occurin young infants and children ifabnormalities exist in the surfactantproduction or breakdown pathways. Theseinclude potentially lethal or severe lungdisease in early life if there are geneticmutations of SP-B, SP-C, ABCA3 and TTF-1.These conditions are important causes ofrespiratory distress syndrome in full term,otherwise normal, babies. Another conditionof variable severity, alveolar proteinosis,occurs in older children and adults whenthere is deficiency of GM-CSF, a substancewhich is vital for the breakdown ofsurfactant.

Surfactant proteins have importantimmunological functions. SP-A increasesmacrophage activity in the lung. It alsofacilitates the destruction of variousmicroorganisms by other immune-modulated cells within the lung. The roles ofSP-B and SP-C in lung inflammation have notyet been fully evaluated. SP-D stimulatesthe phagocytosis of several types of micro-organisms by alveolar macrophages. It also

stimulates neutrophilic destruction ofbacteria, including Staphylococcus aureus,Streptococcus pneumoniae and Escherichia coli.

Exogenous surfactant is not only used in thetreatment of preterm infants but also in avariety of diseases in older children.

During this pseudoglandular period thelungs reach a liquid-filled volume similar tothe air filled FRC after birth of ,25–30 mL?kg-1. Fetal breathing movements atthis gestation are especially important in themaintenance of the developing lungvolumes.

In summary:

N Surfactant is predominantly composed ofphospholipids, principallyphosphatidylcholine.

N Surfactant contains four proteins A, B, C,and D.

N Surfactant proteins have importantsurface tension lowering functions andinnate immune modulating properties.

N Genetic deficiencies of surfactantproteins cause serious, and potentiallylethal, lung disease in neonates andinfants.

Alveolar sac period (27 weeks to term)

This is the final stage of fetal lungdevelopment. It is at this stage of fetal lifethat the lungs are able to sustainindependent breathing. The epithelial liningcells further differentiate and establish theirintimate inter-relationship with the epitheliallining surface of the alveoli. Distal lunggrowth continues as the respiratorybronchioles subdivide into saccules, whichthen form their final specialised structurebecoming alveoli. Alveoli are lined by twodistinct types of cell. Type I alveolar liningcells cover 95% of the alveolar surface andhave a thickness of 0.1–0.01 mm. Type IIalveolar lining cells are thicker, with adiameter of 10 mm. Although covering only5% of the alveolar surface, they play a vitalrole in surfactant production andmetabolism.

During this period the pulmonaryvasculature develops rapidly. The arterial


muscle coat is proportionately thicker thanin later life. This allows for intensevasoconstriction during periods ofintrauterine hypoxia but is a majorcontributory factor to persistent pulmonaryhypertension in the neonatal period (fig. 4).

Control of breathing

The development of control of breathing is acomplex process beginning early in fetal lifeand is continuously changing throughout

childhood. This is covered in detail in thisHandbook in the Sleep-related Disorderssection. Important reflexes that originate inthe chest wall are the Hering–Breuer reflexand the Head’s paradoxical reflex. TheHering–Breuer reflex is an inspiratoryinhibitory response mediated through thevagal nerves. It is particularly active in thecontrol of the rate and depth of breathing inthe neonatal period and during the first2 months of life. The Head’s paradoxical

AgeLength fromTB to pleura

16 weeksgestation

19 weeksgestation

28 weeksgestation

2 months

7 years 4 mm

Birth

0.1 mm

0.1 mm

0.2 mm

TB

TB

TB

TB

TB

TB

TD

TS

TS

ASAt

At

RB3

RB3

RB1

RB1

RB1

RB1 RB2

RB1 RB3RB2

AD2AD6

S1 S2

S3

S1 S2S3

0.6 mm

1.1 mm

1.75 mm

Pleura

Figure 4. Development of the acinus. Stages of acinar development in fetal and post-natal life. TB:terminal bronchiole, RB: respiratory bronchiole; TD: terminal duct; S: saccule; AD: alveolar duct; At:atrium; AS: alveolar sac. Reproduced from Hislop (1974) with permission from the publisher.


reflex is initiated by rapid lung inflation andprecipitates an increase in respiratory effort.The increased compliance of the ribcage inthe neonatal period can lead to distortionduring REM sleep, resulting in respiratoryirregularity and, in some cases, apnoea.

Post-natal lung development

After birth the alveoli become multilocularand progressively increase in size andnumbers with further out budding of thealveolar saccules. By term, approximatelyone-third to one half of the adult alveolarnumbers is present. Thereafter, alveolicontinue to increase in number, especiallyduring the first 2 years of life reaching100–250 million by the end of this period.Adult numbers of alveoli, 300–400 million,are already present by the age of 2–3 years.Boys have more alveoli than girls. Alveolarmultiplication continues at a reduced rateand is finally completed by 8–10 years ofage. After this there is a continuing increasein diameter of the large airways and furtherremodelling of the alveoli until physicalgrowth is complete. The peripheral airwaysincrease in relative size and proportioncompared to the central airways until theage of 5 years. Lung volumes increasethroughout childhood. A final growth spurtoccurs in adolescence associated with aparallel increase in lung volumes which lastslonger in boys than in girls. TLC at birth in a3-kg newborn infant is, on average, 150 mL(50 mL?kg-1) increasing to 6.0 L(75 mL?kg-1) in adult males and 4.2 L(60 mL?kg-1) in adult females. During thefirst 10 years of life the rib cage graduallychanges from a horizontal orientation to thedownward (caudal) slope of the adult.Ossification of the ribs also progressesthroughout childhood into early adult lifereaching completion in the early 20s.

Factors affecting lung growth anddevelopment

A number of factors can adversely affectlung growth and development throughoutboth fetal and post-natal life; these areshown in table 3.

Abnormalities of embryonic and fetaldevelopment, including congenital

malformations, e.g. diaphragmatic hernia,can have profound effects on the growth anddevelopment of both the affected and alsothe contralateral lung, especially if it arisesduring the pseudoglandular period whenairway generation is occurring at itsmaximum rate. Reduced alveolarisation isanother associated complication. Geneticfactors are particularly important and play asignificant role in controlling varioushormone-related influences, includingthyroid hormones (TTF-1), FGF, PDGF,IGF-1 and TGF-b, as well as steroidhormones, specifically oestrogen a and band androgen receptor hormones which areexpressed in developing lung tissue.Maternal malnutrition results in low birth-weight babies as does placentalinsufficiency. These factors can lead toreduced lung growth for gestation. Severematernal malnutrition, studied at the end ofWorld War II, has been shown to result in anincrease in COPD in adult life in affectedoffspring. Fetal breathing movements arefirst seen at 10 weeks gestation and areimportant for lung growth because of theirrole in the development and maintenance oflung volume. Lung cell proliferation isinhibited if fetal breathing movements arediminished. Absence of fetal breathingresults in pulmonary hypoplasia including adecrease in distal lung airspaces.Hypoplastic lungs secondary to reducedfetal breathing movements have impairedsynthesis and secretion of pulmonary

Table 3 Factors affecting lung growth and development

Abnormal embryonic and fetal development

Genetics

Hormones

Maternal and fetal malnutrition

Reduced fetal breathing movements

Reduced fetal lung fluid volumes

Inadequate size of thoracic cage

Impaired adaptation to post-natal life

Preterm birth and its treatment

Maternal smoking in pregnancy

Pre- and post-natal infection


surfactants resulting in abnormal lungmechanics at birth. Reduced amniotic fluidvolumes during pregnancy due to earlyrupture of the membranes or secondary toabnormal renal function, which results inoligohydramnios, can result in pulmonaryhypoplasia. Intrauterine pleural effusions,such as congenital chylothorax, can result ininhibition of lung growth. Syndromesinvolving reduced thoracic cagedevelopment, for example Jeune’sasphyxiating thoracic dystrophy, areassociated with pulmonary hypoplasia andimpaired surfactant secretion. Anothercause of pulmonary hypoplasia relates torespiratory muscle weakness, such asoccurs in congenital myopathies andneuropathies. Impaired adaptation toextrauterine life leading to chronic hypoxiaor treatment-induced hyperoxia, with orwithout long-term ventilation resulting inbarotrauma-induced lung injury, can alsoimpair age-related lung growth anddevelopment. Maternal smoking inpregnancy is a well-described cause ofimpairment of small airway developmentwith immediate and long-termconsequences on small airway developmentand resultant hyperresponsiveness. Severeinfections in early life, such as withadenovirus, can lead to obliterativebronchiolitis and impaired post-natal lungdevelopment.

Thus, the growth and development of thelungs is a continuous process from earlyfetal life, throughout childhood and intoearly adulthood. The most importantchanges occur before birth and in earlychildhood. It is at these times that otheradverse events, such as severe intercurrentinfections, are most likely to have profoundeffects on future structure and function.

Further reading

N Dinwiddie R. Development of the Lungs.In: Dinwiddie R, ed. Diagnosis andManagement of Paediatric RespiratoryDisease. 2nd Edn. Edinburgh, ChurchillLivingstone, 1997; pp. 1–8.

N Gaultier C. Developmental Anatomy andPhysiology of the Respiratory System. In:Taussig LM, et al., eds. PediatricRespiratory Medicine. 1st Edn. St Louis,Mosby, 1999; pp. 18–37.

N Hislop A, et al. (1974). Development ofthe acinus in the human lung. Thorax; 29:90–94.

N Inanlou MR, et al. (2005). The role of fetalbreathing-like movements in lung orga-nogenesis. Histol Histopathol; 20: 1261–1266.

N LeVine AM, et al. The Surfactant System.In: Chernick V, et al., eds. Kendig’sDisorders of the Respiratory Tract inChildren. 7th Edn. Philadelphia,Saunders Elsevier, 2006; pp. 17–22.


Applied respiratoryphysiology

Caroline Beardsmore and Monika Gappa

Knowledge of respiratory physiology isessential for understanding the pathologicalchanges in disease, and the application andinterpretation of respiratory function tests.Pathological changes in lung physiology willvary according to disease or condition, butcommon patterns can be observedaccording to whether the condition isprimarily obstructive or restrictive in nature.This dichotomy may be overly simplistic fordescribing some of the conditions that therespiratory paediatrician will have tomanage, but can serve as a useful startingpoint (fig. 1). Whatever condition is underconsideration, spirometry remains acornerstone of assessment, andmeasurement of lung volume is also vitalfor interpretation. This section will brieflysummarise the underlying measurementprinciples and discuss how to approachclinical questions by applying availablerespiratory function tests. Before

considering the applications of thesemeasurements in a clinical context theunderlying principles of the mostcommonly used measurements will besummarised.

Spirometry and the flow–volume loop

Spirometry is the means of recording thevolumes of inspired and expired air, and themaximum flows during the respiratorymanoeuvres.

Equipment and procedure The originalspirometers used from the inception of thetechnique until the 1980s were mechanicaldevices with a chamber from which thesubject breathed in and out. The chamberincorporated a low-resistance movablesection that accommodated the change involume without any appreciable pressurechange, and the movement was translatedinto a recording, either directly via a pen ona chart or via a transformer into a digitalrecording (fig. 2). These mechanicalspirometers measured changes in volumedirectly, and flow was calculated secondarily.The historical devices have been supersededby electronic spirometers which have theadvantages of portability, simplicity ofcleaning and ease of use. The electronicspirometers usually incorporate apneumotachograph or an ultrasonic flow-meter to measure flow, with volumesubsequently being obtained bydifferentiation.

Children who are able to cooperate withtesting will be asked to make an airtight sealaround the mouthpiece, breathe steadilyand then make maximum inspiratory andexpiratory manoeuvres. The recordings ofvolume change showing tidal breathing and

Key points

N Distinguishing obstructive andrestrictive disorders is simplistic but ahelpful starting point.

N A combination of spirometry and bodyplethysmography is most useful.

N Visual inspection of the flow–volumeloop, including the inspiratory limb, isessential.

N Assessment of inflammation isbecoming increasingly recognised asan important part of the overallevaluation.


a maximum (slow) respiratory manoeuvreare shown in figure 2. In addition to a slowmanoeuvre, a full forced manoeuvre isgenerally recorded. The derivation of a flow–volume loop from the volume–timerecording (the spirogram) is shown (fig. 3).The manoeuvres are repeated several timesin order to achieve the best (highest) valuesand assess repeatability. Internationallyaccepted guidelines exist for the technicalspecifications and performance ofspirometers, the conduct of the test, andquality control. Some modifications may benecessary for children, and the use ofincentive spirometry may be particularlyhelpful in younger children.

Measurements of lung volume

The principal means of measuring absolutelung volumes are gas dilution (usuallyhelium dilution), plethysmography andnitrogen washout, all of which measurefunctional residual capacity (FRC) andderived lung volumes (refer to thePulmonary function testing and otherdiagnostic tests section in this Handbook).The underlying principle forplethysmography differs from the gasdilution or washout techniques, and thismay be utilised to characterise thepathophysiology in different disease states.

Equipment and procedure Whole bodyplethysmography is used to measure(intra)thoracic gas volume. The principle ofthe measurement is such that it includes thevolume of all the air in the chest, whether incommunication with the airway andventilated, or not. In contrast, FRC isgenerally taken to include the volume of thelungs in free communication with the airwayopening and therefore ventilated.Nevertheless, the abbreviation FRCp (FRC byplethysmography) has gained popularity andwill be used hereafter. The measurement ofFRCp is based on Boyle’s law. The subject isenclosed in a cabin, which is almost airtight,and breathes through a pneumotachographthat measures airflow. A shutter is closed inthe device through which the subject isbreathing, transiently occluding the external

a) b)

Vol

ume

L

4.0

TLC

VC

FRC

RV

3.0

2.0

1.0

0.0

Time h

Figure 2. a) Original type of mechanicalspirometer and b) associated recording of changesin volume. The recording shows three tidal breathsat FRC followed by inspiration to TLC, andexpiration of VC to RV.

Restrictive conditions:lnterstitial lung disease,neuromuscular disease(e.g. Duchennne’s muscular dystrophy)andskeletal abnormalities (e.g. scoliosis)

Obstructive conditions: e.g. asthma, includingextrathoracic airway obstruction

The pattern of the flow–volume loop obtained through spirometry canindicate the site of obstruction (intrathoracic or extrathoracic) and whether it is fixed orvariable.Changes in FEV1,FVC and expiratory flows can quantify the extent of intrathoracic obstruction, and perform a similarfunction for extrathoracic obstruction.Lung volume measurements can showthe extent of any hyperinflation or gas trapping.Other investigations (e.g.gas mixing) may show abnormal function beforespirometry becomes abnormal and may behelpful in monitoring individuals and in research.

Spirometry (principally VC) shows the extent of restriction and is helpful for regular monitoring.Lung volume measurements will show the extent of thedeficit at either end ofthe VC range.Measurements of compliance and gas transfer may be helpfulwhere the underlying condition is pulmonary in origin.Tests of respiratory muscle strength can help in the evaluation of neuromuscular disease.

Figure 1. Consideration of abnormalities as eitherrestrictive or obstructive in nature. These are notmutually exclusive and individuals frequently showelements of both.


airway. The subject makes a respiratoryeffort against the shutter and the alveolarpressure change is measured directly fromthe mouthpiece. The change in thoracicvolume as the subject compresses orexpands the chest is measured indirectlyfrom the cabin pressure and used in thecalculation.

Once FRCp has been measured during thetransient period of airway occlusion thesubject continues to breathe through themouthpiece and, after one or two breaths,makes a full inspiration and expiration sothat the TLC and residual volume (RV) canbe determined (refer to the Pulmonaryfunction testing and other diagnostic testssection in this Handbook).

Nitrogen washout The principle behind thistechnique is to quantify the volume ofnitrogen within the lungs and then, knowingthe alveolar concentration of nitrogen,calculate lung volume. Therefore, theequipment combines a means of measuringvolume, usually a pneumotachograph, and anitrogen analyser or equivalent. Thetechnical issues associated with nitrogenanalysers mean that nitrogen is usuallymeasured either by mass spectrometry or byquantification of other gases (oxygen andcarbon dioxide) and subtracting these from100%. The procedure requires the subject tobreathe through a mouthpiece and, whensteady respiration is established, the subject

is switched to breathe 100% oxygen fromeither a reservoir or a bias flow. The expirednitrogen is quantified and the lung volumecalculated. In simple terms, if the alveolarconcentration of nitrogen was 80% and 2 Lof nitrogen was exhaled during the test, thelung volume would be 26100/80 L, or 2.5 L.The measurement is usually continued untilthe expired nitrogen is ,2.5%; continuationbeyond this point results in significantamounts of nitrogen dissolved in the bloodcoming out of solution in the lungs andresulting in an artefactually high estimationof lung volume.

The principle behind the test is notrestricted to nitrogen, and it is possible touse other tracer gases. These are first‘‘washed in’’ to the lungs by giving thesubject a pre-set concentration of inert,nonsoluble gas to breathe until alveolar(end-tidal) concentration is equal to theinspired concentration. One advantage ofother gases can be the avoidance ofbreathing 100% oxygen, which can haveundesired effects on pulmonary blood flowin certain patients (see chapter 3).

Helium dilution Measurement of lungvolume by helium dilution requires amechanical spirometer which, at the start ofthe measurement, is set to a known volumeand contains a known concentration ofhelium (typically 10%). The subject isconnected to breathe tidally from thespirometer, with carbon dioxide beingabsorbed in order not to provokehyperventilation. Oxygen is titrated into thesystem in order to maintain a stablebaseline volume and prevent onset ofhypoxia. As the air in the lungs mixes andequilibrates with that in the spirometer, anew, lower concentration of helium isestablished. When this is stable, the FRC canbe calculated as follows:

V1C15V2C2

where C1 and C2 are the initial and finalconcentrations of helium, V1 is the startingvolume of the spirometer and V2 is the finalvolume, i.e. spirometer and lung volumecombined. Rearranging:

V25V1C1/C2

3.0a) b)

TLCPEF

Vol

ume

L 1.5

0.0

–1.5

3.0

1.5 FEF50

PEF

0.0

RV

0 0 5

Flow L.s-11 2 3 4

Time s

–1.510

50% VC

FEV1FEV1

Figure 3. Relationship between a) spirogram andb) expiratory flow–volume curve, showinginspiration to TLC followed by forced expiration toRV. PEF occurs early in the manoeuvre, followedby smooth decline in flow to RV. Note that FEV1can only be derived from the spirogram.


and

FRC5V2-V1

The calculated value of FRC is likely to needsome small adjustment for the dead space ofthe mouthpiece and any connections to thespirometer. The spirometer will be at roomtemperature, but (by convention) lungvolume is expressed at BTPS (bodytemperature, ambient pressure, saturatedwith water vapour). Most modern equipmentwill have the corrections within the softwareso that the measurement shown will beaccurate. Usually three determinations aremade and a mean value reported.

Which measurement of lung volume is mostappropriate? The measurement of choicewill depend on why the measurement isbeing taken, i.e. what is the question to beanswered. Measurements based on dilutionor washout measure the volume of lung thatis being ventilated, i.e. functional, availablefor gas exchange. Trapped gas will not beincluded. Plethysmography measurestrapped gas in addition to the ventilatedportions of the lung, because all the air inthe thorax (whether trapped or not) issubjected to changes in pressure andvolume that are used in the calculation. Inhealthy individuals the differences in FRCmay be slight but in others they can differconsiderably, and the size of the differencemay be informative. Therefore, in somepatients with complex conditions, it may behelpful to include different methods toassess lung volumes in the evaluation.Measurements based on dilution orwashouts have the advantage that the timetaken to complete the measurements can beinformative. Where pulmonary function isgood, equilibration of gas or the ease withwhich a gas is washed out is rapid. Moreaccurately, the amount of ventilationrequired to achieve equilibration or washoutis less in a healthy individual than in asubject with deranged function, andassessment of this adds valuableinformation. This change in ventilation canbe quantified by parameters of ventilationinhomogeneity such as the Lung ClearanceIndex (LCI) and other indices which havebeen shown to be much more sensitive to

early changes within the small airways thanparameters obtained using full forcedexpiratory manoeuvres.

Assessment of obstruction

Patients with obstructive disorders form thelargest component of the workload of therespiratory paediatrician, with diseasesinvolving the small airways (mainly asthmaand CF) being the most common.Spirometry continues to be an essential partof assessment and monitoring,demonstrating deviation from predictedvalues and changes over time or in responseto treatment. The typical patient withobstructive respiratory disease will have anexpiratory flow–volume loop that shows adistinct concave shape, such that flows athigh lung volumes (peak expiratory flow(PEF) and forced expiratory flow at 25% ofFVC (FEF25)) will be relatively spared andthose at lower lung volumes (FEF50 andFEF75) will show a greater reduction. Visualinspection of the flow–volume loop is anessential part of the evaluation. During thecourse of expiration, the site of flowlimitation moves progressively down thebronchial tree into ever smaller airways,where the extent of any airway narrowing(e.g. caused by oedema of the airwayepithelium mucosa) has a greater effect.

When FEV1 and FVC are compared withpredicted values both indices may be withinnormal limits, but in obstructive airwaydisease the FEV1/FVC ratio is usuallyreduced and this can be helpful ininterpreting spirometry. However, FEV1/FVCshould not be considered in isolation,because it cannot convey whether either orboth component parts are within normallimits or not. For example, when assessingresponse to bronchodilator in an asthmaticpatient, there may be a significantimprovement in both FEV1 and FVC, butlittle change in FEV1/FVC. When assessingchan

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