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Pediatric Anesthesia
Basic PrinciplesState of the ArtFuture
Edited by

Bruno Bissonnette, MD
Department of Anesthesia
Faculty of Medicine
University of Toronto
President and Founder
Children of the World Anesthesia Foundation
Toronto, Ontario, Canada
Subeditors
Brian J. Anderson, MB ChB, PhD - New Zealand
Adrian Bsenberg, MB ChB - USA
Thomas Engelhardt, MD, PhD - Scotland
Linda J. Mason, MD - USA
Joseph D. Tobias, MD - USA
Illustrator: Danny Aguilar - Canada

2011
PEOPLES MEDICAL PUBLISHING HOUSEUSA
SHELTON, CONNECTICUT

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Peoples Medical Publishing House-USA


2 Enterprise Drive, Suite 509
Shelton, CT 06484
Tel: 203-402-0646
Fax: 203-402-0854
E-mail: info@pmph-usa.com
2011 PMPH-USA, Ltd.
All rights reserved. Without limiting the rights under copyright reserved above, no part of this publication may be reproduced, stored in or introduced
into a retrieval system, or transmitted, in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise), without the
prior written permission of the publisher.
11 12 13 14 15/PMPH/9 8 7 6 5 4 3 2 1
ISBN-13: 978-1-60795-093-6
ISBN-10: 1-60795-093-6
Printed in China by Peoples Medical Publishing House
Editor: Linda Mehta
Copyeditor/Typesetter: David Stockhoff, Spearhead Global
Cover designer: Bruno Bissonnette and Mary McKeon
Library of Congress CataloginginPublication Data
Pediatric anesthesia : basic principles, state of the art, future/[edited by] Bruno Bissonnette.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-1-60795-093-6
ISBN-10: 1-60795-093-6
1. Pediatric anesthesia. I. Bissonnette, Bruno.
[DNLM: 1. Anesthesiamethods. 2. Child. 3. Anestheticspharmacology. WO 440]
RD139.P418 2011
617.96083dc22
2010048079

Notice: The authors and publisher have made every effort to ensure that the patient care recommended herein, including choice of drugs and
drug dosages, is in accord with the accepted standard and practice at the time of publication. However, since research and regulation constantly
change clinical standards, the reader is urged to check the product information sheet included in the package of each drug, which includes
recommended doses, warnings, and contraindications. This is particularly important with new or infrequently used drugs. Any treatment
regimen, particularly one involving medication, involves inherent risk that must be weighed on a case-by-case basis against the benefits
anticipated. The reader is cautioned that the purpose of this book is to inform and enlighten; the information contained herein is not intended as,
and should not be employed as, a substitute for individual diagnosis and treatment.

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To All the Children of the World We Care For


Also
To my dear mother Lilianne for her love and encouragement
and
to the loving memories of my father Raymond and my brother Luc Bissonnette

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Contributors
Rita Agarwal, MD, FAAP [130]

Dean B. Andropoulos, MD, MHCM [106]

Associate Professor of Anesthesiology


Pediatric Anesthesia Program Director
The Childrens Hospital of Denver
Aurora, Colorado, USA

Professor of Anesthesiology and Pediatrics


Baylor College of Medicine
Chief of Anesthesiology
The Kurt D. Groten Sr Family Chair of
Pediatric Cardiovascular Anesthesiology
Attending Cardiovascular Anesthesiologist
Texas Childrens Hospital
Houston, Texas, USA

Swati Agarwal, MD [67]


Assistant Professor
Virginia Commonwealth University School of Medicine
Pediatric Critical Care Physician
Inova Fairfax Hospital for Children
Falls Church, Virginia, USA

Asim Ali, BASc, MD, FRCSC [102]


Assistant Professor of Ophthalmology
Department of Ophthalmology and Vision Sciences
University of Toronto
Attending Ophthalmologist
Director of Pediatric Ophthalmology Fellowship Program
Department of Ophthalmology and Vision Sciences
The Hospital for Sick Children
Toronto, Ontario, Canada

Kanwaljeet J. S. Anand, MB BS, DPhil, FAAP,


FCCM, FRCPCH [15]
Professor of Pediatrics, Anesthesiology and Neurobiology
University of Tennessee
St. Jude Childrens Research Hospital Endowed Chair of
Critical Care
Division Chief, Pediatric Critical Care Medicine
Le Bonheur Childrens Medical Center
University of Tennessee Health Science Center
Memphis, Tennessee, USA

Brian J. Anderson, MB ChB, PhD, FANZCA,


FJFICM [17, 18]
Honorary Associate Professor of Anaesthesiology
University of Auckland School of Medicine
Paediatric Anaesthetist and Intensivist
Department of Anaesthesia and Critical Care Medicine
Auckland Childrens Hospital
Auckland, New Zealand

Christian Apitz, MD [7]


Pediatric Cardiologist
Pediatric Heart Centre
University Childrens Hospital
Giessen, Germany

Glen S. Van Arsdell, MD [94]


Professor of Surgery
University of Toronto
Head, Division of Cardiovascular Surgery
Department of Surgery
CIT Chair in Cardiovascular Research
Labatt Family Heart Centre
The Hospital for Sick Children
Toronto, Ontario, Canada

Karim Ashenoune, MD, PhD [63]


Professor of Anesthesiology and Intensive Care Medicine
University of Nantes
Attending Anesthesiologist
Departement of Anesthesiology and Intensive Care Medicine
Htel Dieu
Centre Hospitalier Universitaire de Nantes
Nante, France

Hanan Azzam, MD [82]


Assistant Professor of Clinical Pathology
Faculty of Medicine, Mansoura University Hospital
Department of Clinical Pathology
Mansoura University Hospital
Mansoura, Egypt

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viii Contributors

Mette M. Berger, MD, PhD [124]

Gilles Boulay, MD [1]

Professor of Anesthesia and Critical Care Medicine


University of Lausanne School of Medicine
Consultant, Service of Intensive Care Medicine and Burns
Centre Hospitalier Universitaire Vaudois
Lausanne, Switzerland

Facult de Mdecine, AP-HP


Universit Paris Descartes
Attending Anesthesiologist
Hpital Saint-Vincent de Paul
Paris, France

Marc-Andr Bernath, MD, MER [124]

Nathalie Bourdaud, MD [53, 112]

Mdecin Associ
Universit de Lausanne
Chef du secteur de lAnesthsie Pdiatrique
Service dAnesthsiologie
Centre Hospitalier Universitaire Vaudois (CHUV)
Lausanne, Switzerland

Dominique A. Bettex, MD [73]


Assistant Professor of Anesthesiology
University of Zurich
Chief, Division of Cardiac and Vascular Anesthesia
University Hospital
Zurich, Switzerland

Universit Paris Descartes


Facult de Mdecine, AP-HP
Praticien Hospitalier
Hpital Necker Enfants-Malades
Paris, France

Kenneth M. Brady, MD [15]


Associate Professor, Pediatrics and Anesthesia
Baylor College of Medicine
Attending Anesthesiologist and Intensivist
Department of Anesthesia and Pediatrics
Texas Childrens Hospital
Houston, Texas, USA

Bruno Bissonnette, MD [6]


Professor of Anesthesia
Department of Anesthesia
Faculty of Medicine
University of Toronto
President and Founder
Children of the World Anesthesia Foundation
Toronto, Ontario, Canada

David A. Blacoe, MbChB, MRCP(UK), FRCA [128]


Consultant in Anaesthesia
Anaesthetist
Monklands Hospital
Airdrie, Scotland

Christopher M. Bolton, MB BS, FANZCA, PhD [122]


Attending Anaesthesiologist
Department of Anaesthesia and Pain Management
The Royal Childrens Hospital
Melbourne, Victoria, Australia

Peter D. Booker, MB, BS, MD, FRCA [23, 95]


Senior Lecturer in Paediatric Anaesthesia
University of Liverpool
Honorary Consultant
Paediatric Anaesthetist
Alder Hey Childrens NHS Foundation Trust
Liverpool, England

Alain Borgeat, MD, PhD [44]


Professor of Anesthesiology
Chief, Department of Anesthesiology
Balgrist University Hospital
Zurich, Switzerland

Adrian Bsenberg, MB ChB, FFA(SA) [47,49,132]


Professor of Anesthesiology
University of Washington
Director, Division of Regional Anesthesia
Department Anesthesiology and Pain Management
Seattle Childrens Hospital
Seattle, Washington, USA

Karen A. Brown, MD, FRCP(C) [62]


Professor of Anesthesiology
McGill University
Queen Elizabeth Hospital of Montreal Foundation Chair in
Pediatric Anesthesia
Attending Anesthesiologist
Montreal Childrens Hospital
McGill University Health Center
Montreal, Quebec, Canada

Stephen C. Brown, MD, FRCPC [16]


Associate Professor of Anesthesia
University of Toronto
Medical Director
Divisional Center of Pain Research and Pain Management
The Hospital for Sick Children
Toronto, Ontario, Canada

David Buckley, MBBChB, FANZCA, FCICM [42]


Paediatric Intensivist and Anaesthetist
Starship Children's Hospital
Auckland, New Zealand

Sabine Kost-Byerly, MD [66]


Associate Professor of Anesthesiology
Johns Hopkins University School of Medicine
Director, Pediatric Pain Management
Department of Anesthesiology and Critical Care Medicine
Baltimore, Maryland, USA

Xavier Capdevila, MD, PhD [45]


Professor of Anesthesiology and Critical Care Medicine
Montpellier School of Medicine
Montpellier University I
Chairman, Department of Anesthesiology and
Critical Care Medicine
Lapeyronie University Hospital
Montpellier, France

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Contributors ix

Pierre Carli, MD [68]

Brian Chanpong, DDS, MSc [126]

Professeur dAnesthsiologie et de Ranimation Chirurgicale


Universit Paris Descartes
Chef, Dpartement dAnesthsie et de Ranimation
Professor Hospitalier
Dpartement dAnesthsie-Ranimation
Directeur, SAMU de Paris
Hpital Necker Enfants Malades
Paris, France

Clinical Assistant Professor


Faculty of Dentistry
University of British Columbia
Attending Dental Anesthesiologist
Department of Dentistry
British Columbia Childrens Hospital
Vancouver, British Columbia, Canada

Alison S. Carr, MB BS, FRCA, MSc,


PGCertMEd (Dist) [99]
Consultant Paediatric Anaesthetist and
Honorary Senior Lecturer
Plymouth Hospitals NHS Trust
Derriford Hospital
Plymouth, England

Michael J. Casas, DDS, Dip.Paed, MSc, FRCD(C) [125]

Pierre-Guy Chassot, MD, PhD [73]


Associate Professor of Anesthesia
University Hospital of Lausanne
Head, Division of Cardiac Anesthesia
Director, Division of Intraoperative Transesophageal
Echocardiography
Lausanne, Switzerland

Farha Abd El-Aziz El-Chennawi, MD [82]

Associate Professor of Dentistry


University of Toronto
Director of Dental Clinics
Department of Dentistry
The Hospital for Sick Children
Toronto, Ontario, Canada

Professor of Immunology
Vice-President of Mansoura University
Postgraduate Studies and Research
Faculty of Medicine, Mansoura University
Head of Immunology Unit and Clinical Pathology
Mansoura University Hospital
Mansoura, Egypt

Neroli Chadderton, BHB, MBChB, FANZCA [23]

Olivier Choquet, MD [45]

Specialist Anesthetist
Hutt Valley Hospital
Wellington, New Zealand

Tristan M. B. de Chalain, MSc, MB Ch.B, FCS(SA),


FRCSC, FRACS [123]
University of Auckland
Director, Auckland Plastic Surgical Center
Consultant Plastic Surgeon
Starship Childrens Hospital
Auckland, New Zealand

George A. Chalkiadis, MB BS, FANZCA,


FFPMANZCA, DA (London) [30]
Clinical Associate Professor
University of Melbourne
Consultant Paediatric Anaesthetist and Pain Medicine Specialist
Coordinator of the Childrens Pain Management Services
Attending Paediatric Anaesthetist
Department of Anaesthesia and Pain Management
The Royal Childrens Hospital
Melbourne, Victoria, Australia

John Chandler, FDSRCS, FCARCSI [10]


Fellow in Pediatric Anesthesia
University of British Columbia
British Columbia Childrens Hospital
Vancouver, British Columbia, Canada

Associate Professor of Anesthesia


Montpellier University I
Lapeyronie University Hospital
Montpellier, France

Howard M. Clarke, MD, PhD, FRCS(C),


FACS, FAAP [123]
Professor of Surgery
University of Toronto
Active Staff Surgeon
Department of Surgery, Division of Plastic Surgery
The Hospital for Sick Children
Toronto, Ontario, Canada

John G. Coles, MD, FRCSC [105]


Professor of Surgery
University of Toronto
Attending Cardiovascular Surgeon
The Hospital for Sick Children
Toronto, Ontario, Canada

Mario J. da Coneicao, MD, PhD [34]


Professor of Surgical Techniques and Anesthesia
Blumenau Regional University Foundation
Instructor of Pediatric Anesthesia
Joana de Gusmao Childrens Hospital
Florianopolis, Brazil

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Contributors

Bairbre Connolly, MB BCh, BAO, FRCSI, MCh,


FFRRCSI, LMCC, FRCP(C) [121]
Associate Professor of Radiology
Department of Medical Imaging
University of Toronto
Earl Glenwood Coulson Chair
Pediatric Interventional Radiology
Department of Diagnostic ImagingImage Guided Therapy
The Hospital for Sick Children
Toronto, Ontario, Canada

Isabelle Constant, MD, PhD [75]


Professeure dAnesthsiologie et de Ranimation
AP-HP, UPMC Paris 6
Chef du Service dAnesthsie-Ranimation Chirurgicale
Responsable du Ple Hospital-Universitaire de
Chirurgie-Anesthsie
Coordonnateur du Centre de Traitement des Grands Brls
Hpital Armand Trousseau
Paris, France

Robin G. Cox, MB BS, MRCP(UK), FRCA, FRCPC [36]


Professor of Anesthesia, University of Calgary
Pediatric Anesthesiologist
Department of Anesthesia and Critical Care Medicine
Alberta Childrens Hospital
Calgary, Alberta, Canada

Peter N. Cox, MBChB, DCH, FFARCS (UK),


FRCP(C) [64]
Professor of Anesthesia, Critical Care and Pediatrics
University of Toronto
Associate Chief, Critical Care Unit
Clinical Director, Pediatric Intensive Care Unit
Fellowship Program Director
Department of Critical Care Medicine
The Hospital for Sick Children
Toronto, Ontario, Canada

Mary Cunliffe, MB BS, FRCA, FFPMRCA [91]


Honorary Clinical Lecturer in Anaesthesia
University of Liverpool
Consultant Paediatric Anaesthetist
Jackson Rees Department of Paediatric Anaesthesia
Alder Hey Childrens NHS Foundation Trust
Liverpool, England

Sharon L. Cushing, MD, MSc, FRCS(C) [98]


Assistant Professor of Surgery (ENT)
University of Toronto
Attending Otolaryngologist
The Hospital for Sick Children
Toronto, Ontario, Canada

Souhayl Dahmani, MD, PhD [19]


Universit Paris VII
Service dAnesthsie-Ranimation et Douleur
INSERM U676, Hpital Robert Debr
Paris, France

Andrew Davidson, MBBS, MD, FANZCA [77]


Leonard Travers Professor of Anaesthesia
Clinical Associate Professor
Department of Pharmacology
University of Melbourne
Associate Editor, Anesthesiology
Head, Clinical Research Development
Murdoch Childrens Research Institute
Attending Anaesthetist
Department of Anaesthesia and Pain Management
The Royal Childrens Hospital
Melbourne, Victoria, Australia

Jayant K. Deshpande, MD, MPH [88]


Professor of Pediatrics and Anesthesiology
University of Arkansas for Medical Sciences
Senior Vice President/Chief Quality Officer
Arkansas Childrens Hospital
Little Rock, Arkansas, USA

John Doyle, MD, FRCPC, FAAP [113]


Associate Professor of Anesthesiology
Department of Pediatrics
University of Toronto
Head, Division of Blood and Marrow Transplant Program
The Hospital for Sick Children
Toronto, Ontario, Canada

R. Blaine Easley, MD [15, 58]


Associate Professor, Pediatrics and Anesthesiology
Baylor College of Medicine
Attending in Cardiovascular Anesthesiology and Critical Care
Texas Childrens Hospital
Houston, Texas, USA

David Elliott, MB BS (Lon), MRCP(UK), FRCA,


PgClinUs [99]
Anaesthetic Registrar
Derriford Hospital
Plymouth, England

Steven T. Elliott, MD [89]


Surgery Resident
University of California Davis Medical Center
Sacramento, California, USA

Thomas Engelhardt, MD, PhD [5, 57]


Consultant Paediatric Anaesthetist
Royal Aberdeen Childrens Hospital
Aberdeen, Scotland

Walid A. Farhat, MD, FAAP [109]


Associate Professor of Surgery (Urology)
Department of Surgery, Division of Urology
University of Toronto
Associate Surgeon-in-Chief for Education
The Hospital for Sick Children
Toronto, Ontario, Canada

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Contributors xi

Patrick T. Farrell, MD [97]

Steven Ganzberg, DMD, MS [126]

Conjoint Lecturer, University of Newcastle


Director of Anaesthesia, John Hunter Hospital
Newcastle, New South Wales, Australia

Professor of Clinical Anesthesiology


College of Dentistry
College of Medicine and Public Health
The Ohio State University
Residency Program Director
Department of Dental/Maxillofacial Anesthesiology
Columbus, Ohio, USA

Pierre Fayoux, MD, PhD [8]


Director of the Pediatric Otorhinolaryngology
Head-Neck Surgery
Department of Otorhinolaryngology
Jeanne de Flandre Childrens Hospital
University Hospital of Lille
Lille 2 University
Lille, France

Annie Fecteau, MD [107]


Associate Professor of Surgery
Department of Surgery
University of Toronto
Division of General and Thoracic Surgery
Sick Kids Transplant Center
The Hospital for Sick Children
Toronto, Ontario, Canada

Zipporah Njeri Gathuya, MD [132]


Specialist Anesthesiologist
University of Nairobi
Director, Pediatric Anesthesia
Department Anesthesiology
Mary Gertrude Childrens Hospital
Nairobi, Kenya

J. Ted Gerstle, MD [96]

Associate Professor of Anesthesia


La Conception University Hospital
Marseille, France

Associate Professor of Surgery


Department of Surgery
University of Toronto
Program Director, Division of General and Thoracic Surgery
Project InvestigatorProgram in Cell Biology
Research Institute
The Hospital for Sick Children
Toronto, Ontario, Canada

David M. Fisher, MB BCh, FRCSC, FACS [100]

Peter Gibson, MBBS, FANCZA [110]

Jean-Louis Feugeas, MD [45]

Associate Professor of Surgery (Plastics)


University of Toronto
Medical Director, Cleft Lip and Palate Program
The Hospital for Sick Children
Toronto, Ontario, Canada

Clinical Lecturer in Anaesthesia


The University of Sydney
Staff Anaesthetist
Specialist Paediatric Anaesthetist
The Childrens Hospital at Westmead
Westmead, New South Wales, Australia

James Flowerdew, MD [101]

Jean-Louis Ginis, MD [11]

Attending Anesthesiologist
Director, Medical Student Electives in Anesthesia
Maine Medical Center
Portland, Maine, USA

Christopher R. Forrest, MD, MSc, FRCSC, FACS [116]


Professor of Surgery,
Department of Surgery
University of Toronto
Chief, Division of Plastic Surgery
Medical Director, Craniofacial Program
The Hospital for Sick Children
Toronto, Ontario, Canada

Professor of Pediatrics
University of Angers
Attending Pediatrician
Pediatric Intensive Care Medicine
Centre Hospitalier Universitaire
Angers, France

Jean Godard, MD [71]


Praticien Hospitalier dAnesthsie-Ranimation
Service de Ranimation Pdiatrique
Hpital Femme-Mre-Enfant
Lyon, France

Manuel Garca Grriz, MD [12]

Clinical Senior Lecturer


University of Auckland
Auckland, New Zealand

Assistant Professor of Anesthesia


Universitat Autonoma de Barcelona
Hospital Universitari Vall DHebron
Barcelona, Spain

Mohamed El-Gammal, MD [115]

Marie Granier, MD [103]

Michael J. Fredrickson, MD, MBChB, FANZCA [51]

Assistant Professor of Anesthesia


King Saud bin Abdulaziz University for Health Sciences
Chairman Department of Anesthesia
Head, Division of Pediatric Anesthesia
King Abdulaziz Medical City
Riyadh, Saudi Arabia
Toronto, Ontario, Canada

Pediatric Anesthesiologist
Centre Hospitalier Universitaire Estaing
Clermont-Ferrand, France

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Contributors

Jean-Claude Granry, MD [11]

Brendan OHare, MB [119]

Professor of Anesthesia and Intensive Care


University of Angers
Chief, Department of Anesthesia and Intensive Care
Department of Anesthesia and Critical Care Medicine
Centre Hospitalier Universitaire
Angers, France

Senior Clinical Lecturer


Department of Pediatrics
Trinity Medical School
Trinity College
Consultant in Paediatric Anesthesia and Critical Care Medicine
Our Ladys Childrens Hospital, Crumlin
Dublin, Ireland

George A. Gregory, MD [133]


Professor Emeritus, Anesthesia and Pediatrics
University of California, San Francisco
San Francisco, California, USA

Magalie Gurin, MD [40]


Facult de Mdecine de Marseille
Universit de la Mditerrane
Fellow, Department of Pediatric Anesthesia and
Critical Care Medicine
La Timone University Hospital
Marseille, France

Jean-Daniel Guieu, MD, PhD [76]


Professor Emeritus of Neurophysiology
University of Lille II
Department of Clinical Neurophysiology
University Hospital of Lille
Lille, France

Walid Habre, MD, PhD [61]


Associate Professor of Anesthesia
University of Geneva
Head, Division of Pediatric Anesthesia
University Hospitals of Geneva
Geneva, Switzerland

Gregory B. Hammer, MD [67]


Professor of Anesthesiology and Pediatrics
Departments of Anesthesia and Pediatrics
Stanford University School of Medicine
Attending Anesthesiologist
Director of Pediatric Anesthesia Research
Lucile Packard Childrens Hospital at Stanford
Stanford, California, USA

Jamil Hamza, MD [1]


Professor of Anesthesia and Critical Care Medicine
Facult de Mdecine, AP-HP
Universit Paris Descartes
Head of Pediatric Surgical Intensive Care
Hpital Necker Enfants-Malades
Paris, France

Raafat S. Hannallah, MD [69]


Professor of Anesthesiology and Pediatrics
The George Washington University Medical Center
Attending Pediatric Anesthesiologist
Department of Anesthesiology
Childrens National Medical Center
Washington, DC, USA

Jason A. Hayes, MD [25]


Assistant Professor of Anesthesia
University of Toronto
Attending Anesthesiologist
The Hospital for Sick Children
Toronto, Ontario, Canada

Elise Hon, MD, FRCS(C) [102]


Professor of Ophthalmology
Department of Ophthalmology and Vision Sciences
University of Toronto
Ophthalmologist-in-Chief
Department of Ophthalmology and Vision Sciences
Associate Surgeon-in-Chief
The Hospital for Sick Children
Toronto, Ontario, Canada

Badr-Eddine Hmamouchi, MD [79]


Professor of Anesthesia and Critical Care Medicine
Hassan II Ain Chok University of Casablanca
Department of Anesthesia and Critical Care
Casablanca Childrens Hospital
Casablanca, Morocco

Laura Holmes, BSc, CNIM [74]


Neurophysiology Technologist
Division of Intraoperative Neuromonitoring
The Hospital for Sick Children
Toronto, Ontario, Canada

Osami Honjo, MD, PhD [94, 105]


Assistant Professor of Surgery (Cardiovascular)
Department of Surgery
University of Toronto
Staff Cardiovascular Surgeon,
Division of Cardiovascular Surgery
Department of Surgery
The Hospital for Sick Children
Toronto, Ontario, Canada

David J. Kenny, BSc, DDS (hons), PhD, Dip Ped,


FRCD(C) [125]
Professor of Dentistry
University of Toronto
Attending Pediatric Dentist
The Hospital for Sick Children
Toronto, Ontario, Canada

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Contributors xiii

Rene Krivosic-Horber, MD [81]

Martin Jhr, MD [31]

Professeure dAnesthsie et Ranimation


Universit de Lille 2
Chef, Centre dHyperthermie Maligne de LilleHead,
Lille MH Center
Centre de rfrence des maladies rares neuro-musculaires
Centre Hospitalier Regional Universitaire
Lille, France

Professor of Anesthesia and Intensive Care Medicine


Head, Division of Pediatric Anesthesia
Department of Anesthesia, Intensive Care Medicine,
Emergency Medicine and Pain Therapy
Luzerner Kantonsspital
Luzerne, Switzerland

Rodrigo A. Iniguez, MD [111]


Pediatric Surgeon
Group for Improvement of Intestinal Function and Treatment
Transplant Center, The Hospital for Sick Children
Toronto, Ontario
Tel-Hashomer, Israel

Richard J. Ing, MBBCh, FCA(SA) [83]


Associate Professor of Anesthesia and Critical Care Medicine
Duke University
Attending Anesthesiologist and Intensivist
Division of Pediatric Anesthesia and Critical Care Medicine
Department of Anesthesiology
Duke University Medical Center
Durham, North Carolina, USA

Lisa A. Isaac, MD, FRCP(C) [39]


Assistant Professor of Anesthesia
University of Toronto
Attending Anesthesiologist
Department of Anesthesia and Pain Medicine
The Hospital for Sick Children
Toronto, Ontario, Canada

Giorgio Ivani, MD [48]


Associate Professor of Anesthesia
University of Turin
Chairman, Department of Pediatric Anesthesia and
Intensive Care Medicine
Regina Margherita Childrens Hospital
Turin, Italy

Brenna L. Jacobson, MD [59]


Assistant Professor of Anesthesiology
Loma Linda University School of Medicine
Attending Anesthesiologist
Loma Linda, California, USA

Justin John, MD [113]


Assistant Professor of Anesthesiology and Pediatrics
Department of Pediatrics
Eastern Virginia Medical School
Attending Anesthesiologist
Medical Director of Sedation Services
Department of Anesthesiology
Childrens Hospital of The Kings Daughters
Norfolk, Virginia, USA

Daisy T. Joo, MD, PhD [25]


Attending Anesthesiologist
North York General Hospital
Toronto, Ontario, Canada

Hans Jutzi, MD [44]


Consultant in Anesthesiology
Department of Anesthesiology
Balgrist University Hospital
Zurich, Switzerland

Chaim Kaplinsky, MD [13]


Professor of Medicine (Hematology) and Pediatrics
The Sackler School of Medicine
University of Tel-Aviv
Department of Pediatric Hematology-Oncology
Safra Childrens Hospital
The Chaim Sheba Medical Center
Tel-Hashomer, Israel

Cengiz Karsli, BSc, MD, FRCPC [39]


Assistant Professor of Anesthesia
University of Toronto
Attending Anesthesiologist
The Hospital for Sick Children
Toronto, Ontario, Canada

Katherine Keech, MD [47]


Fellow in Pediatric Anesthesia
Department Anesthesiology and Pain Management
Seattle Childrens Hospital
Seattle, Washington, USA

Cassandra M. Kelleher, MD [107]


Instructor in Surgery
Department of Surgery
Harvard Medical School
Assistant in Surgery
Mass General Hospital for Children
Boston, Massachusetts, USA

Gili Kenet, MD [13]


Professor of Medicine (Hematology) and Pediatrics
The Sackler School of Medicine
University of Tel-Aviv
Institute of Thrombosis and Hemostasis
The Thrombosis Unit and National Hemophilia Center
Department of Hematology
Safra Childrens Hospital
The Chaim Sheba Medical Center
Tel-Hashomer, Israel

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Contributors

Sonia ben Khalifa, MD [90]

Wai-Ching Lam, MD, FRCS(C) [102]

Professor of Anesthesia and Intensive Care Medicine


Faculty of Medicine, Tunis El Manar University
Chairman
Department of Anesthesia and Intensive Care Medicine
University Children Hospital
Tunis, Tunisia

Associate Professor of Ophthalmology


Program Director
Department of Ophthalmology and Vision Sciences
University of Toronto
Attending Ophthalmologist
Department of Ophthalmology and Vision Sciences
The Hospital for Sick Children
Attending Ophthalmologist
Toronto Western Hospital
University Health Network
Toronto, Ontario, Canada

Antoine E. Khoury, MD, FRCSC, FAAP [87]


Professor and Chief of Pediatric Urology
University of California, Irvine
Childrens Hospital of Orange County
Orange, California, USA

Jarmila Kim, MD, FRCPC [37]


Assistant Professor of Anesthesia
University of Ottawa
Attending Anesthesiologist
Childrens Hospital of Eastern Ontario
Ottawa, Ontario, Canada

Peter C. W. Kim, MD, CM, PhD [85]

Frdric Lamy, MD [40]


Facult de Mdecine de Marseille
Universit de la Mditerrane
Fellow, Department of Pediatric Anesthesia and
Critical Care Medicine
La Timone University Hospital
Marseille, France

Vincent P. Laudenbach, MD, PhD [19]

Professor of Surgery
Department of Surgery
University of Toronto
Staff Surgeon, Lead CIGITI
Hospital for Sick Children
Toronto, Ontario, Canada

Professor of Pediatric Anesthesiology and Neonatal


Intensive Care
Charles Nicolle University Hospital
Laboratory Deputy Head
EA 4309 NeoVasc Microvasculature and neonatal brain lesions
Normandy University Institute
Rouen, France

Hannu Kokki, MD, PhD [27]

Emmanule Laureau, MD, MsC [76]

Associate Professor of Anesthesiology


University of Kuopio
Attending Anesthetist
Kuopio University Hospital,
Kuopio, Finland

Staff Neurophysiologist
Department of Clinical Neurophysiology
University Hospital of Lille
Lille, France

Peter C. Laussen, MBBS [119]


Charles D. Kurth, MD [129]
Professor of Anesthesia and Pediatrics
University of Cincinnati College of Medicine
Anesthesiologist in Chief
Chairman, Department of Anesthesiology
Cincinnati Childrens Hospital Medical Center
Cincinnati, Ohio, USA

Frdric Lacroix, MD [45]


Praticien Hospitalier
Facult de Mdecine de Marseille
Universit de la Mditerrane
Anesthsiste-Ranimateur Pdiatrique
Dpartment dAnesthsiologie et Ranimation
Centre Hospitalier Universitaire La Timone
Assistance PubliqueHpitaux de Marseille
Marseille, France

Carol L. Lake, MD, MBA, MPH [95]


Hummelstown, Pennsylvania, USA

Professor of Anesthesia
Harvard Medical School
DD Hansen Chair in Pediatric Anesthesia
Chief, Division Cardiovascular Critical Care
Childrens Hospital Boston
Boston, Massachusetts, USA

Charles Lee, MD [108]


Assistant Professor of Anesthesiology
Loma Linda University School of Medicine
Director of Acute/Perioperative Pain Service
Director of Organ Transplantation Anesthesia
Clinical Director of Pediatric Anesthesia
Loma Linda University Medical Center
Loma Linda, California, USA

Corinne Lejus, MD, PhD [63]


Professor of Anesthesiology and Surgical
Intensive Care Medicine
University of Nantes
Chief of Department of Anesthesiology and Surgical
Intensive Care Medicine
Htel Dieu
Centre Hospitalier Universitaire de Nantes
Nantes, France

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Mark F. Levine, MBBCh, FRCPC [117]

Barry Lyons, MB, FFARCSI [64]

Associate Professor of Anesthesia


Program Director
Department of Anesthesia
University of Toronto
Attending Anesthesiologist
The Hospital for Sick Children
Toronto, Ontario, Canada

Consultant Anaesthetist
Department of Anaesthesia and Critical Care Medicine
Our Ladys Hospital for Sick Children
Dublin, Ireland

Jonathan de Lima, MBBS, PhD (UCL), FANCZA [110]


Clinical Senior Lecturer
The University of Sydney
Deputy, Department of Pain Medicine and Palliative Care
Senior Staff Anaesthetist
Specialist Paediatric Anaesthetist
The Childrens Hospital at Westmead
Westmead, New South Wales, Australia

Tsz-Yan Milly Lo, MB ChB, DCH, MRCP (UK),


MRCPCH, PhD [64]
Honorary Senior Lecturer
University of Edinburgh
Consultant in Paediatric Intensive Care Medicine
The Royal Hospital for Sick Children
Edinburgh, Scotland

Justin L. Lockman, MD [58]


Fellow in Anesthesiology and Critical Care Medicine
Pediatric Critical Care Medicine and Anesthesiology
The Johns Hopkins School of Medicine
Fellow in Anesthesiology
Childrens Hospital
The Johns Hopkins Hospital
Baltimore, Maryland, USA

Per-Arne Lnnqvist, MD, DEAA, FRCA, PhD [86]


Professor of Pediatric Anesthesia and Intensive Care Medicine
Department of Physiology and Pharmacology
Karolinska Institute
Senior Consultant, Karolinska University Hospital
Stockholm, Sweden

Armando J. Lorenzo, MD, MSc, FAAP [109]


Assistant Professor of Surgery (Urology)
Department of Surgery, Division of Urology
University of Toronto
Attending Surgeon
The Hospital for Sick Children
Toronto, Ontario, Canada

Igor Luginbuehl, MD [14]


Associate Professor of Anesthesia
University of Toronto
Attending Anesthesiologist
The Hospital for Sick Children
Toronto, Ontario, Canada

Ruth Oelhafen Luginbuehl, MD, DTATI [2]


Pediatrician FMH
Medical Art Therapist DTATI
Toronto, Ontario, Canada

Jean Mantz, MD, PhD [19]


Professeur dAnesthsie-Ranimation
Universit Paris VII, Paris Diderot
Chairman, Service dAnesthsie-Ranimation
INSERM U676, Hpital Beaujon
Clichy la Garenne, France

Bruno Marciniak, MD [8]


Attending Anesthesiologist
Jeanne de Flandre Childrens Hospital
University Hospital of Lille
Lille, France

Peter Marhofer, MD [46]


Professor of Anesthesiology
Medizinische Universitt Wien
Univ. Klinik fr Ansthesie, Intensivmedizin and
Schmerztherapie
Vienna, Austria

Giuseppe Marraro, MD [72]


Associate Professor of Anesthesia and
Intensive Care Medicine II Specialization
School of Anesthesia and Intensive Care
Faculty of Medicine and Surgery
University of Milan
Honorary Consultant in Anesthesia and
Intensive Care Medicine
Director of Pediatric Anesthesia and Intensive Care Medicine
Pediatric Intensive Care Unit
Fatebenefratelli and Ophthalmiatric Hospital
Milan, Italy

Lynn D. Martin, MD, FAAP, FCCM [131]


Professor of Anesthesiology and Pediatrics (Adj.)
University of Washington School of Medicine
Director, Department of Anesthesiology and Pain Medicine
Medical Director, Bellevue Clinics and Surgery Center
Seattle Childrens Hospital
Seattle, Washington, USA

Linda J. Mason, MD [59, 95]


Professor of Anesthesiology and Pediatrics
Loma Linda University School of Medicine
Director of Pediatric Anesthesiology
Loma Linda University Medical Center
Loma Linda, California, USA

Lynne G. Maxwell, MD, FAAP [66]


Associate Professor Anesthesiology and Critical Care
University of Pennsylvania
Deputy Director, General Anesthesia Division
The Childrens Hospital of Philadelphia
Philadelphia, Pennsylvania, USA

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Contributors

Jean Xavier Mazoit, MD, PhD [28]

Neil S. Morton, MD, FRCA, FRCPCH, FFPMRCA [41]

Attending Anesthesiologist
Dpartement dAnesthsie-Ranimation
Hpital Bictre AP-HP
Laboratoire dAnesthsie UMR788
Neuroprotection, rgnration des axones et de la myline
Universit Paris-Sud
Facult de Medecine du Kremlin-Bictre
Bictre, France

Reader in Paediatric Anaesthesia and Pain Management


University of Glasgow
Consultant in Paediatric Anaesthesia and Pain Management
Royal Hospital for Sick Children
Editor-in-Chief, Pediatric Anesthesia
Glasgow, Scotland

Craig D. McClain, MD, MPH, FAAP [93]


Assistant Professor of Anesthesia
Harvard Medical School
Associate in Anesthesia
Childrens Hospital Boston
Boston, Massachusetts, USA

Valeria Mossetti, MD [48]


Attending Anesthesiologist
Division of Pediatric Anesthesiology and
Intensive Care Medicine
Regina Margherita Childrens Hospital
Turin, Italy

Etsuro K. Motoyama, MD [9]

Assistant Professor of Anesthesia


University of Toronto
Staff Anesthesiologist
The Hospital for Sick Children
Toronto, Ontario, Canada

Professor Emeritus of Anesthesiology and Pediatrics


University of Pittsburgh School of Medicine
Attending Anesthesiologist and Pulmonologist
Director Emeritus, Respiratory Physiology Laboratory
Childrens Hospital of Pittsburgh
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, USA

Patricia A. McGrath, PhD [16]

Isabelle Murat, MD, PhD [127]

Conor McDonnell, MD, MB [20]

Professor of Anesthesia
University of Toronto
Scientific Director
Chronic Pain Program Psychology
Research Institute
Senior Associate Scientist
Neurosciences and Mental Health
The Hospital for Sick Children
Toronto, Ontario, Canada

Professor of Anesthesia
AP-HP, University Paris 6
Chairman, Departement of Anesthesia and
Critical Care Medicine
Armand Trousseau Hospital
Paris, France

Laura B. Myers, MD [120]

Professor of Anesthesiology
University of Helsinki
Hospital for Children and Adolescents
Helsinki, Finland

Assistant Professor of Anesthesia


Harvard Medical School
Research Associate in Anesthesia
Children's Hospital Boston
Staff Anesthesiologist
Newton-Wellesley Hospital
Boston, Massachusetts, USA

Hawa Keta-Meyer, MD, PhD [19]

Sif-Eddine Nejmi, MD [79]

Professor of Anesthesia
AP-HP, University Paris 7
Director, Division of Anesthesia
Louis Mourier Hospital
Colombes, France

Professor of Anesthesia and Critical Care Medicine


Hassan II Ain Chok University of Casablanca
Department of Anesthesia and Critical Care
Casablanca Childrens Hospital
Casablanca, Morocco

Gregory Moloney, MBBS, FANZCA [43]

David G. Nykanen, MD [118]

Attending Anaesthetist
Mater Childrens Hospital
Brisbane, Queensland, Australia

Associate Professor of Paediatrics (Cardiology)


University of Central Florida College of Medicine
Director, Cardiology and Cardiac Catheterization
Arnold Palmer Medical Center
Orlando, Florida, USA

Olli A. Meretoja, MD [27]

Victor H. Espinal Montoya, MD [65]


Attending Anesthesiologist
Department of Anesthesia
Cape Breton Regional Hospital
Sydney, Nova Scotia, Canada

Kar-Binh Ong, MBBS (London), FRCA(UK) [56]


Honorary Senior Lecturer (Institute of Child Health)
Consultant Anaesthetist (Great Ormond Street Hospital)
Great Ormond Street Hospital
London, England

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Gilles Orliaguet, MD, PhD [53, 112]

Aurelia Peraud, MD, PhD [92]

Professeur dAnesthsiologie et Ranimation


Universit Paris Descartes Facult de Mdecine, AP-HP
Vice Chairman
Dpartement dAnesthsie et Ranimation
Hpital Necker Enfants-Malades
Paris, France

Associate Professor of Surgery (Neurosurgery)


Ludwig-Maximilian University of Munich
Chief, Division Pediatric Neurosurgery
Attending Pediatric Neurosurgeon and Epilepsy Surgeon
Department of Neurosurgery
Klinikum Grosshadern
Munich, Germany

Nicholas Pace, FRCA, FRCP, MPhil, PhD [128]


Clinical Director
Department of Anaesthesia
Gartnavel General Hospital
Glasgow, Scotland

Greta M. Palmer, MBBS, FANZCA, FFPMANZCA [26]


Clinical Associate Professor
University of Melbourne
Deputy Head, Childrens Pain Management Service
Paediatric Anaesthetist and Pain Management Specialist
Royal Childrens Hospital
Murdoch Childrens Research Institute
Melbourne, Victoria, Australia

Blake C. Papsin, MD, MSc, FRCSC, FACS, FAAP [98]


Professor of Otolaryngology
Faculty of Medicine
The University of Toronto
Cochlear Chair in Auditory Development
Director of the Cochlear Implant Program
Attending Otolaryngologist
Associate Scientist, Neurosciences and Mental Health
The Research Institute
The Hospital for Sick Children
Toronto, Ontario, Canada

Catherine Paquet, MD, FRCPC [54]


Assistant Professor of Anesthesia
McGill University
Attending Anesthesiologist
Montreal Childrens Hospital
Montreal, Quebec, Canada

Olivier Paut, MD [40]


Professor of Anesthesia and Critical Care Medicine
Facult de Mdecine de Marseille
Universit de la Mditerrane
Head, Department of Pediatric Anesthesia and
Critical Care Medicine
La Timone University Hospital
Marseille, France

Dilip Pawar, MBBS, DA, MD, FAMS, FAMS(S) [29]


Professor of Anesthesiology
All India Institute of Medical Sciences
New Delhi, India

Daniel A. Peters, MD, MBA, FRCSC [116]


Assistant Professor of Surgery (Plastic Surgery)
Department of Surgery
Telfer School of Management
University of Ottawa
Childrens Hospital of Eastern Ontario
Ottawa, Ontario, Canada

Robert Plant, FCARCSI, FJFICM(Ireland),


FJFICM(Aus/NZ) [10]
Director of Intensive Care
Cork University Hospital
Cork, Ireland

David M. Polaner, MD, FAAP [130]


Professor of Anesthesiology and Pediatrics
University of Colorado School of Medicine
Chief, Acute Pain Service
Anesthesia Informatics
The Childrens Hospital of Denver
Aurora, Colorado, USA

George D. Politis, MD, MPH [21]


Associate Professor of Anesthesiology and Pediatrics
University of Virginia
Attending Anesthesiologist
Co-Director of the University of Virginia
Outpatient Surgical Center
University of Virginia Health System
Charlottesville, Virginia, USA

Elizabeth Prentice, MBBS, FANZCA [70]


Attending Paediatric Anaesthetist
Department of Anaesthesia and Pain Management
The Royal Childrens Hospital
Melbourne, Victoria, Australia

Carlos Hervs Puyal, MD [12]


Consultant Pediatric Anesthesiologist
Department of Anesthesia
Hospital Universitario Vall dHebron
Barcelona, Spain

Abdullah A. Al-Rabeeah, MD, FRCSC [114]


Minister of Health, Kingdom of Saudi Arabia
Professor of Surgery
King Saud bin Abdulaziz University for Health Sciences
Senior Pediatric Surgeon
King Abdulaziz Medical City (National Guard Health Affairs)
Riyadh, Saudi Arabia

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xviii Contributors

Carmen T. Ramos, MD, MSc [85]

Sophie Saindon, MD, FRCP(C) [55]

Ad Honorem Associate Professor of Surgery


University of Puerto Rico
Chief, Division of Pediatric Surgery
Department of Surgery
San Jorge Childrens Hospital
San Juan, Puerto Rico

Clinical Assistant Professor of Anesthesia


University of Montreal
Attending Anesthesiologist
Centre Hospitalier Universitaire Ste-Justine
Mother and Child University Hospital Center
Montreal, Quebec, Canada

Sally E. Rampersad, MD [131]

Michela Salvadore, MBChB, FRCA [57]

Associate Professor of Anesthesiology


Department of Anesthesiology
University of Washington School of Medicine
Director, Quality Improvement
Department of Anesthesiology and Pain Medicine
Childrens Hospital and Regional Medical Center
Seattle, Washington, USA

Pramod P. Reddy, M.B.B.S. [87]


Associate Professor of Urology
University of Cincinnati
Director, Division of Pediatric Urology
Cincinnati Childrens Hospital Medical Center
Cincinnati, Ohio, USA

Andrew N. Redington, MB, BS, MRCP (UK), MD, FRCP


(UK), FRCP (C) [7]
Professor of Pediatrics
University of Toronto
BMO Financial Group Chair in Cardiology
Labatt Family Heart Centre
Head, Division of Cardiology
The Hospital for Sick Children
Senior Associate Scientist
Physiology and Experimental Medicine
The Hospital for Sick Children Research Institute
Toronto, Ontario, Canada

Bndicte Ringuier, MD [11]


Department of Pediatrics
University of Angers
Attending Pediatrician
Pediatric Anesthesia and Intensive Care
Centre Hospitalier Universitaire
Angers, France

Allison Kinder Ross, MD [83]


Associate Professor of Anesthesia
Duke University
Chief, Division of Pediatric Anesthesia
Division of Pediatric Anesthesia and Critical Care Medicine
Department of Anesthesiology
Duke University Medical Center
Durham, North Carolina, USA

Specialist Registrar in Anaesthesia


Royal Aberdeen Childrens Hospital
Aberdeen, Scotland

Paul J. Samuels, MD [129]


Associate Professor of Anesthesiology and Pediatrics
Director of Education
Cincinnati Childrens Hospital
Cincinnati, Ohio, USA

Anthony D. Sandler, MBChB [89]


Diane and Norman Bernstein Chair
Professor of Surgery and Pediatrics
George Washington University
Chief, Division of Thoracic and Abdominal Surgery
Childrens National Medical Center
Washington, DC, USA

Rosario Nuo Sanz, MD [12]


Pediatric Anesthetist
Department of Anesthesiology
Hospital Universitario Vall dHebron
Barcelona, Spain

Frdrique Sauvat, MD, PhD [112]


Praticien Hospitalier
Pediatric Surgeon
Centre Hospitalier Regional F. Guyon
Saint Denis de la Runion, France

Ahmed Mohamed Shalabi, MSC, MD [80]


Assistant Lecturer in Anesthesiology and
Surgical Intensive Care Medicine
Faculty of Medicine
Alexandria University
Attending Anesthesiologist and Intensivist
Alexandria University Hospitals
Alexandria, Egypt

Lionel Simon, MD (Deceased) [1]


Facult de Mdecine, AP-HP
Universit Paris Descartes
Anesthesiologist
Hpital Saint-Vincent de Paul
Paris, France

David A. Rowney, MB ChB, FRCA [78]


Consultant in Paediatric Anaesthesia and
Intensive Care Medicine
Royal Hospital for Sick Children
Edinburgh, Scotland

Craig Sims, MB BS FANZCA [35]


Clinical Senior Lecturer in Anaesthesia
School of Paediatrics and Child Health
University of Western Australia
Paediatric Anaesthetist
Princess Margaret Hospital for Children
Perth, Western Australia, Australia

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Jonathan H. Smith, BSc (Hons), MB, BS, FRCA [56]

Michael R. J. Sury, FFARCS [56]

Honorary Senior Lecturer in Anaesthesia


Portex Unit of Paediatric Anaesthesia
UCL Institute for Child Health
Consultant Paediatric Anaesthetist
Great Ormond Street Hospital for Children
London, England

Honorary Senior Lecturer in Anaesthesia


PORTEX Unit of Paediatric Anaesthesia
Institute of Child Health
University College London
Consultant Anaesthetist
Department of Anaesthesia
Great Ormond Street Hospital NHS Trust
London, England

Raz Somech, MD, PhD [13]


Professor of Medicine (Immunology) and Pediatrics
The Sackler School of Medicine
Tel-Aviv University
Director, Division of Pediatric Immunology
Department of Pediatric
Edmond and Lily Safra Childrens Hospital
The Chaim Sheba Medical Center
Institute of Hematology
The Sheba Cancer Research Center
Tel Hashomer, Israel

Sulpicio G. Soriano, MD, FAAP [93]


Professor of Anesthesia
Harvard Medical School
Childrens Hospital Boston Endowed Chair in
Pediatric Neuroanesthesia
Attending Pediatric Anesthesiologist
Childrens Hospital Boston
Boston, Massachusetts, USA

William M. Splinter, MD, FRCPC [37]


Associate Professor of Anesthesia
University of Ottawa
Attending Anesthesiologist
Childrens Hospital of Eastern Ontario
Ottawa, Ontario, Canada

Samuel Strantzas, MSc, D.ABNM [74]


Associate Clinical Neurophysiologist
Director, Division of Intraoperative Neuromonitoring
The Hospital for Sick Children
Toronto, Ontario, Canada

Pascal Stucki, MD, MER [124]


Mdecin Associ
Service de Soins Intensifs Mdicochirurcaux de Pdiatrie
Centre Hospitalier Universitaire Vaudois (CHUV)
Lausanne, Switzerland

Santhanam Suresh, MD [50]


Professor of Anesthesiology and Pediatrics
Northwestern Universitys Feinberg School of Medicine
Vice Chairman
Director of Research and Pain Medicine
Department of Anesthesiology
Childrens Memorial Hospital
Chicago, Illinois, USA

Dale F. Szpisjak, MD, MPH [54]


Associate Professor of Anesthesiology
Uniformed Services University of the Health Sciences
Interim Chair, Department of Anesthesiology
Bethesda, Maryland, USA

Elsa Taylor, MBChB, FANZCA [24]


Specialist Paediatric Anaesthetist
Starship Childrens Hospital
Starship Childrens Health
Auckland, New Zealand

Nasrin Najm-Tehrani, MB BCh, MSc,


FRCS Ed (Ophth) [102]
Assistant Professor of Ophthalmology
Department of Ophthalmology and Vision Sciences
University of Toronto
Attending Ophthalmologist
Leader of ROP Program
Department of Ophthalmology and Vision Sciences
The Hospital for Sick Children
Toronto, Ontario, Canada

Caroline Telion, MD [68]


Practicien Hospitalier
Dpartement dAnesthsie Ranimation
Hpital Necker Enfants Malades
Paris, France

Michael J. Temple, MD, FRCPC [121]


Assistant Professor of Radiology
Department of Medical Imaging
University of Toronto
Attending Radiologist
Pediatric Interventional Radiology
Department of Diagnostic ImagingImage Guided Therapy
The Hospital for Sick Children
Toronto, Ontario, Canada

Priya Thalayasingam, MBBS, FANZCA [104]


Consultant Paediatric Anaesthetist
Department of Anaesthesia and Pain Management
Princess Margaret Hospital for Children
Perth, Western Australia, Australia

Joseph D. Tobias, MD [4, 15, 57]


Professor of Anesthesiology and Pediatrics
The Ohio State University
Chairman, Department of Anesthesiology and Pain Medicine
Nationwide Childrens Hospital
Columbus, Ohio, USA

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Contributors

Dalia Mohamed Tohlob, MD [82]

Polina Voronov, MD [50]

Assistant Lecturer of Clinical Pathology


Faculty of Medicine, Mansoura University Hospital
Mansoura, Egypt

Assistant Professor of Anesthesiology


Northwestern Universitys Feinberg School of Medicine
Attending Anesthesiologist
Childrens Memorial hospital
Chicago, Illinois, USA

Jon Tomasson, MD [129]


Attending Pediatric Anesthesiologist
Childrens Hospital and Clinics of Minnesota
Minneapolis, Minnesota, USA

Peter H. Tonner, MD [22]


Professor and Chairman
Department of Anesthesia and Intensive Care Medicine
Klinikum Links der Weser, Bremen
Department of Anesthesia and Intensive Care Medicine
Klinikum Bremen Nord
Bremen, Germany

Mehdi Trifa, MD [90]


Associate Professor of Anesthesia
Faculty of Medicine, Tunis El Manar University,
Attending Anesthetist and Intensivist
Department of Anesthesia and Intensive Care Medicine
University Children Hospital
Tunis, Tunisia

Pedro Paulo Vanzillotta, MD [84]


Chief, Department of Anesthesia
Hospital Municipal Jesus
Rio de Janeiro, Brazil

Laszlo Vutskits, MD, PhD [3]


Senior Lecturer in Anesthesia
Faculty of Medicine
University of Geneva Medical School
Head, Neuroscience-Oriented Anesthesia Research Group
Department of Fundamental Neuroscience
Attending Anesthesiologist
Division of Pediatric Anesthesia
Department of Anesthesiology, Pharmacology and
Intensive Care
University Hospital of Geneva
Geneva, Switzerland

Samuel H. Wald, MD [59]


Clinical Professor, Pediatric Anesthesiology
Associate Vice-Chair of Education
Associate Director, Residency Program
Department of Anesthesiology
David Geffen School of Medicine at UCLA
Los Angeles, California, USA

Paul W. Wales, BSc, MD, MSc, FRCSC, FACS [111]

Professor of Anesthesiology and Pediatrics


The George Washington University Medical Center
Department of Anesthesia
Childrens National Medical Center
Washington, DC, USA

Associate Professor of Surgery


Department of Surgery
University of Toronto
Neonatal and Pediatric Surgeon
Director, Group for Improvement of Intestinal Function and
Treatment
Associate Scientist, Child Health Evaluative Sciences
Research Institute, The Hospital for Sick Children
Toronto, Ontario, Canada

Anne Laffargue Vetter, MD [52]

Robert Whitty, FCARCSI [33]

Susan T. Verghese, MD [69]

Director of Pediatric Anaesthesia Division


Jeanne de Flandre Childrens Hospital
University Hospital of Lille
University of Lille
Lille, France

Francis Veyckemans, MD [38, 60]


Clinical Professor of Anesthesiology
Universit Catholique de Louvain (Woluw)
Attending Anesthesiologist
Cliniques Universitaires St-Luc
Brussels, Belgium

Daniel Vischoff, MD [55]


Clinical Assistant Professor of Anesthesia
University of Montreal
Attending Anesthesiologist
Centre Hospitalier Universitaire Ste-Justine
Mother and Child University Hospital Center
Montreal, Quebec, Canada

Consultant Pediatric Anesthetist


Childrens University Hospital
The Adelaide, Meath, and National Childrens Hospital
Dublin, Ireland

Suzanne Wiener, MD [4]


FMH Pediatrics
FMH Acupuncture
University of Geneva
Pediatric Pain Fellow
Department of Anesthesiology and Reanimation
University Hospital of Geneva, Switzerland
Geneva, Switzerland

Niall Wilton, MRCP, FRCA [42]


Clinical Director
Pediatric Anesthesia and Operating Rooms
Starship Childrens Hospital
Starship Childrens Health
Auckland, New Zealand

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Contributors xxi

William Wisden, MA, PhD [5]

Myron Yaster, MD [66]

Professor of Molecular Neuroscience


Imperial College South Kensington, London
Head, Cell Biology and Functional Genomics Section
Blackett Laboratory
London, England

Richard J. Traystman Distinguished Professor of Pediatric


Anesthesia, Critical Care Medicine, and Pain Management
The Johns Hopkins University School of Medicine
Attending Anesthesiologist
Division of Pediatric Anesthesia
Departments of Anesthesiology, Critical Care Medicine and
Pediatrics
Childrens Hospital, The Johns Hopkins Hospital
Baltimore, Maryland, USA

Andrew R. Wolf, MA, MBBChir, MD, FRCA [15]


Honorary Professor of Anaesthesia
Faculty of Medicine
University of Bristol
Consultant in Paediatric Anesthesia and Intensive Care Medicine
Bristol Royal Hospital for Children (Bristol Childrens Hospital)
Bristol, England

Gordon T. C. Wong, MB BS, FANZCA [32]


Clinical Assistant Professor of Anesthesiology
Department of Anesthesiology
University of Hong Kong
Honorary Associate Consultant
Queen Mary Hospital
Hong Kong, China

Maysaa El Sayed Zaki, MD, PhD [82]


Professor of Clinical Pathology
Faculty of Medicine, Mansoura University
Department of Clinical Pathology
Mansoura University Hospital
Mansoura, Egypt

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Preface
Pediatric anesthesia is no longer a subspecialty of anesthesia; in
the twenty-first century, it is considered a professional entity. The
growing complexity of this specialty is well demonstrated in this
major addition to the medical and surgical literature. The academic
and scientific development in recent years can be well appreciated
through the exceptional contributions of the 220 collaborators
who invested a great deal of time to share their knowledge
and expertise in writing this textbook. They have successfully
demonstrated, once again, that children are not small adults in
modern anesthesia and surgery. I take this opportunity to express
to each and every one of them my sincere thanks for their
participation in this international venture.
Because of the extent of the information to be shared with
the readers, Pediatric Anesthesia: Basic PrinciplesState of the
ArtFuture is divided into six parts: Developmental Considerations; Pharmacology; Anesthesia Management and Techniques;
Special Monitoring and Resuscitation Techniques; Anesthetic,
Surgical, and Interventional Procedures Considerations; and
Specific Considerations. I hope that this approach will facilitate
consultation and optimize reading. To further demonstrate
the scientific importance of each section, an international group of
subeditors was invited to assist me with the giant task of providing
the highest quality and most in-depth information. Their
exceptional knowledge, based on a well-established international
reputation and recognized wisdom in academic pediatric
anesthesia, elevates the status of this book. I am profoundly grateful
to Drs. Brian Anderson, Adrian Bsenberg, Thomas Engelhardt,
Linda Mason, and Joseph Tobias for their extensive investment of
time and determination in making this exceptional book the
premier text in pediatric anesthesia. I wish to express to them all
my deepest gratitude for their support, enthusiasm and intellectual
generosity.

The children of the world we care for, represented by the


Children of the World Anesthesia Foundation, are the ultimate
recipients of Pediatric Anesthesia: Basic PrinciplesState of the
ArtFuture. This international organization, which I founded in
2005, is dedicated to the promotion and dissemination of
continuing education in pediatric anesthesia and critical care
medicine through the development and acquisition of basic
principles of safe practice of anesthesia for infants and children
around the world. This book will provide expanded knowledge
and substantial clinical information to healthcare professionals
to ensure that every child can aspire to the best care possible
wherever they live. The extensive electronic version of this book is
available on the Foundations website.
This unique textbook would not have been possible without
the contribution and dedication of numerous other professionals.
I would like to extend my very special thanks to Ms. Linda Mehta
and Mr. Martin Wonsiewicz at PMPH-USA for their enthusiasm,
support, and determination to make this project a reality. I am also
truly grateful to Mr. David Stockhoff and members of his team at
Spearhead Global, Inc. for their dedicated support in the making
of a book that is beyond compare. I also express my gratitude to
Mr. Danny Aguilar, medical graphic artist and illustrator, for his
unique contribution to the visual beauty of this book.
Finally, on behalf of the subeditors, collaborators, and everyone
else involved in this venture, I would like to express to each reader
our sincere thanks for your interest in pediatric anesthesia and
your intellectual curiosity. We hope you will find it a thoughtful
and useful resource in your everyday professional activities and
immediately adopt it as your best academic friend.

Merci!
Bruno Bissonnette

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Contents
PART I
DEVELOPMENTAL CONSIDERATIONS

Subeditor: Joseph D. Tobias

CHAPTER 1
Prenatal Normal and Abnormal Development

20

43

58

71

80

Bruno Bissonnette

CHAPTER 7
Normal and Abnormal Development
of the Heart and the Circulation

181

CHAPTER 13
Principles of Hematopoiesis,
Immunity, and Coagulation

203

CHAPTER 14
Temperature Regulation: Physiology
and Pharmacology

221

Igor Luginbuehl

Thomas Engelhardt and William Wisden

CHAPTER 6
Central Nervous System: Anatomy and Physiology

CHAPTER 12
Endocrine System

Chaim Kaplinsky, Raz Somech, and Gili Kenet

Suzanne Wiener and Joseph D. Tobias

CHAPTER 5
Central Nervous System:
Neurotransmitters and Anesthesia

170

Carlos Hervs Puyal, Manuel Garca Grriz,


and Rosario Nuo Sanz

Laszlo Vutskits

CHAPTER 4
Nociception and Pain Perception
in Infants and Children

CHAPTER 11
Digestive System, Metabolic
Functions, and Nutrition
Bndicte Ringuier, Jean-Louis Ginis,
and Jean-Claude Granry

Ruth Oelhafen Luginbuehl

CHAPTER 3
Anesthesia and the Developing Brain

140

John Chandler and Robert Plant

Gilles Boulay, Lionel Simon, and Jamil Hamza

CHAPTER 2
General Growth and Tissue
Development Throughout Childhood

CHAPTER 10
Renal Function, Acid-Base, and
Electrolyte Homeostasis

CHAPTER 15
Development and Evaluation of Pain
and the Stress Response
R. Blaine Easley, Kenneth M. Brady, Andrew R. Wolf,
Kanwaljeet J. S. Anand, and Joseph D. Tobias

CHAPTER 16
Chronic and Recurrent Pain in the
Pediatric Patient
91

259

273

Stephen C. Brown and Patricia A. McGrath

Christian Apitz and Andrew N. Redington

CHAPTER 8
Airway Development

PART II
PHARMACOLOGY
100

Pierre Fayoux and Bruno Marciniak

CHAPTER 9
Respiratory Physiology
Etsuro K. Motoyama

106

291

Subeditor: Brian J. Anderson

CHAPTER 17
An Introduction to the Intricacies
of Pharmacology in Pediatrics
Brian J. Anderson

291

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Contents

CHAPTER 18
Using Pharmacokinetics and Pharmacodynamic
Models to Prevent Adverse Events in Neonates,
Infants, and Children

CHAPTER 31
Pharmacology of Vagal Blockers and
Antagonist Agents
297

507

Martin Jhr

Brian J. Anderson

CHAPTER 19
Mechanisms of Action of General Anesthetics

CHAPTER 32
Anticoagulants
310

Vincent P. Laudenbach, Souhayl Dahmani,


Hawa Keta-Meyer, and Jean Mantz

CHAPTER 20
Nitrous Oxide

CHAPTER 33
Pharmacology of Vasopressive Agents

323

544

CHAPTER 35
Resuscitation Agents

552

Craig Sims

347

Peter H. Tonner

CHAPTER 23
Intravenous Agents

CHAPTER 34
Antiemetic Agents
Mario J. da Coneicao

George D. Politis

CHAPTER 22
Xenon and Anesthesia: Pharmacology

535

Robert Whitty

317

Conor McDonnell

CHAPTER 21
Volatile Anesthetics

525

Gordon T. C. Wong

PART III
ANESTHESIA MANAGEMENT
AND TECHNIQUES

355

Subeditor: Adrian Bsenberg

376

CHAPTER 36
Preoperative Evaluation, Laboratory Testing,
and Preparation for Anesthesia and Surgery

571

Peter D. Booker and Neroli Chadderton

CHAPTER 24
Ketamine

571

Elsa Taylor

Robin G. Cox

CHAPTER 25
Opioid Analgesic Agents

CHAPTER 37
Premedication, Sedation, and Preoperative Fasting 584

387

William M. Splinter and Jarmila Kim

Jason A. Hayes and Daisy T. Joo

CHAPTER 26
Non-Opioid Analgesic Agents

406

Greta M. Palmer

CHAPTER 27
Neuromuscular Blocking Agents in Children

416

Olli A. Meretoja and Hannu Kokki

CHAPTER 28
Pharmacology of Local Anesthetics

441

Jean Xavier Mazoit

CHAPTER 29
Adjuvants to Local Anesthetics

473

CHAPTER 38
Anesthesia Equipment
Francis Veyckemans

CHAPTER 39
Induction of Anesthesia

CHAPTER 40
Maintenance of Anesthesia: Inhalational Agents

690

Olivier Paut, Frdric Lamy, and Magalie Gurin

CHAPTER 41
Maintenance of Anesthesia: Total
Intravenous Anesthesia
Neil S. Morton

CHAPTER 30
Pharmacology of Premedication
and Sedative Agents in Children

CHAPTER 42
Modern Modes of Ventilation in
the Operating Room

491

669

Cengiz Karsli and Lisa A. Isaac

Dilip Pawar

George A. Chalkiadis

594

Niall Wilton and David Buckley

709

716

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Contents

CHAPTER 43
Which Endotracheal Tube in Neonates,
Infants, and Small Children?

747

CHAPTER 56
Sedation and Anesthesia for Procedures
Outside Operating Theaters

Gregory Moloney

Jonathan H. Smith, Kar-Binh Ong, and Michael R. J. Sury

CHAPTER 44
Regional Anesthesia: Principles of
Localization Using Manual Approaches

CHAPTER 57
Acute Complications During Anesthesia
753

xxvii

886

905

Michela Salvadore, Thomas Engelhardt, and Joseph D. Tobias

Hans Jutzi and Alain Borgeat

CHAPTER 45
Regional Anesthesia: Principles of
Localization Using Electrical Stimulation

CHAPTER 58
Emergence and Postoperative Care
Justin L. Lockman and R. Blaine Easley

757
CHAPTER 59
Anesthesia for the Patient With
Coexisting Diseases

Jean-Louis Feugeas, Frdric Lacroix,


Olivier Choquet, and Xavier Capdevila

CHAPTER 46
Regional Anesthesia: Principles of Localization
Using Ultrasound Techniques

924

942

Brenna L. Jacobson, Samuel H. Wald, and Linda J. Mason

767

Peter Marhofer

CHAPTER 60
Anesthesia for Laparoscopic Procedures

968

Francis Veyckemans

CHAPTER 47
Regional Anesthesia: Upper Limb Blocks

783

Katherine Keech and Adrian Bsenberg

CHAPTER 48
Regional Anesthesia: Lower Limb Blocks

806

Adrian Bsenberg

CHAPTER 50
Regional Anesthesia: Head and Neck Blocks

823

CHAPTER 51
Regional Anesthesia: Thorax and Abdomen Blocks 833
Michael J. Fredrickson

843

Nathalie Bourdaud and Gilles Orliaguet

CHAPTER 54
Perioperative Blood Sparing Techniques
in Pediatric Patients

994

Corinne Lejus and Karim Ashenoune

CHAPTER 64
Pediatric Critical Care

1008

Barry Lyons, Tsz-Yan Milly Lo, and Peter N. Cox

1043

Victor H. Espinal Montoya

CHAPTER 66
Pediatric Pain Management
850

988

Karen A. Brown

CHAPTER 65
Intrahospital Patient Transportation

Anne Laffargue Vetter

CHAPTER 53
Transfusion for the Pediatric Patient

CHAPTER 62
A Pragmatic Approach to Pediatric
Obstructive Sleep Apnea
CHAPTER 63
Anesthesia for the Acutely Ill Patient

Polina Voronov and Santhanam Suresh

CHAPTER 52
Fluid Therapy for the Pediatric Surgical Patient

981

Walid Habre

793

Giorgio Ivani and Valeria Mossetti

CHAPTER 49
Regional Anesthesia: Central Neuraxial Blocks

CHAPTER 61
Anesthesia for Non-Cardiac Surgery
in Children With Congenital Heart Disease

1048

Sabine Kost-Byerly, Lynne G. Maxwell, and Myron Yaster

PART IV
SPECIAL MONITORING AND
RESUSCITATION TECHNIQUES
861

Subeditor: Bruno Bissonnette

873

CHAPTER 67
Cardiopulmonary Resuscitation
of the Infant and the Child

1065

Dale F. Szpisjak and Catherine Paquet

CHAPTER 55
Outpatient Anesthesia
Daniel Vischoff and Sophie Saindon

Swati Agarwal and Gregory B. Hammer

1065

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xxviii Contents

CHAPTER 68
Prehospital Cardiorespiratory
and Trauma Resuscitation

CHAPTER 81
Pediatric Features of Malignant Hyperthermia
1081

Rene Krivosic-Horber

1097

CHAPTER 82
Influence of Anesthesia on the Immune
System in Children

1362

Pierre Carli and Caroline Telion

CHAPTER 69
Peripheral Vascular Access
Susan T. Verghese and Raafat S. Hannallah

CHAPTER 70
Central Vascular Access

1114

Elizabeth Prentice

CHAPTER 71
Prolonged Vascular Access

1155

1167

1186

Dominique A. Bettex and Pierre-Guy Chassot

CHAPTER 74
Principles of Neuroelectrophysiology Monitoring

1213

Samuel Strantzas and Laura Holmes

CHAPTER 75
Brain Monitoring

1392

CHAPTER 84
Miscellaneous Techniques

1406

Pedro Paulo Vanzillotta

Giuseppe Marraro

CHAPTER 73
Transesophageal Echocardiography
in Congenital Heart Disease

CHAPTER 83
Specific Problems and Anesthesia Management
of Extremely Low Birthweight Infants
Richard J. Ing and Allison Kinder Ross

Jean Godard

CHAPTER 72
Airway Management

1379

Farha Abd El-Aziz El-Chennawi, Maysaa El Sayed Zaki,


Hanan Azam, and Dalia Mohamed Tohlob

PART V
ANESTHETIC, SURGICAL, AND
INTERVENTIONAL PROCEDURES:
CONSIDERATIONS

1421

Subeditor: Linda J. Mason

CHAPTER 85
Management of the Neonate:
Surgical Considerations

1421

Carmen T. Ramos and Peter C. W. Kim

1245

Isabelle Constant

CHAPTER 86
Management of the Neonate:
Anesthetic Considerations

1437

Per-Arne Lnnqvist

CHAPTER 76
Spinal Cord Monitoring

1262

Emmanule Laureau and Jean-Daniel Guieu

CHAPTER 87
Genitourinary Tract: Surgical Considerations

1476

Pramod P. Reddy and Antoine E. Khoury

CHAPTER 77
Depth of Anesthesia Monitoring
and Awareness

1285

1304

David A. Rowney

CHAPTER 79
Gastrointestinal Procedures

1334

CHAPTER 89
Digestive Tract Procedures:
Surgical Considerations
CHAPTER 90
Digestive Tract Procedures:
Anesthetic Considerations
Sonia ben Khalifa and Mehdi Trifa

CHAPTER 80
Patient Positioning and Precautions
During Anesthesia and Surgery

CHAPTER 91
Bone and Joint Surgery: Anesthetic
Considerations and Postoperative Management

1341

1501

Steven T. Elliott and Anthony D. Sandler

Sif-Eddine Nejmi and Badr-Eddine Hmamouchi

Ahmed Mohamed Shalabi

1496

Jayant K. Deshpande

Andrew Davidson

CHAPTER 78
Cardiovascular Monitoring and
Cardiothoracic Procedures

CHAPTER 88
Genitourinary Tract: Anesthetic Considerations

Mary Cunliffe

1520

1527

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Contents

CHAPTER 92
Neurosurgery and Neurotraumatology:
Surgical Considerations

1551

CHAPTER 105
Heart and Lung Transplantation:
Surgical Considerations

Aurelia Peraud

Osami Honjo and John G. Coles

CHAPTER 93
Neurosurgery and Neurotraumatology:
Anesthetic Considerations

CHAPTER 106
Heart and Lung Transplantation:
Anesthetic Considerations

1569

Craig D. McClain and Sulpicio G. Soriano

Dean B. Andropoulos

CHAPTER 94
Cardiovascular Procedures:
Surgical Considerations

CHAPTER 107
Liver Transplantation: Surgical Considerations
1589

Osami Honjo and Glen S. Van Arsdell

CHAPTER 95
Cardiovascular Procedures:
Anesthetic Considerations

1609

1641

1655

1668

CHAPTER 99
Otorhinolaryngology: Anesthetic Considerations 1699
Alison S. Carr and David Elliott

1722

David M. Fisher

CHAPTER 101
Plastic Procedures: Anesthetic Considerations

1728

1738

Priya Thalayasingam

CHAPTER 111
Intestinal and Pancreatic Transplantation:
Surgical Considerations

1843

Rodrigo A. Iniguez and Paul W. Wales

CHAPTER 112
Intestinal and Pancreatic Transplantation:
Anesthetic Considerations

1850

Nathalie Bourdaud, Frdrique Sauvat, and Gilles Orliaguet

CHAPTER 113
Bone Marrow Transplantation:
Hematological and Anesthetic Considerations

1859

CHAPTER 114
Conjoined Twins: Surgical Considerations

1867

CHAPTER 115
Conjoined Twins: Anesthetic Considerations

1877

Mohamed El-Gammal

CHAPTER 116
Craniofacial Malformations:
Surgical Considerations
1757

Daniel A. Peters and Christopher R. Forrest

1768

CHAPTER 117
Craniofacial Malformations:
Anesthetic Considerations

Marie Granier

CHAPTER 104
Anesthesia for Organ Retrieval

CHAPTER 110
Renal Transplantation: Anesthetic Considerations 1836

Abdullah A. Al-Rabeeah

Asim Ali, Nasrin Najm-Tehrani, Wai-Ching Lam,


and Elise Hon

CHAPTER 103
Ophthalmological Procedures:
Anesthetic Considerations

1821

John Doyle and Justin John

James Flowerdew

CHAPTER 102
Ophthalmological Procedures:
Surgical Considerations

CHAPTER 109
Renal Transplantation: Surgical Considerations

Jonathan de Lima and Peter Gibson

Blake C. Papsin and Sharon L. Cushing

CHAPTER 100
Plastic Procedures: Surgical Considerations

1807

Cassandra M. Kelleher and Annie Fecteau

Walid A. Farhat and Armando J. Lorenzo

Patrick T. Farrell

CHAPTER 98
Otorhinolaryngology: Surgical Considerations

1793

Charles Lee

J. Ted Gerstle

CHAPTER 97
Thoracic Surgery: Anesthetic Considerations

1781

CHAPTER 108
Liver Transplantation: Anesthetic Considerations 1816

Carol L. Lake, Linda J. Mason, and Peter D. Booker

CHAPTER 96
Thoracic Surgery: Surgical Considerations

xxix

Mark F. Levine

1891

1920

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Contents

CHAPTER 118
Interventional Cardiac Catheterization
Procedures: Cardiology Considerations

CHAPTER 126
Dental Procedures: Anesthetic Considerations
1934

2080

Steven Ganzberg and Brian Chanpong

David G. Nykanen

CHAPTER 119
Interventional Cardiac Catheterization
Procedures: Anesthetic Considerations

PART VI
SPECIFIC CONSIDERATIONS
1952

Subeditor: Thomas Engelhardt

1971

CHAPTER 127
Mortality, Morbidity, and
Outcome in Pediatric Anesthesia

2091

Peter C. Laussen and Brendan OHare

CHAPTER 120
Fetal Anesthesia
Laura B. Myers

Isabelle Murat

CHAPTER 121
Interventional Radiology:
Radiological Considerations

CHAPTER 128
Consent, Research, and Withdrawing Treatment
2002

2091

2109

Nicholas Pace and David A. Blacoe

Michael J. Temple and Bairbre Connolly

CHAPTER 122
Interventional Radiology: Anesthetic
Considerations and Postprocedural
Management

CHAPTER 129
Training and Education in Pediatric Anesthesia

2119

Paul J. Samuels, Jon Tomasson, and Charles D. Kurth

2015

Christopher M. Bolton

CHAPTER 130
Acute Pain Service

2132

Rita Agarwal and David M. Polaner

CHAPTER 123
Burns and Post-Burn Care:
Surgical Considerations

2031

CHAPTER 131
Quality Improvement

Howard M. Clarke and Tristan M.B. de Chalain

Sally E. Rampersad and Lynn D. Martin

CHAPTER 124
Burns and Post-Burn Care:
Anesthetic Considerations

CHAPTER 132
Special Problems in Developing Countries
2049

Marc-Andr Bernath, Pascal Stucki,


and Mette M. Berger

CHAPTER 125
Dental Procedures: Surgical Considerations
David J. Kenny and Michael J. Casas

2143

2155

Adrian Bsenberg and Zipporah Njeri Gathuya

CHAPTER 133
Implications for Humanitarian Anesthesia

2173

George A. Gregory

2071
Index

2183

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Page 1

Developmental Considerations

P A R T

1
C H A P T E R

Prenatal Normal and Abnormal


Development
Gilles Boulay, Lionel Simon, and Jamil Hamza

INTRODUCTION
The subspecialties of pediatric anesthesiology and pediatric
intensive care medicine have seen remarkable growth since the
1980s. This growth has included the establishment of fellowship
programs, the establishment of guidelines for the accreditation of
these programs, the institution of a formal written examination
process for pediatric intensive care medicine leading to board
certification, and the plans for a written examination in pediatric
anesthesiology. There has also been increasing recognition of the
value of such training and the attainment of board certification
not only by pediatricians and pediatric surgeons but also by
physicians outside of our own subspecialty. The recognition that
neonates, infants, and children may require subspecialists to
provide their perioperative care has partly grown from the
acceptance that the anatomy, physiology, and pharmacology of
pediatric patients differ from those of their adult counterparts.
That being said, it becomes obvious that children are not just little
adults and that variability in the response to many pharmaceutical agents is just one of many variations that may exist in this
population.
When dealing with infants and children, the anesthesiologist
is faced with variations not only in size, gestational age, and anatomic parameters but also in metabolic, cellular, and subcellular
ones. Pediatric anesthesiologists are frequently called upon to
anesthetize children with various congenital anomalies and malformations. As outlined in the chapters that follow in this section,
a myriad of processes must occur for normal development to take
place. Given the intricacies of these processes, it is amazing that
the majority of these defects are relatively uncommon in the
general population. By understanding the processes that must
occur for normal development, we can gain an understanding of
how defects during the embryonic period can result in devastating
anatomic abnormalities. Given that numerous processes occur
simultaneously in various organ systems, congenital anomalies in
several organ systems may coexist. In addition to the deviations
from normal development that may result in congenital anomalies, even the normal developmental processes, which continue

following birth, have specific implications for the perioperative


care of infants and children. These normal developmental processes may affect the response of infants and children to various
anesthetic agents.
Knowledge of the normal and abnormal prenatal development
is necessary for the pediatric anesthesiologist who is becoming
increasingly involved in fetal-neonatal surgical procedures, which
may occur immediately after birth or even before with the growing
field of in utero surgery. The goals of this, the first chapter of this
textbook on pediatric anesthesiology, are to (1) describe the
normal and abnormal developmental stages of the embryonic and
fetal periods, (2) show how some maternal disorders (hypertension, diabetes) or drug ingestions (tobacco, alcohol, cocaine)
during this critical period can alter normal fetal development,
(3) discuss the fetal and neonatal problems associated with
intrauterine growth retardation (IUGR) and premature birth,
which remain the two primary causes of perinatal mortality and
morbidity, (4) explain why and how acute fetal distress can lead to
definitive neurologic impairment, and (5) develop a comprehensive approach to diagnosis and therapy.

NORMAL AND ABNORMAL


EMBRYOLOGIC DEVELOPMENT
The human pregnancy usually lasts 266 days (38 wk) from fertilization to birth. Prenatal growth can be divided in two periods:
(1) embryonic and (2) fetal. During the embryonic period, most
major organ systems are formed (organogenesis). During the fetal
period (from 8 wk to birth), functional development of organ
systems and maturation take place.

Normal Embryonic Development


(First 8 Weeks)15
The embryonic development begins when the zygote containing a
single diploid nucleus forms as a spermatocyte and an oocyte join
during the process of fertilization. While a series of cell divisions
occur, the embryo travels toward the uterus. Further cleavage

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Developmental Considerations

Figure 1-1. Formation of the blastocyst.

results in the zygote with 16 cells that organize in two separate


groups of cells. The peripheral outer cell mass (trophoblast) will
yield the placenta and membranes, whereas the central inner cell
mass (embryoblast) will form the embryo. By the 30-cell stage, the
blastocyst cavity develops (morula). At the end of the first week,
the embryo enters the uterine cavity and implants into the
endometrial lining of the uterine wall. At this point, it is then
designated a blastocyst (Figure 11). At the beginning of the
second week, the embryoblast splits into the epiblast or primary
ectoderm and the hypoblast or primary endoderm, thus creating
a dorsoventral axis in the embryo (bilaminar embryo). The
trophoblast differentiates into two tissues: the cytotrophoblast and
the syncytiotrophoblast. During the second week, the amniotic and
chorionic cavities appear. Gastrulation begins at the third week as
the bilaminar germ disk becomes trilaminar with the formation
of the mesoblast (Figure 12). The neural plate and groove appear.

Figure 1-2. Formation of the trilaminar germ disk. (1) Amniotic


cavity. (2) Hensen node and primitive streak, then neural groove.
(3) Chorionic cavity. (4) Epiblast. (5) Hypoblast. (6) Migration of
epiblastic cells. (7) Mesoblast.

The caudal eminence and first somites form (Figure 13) while
neuromeres develop into the presumptive brain vesicles. At the
end of the third week, a primitive heart tube is formed and the
embryologic vasculature begins.
From the fourth to eighth week of gestation (organogenesis
period), the three primitive layers (ectoblast, mesoblast, and endoderm) differentiate into different tissues and organs. The
embryonic plate folds laterally; its cranial and caudal ends expand
and the limbs begin to develop. The embryonic plate acquires a
human-like shape. The ectoderm differentiates into tissues and
organs that will eventually have contact with the external environment (central and peripheral nervous system, skin, sweat glands,
mammary glands, teeth, and epithelial structures of the eyes, ears
and neck). The mesoderm yields the somites, dermis, epidermis,
cardiovascular system (heart, arteries, venous and lymphatic
vessels), urogenital system (kidney, gonads), spleen, and adrenal
cortex. The endoderm provides the epithelium of the digestive
system, respiratory tract, and bladder as well as forming the
parenchyma of the liver, pancreas, and some glandular structures
(thyroid, parathyroid, thymus, salivary). The myocardium develops and the heart begins to beat during the fourth week. The
process of neurulation converts the neural plate into a neural tube,
which begins the differentiation of the brain and spinal cord. At
the same time, the pulmonary primordium and hepatic plate
appear. The optic system begins to form (sulci, vesicles, and pit).
The somites divide into three structures: (1) myotomes,
which provide the segmental musculature of the back and the

Figure 1-3. The development of the somites and neural tube.


(1) Somite. (2) Neural tube.

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CHAPTER 1
anterolateral body wall; (2) dermatomes, which form the dermis
of the scalp, neck, and trunk; and (3) sclerotomes, which develop
into vertebral bodies and arches. Spinal defects such as scoliosis or
spina bifida result from the abnormal induction of the sclerotome
and the neural tube at the level of the first five somites (from day
22 onward). The two opposite orifices of the neural tube are
termed the cranial and the caudal neuropores. The cranial neuropore closes on day 24 and the caudal neuropore on day 26.
Neural crest cells migrate to several locations in the body where
they differentiate into different structures and cell types. The fifth
week is critical for the development of the peripheral nervous
system. At day 28, motor neurons appear in the central column of
the neural tube (starting in the cervical region). Spinal nerves
begin to sprout and grow into myotomes on day 32 and the three
main subdivisions of the brain (forebrain, midbrain, and hindbrain) become identifiable. At the end of the embryonic period,
the gross structure of the nervous system is developed.

Figure 1-4. Formation of the heart


(timeline). From Larsen WJ. Human
Embryology. 2nd ed. New York: Churchill
Livingstone; 1997. Chapter 7, p. 152.

Prenatal Normal and Abnormal Development

The lung bud appears at approximately day 24. It elongates to


form the primordial trachea and branches to form the bronchial
tree and the epithelial lining of the lungs (including the alveoli).
Segmental bronchi develop and the diaphragm is complete at day
52. The primitive heart tube appears around day 20 and its folding
is completed by day 30. Between weeks 5 and 8, the primitive heart
tube undergoes a process of looping, remodeling, and septation
that transforms the single lumen into four cavities. During the
fifth and sixth weeks, a pair of septa (septum primum and
secondum) develop to separate the right and left atria. A pair of
foramina that perforate these septa (ostia primum and secundum)
allow the right-to-left shunting of blood. The mitral and tricuspid
atrioventricular valves develop during this period. They are
finalized by the third month. The coronary sinus is formed at day
52 (Figure 14). The gut tube is formed at day 24. By the fifth
week, the abdominal portion of the foregut divides into three
parts: esophagus, stomach, and proximal duodenum. During the

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Developmental Considerations

sixth and seventh weeks, the stomach rotates. This rotation and
the secondary fusion of the duodenum to the dorsal body wall
create the lesser sac of the peritoneal cavity, and the remaining
cavity develops as the greater sac. By the fifth week, rapid elongation of the ileum produces a primary intestinal loop that herniates
through the umbilicus. This herniated organ fully retracts into the
abdominal cavity during the 10th week. The rotation of the midgut
produces the definitive configuration of the small and large
intestines (Figure 15). The distal hindgut gives rise to the rectum
and the urogenital sinus. The major stages of the embryonic
development from day 1 to day 56 are summarized in Table 11.

Normal Fetal Development


(From 8 Weeks to Term)
The embryo becomes a fetus at the beginning of the third month.
During the fetal period, there is an increase in cell number and
size and a remodeling of several organ systems concomitant with
their maturation. The growth in length is particularly rapid from
the third to the fifth month (~5 cm/mo). The weight of the fetus

increases from 8 g at the eighth week to 3400 g at birth (a 425-fold


increase) (Figure 16). Weight gain occurs in the third trimester,
mainly in the last 2 months of pregnancy (700 g/mo). Major
changes in body proportions occur concomitantly. The head
represents half of the crown-rump length at 9 weeks, one third
of this length at the end of the fifth month, and one fourth at
birth. Fetal life is supported by the placenta, an organ with
maternal (decidua basalis) and fetal (chorion) components. The
placenta provides the fetus with oxygen and nutrients from
maternal blood and eliminates the metabolic waste of the fetus.
By 10 weeks, there is a 180-degree counter-clockwise rotation of
the midgut returning from the umbilical cord into the abdomen,
bringing the stomach and the small and large intestine into their
normal positions.
By 12 weeks, the glandular stage of pulmonary development induces the formation of intrasegmental airways and
associated vessels. The gender of the external genitalia becomes
identifiable. From the 16th to the 24th week, the canalicular stage
involves growth of the liquid-filled airways. The lung develops a
viable gas-exchanging surface and surfactant production begins.

Figure 1-5. Herniation and


rotations of intestine. (1) Primary
intestinal loop. (2) Stomach.
(3) Aorta. (4) Superior mesenteric
artery. (5) Liver. (6) Small intestine.
(7) Colon. (8) Rectum. From
Larsen WJ. Human Embryology.
2nd ed. New York: Churchill
Livingstone; 1997. Chapter 9,
p. 241.)

Blastocyst

Upper limb bud


forms
Optic cup
Otic invagination
Closure of neural
tube
Lower limb bud
forms
Lens invagination
Otic vesicle
Olfactory
placodes

Thyrod and
parathyrods
develop
Nasal swellings

Secondary palate Early muscle is


formed
present

Facial swellings
fused

Metanephric
blastema appear

Secondary bronchi Ureteric bud enter


metanephric
buds
blastema
Major calyces form
Minor calyces form

Kidneys ascend

Stomach rotation
Duodenal lumen Tertiary bronchi
Aorta
obliterated,
Pulmonary artery
cecum rotates
Valves
Membrane
right
Ventricular
septum
Tracheal cartilage
Coronary sinus
formed
Anorectal canal
completed

Sympathetic trunks
begin to form
Limb buds are
innervated as
they form
Vagal fibers
innervate heart

Most of spinal
ganglia formed

34 (7)

38 (11)

52 (23)

Adapted from reference 6.

55 (28)

CHAPTER 1

44 (17)

24 (2)
Primary bronchi

Extremities
and Other

Ventral roots begin Complete folding


to form

30 (4)

Face

Optic evagination
Otic placode

Allantois

Urologic

Mandible
Hyoid arches

Gut tube

Lung

Mesonephric
ridge

Heart beats at
22 d

Yolk sac

Gut

Lung bud appears

Enlargement of
anterior neural
plate
Neural crest cells
migrated

Heart

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19 (1)

Central Nervous
System

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714 (0.1)

Appearance

Age, d
(Length, mm)

TABLE 1-1. Normal Embryonic Development and Malformation

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Prenatal Normal and Abnormal Development


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TABLE 1-2. Relative Timing and Developmental Pathology of Some Malformations


Tissues

Cause Prior to

Comment

Central nervous Anencephaly


Meningomyelocele
system

26 d
28 d

Face

Closure of anterior neural tube


Closure in a portion of the
posterior neural tube
Cleft lip
Closure of lip
Cleft maxillary palate
Fusion of maxillary palatal
shelves
Branchial sinus and/or cyst Resolution of branchial cleft
Esophageal atresia and
Lateral septation of foregut into
tracheoesophageal fistula
trachea and foregut
Rectal atresia with fistula
Lateral septation of cloaca
into rectum and urogenital
sinus
Duodenal atresia
Recanalization of duodenum
Malrotation of gut
Rotation of intestinal loop

36 d
10 wks

Subsequent degeneration of
forebrain
80% lumbosacral
42% associated with cleft palate

Omphalocele

Return of midgut from yolk sac


to abdomen
Obliteration of vitelline duct
Closure of pleuroperitoneal
canal
Migration of infraumbilical
mesenchyme
Fusion of lower portion of
mllerian ducts
Fusion of urethral folds
Descent of testicle into scrotum
Directional development of
bulbus cordis septum
Closure of ventricular septum
Closure of ductus arteriosus
Genesis of radial bone

10 wk

Separation of digital rays


Prechordal mesoderm
development
Development of posterior axis

6 wk
23 d

Gut

Malformation

Meckels diverticulum
Diaphragmatic hernia
Genitourinary
system

Extroversion of bladder
Bicornuate uterus

Limb

Hypospadias
Cryptorchidism
Transposition of great
vessels
Ventricular septal defect
Patent ductus arteriosus
Aplasia of radius

Complex

Syndactyly
Cyclopia

Heart

Sirenomelia

Defect in

8 wk
30 d
6 wk
78 wk
10 wk

10 wk
6 wk
30 d

Associated incomplete or
aberrant mesenteric
attachment
May contain gastric and/or
pancreatic tissue
Associated mllerian and
wolffian duct defects

10 wk
12 wk
79 mo
34 d
6 wk
910 mo
38 d

23 d

Often accompanied by other


defects of radial side of distal
limb
Secondary defects of midface
and forebrain
Associated defects of cloacal
development

Adapted from reference 6.

Abnormal Development69
Abnormal development may result from chromosomal anomalies
that cause approximately 40 to 50% of spontaneous abortions
(when the products of conception are examined) (Table 12).
Many chromosomal anomalies are not lethal and lead to abnormal
developmental syndromes (Down syndrome). Other chromosomal anomalies include monosomy, trisomy, mosaic, translocations, triploidy, or tetraploidy. They may result in any of three
types of developmental pathology including (1) malformation
(poor tissue formation), (2) deformation (because of altered
mechanical forces on a normal tissue), and (3) disruption (breakdown of a previously normal tissue). Apart from chromosomal
anomalies, several types of malformations can be observed.
Incomplete morphogenesis is due to an incomplete stage in the
development of a structure. To this group belong syndactyly

(incomplete separation of fingers), cleft palate (incomplete closure


of the palate), and malrotation of the gut (incomplete rotation of
the gut). Another type of malformation is the aberrant form,
which never exists at any stage of normal development. Accessory
tissues such as polydactyly or accessory spleens belong to another
type of malformation. The accessory tissue is initiated at the same
time as the normal tissue. Hamartomas are organizational defects
leading to an abnormal admixture of tissues. Somesuch as
hemangiomas, melanomas, fibromas, and adenomashave a
malignant potential.

Congenital Diaphragmatic Hernia


This malformation occurs in 1 of 2500 live births, affecting the left
side four to eight times more than the right side. It results from
closure anomaly of the pericardioperitoneal canal. Consequently,

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abdominal organs develop in the pleural cavity, which impairs the
growth of the ipsilateral lung. Although surgical correction can be
achieved while the fetus is still in utero, in most cases, it is performed after birth.

Esophageal Atresia
This disorder seems to result from the failure of the esophageal
endoderm to proliferate rapidly enough during the fifth week to
coincide with the elongation of the embryo. Five different types
are described, with or without an esophagotracheal fistula. This
anomaly should be rapidly repaired at birth because of the risk of
aspiration.

Spina Bifida
Spina bifida is a closure anomaly of the spinal canal during the
third week. It occurs most frequently in the lumbosacral region.
The consequences of this defect in neural tube closure can be
severe, with the dura and/or the arachnoid protruding from the
vertebral canal (meningocele and/or meningomyelocele). The
mildest form of spina bifida is termed occulta; in this, the vertebral
arches of a single vertebra fail to fuse without protrusion of neural
structures from the spinal canal and any defect in the skin and
overlying structures.

Hirschsprung Disease
Hirschsprung disease is a congenital defect of neural crest migration giving rise to an area of constriction and paralysis of
the colonic segment. The consequence of this malformation is the
development of a characteristic dilated colon proximal to the
constricted area.

Omphalocele
Omphalocele occurs in 2.5 of 10,000 births and results from an
incomplete closure of the umbilicus. The gastrointestinal structures protrude through an unclosed umbilical ring. The omphalocele often occurs with defects in other organ systems (cardiac,
renal) or as a part of a chromosomal anomaly.

Gastroschisis
Gastroschisis occurs in approximately 1 of 10,000 births. In this
malformation, the umbilical ring closes normally. The abdominal
wall defect occurs between the developing rectus muscles just
lateral to the umbilicus, usually on the right side. The cause of this
anomaly is an abnormality in the involution of the right umbilical
vein during the fifth to sixth week. The visceral organs rarely
protrude through this defect. Gastroschisis is less often associated
with other defects than omphalocele and is not associated with
chromosomal anomalies.

MATERNAL DISORDERS:
INTRAUTERINE DEVELOPMENT
Pregnancy-Induced Hypertension
The diagnosis of preeclampsia is based on the triad of elevated
blood pressure accompanied by proteinuria and edema. This
pathology, which is unique to human pregnancy, is a complex

Prenatal Normal and Abnormal Development

phenomenon characterized by an inadequate maternal vascular


response to the development of the placenta. In normal pregnancies, the development of uteroplacental arteries into spiral
arteries should convert the uteroplacental arterial bed into a lowresistance, low-pressure, and highblood flow system. The
mechanism responsible for such an evolution reflects important
and complex interactions between the trophoblastic and the
maternal endothelial cells.
In preeclampsia, a defect in trophoblastic invasion impairs the
normal development of uteroplacental arteries. The development
of large spiral arteries is limited to the decidua and a constricting
segment remains present in the external part of the myometrium.
Damage to endothelial cells, platelets, and trophoblast cells is
responsible for an intravascular activation of the coagulation
cascade and increased vascular resistance, leading to a decrease in
placental blood flow. The etiology of the original defect in trophoblastic invasion is unknown, although both genetic and immunologic factors may be involved. Vascular lesions are present in
uteroplacental arteries from the 16th week of pregnancy, long
before the development of maternal hypertension. It is postulated
that placental ischemia is a very early mechanism responsible for
the clinical manifestations of preeclampsia. No prophylactic
therapy has been shown to be effective in preventing preeclampsia.
The goal of the antihypertensive therapy in preeclampsia is to
avoid the occurrence of maternal complications of the hypertension. However, none of these treatments has clearly been shown
to improve fetal outcome. Although low-dose aspirin has been
recommended to prevent preeclampsia and to improve perinatal
outcome in women at risk for preeclampsia, such therapy has been
shown to be ineffective.10,11 Progressive deterioration in both
maternal and fetal conditions is usual in severe preeclampsia, and
delivery is the only effective treatment for this situation. Therefore,
cesarean section should be considered even at a very early stage to
avoid dramatic complications for both the mother and the infant.
Delivery of a preterm infant must be anticipated and, if the
hospital is not designed for this event, the mother should be
referred to a level III obstetric center that includes a neonatal
intensive care unit. The decision to deliver the patient is often easy
in cases of severe preeclampsia after 32 weeks of gestation.
Between 28 and 32 weeks, a short delay is often utilized before
delivery to accelerate fetal pulmonary maturation through the
administration of maternal steroid therapy.12
The incidence of growth retardation and perinatal morbidity
and mortality rates are increased in pregnancies complicated with
severe preeclampsia or eclampsia. Some authors have reported
high rates of stillbirth and/or severe neonatal complications
resulting in cerebral palsy and mental retardation in neonates born
to eclamptic women.13,14 In spite of this, several studies have
demonstrated a reduced incidence of cerebral hemorrhage in very
low birthweight (VLBW) infants when they were born to mothers
with preeclampsia. Nelson and Grether suggested that magnesium
sulfate therapy used in preeclamptic women may be responsible
for this protective effect against cerebral palsy in VLBW infants.15
The primary factors associated with a poor neonatal prognosis
include the early onset of preeclampsia (before 37 wk), prematurity, multiple pregnancy, severity of the disease, and previous
maternal hypertension or renal disease. Several authors have tried
to test the value of Doppler-derived patterns in determining fetal
prognosis in pregnancy complicated with preeclampsia.1618 These
studies have led to contradictory results because of a difficult
interpretation caused by to the complexity of the uteroplacental

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Developmental Considerations

circulation. Absent or reversed end-diastolic velocity waveform in


the umbilical artery seems to be associated with a poor neonatal
outcome.17,19 Ultrasonography may also be useful to ensure fetal
well-being. Obstetric ultrasound can evaluate fetal movements,
breathing activity, and muscle tone20 as well as provide an assessment of fetal anatomy, fetal growth, and amniotic fluid volume.
Identification of other conditions associated with maternal
hypertension, such as trisomy 13 and 18, is also possible with the
use of ultrasound.19 IUGR is important to quantify, and oligohydramnios appears to be associated with a neonatal outcome.

Epilepsy
Two major risks have to be considered in an epileptic woman who
wants to become pregnant: (1) an increase in the incidence of
seizures may be observed during pregnancy and (2) the anticonvulsant medications may have teratogenic effects. These two
risks may be limited if pregnancy is correctly planned with good
patient information and counseling. An increase in the incidence
of seizures may be observed during pregnancy in 21 to 46% of the
women.21,22 Many factors have been involved to explain this
increase in the number and severity of seizures: (1) some women
discontinue or reduce the dose of their anticonvulsant medication
to limit the risk of teratogenicity23 and (2) the pharmacokinetics of
anticonvulsant medications can be impaired by pregnancy. However, the decrease in the plasma concentration of many anticonvulsant medications during pregnancy does not involve the
free fraction of these drugs,24 and when the patients are monitored,
an adjustment of these medications to maintain the plasma
concentration of antiepileptic drugs throughout pregnancy does
not necessarily prevent the increase in the incidence of seizures.25
Generalized convulsions can lead to hypoxemia and hemodynamic disorders and, as such, represent a serious risk to fetal wellbeing. Therefore, the optimal control of seizure activity and strict
compliance should be obtained before pregnancy.
The incidence of congenital malformations in infants born to
epileptic mothers is two to three times greater than in nonepileptic
mothers.21 Important differences exist in the teratogenic effects of
anticonvulsant medications. Neural tube defects such as spina
bifida are associated with first trimester exposure to valproic acid
or carbamazepine. Phenytoin21 and valproic acid26,27 are the two
treatments that appear to be associated with the higher risk of
malformation syndromes. A fetal hydantoin syndrome occurs in
10 to 30% of exposed pregnancies.23 Hydantoin exposure in pregnancy may be associated with multisystemic anomalies including
the prenatal onset of growth deficiency, central nervous system
malformations, craniofacial anomalies, and nail/digital hypoplasia.
Multiple malformations including lip and palatal malformations,
congenital heart disease, and facial and digital anomalies have also
been described after exposure to valproic acid, phenobarbital, and
carbamazepine.23 The risk for neural tube defect associated with
valproic acid and carbamazepine is increased by low folate
concentrations during pregnancy.28 Genetic factors also play a role
because the relative risk for giving birth to an infant with a neural
tube defect is increased by a factor of 10 in a woman who has
already delivered an affected infant in a previous pregnancy.29
When possible, monotherapy for seizure control is preferred
in a woman who may become pregnant because the risk of birth
defects dramatically increases with multiple treatments. The risk
has been reported to be as high as 58% when carbamazepine,
phenobarbital, and valproic acid were combined.29 The presence of

a neural tube defect in infants whose mothers are treated with


valproic acid or carbamazepine can be assessed with ultrasound
examinations27 or -fetoprotein blood level measurements. The
teratogenic risk of anticonvulsants is reduced by folic acid
supplementation throughout pregnancy and adaptation of the
anticonvulsant treatment to the lowest effective doses. An
increased rate of neonatal deaths has been suspected in infants
born to epileptic mothers. These newborns are more likely to need
hospitalization in a neonatal intensive care unit,21 but the incidence of prematurity, low birthweight (LBW), and neonatal head
circumference seems similar to that in normal neonates. Fortunately, most epileptic mothers have uncomplicated pregnancies
and normal babies.

Diabetes Mellitus
Insulin-dependent diabetes can seriously alter the prognosis of
pregnancy. Spontaneous abortions, stillborns, and congenital
malformations occur more often in fetuses of diabetic mothers.
The relative risk for major malformations in these infants is 7.9
times higher than in neonates born to mothers without diabetes.30
The percentage of newborns with a birthweight greater than the
90th percentile is increased in diabetic women. The factors
involved in maternal and fetal weight gain during pregnancy are
not fully elucidated.31 Leptin, a small peptide, usually produced by
adipocytes and involved in many endocrine regulations, is also
synthesized in the placenta. The placental production of leptin can
be regulated by insulin and may be involved in the fetal weight
control. The increased rate of high birthweights is also present in
women with gestational diabetes and those at increased risk of
diabetes including those with an abnormal oral glucose tolerance
test during pregnancy.32 The rigorous control of the blood glucose
levels in diabetic women attempting to become pregnant and
during pregnancy can reduce these risks. One study showed that
the incidence of spontaneous abortion and congenital malformations in diabetic women receiving intensive insulin therapy was
identical to that in nondiabetic women.33 Ideally, the intensive
therapy should begin before conception and maintain normal
blood glucose levels (fasting blood glucose level of 70100 mg/dL
and a 1-h postprandial level < 140 mg/dL).

Drug Abuse
Alcohol
Alcohol consumption impairs the pregnancy and offspring
outcome. Alcohol has a direct toxic effect on the fetus, whereas
malnutrition associated with alcoholism can also impact on the
normal course of pregnancy. Indirect fetal toxicity may result from
zinc deficiency, alterations in placental functions, and effects on
prostaglandins. The amount of alcohol consumption is critical for
fetal prognosis. Normal development is impaired when maternal
consumption exceeds 1 to 2 glasses of wine per day, with major
consequences when more than 3 glasses per day are consumed.
These anomalies, termed the fetal alcohol syndrome, include
IUGR, microcephaly with characteristic craniofacial anomalies,
and central nervous system anomalies with intellectual deficiency.34 Major congenital malformations of other organs (heart,
urinary tract) are also more frequent in infants of alcoholic
mothers, even though they are less specific for the syndrome.
Growth retardation is linked to the amount of alcohol consumption. At birth, infants born to alcoholic mothers weigh up to

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160 g less than those born to nonalcoholic women. Alcohol abuse
has also been linked to an increased incidence of placental abruption and spontaneous abortion. In utero exposition to alcohol
impairs postnatal development and is associated with school
problems in late childhood.

Tobacco
A 1995 French study showed that 25% of pregnant women smoked
cigarettes.35 Sixty percent of them smoked fewer than 10 cigarettes
per day, whereas only 10% smoked more than 20 cigarettes per
day. Although this French study did not show a link between
smoking and prematurity, many other studies performed in the
United States, England, and Australia found a positive correlation
between the risk of preterm birth and maternal tobacco consumption.36,37 These discordant results may be related to quantitative
differences in maternal smoking between the studied populations.
In the study of Schwartz and coworkers, the stillbirth rate was
increased in smokers especially in those who inhaled.38 In this
study, mothers who ceased smoking at the beginning of their
pregnancy enjoyed the same prognosis for their pregnancy and
their offspring as the nonsmokers. Cigarette smoking during
pregnancy has also been related to other obstetric complications
including ectopic pregnancy, placental abruption, and placenta
previa.34 At term, the mean birthweight is usually 150 to 300 g
lower in infants born to smokers than to nonsmokers. The rate of
congenital anomalies and especially orofacial clefts may be increased with maternal smoking. However, the teratogenic effects
of tobacco, if present, are probably minimal. Cigarette smoking
interacts with the efficacy of dietary folate in women whose intake
is low,23 and therefore, smokers are at risk for folate deficiency,
which may increase the incidence of birth defects.

Cocaine
Cocaine abuse is a serious health problem. In the United States,
its prevalence is estimated between 7.5 and 45% in the obstetric
population, resulting in a very high incidence in both maternal
and neonatal morbidity and mortality.39 Adverse effects on the
mother are multiple, many of them being related to hypertensive
effects. Women who abuse cocaine have higher rates of
spontaneous abortion and preterm labor. Burkett and colleagues
reported an incidence of 41% of spontaneous or therapeutic
abortions in 139 women who used cocaine during pregnancy.40
Cocaine abuse favors the occurrence of placental abruption even
if the use is limited to the first trimester of gestation.41 In the
absence of placental abruption, cocaine use can be associated with
chorionic villus hemorrhage and villus edema.42 The influence
of these placental abnormalities on the fetal outcome remains
to be determined. Other obstetric complications such as meconium staining, prolonged membrane rupture, and precipitous
deliveries are more frequent in women who abuse cocaine. The
development of fetus exposed to cocaine is impaired in several
different ways:
1. Cocaine induces uteroplacental vasoconstriction, resulting in
uteroplacental insufficiency and fetal hypoxemia. This may
cause reduced birthweight, IUGR, microcephaly, and prematurity. The rate of premature deliveries in women exposed to
freebase cocaine (crack) may exceed 50%.43
2. Different authors have suspected, both in experimental and
in human studies, an increased rate of fetal malformations

3.

4.

5.

6.

7.

8.

Prenatal Normal and Abnormal Development

associated with cocaine exposure. The mechanism involved


can be either direct teratogenicity or a consequence of vasopressor effects of cocaine in both the mother and the fetus.
Congenital heart defects are associated with cocaine use and
can result from the lower intracardiac fetal blood flow with
subsequent impairment of the development of some parts of
the heart.
An increased incidence of neonatal distress with lower Apgar
scores at 1 minute (but not at 5 min) has been reported in
neonates exposed prenatally to cocaine.44 Cocaine exposure
during pregnancy may also produce LBW; however, this is not
observed if exposure is limited to the first trimester of gestation.41
Hyperreflexia, prolonged periods of scanning eye movements,
excessive irritability, and tachypnea in a neonate can reflect
acute cocaine intoxication.
Differences in neurobehavioral capabilities, clinical seizures,
and electroencephalographic abnormalities are also seen in
neonates who were (chronically) exposed to cocaine in utero.
Cerebral infarctions and hemorrhages are other possible
neonatal complications that can result from alterations in
cerebral blood flow induced by cocaine.
Gastrointestinal tract disorders and renal dysfunction have also
been reported in such neonates. Some authors reported a decreased incidence of respiratory distress syndrome in neonates
after prenatal exposure to cocaine.45 This is supported by experimental data showing enhanced maturation of the fetal lung
in animals exposed to cocaine.46,47

Benzodiazepines
Dysmorphic characteristics similar to those of fetal alcohol syndrome, growth aberrations, and central nervous system abnormalities have been reported in infants born to mothers consuming
benzodiazepines during pregnancy.48 However, a clear link between maternal use of benzodiazepine and teratogenicity has not
been clearly demonstrated. Bergman and associates reported that
6 of 64 infants with major exposure to benzodiazepines exhibited
clinical features of developmental teratogenicity49; however, many
mothers exhibited other potentially confounding factors such as
alcohol dependence, multiple-drugs dependence, or convulsions.
Addiction associated with other teratogenic drugs has also been
suspected.50 Even though more recent studies did not find any
teratogenic effects of benzodiazepine,29 massive use of benzodiazepines should be avoided during pregnancy. Sedation and withdrawal symptoms have been reported in neonates whose mothers
took benzodiazepines up to delivery.49

Infectious Diseases
Rubella
Primary infection with rubella virus during pregnancy can induce
fetal death, chromosomal alterations leading to IUGR, ocular
lesions, deafness, congenital cardiomyopathy, and other malformations. A rubella titer should be made in every woman before
pregnancy to know her immune status. Congenital rubella can be
avoided with a policy of preventive immunization of all seronegative women before pregnancy. In case of primary infection with
rubella virus during pregnancy, the incidence of fetal infection is
approximately 90% in the first trimester, decreasing to 25% if
infection occurs during the 23rd and the 26th week. If maternal

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Developmental Considerations

infection occurs during the last trimester, fetal infection is very


frequent (>90%), but the consequences for the neonate will be
minimal or absent. The diagnosis of fetal infection is made by
detection of specific immunoglobulin M (IgM) antibodies in the
fetal blood after 22 weeks. Direct detection of the virus after
chorionic villus sampling using polymerase chain reaction is also
possible during the first trimester. The risk of severe congenital
abnormalities seems to be maximal (>90%) for the infant when
the infection occurs before the 11th week.

Toxoplasmosis
Humans can be incidental hosts for Toxoplasma gondii, a protozoan whose definitive host is the domestic cat. Toxoplasma
infection in humans is often asymptomatic and results in the
development of antibodies, first IgM 1 to 2 weeks after exposure,
then IgG after 3 to 4 weeks. In case of acute infection during
pregnancy of a nonimmune mother, the organism can be transmitted to the fetus in up to 60% of cases. Fetal infection may cause
IUGR, nonimmune hydrops, hydrocephalus, or microcephaly.
Some infected infants are asymptomatic at birth but develop
neurologic issues later in development.51 Nonimmune pregnant
women should be advised to eat only well-cooked or hard
frozen meat, wash every utensil or surface after contact with raw
meat, avoid contact with cats and their litterbox, and wash fruits
and vegetables thoroughly. When an acute infection occurs before
the third trimester of pregnancy, treatment with spiramycin if
started promptly and continued until delivery reduces the risk of
fetal transmission by 50%.

Human Immunodeficiency Virus


Pregnancy is a frequent event in young women infected by HIV.
Pregnancy does not appear to influence the course of HIV infection in asymptomatic women,52,53 although some studies have
suggested an impairment of the outcome in women with HIV/
AIDS after pregnancy.54 Although HIV transmission to the fetus
can occur very early in pregnancy, before 15 weeks, fetal transmission seems rare during the first trimester. The spontaneous
rate of fetal transmission of HIV from an infected mother is 12 to
30%,52,55,56 depending largely on the characteristics of maternal
infection (Table 13).57 Cesarean section may reduce the risk of
fetal contamination at delivery, but this is controversial and vaginal delivery is generally preferred whenever possible. A doubleblind, prospective study was designed in asymptomatic pregnant
women infected with HIV with T4 lymphocyte counts of 200/mm3
or greater to compare zidovudine therapy versus placebo during
pregnancy and delivery. The transmission rate of HIV from the
mother to the infant was significantly reduced in the zidovudine
group (8% vs 25%). Moreover, no teratogenic effect of zidovudine
has been reported despite its fetoplacental passage.58 Antiretroviral
drugs may also be indicated for maternal therapy, and these agents
should not be withheld during pregnancy. HIV-infected infants
look normal at birth, and early on, the diagnosis of HIV infection
is difficult because of the presence of maternal antibodies.
Detection of the P24 in the neonates serum is a very specific
method for the diagnosis of infection at birth, but its sensitivity is
only 18%. Its presence at birth seems to be associated with poor
prognosis. Viral culture can also allow an early diagnosis of neonatal HIV infection with excellent specificity, but the technique is
not easy. Its sensitivity is around 50% at birth and 80% between

TABLE 1-3. Maternal Factors That Significantly Influenced


the Perinatal HIV-1 Transmission in the French Cohort
Study
Maternal Factors Associated With an Increased
Rate of HIV Transmission to the Fetus
Clinical signs, AIDS
CDC stage I
II
III
IV
CD4+ lymphocyte counts
<200/mm3
200400/mm3
400600/mm3
>600/mm3

% of Infected
Children
18
19
26
35
43
26
20
15

P24 antigenemia
Negative
Positive

19
46

Age of the mother, y


<25
2530
3035
>35

16
21
24
30

AIDS = acquired immunodeficiency syndrome; CDC = Centers for Disease


Control and Prevention.
After pregnancy, breast feeding was also associated with an increased rate of
transmission.
Adapted from reference 57.

1 and 3 months of age.59 The first signs of the disease usually


appear at 6 months of age, and the median survival rate is
approximately 38 months.60

Herpes
Neonatal infections with herpes simplex virus have a high morbidity and mortality rate. Therefore, maternal infections require
special attention to prevent fetal contamination at birth. Asymptomatic genital infections are responsible for two thirds of the
neonatal infections with herpes simplex virus at delivery. Four
situations can be individualized to decide the best policy to
identify and prevent neonatal infection with herpes simplex virus
(Table 14).

ABNORMAL FETAL DEVELOPMENT


IUGR
IUGR complicates 3 to 7% of all pregnancies and remains one of
the main causes of perinatal morbidity and mortality. The prognosis associated with IUGR depends on its cause. Up to 8% of
newborns with IUGR have a major malformation that will impair
their outcome. Head growth is of particular concern in the
determination of the prognosis, and harmonious IUGR with head
circumference lower than the 3rd percentile is associated with
poor neurodevelopmental outcomes.61
Hemodynamic changes and/or infectious diseases are often
involved in the pathophysiology of IUGR.62 In normal situations,

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Prenatal Normal and Abnormal Development

11

TABLE 1-4. Relationship Between the Maternal Manifestations of Herpes Infection and the Risk for the Newborn to Develop
an Infection With HSV
Clinical Manifestations
in the Mother

Incidence in Mothers
of Infected Newborns

Risk for the Newborn to Develop


an Infection with HSV

Primary infection with HSV


in the month before delivery
Recurrent maternal infection
Antecedent of genital infection
with HSV

Rare

75%

+
++

25%
1/1000

None antecedent

+++
2/3

1/10,000

Management of Delivery
Cesarean section acyclovir for the
infant
Cesarean section
Vaginal delivery after disinfection
identification of HSV acyclovir
for the infant.
No possibility of oriented prevention
of neonatal infection with HSV

HSV = herpes simplex virus.

the oxygenated blood from the umbilical vein flows through the
ductus venosus to the right atrium to the left lobe of the liver and
to the portal vein, resulting in a preferentially mesenteric blood
flow. Impaired uteroplacental perfusion induces a reduction in
fetal oxygen delivery responsible for a progressive hemodynamic
adaptation of the fetus with differential shunting of blood to vital
organs such as brain, heart, or adrenals. The blood flow to these
vital organs can be increased to 300%, whereas the increase in the
vascular resistances in the other fetal organs can reduce the cardiac
output by 40%. This redistribution of flow is an adaptive phenomenon that does not imply fetal distress but a brain-sparing
effect. Placental insufficiency can result in metabolic disorders
often associated with IUGR. In spite of low levels of insulin
(hypoperfusion of the pancreas), hypoglycemia is often noted.63
Triglycerides and fatty acids levels are increased, whereas the ratio
of essential to nonessential amino acids is often low, reflecting
the reduced anabolism of the fetus. This ratio is negatively
correlated to the degree of fetal hypoxemia. Biologic signs of
hypothyroidism can appear in the hypoxemic fetus, whereas
hypervascularization of the adrenals increases cortisol levels in
response to hypoglycemia.
The diagnosis of IUGR can be assessed by ultrasonographic
examination. In the first trimester, measurements of the crownrump length and the biparietal diameter allow for precise dating
of pregnancy.64 In late pregnancy, the diagnosis of IUGR is much
more difficult when the gestational age is not precisely known.
Many Doppler and morphometric indices have been proposed to
detect a fetus who is smallforgestational age (SGA). Abdominal
circumference and estimated fetal weight appear to be accurate
predictive indicators of infants who are SGA.65 Doppler ultrasonographic examination also gives information on the fetal condition
and can predict fetal asphyxia.66 Compensatory redistribution of
arterial blood flow to the brain and myocardium and decreased
flow to peripheral organs are additional physiologic adaptive
changes beneficial in preventing brain hypoxemia rather than a
sign of impending brain damage.64 Loss of variability and late
decelerations are pejorative features. Absent or reversed enddiastolic velocity waveforms in umbilical arteries of fetuses who
are SGA indicate a serious risk of adverse outcome with a 28%
perinatal mortality rate.64,67 Absent end-diastolic blood flow
and/or anomalies in heart rate reactivity (nonstress test) have been
associated with fetal hypoxemia and acidosis.68 Fetal cardiac
function should be assessed in an IUGR infant. The ductus
venosus blood velocity may be used to assess the left ventricle

function,62 with absent or inversed flow signs being a sign of


imminent heart failure. Decreases in cardiac output and aortic and
pulmonary peak velocities are directly related to the umbilical pH
at birth.69
Delivery is probably the more efficient treatment for IUGR. Its
timing is based on an evaluation of the fetal heart rate (FHR),
biophysical profile including amniotic fluid volume, Doppler
velocimetry, and the level of fetal maturation.64 The progress of
neonatal care and the benefits of antenatal corticosteroids in
reducing the risks of prematurity allow early deliveries of fetuses
with progressively deteriorating IUGR status. Nevertheless, the
right time for delivery before progressive deterioration of the fetus
often represents a difficult choice for the obstetric team. Growthrestricted fetuses may benefit from repeated noninvasive tests such
as FHR, ultrasound examinations with Doppler sonograms, and
occasionally, fetal blood sampling that may help in determining
the fetal condition and the appropriate timing of delivery.

Prematurity: Main
Pathophysiologic Implications
The incidence of prematurity is approximately 6 to 11% of all life
births.7073 These infants have a high morbidity and mortality rate
because of the incompleteness of organ maturation. They are not
able to maintain their body temperature and have difficulties with
sucking, swallowing, eating, and sustaining ventilation. They are
prone to cerebral damage, intraventricular hemorrhage, respiratory distress syndrome, and necrotizing enterocolitis. However,
since the mid-1990s, major advances in the neonatal and perinatal
care of preterm infants have reduced the mortality rate, even in
very small infants.

Definitions
According to the World Health Organization nomenclature,
preterm labor (prematurity) is now defined as a gestational age less
than 37 completed weeks or less than 259 days, irrespective of
birthweight, because decreased weight per se can be due to IUGR.
Classification according to the gestational age:74
1.
2.
3.
4.

Preterm infant: born before 37 weeks of gestation (<259 days).


Moderately premature: born at 31 to 36 weeks of gestation.
Severely premature: born at 24 to 30 weeks of gestation.
Postterm infant: born after 42 weeks of gestation.

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Classification according to the birthweight:


1. An LBW infant is one weighing less than 2500 g irrespective
of the duration of pregnancy (only 54% of LBW infants are
preterm).
2. A VLBW infant is one weighing less than 1500 g.
3. VLBW is associated with maternal malnutrition, excessive
smoking, chronic alcohol ingestion, drug abuse, toxemia, or
placental insufficiency.

Mortality, Morbidity, and Outcome


In North America and Europe, preterm birth is the most important cause of perinatal mortality. In Great Britain, preterm birth
accounts for 85% of early neonatal deaths not caused by lethal
congenital malformations.72 In the United States, preterm birth
occurs in 7.5% of all deliveries and accounts for 75% of the
perinatal deaths.71 In another study, preterm infants weighing less
than 750 g accounted for 41% of early neonatal deaths and 25% of
infant deaths.73 There is a relationship between the survival rate
of premature infants and increasing gestational age. From 1979 to
1981, a survival rate above 90% was reported for neonates born
after 32 weeks of gestation, decreasing to less than 50% when the
gestational age was less than 26 weeks.75
Preterm birth is associated with a major increase in neonatal
and infant morbidity, including neurodevelopmental disorders,
chronic respiratory problems, intraventricular hemorrhage, infection, retrolental fibroplasias, and necrotizing enterocolitis.76,77 There
is a long-term risk of neurologic and developmental impairment.78
82
In one study, McCarton and associates found that, irrespective of
the degree of prematurity, SGA infants were at greater risk for
neurodevelopmental impairment than appropriateforgestational
age (AGA) infants. Cognitive impairment can be attributed to a
higher incidence of neurologic abnormalities in SGA infants at
each gestational age.83 Table 15 presents the immediate complications and the late sequelae of preterm infants. Prevention of preterm birth is, thus, a major public health goal in many developed
countries and is cost-effective.84 In France, there was a reduction of
the preterm birth rate from 8.2% in 1972 to 6.8% in 1976 and 5.6%
in 1981, with a parallel decrease in the incidence of infants
weighing less than 1500 g from 0.8% in 1972 to 0.4% in 1981.85

Risk Factors for Preterm Birth


The causes of prematurity are (1) low socioeconomic status,
(2) multiple gestation, (3) uteroplacental insufficiency, (4) maternal illness with preeclampsia, and (5) idiopathic IUGR.8691 These
risk factors are summarized in Table 16.

Problems and Complications Associated


With Preterm Birth
RESPIRATORY PROBLEMS: Respiratory distress is common in
preterm infants because of the immaturity of the respiratory
system (Table 17). The limit of viability is approximately 22 to
24 weeks when the lungs have developed a gas-exchanging surface
and surfactant production has begun. Anatomic issues are critical
at this stage. Breathing is exclusively nasal and nasal occlusion can
induce hypoxemia with a reduction of ventilation.92 Spontaneous
neck flexion can induce an airway obstruction with apnea.93
Pulmonary compliance is decreased in cases of hyaline membrane
disease (HMD) because of a reduction of the functional residual

TABLE 1-5. Immediate Complications and Late Sequelae


of Preterm Infants
Immediate Complication

Late Sequelae

Hypoxia, ischemia

Mental retardation, spastic diplegia,


microcephaly, seizures, poor
school performance
Mental retardation, spasticity,
seizures, hydrocephalus
Hearing, visual impairment,
retinopathy of prematurity,
strabismus, myopia
Bronchopulmonary dysplasia, cor
pulmonale, bronchospasm,
malnutrition, iatrogenic cleft
palate, recurrent pneumonia
Short bowel syndrome,
malabsorption, malnutrition,
infectious diarrhea
Cirrhosis, hepatic failure,
carcinoma, malnutrition
Osteopenia, fractures, anemia,
vitamin E, growth failure
Child abuse or neglect, failure to
thrive
Sudden infant death syndrome,
infections, inguinal hernia,
cutaneous scars, gastroesophageal
reflux, hypertension,
craniosynostosis, cholelithiasis,
urolithiasis, cutaneous
hemangiomas

Intraventricular
hemorrhage
Sensorineural injury
Respiratory failure

Necrotizing
enterocolitis
Cholestatic liver
disease
Nutrient deficiency
Social stress
Other

capacity.94 Chest wall compliance is higher in preterm infants


(6.4 mL/cmH2O/kg at 32 wk vs 4.2 mL/cmH2O/kg at term.95 Airway resistance is increased in premature infants because of a
smaller diameter of the bronchi.96 Accessory inspiratory muscles
are relatively inefficient because of an unfavorable anatomic rib
configuration, leading to easy distortion of the chest wall and
paradoxical ventilation. The diaphragm is the most important
respiratory muscle in preterm infants. There is a tendency for
respiratory muscle fatigue, which results from metabolic characteristics of the diaphragm with a reduction of the content of type
1 muscle fibers (slow-twitch, high oxidative capacity) that account
for only 10% in preterm infant versus 20 to 30% in the full-term
infant.97,98 The diaphragmatic work to maintain tidal volume in
preterm infants is increased and may lead to diaphragmatic
fatigue, respiratory distress, or apnea.99,100
At the end of the canalicular stage of pulmonary differentiation
(1624 wk), a reliable gas-exchanging surface appears and surfactant production begins.101103 During the alveolar stage of
differentiation (from 24 wk to term), surfactant secretion in the
amniotic liquid increases, providing a useful indicator of lung
maturity.104 The insufficiency in surfactant production explains
why preterm infants are predisposed to develop HMD. At this
stage, maternal administration of betamethasone or dexamethasone 48 hours before delivery increases surfactant production
and significantly decreases respiratory morbidity in preterm
infants born after 30 weeks of gestation.74,105,106

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TABLE 1-6. Risk Factors of Preterm Birth
Obstetric factors

Maternal factors

Socioeconomic
factors

Fetal factors
Iatrogenic
prematurity

Multiple gestation
Overdistention of the uterus
Placenta previa
Uteroplacental insufficiencies
Intrauterine growth retardation
Placental abnormalities
Gestational bleeding
Cervical and uterine anomalies (multiple
fibroids, septate uterus)
In utero diethylstilbestrol exposure
Trauma: spontaneous, precipitous
delivery, or iatrogenic (e.g., dilation and
curettage)
Premature rupture of the fetal membranes
Multiple second trimester spontaneous
abortions
In vitro fertilization pregnancy
Infection (vaginitis, cervicitis,
chorioamniotitis, or urinary tract
infection)
Preeclampsia
Severe cardiac disease
Severe renal disease
Thyrotoxicosis
Diabetes
Previous history of preterm labor
Smoking
Cocaine use
African origin
Single marital status
Low socioeconomic status
Poor antenatal care
Poor personal hygiene
Extremes of maternal age
Stress
Fetal anomalies

Hypercapnic ventilatory response is decreased in the preterm


infant, and hypoxia may depress this response in term or preterm
infants.107,108 There is also decreased ventilation during oral feeding
in preterm infants.109 Clinical apneas are frequent, occurring in as
many as 25% of all preterm infants, especially the most immature.
These events can be life-threatening. They are associated with a
decrease in arterial oxygen saturation, bradycardia, and loss of
muscle tone. Factors involved in these apneas include brainstem
immaturity, decreased hypercarbic and hypoxic responses, and
respiratory fatigue precipitated by chest wall distortion.110,111
Treatment of apnea is directed at increasing the central drive to
ventilation using theophylline or caffeine preparations, stabilizing
the chest wall (positive end-expiratory pressure), and stimulating
by rocking or stroking. The risk of apnea after general anesthesia
is inversely related to the gestational age, affecting mainly infants
with a postconceptional age of 50 weeks or less.112

CARDIOVASCULAR PROBLEMS: Preterm infants often have a


patent ductus arteriosus that appears 3 to 5 days after birth,

Prenatal Normal and Abnormal Development

13

TABLE 1-7. Complications Associated With Preterm Infants


Respiratory

Cardiovascular

Neurologic

Hematologic

Gastrointestinal
Metabolicendocrine

Renal

Other

Respiratory distress syndrome hyaline


membrane disease
Bronchopulmonary dysplasia
Pneumothorax
Pneumomediastinum
Congenital pneumonia
Pulmonary hypoplasia
Pulmonary hemorrhage
Apnea
Patent ductus arteriosus
Hypotension
Hypertension
Bradycardia (with apnea)
Congenital malformations
Intraventricular hemorrhage
Periventricular leukomalacia
Hypoxic-ischemic encephalopathy
Seizures
Retinopathy of prematurity (retrolental
fibroplasia)
Hypotonia
Congenital malformations
Kernicterus (bilirubin encephalopathy)
Anemia
Hyperbilirubinemia (direct or indirect)
Subcutaneous or organ hemorrhage (liver,
adrenal)
Disseminated intravascular coagulopathy
Vitamin K deficiency
Hydrops
Necrotizing enterocolitis
Poor gastrointestinal function or motility
Hypocalcemia
Hypoglycemia
Hyperglycemia
Late metabolic acidosis
Hypothermia
Hyponatremia
Hypernatremia
Hyperkalemia
Renal tubular acidosis
Renal glycosuria
Edema
Infections (congenital, perinatal, or
nosocomial)

concurrently with the decrease in pulmonary vascular resistance


associated with recovery from HMD and normal postnatal
changes (see Table 17).113,114 The medical treatment of patent
ductus arteriosus includes fluid restriction, diuretics, and the
administration of either indomethacin or ibuprofen.115,116 Indomethacin and ibuprofen induce closure of patent ductus arteriosus
by inhibiting prostaglandin synthesis117; however, efficacy is not
always complete in extremely premature infants (<28 wk) and
surgical closure may be required.118,119 Heart rate is greater in
preterm than in full-term infants (160 vs 120 beats/min) and
decreases progressively from 160 to 130 beats/min from 26 to
40 weeks of gestation.120 Blood pressure is lower in preterm than

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in full-term infants. Cardiac output is higher in preterm than in


full-term infants, which may reflect their higher metabolic rate
and oxygen consumption when compared with adults.121,122
Diastolic function is insufficient and cardiac output is dependent
on heart rate. Therefore, any bradycardia decreases cardiac output.
There is also a limited left ventricular response to volume overload
in preterm infants.123 Autonomic control of the heart is predominantly mediated by the parasympathetic nervous system because
the sympathetic system is immature. There is a decreased responsiveness to vasoconstrictor and vasodilator agents.124 Hypoxia
(apnea) produces a bradycardia with a decrease of cardiac output
associated with an increase of systemic and pulmonary resistances,
which then further potentiates the hypoxemia. There is impairment of the autoregulation of cerebral blood flow.125 Perlman and
coworkers described a fluctuation of cerebral blood flow in
preterm infants with respiratory distress syndrome that correlated
with an increasing rate of intracerebral hemorrhage.126

GASTROINTESTINAL PROBLEMS: Necrotizing enterocolitis is a

RENAL PROBLEMS: Urine production begins in utero at 10 to

because the production of red blood cells is reduced (see Table


17). Anemia has been shown to increase the risk of apnea.139
Immaturity of hepatic function can explain the abnormalities of
coagulation with decreases of vitamin Kdependent factors
leading to prolongation of the prothrombin time.

12 weeks of gestation. Urinary flow is important to maintain the


amniotic fluid volume. Glomerular filtration is decreased in
preterm infants compared with full-term infants.127 Because the
fetus maintains its metabolic homeostasis through the placenta, it
is only after birth that the kidney assumes this function. Tubular
function begins to develop after 34 weeks of gestation.128 The renal
tubular threshold for sodium is decreased, which explains the
propensity for neonates, especially preterm ones, to develop
hyponatremia (see Table 17).129 The tubular threshold for glucose
is low and responsible for frequent glycosuria with dehydration
induced by an osmotic polyuria.130 Metabolic acidosis is common
owing to diminished renal tubular threshold for sodium bicarbonate.131 The infusion of sodium bicarbonate may be necessary to
control acidosis in preterm infants. These infants are at increased
risk of dehydration because insensible water loss is increased.132
Immaturity of distal tubular function and relative hypoaldosteronism can explain the risk of hyperkalemia in preterm infants.133

NEUROLOGIC PROBLEMS: Brain development differs from that in


other organs. The brain has two growth spurts: (1) neuronal cell
multiplication between 15 and 20 weeks of gestation and (2) a
phase of glial cell multiplication from 25 weeks of gestation to the
second year of life. Preterm blood vessel fragility is increased by
several respiratory or hemodynamic factors, thereby increasing
the risk of intracerebral hemorrhage during the first days of life
(see Table 17).125,126,134 Periventricular leukomalacia is an ischemic
cerebral complication with a risk of delayed neurologic development. Its incidence ranges from 12 to 25% in LBW infants less
than 1500 g to 8% in infants born after 34 weeks.135 Retrolental
fibroplasia is a complication depending on the gestational age, the
duration of oxygen therapy, and the partial pressure of oxygen in
the arterial blood.136

THERMAL PROBLEMS: Thermal regulation is immature in the


preterm infant. Exposure to cold may induce an elevation of metabolic rate and oxygen consumption that increases the risks of
hypoxemia, acidosis, apnea, or respiratory distress (see Table 17).
Body heat can be dissipated by conduction, convection, radiation,
and also evaporation, which is the most important mechanism.137
The surface-to-volume ratio is more important in preterm than
in full-term infants, increasing heat losses. It is essential to protect
these infants in an incubator, dry them off immediately after birth,
and provide them with warmed and humidified inspired gases.

major digestive problem that remains a frequent complication in


preterm infants (see Table 17). It generally occurs after the
beginning of enteral feedings, but may also occur in infants who
have never been fed.138 The usual clinical manifestations include
abdominal distention, vomiting, bloody stools, and shock.

METABOLIC-ENDOCRINE PROBLEMS: As mentioned previously,


metabolic acidosis is common in preterm infants (see Table 17).
In addition, hypocalcemia can also be seen because calcium
transfer occurs mainly during the third trimester of gestation and
because preterm infants have diminished concentrations of serum
proteins. Because of the immaturity of glucose regulation, preterm
infants tolerate glucose loads poorly. Therefore, excessive glucose
infusion can be deleterious to the central nervous system. There is
also a risk of hypoglycemia that requires appropriate correction.

HEMATOLOGIC PROBLEMS: Anemia is frequent in preterm infants

INFECTION: The development of infections such as pneumonia,


sepsis, or meningitis is common in the preterm infant because
of significant reduction in cellular and tissue immunity (see
Table 17).

Prevention of Premature Birth


The strategies to prevent preterm birth are reviewed in an article
from Goldenberg and colleagues.75 These factors are outlined in
Table 18. Two categories of strategies are used to reduce adverse
outcomes associated with prematurity: (1) those intended to
prevent or delay preterm birth and (2) those aiming at reducing
the morbidity and mortality of prematurity. The regionalization
of perinatal care ensures that most preterm infants are delivered
close to a neonatal intensive care unit with appropriate equipment
and trained personnel. In these units, specialized therapies can be
used such as specific methods of mechanical ventilation, exogenous surfactant therapy, and other supportive therapies (antibiotic
treatment, and fluid and electrolyte management). Effective
obstetric interventions include use of prenatal corticosteroids for
fetal pulmonary maturation, intrapartum antibiotics to reduce
neonatal sepsis, and prevention or prompt treatment of fetal
hypoxia. These interventions are effective in decreasing the
mortality of preterm infants.

Acute Fetal Distress


Fetal distress can be chronic (antepartum period) or acute (intrapartum period only). Clinical features of antenatal fetal distress
include IUGR, fetal hypoxia, increasing vascular resistance in fetal
blood vessels, and fetal acidosis. Antepartum fetal distress is
frequently associated with uteroplacental insufficiency. Acute fetal
distress occurs during labor. It is a nonspecific and imprecise
diagnosis often associated with surgical delivery. Parer and
Livingston define fetal distress as a progressive fetal asphyxia
which without treatment induces a decompensation of adapted
physiological responses and causes definitive neurologic impairment and other damage or death.140 If birth asphyxia is defined by

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TABLE 1-8. Interventions to Prevent Premature Birth
Prenatal care (routine or enhanced)
Risk-scoring systems
Cervical circling
Progestin supplementation
Programs for cessation of tobacco, drug, and alcohol use
Psychological support
Nutritional interventions
Counseling
Caloric supplementation
Protein supplementation
Vitamin or mineral supplementation
Patient education (to detect signs of preterm labor)
Home uterine-activity monitoring
Frequent contact with a nurse
Tocolytic therapy
Bed rest
Hydration
Screening for and treatment of infection (urinary tract infection
or bacterial vaginosis)
Antibiotics for preterm labor or premature rupture of
membranes
Low-dose aspirin
Calcium supplementation
From Goldenberg RL, Dwight JR. Prevention of premature birth. N Engl J Med.
1998;339:313320.

an Apgar score below 7, its incidence is 5.3%.141 If the definition is


the requirement of more than 1 minute of positive-pressure
ventilation at birth, the incidence decreases to 1.16%.142 However,
if measurements of blood gas and acid-base status in the umbilical
artery are used just after delivery, the incidence is 2%.143
The morbidity of acute fetal distress is most important. In 1979,
a consensus conference estimated that intrapartum events accounted for 20 to 40% of cerebral palsy and 10% of severe mental
retardation.144 Freeman in 1985 concluded that asphyxia played a
major role in cerebral palsy, but not in the occurrence of mild or
severe mental retardation with epilepsy.145 Currently, the incidence
of cerebral palsy caused by birth asphyxia is less than 10%.145147
The consequences of birth asphyxia are variable, because some
fetuses die or have severe and irreversible brain injury whereas
others survive without apparent neurologic deficiencies.148150 In
the absence of any history of chronic fetal distress, there are three
major causes of acute fetal distress:
1. Maternal arterial hypotension: Hypotension can occur when
analgesia for labor is established (epidural or spinal anesthesia)
or following uteroplacental hemorrhage. Hypotension can also
occur or be enhanced by maternal malposition.151
2. Umbilical cord compression: Cord prolapse is positionally
dependent. It is 20 times more frequent in abnormal than in
vertex presentation.152 Abnormal presentations are more frequent in preterm infants. At 28 weeks, 25% of fetus are found
in breech presentation.153 Cord prolapse is, therefore, also
indirectly related to gestational age.
3. Uterine hypertonia: Uterine hypertonia is responsible for a
decrease in umbilical blood flow. The most frequent cause
of hypertonia is an excessive exogenous oxytocin administration.

Prenatal Normal and Abnormal Development

15

Fetal oxygen delivery depends on the umbilical blood flow and


umbilical venous oxygen content and tension. Although some
cases are caused to changes in cardiac output (fetal arrhythmias)
or to modifications of fetal oxygen content (fetal anemia), major
acute fetal distress is mainly related to a decrease of umbilical
blood flow. Three mechanisms are responsible for this decrease:
(1) increase of uterine venous pressure (mainly uterine hypertonia), (2) decrease of uterine arterial pressure (mainly maternal
hypotension), and (3) increase of uterine vascular resistance
(mainly maternal hypertension). The fetal response to hypoxia is
a redistribution of blood flow to vital organs (heart and brain).
Fetal hypoxia results in hypertension with bradycardia without
initial modification of the cardiac output. In severe or prolonged
hypoxemia, fetal cardiac output decreases. During moderate
hypoxemia, absolute umbilical blood flow tends to be maintained.
Blood flow to brain, heart, and adrenals can increase from 100 to
200% while the cardiac output of the fetus decreases to 30%.154 The
umbilical venous blood flow that returns from the placenta either
enters the hepatic circulation or bypasses the liver via the ductus
venosus. The double phenomenon of increasing myocardial blood
flow and redistribution of umbilical venous blood (increasing the
proportion of oxygen-rich blood) maintains oxygen delivery to
the myocardium of the fetus during hypoxemia.155157 Autoregulation of cerebral blood flow protects the brain by increasing oxygen
delivery via vasodilatation associated with the hypertensive
response to hypoxemia. Severe and prolonged hypoxemia induces
ischemic cerebral lesions by a phenomenon of alteration of the
cerebral blood flow associated with hypotension. The evolution of
these ischemic lesions depends on the severity and timing of
cerebral hypoxemia.
Antenatal fetal distress can be suspected in cases of (1) diagnosis of IUGR by ultrasound, (2) Doppler anomalies of the
umbilical artery or fetal aorta blood flow,158160 (3) alterations of
the FHR (spontaneously or during contractions), and (4) diagnosis
of hypoxia or acidosis during percutaneous umbilical venous
blood sampling. Acute fetal distress is suspected during labor
when there are (1) anomalies of the FHR (tachycardia or bradycardia), (2) low variability or abnormal evolution of FHR with
uterine contractions (decelerations), or (3) anomalies of the acidbase status from fetal scalp blood sampling. A pH less than 7.25
suggests fetal distress and a pH less than 7.20 is an indication for
early surgical delivery. Parer and Livingston suggest that adding
the determination of FHR variability to the FHR pattern interpretation is the best indicator of fetal vigor at birth.140 If FHR
variability is absent, then a fetal stimulation test or fetal blood
sampling for acid-base status determination may be indicated.
Chronic fetal distress can be responsible for premature delivery
or IUGR. Acute fetal distress in full-term infants without a
previous problem can be associated with immediate or delayed
complications. Neurologic injuries represent the major factor in
the morbidity of the child. Outcome after birth asphyxia is difficult
to predict because it varies from intrauterine death to normal
survival without any apparent deficit.

CONCLUSIONS
The knowledge of normal and abnormal development of the fetus
is increasingly necessary for the pediatric anesthesiologists who
are involved in the care of preterm and term neonates undergoing
surgical treatments of a congenital malformation or a specific

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complication of prematurity. Diagnosis of major malformations is


now more predictable and effective with the development of
reliable in utero evaluation techniques and better pregnancy
supervision. These anomalies should be evaluated as soon as
possible and can lead to the transfer of the obstetric patient to a
tertiary perinatal center where a suitable therapeutic strategy can
be decided. Many innovations have been made, thus reducing the
mortality rate even in very small infants. Much of this decrease in
mortality can be attributed to improvements in the neonatal and
perinatal care of preterm infants. Another consequence of this
improvement in neonatal care is a reduction of the viable gestational age compatible with long-term survival with an increase in the
number of preterm infants needing surgery. Therefore, the pediatric anesthesiologist must be fully trained in dealing with the
problems associated with extreme prematurity.

REFERENCES
1. Larsen WJ. Human Embryology. 2nd ed. Churchill, New York:
Livingstone; 1997.
2. ORahilly R, Muller F. Developmental Stages in Human Embryos.
Washington, DC: Carnegie Institution of Washington; 1987.
3. Kliegman RM. Fetal growth and maturity. In: Nelson WE, editor:
Textbook of Pediatrics. 15th ed. Philadelphia: WB Saunders; 1996.
4. Needlman RD. Fetal growth and development. In: Nelson WE, editor:
Textbook of Pediatrics. 15th ed. Philadelphia: WB Saunders; 1996.
5. Warshaw JB. The fetus and the newborn. General principles of
growth and development. In: Oski FA, editor: Principles and Practice
of Pediatrics. 2nd ed. Philadelphia: JB Lippincott; 1994.
6. Jones KL. Smiths Recognizable Patterns of Human Malformation. 4th
ed. Philadelphia: WB Saunders; 1988.
7. Bergsma D. Birth Defects Atlas and Compendium. 2nd ed. The
National Foundation March of Dimes. Baltimore: Williams &
Wilkins; 1974.
8. Jones KL. Dysmorphology. In: Nelson WE, editor: Textbook of
Pediatrics. 15th ed. Philadelphia: WB Saunders; 1996.
9. Romero R, Pilu G, Jeanty P, et al. Prenatal Diagnosis of Congenital
Anomalies. ed. Norwalk, Conn: Appleton and Lange; 1988.
10. Caritis S, Sibai B, Hauth J, et al. Low dose aspirin to prevent preeclampsia in women at high risk. N Engl J Med. 1998;338:701705.
11. CLASP: A randomised trial of low dose aspirin for the prevention
and treatment of preeclampsia among 9364 pregnant women. Lancet.
1994;343:619629.
12. Sibai BM, Mercer BM, Schiff E, et al. Aggressive versus expectant
management of severe preeclampsia at 28 to 32 weeks gestation: a
randomized controlled trial. Am J Obstet Gynecol. 1994;171:818822.
13. Brazy JE, Grimm JK, Little VA. Neonatal manifestations of severe
maternal hypertension occurring before the thirty sixth week of
pregnancy. J Pediatr. 100:165,1982.
14. Sibai BM, Anderson GD, Abdella TN, et al. Eclampsia III: neonatal
outcome, growth and development. Am J Obstet Gynecol. 1983;146:307.
15. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of
cerebral palsy in very low birthweight infants? Pediatrics. 1995;95:263.
16. Almstrom H, Axelsson O, Cnattingus S, et al. Comparison of
umbilical artery velocimetry and cardiotocography for surveillance of
small-for-gestational-age fetuses. Lancet. 1992;340:936.
17. Ducey J, Schulman H, Farmakides G, et al. A classification of
hypertension in pregnancy based on Doppler velocimetry. Am J
Obstet Gynecol. 1987;157:860.
18. Havretty K, White MJ, Rubin PC. Doppler uteroplacental waveforms
in pregnancy induced hypertension: a reappraisal. Lancet. 1988;1:650.
19. Uzan S, Beaufils M, Uzan M. HTA et grossesse. In: Papiernik E, Cabrol
D, Pons JC, editors. Obstetrique. Paris : Flammarion, MdecineSciences ; 1995. pp. 793824.

20. Manning FA, Menticoglou S, Harman CR, et al. Antepartum fetal risk
assessment: the role of the biophysical profile score. Clin Obstet
Gynecol. 1987;1:157.
21. Sabers A, Rogvi-Hansen B, Dam M, et al. Pregnancy and epilepsy: a
retrospective study of 151 pregnancies. Acta Neurol Scand. 1998;97:
164.
22. Hauser WA, Hesdorffer DC. Pregnancy and teratogenesis. In: Hauser
WA, editor: Epilepsy, Frequency, Causes and Consequences. New York:
Demos; 1990, pp. 147156.
23. Chang SI, McAuley JW. Pharmacotherapeutic issues for women of
childbearing age with epilepsy. Ann Pharmacother. 1998;32:794801.
24. Yerbi MS, Friel PN, McCormick K, et al. Pharmacokinetics of
anticonvulsants in pregnancy: alterations in plasma protein binding.
Epilepsy Res. 1990;5:223228.
25. Lander CM, Eadie MJ. Plasma antiepileptic drug concentrations
during pregnancy. Epilepsia. 1991;32:257266.
26. Samren EB, van Duijn, Koch S, et al. Maternal use of antiepileptic
drugs and the risk of major congenital malformations: a joint
European prospective study of human teratogenesis associated with
maternal epilepsia. Epilepsia. 1997;38:981990.
27. Bradai R, Robert E. Prenatal ultrasonic diagnosis in the epileptic
mother on valproic acid. Retrospective study of 161 cases in the
central eastern France register of congenital malformations. J Gynecol
Obstet Biol Reprod. 1998;27:413419.
28. Shojania AM. Folic acid and vitamin B12 deficiency in pregnancy
and in the neonatal period. Clin Perinatol. 1984;11:433459.
29. Lewis DP, Van Dyke DC, Stumbo PJ, et al. Drug and environmental
factors associated with adverse pregnancy outcomes. Part I: antiepileptic drugs, contraceptives, smoking and folate. Ann Pharmacother. 1998;32:802817.
30. Becerra JE, Khoury MJ, Cordero JF, et al. Diabetes mellitus during
pregnancy and the risk for specific birth defects: a population-based
case control study. Pediatrics. 1990;85:19.
31. Lepercq J, Cauzac M, Lahlou N, et al. Overexpression of placental
leptin in diabetic pregnancy: a critical role for insulin. Diabetes.
1998;47:847850.
32. Aparicio NJ, Joao MA, Cortelezzi M, et al. Pregnant women with
impaired tolerance to an oral glucose load in the afternoon: evidence
suggesting that they behave metabolically as patients with gestational
diabetes. Am J Obstet Gynecol. 1998;178:10591066.
33. The Diabetes Control and Complications Trial Research Group.
Pregnancy outcomes in the diabetes control and complications trial.
Am J Obstet Gynecol. 1996;174:13431353.
34. Kaminski M. Tabac, alcool et grossesse. In: Papiernik E, Cabrol D,
Pons JC, editors. Obstetrique. Paris : Flammarion, Mdecine-Sciences,
1995. pp. 10191027.
35. Blondel B, Du Mazaubrun C, Breart G. Enqute Nationale Prinatale
1995. Rapport de Fin dtude. Paris: INSERM; 1996.
36. Groupe dexperts de lINSERM. Tabac, alcool, facteurs nutritionnels
et environnementaux. In: Grande Expertise Collective INSERM
Prmaturit. Paris: INSERM; 1997, pp. 6574.
37. Shiono PH, Klebanoff MA, Roads GG. Smoking and drinking during
pregnancy: their effects on preterm birth. JAMA. 1986;255:8284.
38. Schwartz D, Goujard J, Kaminski M, et al. Smoking and pregnancy
results of a prospective study of 6989 women. Rev Eur Etudes Clin
Biol. 1972;17:867.
39. Kain Z, Rimar S, Barash P. Cocaine abuse in the parturient and effects
on the fetus and neonate. Anesth Analg. 1993;77:835845.
40. Burkett G, Yasin S, Palow D. Perinatal implications of cocaine
exposure. J Reprod Med. 1990;35:3542.
41. Chasnoff IJ, Griffith DR, MacGregor S, et al. Temporal patterns of
cocaine use in pregnancy: perinatal outcome. JAMA. 1989;261:1741
1744.
42. Mooney EE, Boggess KA, Herbert WNP, et al. Placental pathology in
patients using cocaine: an observational study. Obstet Gynecol.
1998;91:925929.

Bissonette-001-(F)

4/13/11

4:17 PM

Page 17

CHAPTER 1
43. Cherukuri R, Minkoff H, Feldeman J, et al. A cohort study of
alkaloidal cocaine (crack) in pregnancy. Obstet Gynecol. 1988;72:
147151.
44. Oro AS, Dixon SD. Perinatal cocaine and metamphetamine exposure:
maternal and neonatal correlates. J Pediatr. 1987;111:571578.
45. Zuckerman B, Maynard EC, Cabral H. A preliminary report of
prenatal cocaine exposure and respiratory distress syndrome in
premature infants. Am J Dis Child. 1991;145:696698.
46. Kain ZN, Chinoy MR, Antonio-Santiago MT, et al. Enhanced lung
maturation in cocaine exposed rabbit fetuses. Pediatr Res. 1991;29:
534537.
47. Sosenko IRS. Cocaine administration to pregnant rats produces
increased surfactant maturation without affecting antioxidant
enzyme development [abstract]. Pediatr Res. 1991;29:330A.
48. Laegreid L, Olegard R, Walstrom J, et al. Teratogenic effects of benzodiazepine use during pregnancy. J Pediatr. 1989;114:126131.
49. Bergman U, Rosa FW, Baum C, et al. Effects of exposure to
benzodiazepine during fetal life. Lancet. 1992;340:694696.
50. Laegreid L, Kyllerman M, Hedner T, et al. Benzodiazepine amplification of valproate teratogenic effects in children of mothers with
absence epilepsy. Neuropediatrics. 1993;24:8892.
51. Wilson C, Remington J, Stagno S, et al. Development of adverse
sequelae in children born with subclinical Toxoplasma infection.
Pediatrics. 1980;66:767.
52. Blanche S, Rouzioux C, Moscato MLG, et al. A prospective study of
infants born to women seropositive for human immunodeficiency
virus type 1. N Engl J Med. 1989;320:1643.
53. Gloeb DJ, OSullivan MJ, Efantis J. Human immunodeficiency virus
in women: I. The effects of human immunodeficiency virus on
pregnancy. Am J Obstet Gynecol. 1988;159:756.
54. Lindgren S, Anzen B, Bohlin AB, et al. HIV and child bearing: clinical
outcome and aspects of mother to infant transmission. AIDS.
1991;5:11111116.
55. European Collaborative Study. Children born to women with HIV 1
infection: natural history and risk of transmission. Lancet. 1991;
1:253260.
56. Delfraissy JF, Goujard C, Boue F, et al. Transmission prinatale du
VIH. Rep Hum Horm. 1992;5:543.
57. Mayaux MJ, Blanche S, Rouzioux C, et al. Maternal factors associated
with perinatal HIV-1 transmission: The French cohort study: 7 years
of follow up observation. J Acquir Immun Defic Syndr. 1995;8:188
194.
58. Gillet JY, Garraffo R Abrar D, et al. Fetoplacental passage of
zidovudine. Lancet. 1989;ii:269270.
59. Burgard M, Mayaux MJ, Blanche S, et al. The use of viral culture and
p24 antigen testing to diagnosis human immunodeficiency virus
infection in neonates. N Engl J Med. 1992;327:11921197.
60. Scott GB, Hutto C, Makuch RW, et al. Survival in children with
perinatally acquired human immunodeficiency virus type I infection.
N Engl J Med. 1989;321:1791.
61. Hadders-Algra M, Touwen BCL. Body measurements, neurological
and behavioral development in six year old children born preterm
and/or small-for-gestational age. Early Hum Dev. 1991;22:113.
62. Ville Y. Retard de croissance intrautrin dorigine vasculaire. 9e
Sminaire Guigoz-GENEUP-RP. Paris. Guigoz et la Fdration des
groupes dtudes en Nonatologie; 1997.
63. Economides DL, Nicolaides KH. Blood glucose and oxygen tension
levels in small for gestational age fetuses. Am J Obstet Gynecol.
1989;160:385389.
64. Lepercq J, Mahieu Caputo D. Diagnosis and management of intrauterine growth retardation. Horm Res. 1998;49:1419.
65. Chang TC, Robson SC, Boys RJ, et al. Prediction of the small for gestational age infant: which is the best? Obstet Gynecol. 1992;80:1030
1038.
66. Bilardo CM, Nicolaides KH, Campbell S. Doppler measurements of
fetal and uteroplacental circulations: relationship with umbilical

67.

68.
69.

70.

71.

72.
73.

74.

75.

76.
77.
78.

79.

80.
81.

82.

83.

84.

85.

86.
87.
88.

89.

Prenatal Normal and Abnormal Development

17

venous blood gases measured at cordocentesis. Am J Obstet Gynecol.


1990;162:115120.
Karsdorp VHM, Van Vugt JMG, Van Geijn HP. Clinical significance
of absent or reversed end diastolic velocity waveform in umbilical
arteries. Lancet. 1994;344:16641668.
Rizzo G, Arduini D. Fetal cardiac function in intrauterine growth
retardation. Am J Obstet Gynecol. 1991;165:876882.
Donner C, Vermeylen D, Kirkpatrick C, et al. Management of the
growth restricted fetus: the role of non invasive tests and fetal blood
sampling. Obstet Gynecol. 1995;85:965970.
U.S. Department of Health and Human Services, Public Health
Service, The National Center for Health Statistics (NCHS). Vital
Statistics of the United States, 1980. Vol 1. Hyattsville, MD: 1984.
Quilligan EJ, Little AB, Oh WM. 1983 An elevation and assessment
of the state of the science. In: Pregnancy, Birth and Infant. NIH
Publication N8. 82-02304. Bethesda, Md: National Institutes of
Health; 1983.
Rush RW, Keirse MJ, Howat P, et al. Contribution of preterm delivery
to perinatal mortality. Br Med J. 1976;2:965968.
Overpeck MD, Hoffman HJ, Prager K. The lowest birth-weight
infants and the US infant mortality rate: NCHS 1983 linked
birth/infant death. Am J Public Health. 1992;82:441444.
Creasy RK. Preterm labor and delivery. In: Creasy RK, Resnik R,
editors. Maternal-Fetal Medicine, Principles and Practice, 2nd ed.
Philadelphia: WB Saunders; 1989. pp 477504.
Goldenberg RL, Nelson KG, Hale CD, et al. Survival of infants with
low birth weight and early gestational age. Am J Obstet Gynecol.
1984;149:508511.
Institute of Medicine, National Academy of Sciences. Preventing Low
Birth Weight. Washington, DC: National Academy Press; 1985.
Arias F, Tomich P. Etiology and outcome of low birth weight and
preterm infant. Obstet Gynecol. 1982;60:277281.
Teberg AJ, Wather FJ, Pena IC. Mortality, morbidity and outcome of
the small-for-gestational age preterm infant. Semin Perinatol.
1988;12:8489.
Vohr BR, Oh W, Rosenfield AG, et al. The premature small for
gestational age infant: a 2-year follow-up study. Am J Obstet Gynecol.
1979;133:425431.
Commey JO, Fitzhardinge PM. Handicap in the preterm small for
gestational age infant. J Pediatr. 1979;94:779786.
Kitchen W, Ford G, Orgill A, et al. Outcome in infants with birth
weight 500 to 999 gm: a regional study of 1979 and 1980 births.
J Pediatr. 1984;104:921927.
Sung IK, Vohr B, Oh W. Growth and neurodevelopmental outcome
of very low birth weight infants with intrauterine growth retardation:
comparison with control subjects matched by birth weight or for
gestational age. J Pediatr. 1990;116:1926.
McCarton CM, Wallace IF, Divon M, et al. Cognitive and neurologic
development of the premature, small for gestational age infant
through age 6: comparison by birth weight and gestational age.
Pediatrics. 1996;98:11671178.
Korenbrot CC, Aalto LJ, Laros RK. The cost effectiveness of stopping
preterm labor with -adrenergic treatment. N Engl J Med. 1984;
310:691696.
Rumeau-Rouquette C, Du Mazaubrun C, Rabarison Y, et al. Natre
en France: 10 ans dEvolution, 19721981. Paris: INSERM/Doin;
1984.
Gonik B, Creasy RK. Preterm labor: its diagnosis and management.
Am J Obstet Gynecol. 1986;154:38.
McKeown T, Record R. Observations on fetal growth in multiples
pregnancies. J Endocrinol. 1952;8:386401.
Linn S, Schoenbaum S, Manson R. The relationship between induced
abortion and outcome of subsequent pregnancies. Am J Obstet
Gynecol. 1983;146:136140.
Parisi VM. Cervical incompetence and preterm labor. Clin Obstet
Gynecol. 1988;31:585598.

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Developmental Considerations

90. Gravett MG, Nelson HP, DeRouen T. Independent associations of


bacterial vaginosis and Chlamydia trachomatis infection with
adverse pregnancy outcome. JAMA. 1986;256:18991903.
91. Berkowitz GS, Papiernik E. Epidemiology of preterm birth.
Epidemiol Rev. 1993;15:414443.
92. Miller MJ, Carlo WA, Strohl KP, et al. Effect of maturation on oral
breathing in sleeping premature infants. J Pediatr. 1986;109:
515519.
93. Thach BT, Stark AR. Spontaneous neck flexion and airway obstruction during apneic spells in preterm infants. J Pediatr. 1979;94:275.
94. Bancalari E, Garcia OL, Jesse ML. Effects of continuous negative
pressure and lung mechanics in idiopathic respiratory distress
syndrome. Pediatrics. 1973;51:485.
95. Gerhardt T, Bancalari E. Chest wall compliance in full term and
premature infants. Acta Paediatr Scand. 1980;69:359364.
96. Stocks J, Godfrey S. Specific airways conductance in relationship
to postconceptional age in early infancy. J Appl Physiol. 1977;43:
144154.
97. Keens TG, Bryan AC, Levison H, et al. Development pattern of
muscle fiber types in human ventilatory muscles. J Appl Physiol.
1978;44:909913.
98. Muller NL, Gulston G, Cade D, et al. Diaphragmatic muscle fatigue
in the newborn. J Appl Physiol. 1979;46:688695.
99. Heldt GP. Development of stability of respiratory system in preterm
infants. J Appl Physiol. 1988;65:441444.
100. Guslits BG, Gaston SE, Bryan MH, et al. Diaphragmatic work of
breathing in premature human infants. J Appl Physiol. 1987;62:
14101415.
101. Boyden EA. Development and growth of the airways. In: Hodsen
WA, editor. Development of the Lung. New York: Marcel Dekker;
1977.
102. Hislop A, Reid L. Lung development in relation to gas exchange
capacity. Bull Physiopathol Respir. 1973;92:13171343.
103. Campiche MA, Gautier A, Hernandez EI, et al. An electron
microscope study of the fetal development of human lung. Pediatrics. 1963;32:976994.
104. Gluck L, Kulovich MV. Lecithin/sphingomyelin ratios in amniotic
fluid in normal and abnormal pregnancy. Am J Obstet Gynecol.
1973;115:539546.
105. Liggins GC, Howie RN. A controlled study of antepartum glucocorticoid treatment of the respiratory distress syndrome in premature
infants. Pediatrics. 1972;50:515525.
106. Morales WJ, Diebel D, Lazar AJ, Zadrosny D. The effect of antenatal
dexamethasone administration on the prevention of respiratory
distress syndrome in preterm gestations with premature rupture of
membranes. Am J Obstet Gynecol. 1986;154:591595.
107. Rigatto H, Brady JP, Chir B, et al. Chemoreceptor reflexes in preterm
infants: I: the effect of gestational age and postnatal age on the ventilatory response to inhaled carbon dioxide. J Appl Physiol. 1975;
55:604.
108. Rigatto H, Verduzco RT, Cates DB. Effects of O2 on the ventilatory
response to carbon dioxide in preterm infants. J Appl Physiol.
1975;39:896899.
109. Shivpuri CR, Martin RJ, Carlo WA, et al. Decreased ventilation in
preterm infants during oral feeding. J Pediatr. 1985;106:625.
110. Heldt GP, McIloroy MB. Distortion of chest wall and work of
diaphragm in preterm infants. J Appl Physiol. 1987;62:164169.
111. Henderson-Smart DJ, Pettigrew AG, Campbell DJ. Clinical apnea
and brainstem neural function in preterm infants. N Engl J Med.
1983;308:353357.
112. Kurtz CD, Spitzer AR, Broennle AM, et al. Postoperative apnea in
preterm infants. Anesthesiology. 1987;66:483488.
113. Siassi B, Blanco C, Cabal L, et al. Incidence and clinical features
of patent ductus arteriosus in low birth weight infants: a prospective analysis of 150 consecutively born infants. Pediatrics. 1976;
57:347.

114. Thibeault DW, Emmanouilides GC, Nelson RJ, et al. Patent ductus
arteriosus complicating the respiratory distress syndrome in preterm infants. J Pediatr. 1975;86:120.
115. Rudolph AM, Heymann MA. Medical treatment of ductus
arteriosus. Hosp Pract. 1977;12:57.
116. Stevenson JG. Fluid administration in the association of patent
ductus arteriosus complicating respiratory distress syndrome.
J Pediatr. 1977;90:257.
117. Heymann MA, Rudolph AM, Silverman NH. Closure of the ductus
arteriosus in premature infants by inhibition of prostaglandin
synthesis. N Engl J Med. 1976;295:530.
118. Merritt TA, Disessa TG, Feldman BH, et al. Closure of the patent
ductus arteriosus with ligation and indomethacin: a consecutive
experience. J Pediatr. 1978;93:639.
119. Mellander M, Leheup B, Lindstrom DP, et al. Recurrence of symptomatic patent ductus arteriosus in extremely premature infants
treated with indomethacin. J Pediatr. 1984;104:419425.
120. Siassi B, Hodgman J, Cabal L, et al. Cardiac and respiratory activity
in relation to gestation and sleep states in newborn infants. Pediatr
Res. 1979;13:1163.
121. Walther FJ, Siassi B, Ramadan NA, et al. Pulsed Doppler determination of cardiac output in neonates: normal standards for clinical use.
Pediatrics. 1985;76:829833.
122. Walther FJ, Siassi B, King J, et al. Echocardiographic measurements
in normal preterm and term neonates. Acta Paediatr Scand. 1986;
75:563568.
123. Romero TE, Friedman WF. Limited left ventricular response to
volume over load in the neonate period: a comparative study with
adult animal. Pediatr Res. 1979;13:910915.
124. Manders WT, Pagani M, Vatner SF. Depressed responsiveness to
vasoconstrictor and dilatator agents and baroreflex sensitivity in
conscious newborn lambs. Circulation. 1979;60:945955.
125. Lou HC, Lassen NA, Friis-Hansen B. Impaired autoregulation of
cerebral blood flow in the distressed newborn infant. J Pediatr.
1979;94:118.
126. Perlman JM, McMenamin JB, Volpe JJ. Fluctuating cerebral blood
velocity in respiratory distress syndrome. N Engl J Med. 1983;309:
204209.
127. Guignard JP. Assessment of renal function without urine collection.
Arch Dis Child. 1977;52:424.
128. Arant BS. Developmental patterns of renal functional maturation
compared in the human neonate. J Pediatr. 1978;92:705712.
129. Engelke SC, Shah BL, Vasan V, et al. Sodium balance in very low
birth weight infants. Pediatrics. 1984;74:259.
130. Stonestreet BS, Rubin L, Pollack A, et al. Renal functions of low birth
weight infants with hyperglycemia and glycosuria produced by
glucose infusions. Pediatrics. 1981;66:561.
131. Guignard JP, John EG. Renal function in the tiny, premature infant.
Clin Perinatol. 1986;13:377401.
132. Wu PYK, Hodgman JE. Insensible water loss in preterm infants:
changes with postnatal development and non ionizing radiant
energy. Pediatrics. 1974;54:704712.
133. Gruskay J, Costarino AT, Polin RA, et al. Nonoliguric hyperkaliemia
in the premature infant weighing less than 1000 grams. J Pediatr.
1988;113:381386.
134. Ment LR, Duncan CC, Ehrenkranz RA, et al. Intraventricular
hemorrhage in the preterm neonate: timing and cerebral blood flow
changes. J Pediatr. 1984;104:419425.
135. Fawer CL, Diebold P, Calame A. Periventricular leukomalacia and
neurodevelopmental outcome in preterm infants. Arch Dis Child.
1987;62:3036.
136. Kinsey VE, Arnold HJ, Kalina RE, et al. PaO2 levels and retrolental
fibroplasia: a report of the cooperative study. Pediatrics. 1977;60:655.
137. Hammarlund K, Stromberg B, Sedin G. Heat loss from skin of
preterm and fullterm newborn infants during the first weeks after
birth. Biol Neonate. 1986;50:110.

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CHAPTER 1
138. Salle B, Berthier JC. Entropathie aigu ncrosante du nouveau-n.
Pdiatrie. 1979;34:461471.
139. Dallman PR. Anemia of prematurity. Annu Rev Med. 1981;32:
143160.
140. Parer JT, Livingston EG. What is fetal distress? Am J Obstet Gynecol.
1990;162:14211427.
141. Drage J, Kennedy C, Schwarz B. The Apgar score as an index of
neonatal mortality: a report from the Collaborative Study of
Cerebral Palsy. Obstet Gynecol. 1964;24:222.
142. MacDonald H, Mullingan J, Allen A, et al. Neonatal asphyxia.
I. Relationship of obstetric and neonatal complications to neonatal
mortality in 38,405 consecutive deliveries. J Pediatr. 1980;96:898902.
143. Low JA. The role of blood gas and acid-base assessment in the
diagnosis of intrapartum fetal asphyxia. Am J Obstet Gynecol. 1988;
159:12351240.
144. Antenatal diagnosis: Report of a Consensus Development Conference, National Institute of Child Health and Human Development.
Vol. 79. Washington, DC: Government Printing Office; 1979. p. 1973.
145. Freeman J. Summary in prenatal and perinatal factors associated
with brain disorders. Washington, DC: Government Printing Office;
1985. NIH Publication no. 85-1149.
146. Nelson K. What proportion of cerebral palsy is related to birth
asphyxia? J Pediatr. 1988;112:572574.
147. Blair E, Stanley FJ. Intrapartum asphyxia: a rare cause of cerebral
palsy. J Pediatr. 1988;112:515519.
148. Freeman JM, Nelson KB. Intrapartum asphyxia and cerebral palsy.
Pediatrics. 1988;82:240249.
149. Paneth N, Stark R. Cerebral palsy and mental retardation in relation
to indicators of perinatal asphyxia. Am J Obstet Gynecol. 1983;
147:960966.

Prenatal Normal and Abnormal Development

19

150. Low JM, Gaibraith RS, Muir DW, et al. Motor and cognitive deficits
after intrapartum asphyxia in the mature fetus. Am J Obstet Gynecol.
1988;158:356361.
151. Eckstein KL, Marx GF. Aortocaval compression and uterine
displacement. Anesthesiology. 1974; 40:9296.
152. Johnson CE. Transverse presentation of fetus. JAMA. 1964;187:
642.
153. Collea JV. Current management of breech presentation. Clin Obstet
Gynecol. 1980;23:525.
154. Behrman RE, Lees MH, Peterson EN, et al. Distribution of the
circulation in the normal and the asphyxiated fetal primate. Am J
Obstet Gynecol. 1970;108:956969.
155. Cohn HE, Sacks EJ, Heymann MA, et al. Cardiovascular responses
to hypoxemia and acidemia in fetal lambs. Am J Obstet Gynecol.
1974;120:817824.
156. Goodlin R. Fetal cardiovascular responses to distress. Obstet
Gynecol. 1977;49:371381.
157. Cohn H, Piasecki G, Jackson B. The effect of fetal heart rate on
cardiovascular function during hypoxemia. Am J Obstet Gynecol.
1980;138:11901199.
158. Burke G, Stuart B, Crowley P, et al. Is intrauterine growth retardation
with normal umbilical artery blood flow a benign condition? Br
Med J. 1990;300:1044.
159. Nicolaides KH, Bilardo CM, Soothill PW, et al. Absence of end
diastolic frequencies in umbilical artery: a sign of fetal hypoxia and
acidosis. Br Med J. 1988;297:10261027.
160. Arduini D, Rizzo G, Romanini C, et al. Fetal haemodynamic response to maternal hyperoxygenation as predictor of fetal
distress in intrauterine growth retardation. Br Med J. 1989;298:
15611562.

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General Growth and Tissue


Development Throughout
Childhood
Ruth Oelhafen Luginbuehl

INTRODUCTION

Postnatal

The first two decades of a human life are characterized by


significant growth and changes in both form and function. As a
human being progresses through fetal life, infancy, childhood, and
adolescence towards adulthood, tremendous physical, cognitive,
and emotional maturation occurs. Therefore, a physician dealing
with a pediatric population will be confronted with remarkable
physical and psychological differences in development and maturity
based on the chronological age of a child. A proper understanding
of this developmental progression is crucial for an anesthesiologist
to provide optimal care. As a detailed review in developmental
pediatrics is beyond the scope of this chapter, a general overview of
issues relevant to the practice of anesthesia is presented.

Birth is a dramatic event during which the fetus must adapt rapidly
to the abrupt change from the intrauterine to the extrauterine
environment. However, it is merely the beginning of a long process
of changes during human growth and development. Physical
growth continues at a rapid pace during the first 6 months of
extrauterine life and slows down gradually by about 2 years of age,
only to accelerate eventually again during the pubertal growth
spurt. On average, birthweight is doubled by 6 months of age and
tripled by 1 year. Length is doubled by 4 years of age. Growth
curves, including head circumference and body mass index (BMI)
curves, for healthy boys and girls are presented in Figures 22 to
29. Significant changes in body proportion take place over the
course of childhood. At birth the head is large relative to body size
(approximately 1/4 of total body length compared with 1/8 in
adulthood), the trunk is long, and the limbs are short (trunk to
limb ratio of 1:1 compared with 3:4 in adulthood). The upper body
to lower body ratio of about 1.7:1 in newborns decreases to
approximately 1:1 in adulthood.3 As Figure 210 shows, the total
body water content is almost 70% of body weight in the term
newborn (80% in the preterm baby), 62% at 1 year of age, and 65%
in adulthood.4 The decrease in the proportion of total body water
between the premature neonate and the older infant is attributed
to an increase in the proportion of body fat. The body surface area
to volume ratio is highest in the preterm newborn and decreases
into adulthood. Because of their increased relative surface area,
neonates may become hypothermic more quickly if they are
unprotected. The higher relative surface area also results in greater
evaporative water loss. The skin of the premature infant is thin
and gelatinous, further increasing evaporative heat losses in the
first few days of life.5 Figure 211 illustrates the nomogram for
approximating body surface area based on height and weight.
Mostellers formula allows a more accurate calculation of body
surface area6:

GENERAL GROWTH
Prenatal
The most rapid growth in human development occurs during the
prenatal stage.1 Although well protected in the uterus, the human
embryo may be affected in a negative way by environmental
agents or so-called teratogens.2 Teratogens, in biological (such as
bacterial and viral infections), chemical (such as drugs), and
physical form (such as radiation) may cause developmental
disruptions following maternal exposure. The damage caused by
these agents is very much dependent on the prenatal stage at the
time of exposure. During the first 2 weeks of gestation, maternal
exposure to teratogens may result in embryonic death and
spontaneous abortion or full repair. During organogenesis,
which is completed by the end of the eighth gestational week, the
embryo is most vulnerable to environmental agents. During this
stage, teratogenic insults may give rise to major congenital
malformations. The fetal period (beginning at the ninth
gestational week and lasting until term) is characterized by a
striking rate of somatic growth with continued differentiation
of organ systems. Environmental insults during this phase may
cause functional defects of organ systems or impair general growth
and result in a small-for-gestational-age (SGA) infant. Other
conditions including genetic defects, maternal illness, tobacco use,
and malnutrition may also compromise growth. By contrast,
poorly controlled maternal diabetes mellitus may result in a baby
that is large for gestational age (LGA). Figure 21 illustrates the
approximate birthweight at various gestational ages.

Body surface area m 2 = Body length cm x body weight kg 36000

Adolescence, the developmentally transitional stage between


childhood and adulthood, marks a time of dramatic physical and
psychological changes. Growth and physical changes including the
development of secondary sexual characteristics (facial, axillary,
and pubic hair as well as breast, testicular, penile, and laryngeal
development) are the result of endocrine maturation.78 The first

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Figure 2-1. Growth percentiles for preterm neonates.


Adapted from reference 6.

General Growth and Tissue Development Throughout Childhood 21

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Figure 2-2. Growth percentiles for boys aged 0 to 36 months.


Adapted from reference 3.

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Figure 2-3. Growth percentiles for girls aged 0 to 36 months.


Adapted from reference 3.

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Figure 2-4. Growth percentiles for boys aged 2 to 20 years.


Adapted from reference 3.

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Figure 2-5. Growth percentiles for girls aged 2 to 20 years.


Adapted from reference 3.

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Figure 2-6. Head circumference percentiles for boys aged 0 to 36 months.


Adapted from reference 3.

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Figure 2-7. Head circumference percentiles for girls aged 0 to 36 months.


Adapted from reference 3.

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Figure 2-8. Body mass index (BMI) percentiles for boys aged 2 to 20 years.
Adapted from reference 3.

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Figure 2-9. Body mass index (BMI) percentiles for girls aged 2 to 20 years.
Adapted from reference 3.

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Figure 2-10. Age dependent changes in body composition.


Adapted from reference 5.

sign of pubertal onset in boys is testicular enlargement, beginning


as early as 9 to 10 years of age. The first visible sign of puberty in
girls is the appearance of breast buds, which general begins
between 8 and 12 years of age. Menarche (age of first menses)
typically follows 2.5 years later, and marks the onset of fertility.
Staging of puberty is based on the sexual maturity rating (SMR)
criteria described by Tanner (Table 21).9 On average, the peak
growth velocity during the pubertal growth spurt occurs in girls at
11 to 12 years of age and in boys at around 14 years of age. During
the 2 years following menarche, girls gain on average another 5
8 cm until finally reaching adult height.10

FLUIDS AND NUTRITION


Rapid growth and the relatively high maintenance rates due to
higher metabolic and nutrient turnover explain the significantly
higher caloric needs in infants and children compared with
adults.11 Lack or too low a caloric intake has a negative impact on
a childs development, causing the weight curve to decline first.
A more chronic situation will eventually have a negative influence
on body size, and later on psychomotor development (failure to
thrive [FTT:). During the first 5 to 6 months of life, nutrition of a
healthy infant is provided entirely by breast milk (preferably) or by
special infant formulas, which have been adapted to age-related

needs. Around the age of 6 months, infants are generally ready for
the introduction of complementary solid food. The timing and
order of the introduction of solids varies considerably and is
influenced by social and cultural factors. However, there are
recommendations for the introduction of solid food by the
World Health Organization (WHO).12 These recommendations
take into consideration not only the risk of nutrients to act as
potential allergens, but also their potential to negatively influence
the risk of cardiovascular problems later on in adulthood.1314
Complementary food should be introduced step by step. The age
when children become entirely self-feeding varies and depends
on sociocultural factors and the willingness of the parents to
tolerate a mess at mealtimes. Caloric intake per kilogram of body
weight falls steadily after the age of 1 year. Table 22 illustrates the
recommended energy intake in a healthy and active child. Caloric
requirements in a hospitalized child vary depending on the illness
and most often lie between the basal metabolic requirements
and the normal energy needs of an active child. Because the
metabolism of 1 calorie of energy results in net consumption of
1 mL of water, fluid requirements are thought to reflect caloric
requirements. A simple formula known as the HollidaySeger
method for calculating daily maintenance fluid requirements
based on body weight may also help to estimate the daily energy
needs.15

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Figure 2-11. Nomogram for estimation of body surface area. A: For patients of approximately normal body size, the surface area
can be estimated from the body weight alone. B: The intersection of the line connecting patients height (left column) with patients
weight (right columns) yields the patients body surface area.
Adapted from reference 7.

0 to 10 kg body weight:
11 to 20 kg body weight:
20 kg body weight:

Daily fluid
requirement
100 mL/kg
1000 mL 
50 mL/kg
1500 mL 
20 mL/kg

Daily energy
requirement
100 kcal/kg
1000 kcal 
50 kcal/kg
1500 kcal 
20 kcal/kg

The body surface area method serves the same purpose, but is
based on the body surface area.16 Daily fluid requirements are 1500
mL/m2 per 24 hours and daily energy requirements are 1500
mL/m2 per 24 hours. Recommended daily allowances for
electrolytes, minerals, vitamins, and other nutrients can be found
in various references.11,1416

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TABLE 2-1. Classification of Sexual Maturity Rating in Boys and Girls


Girls
Sexual Maturity
Rating Stage
1
2

3
4

Boys

Breasts

Pubic Hair

Pubic Hair

Penis

Testes

Preadolescent
Brest and papilla
elevated as small
mound; areola
diameter increased
Breast and areola
enlarged, no contour
separation
Areola and papilla form
secondary mound

Preadolescent
Preadolescent
Sparse, lightly
Scanty, long, slightly
pigmented, straight,
pigmented
medial border of labia

Preadolescent
Slight enlargement

Darker, beginning to
curl, increased
amount
Coarse, curly, abundant
but amount less than
in adult

Longer

Preadolescent
Enlarged
scrotum,
pink texture
altered
Larger

Mature; nipple projects,


areola part of general
breast contour

Adult feminine triangle,


spread to medial
surface of thighs

Darker, starts to
curl, small
amount
Resembles adult
type, but less in
quantity; coarse,
curly
Adult distribution,
spread to medial
surface of thighs

Larger; glans
and breadth
increase in
size
Adult size

Larger, scrotum
dark
Adult size

Adapted from references 10, 11.

TABLE 2-2. Recommended Daily Energy Intake (kcal),


by Age
Age, Years

Per Kilogram Body Weight

Per Day

108
98
102
90
70
55
45
47
40

650
850
1300
1800
2000
2500
3000
2200
2200

00.5
0.51.0
13
46
710
1114 Males
1518
1114 Females
1518
Adapted from reference 17.

SPECIFIC ORGAN SYSTEMS


Airway and Respiratory System
The respiratory system serves the two main functions of supplying
sufficient oxygen to meet metabolic demands and removing
carbon dioxide. A variety of processes including ventilation,
perfusion, and diffusion are involved in fulfilling these functions.
The development of the respiratory system begins during the
fourth week of gestation.1 The respiratory tree is formed by
successive branching of the airways. By 24 weeks of gestation,
some thin-walled primitive alveoli have developed at the end of
the respiratory bronchioles. These regions are well vascularized
and therefore, at this point, the conditions exist for effective gas
exchange and breathing. However, at 24 weeks, the primitive
alveoli are mainly lined by type I pneumocytes, which means there
is no surfactant production. Surfactant is produced by type II
pneumocytes and spreads out in the form of a monomolecular
film over the walls of the primitive alveoli. Its function is to
counteract surface tension forces and to facilitate alveolar
expansion. By 26 to 28 weeks of gestation, sufficient alveoli and

surfactant are present to permit survival of some infants without


exogenous surfactant. Infants born without adequate surfactant
develop infantile respiratory distress syndrome (RDS). If
premature delivery can be anticipated 48 hours ahead of time,
surfactant production may be induced by the administration of
glucocorticoids to the mother. More importantly, several
preparations of exogenous surfactant are now available and have
improved morbidity and mortality in this population.5, 17
Approximately 12% to 16% of the adult number of alveoli are
present at birth. The number and size of alveoli continue to
increase until the child is about 8 years of age, after which time
lung growth occurs only by increasing alveolar size.1 Before birth,
the lungs are filled with fluid. To make the transition to extra
uterine life and allow the lungs to take over their function, this
fluid must be replaced by air. The majority of the fluid is removed
from the lungs by compression of the highly compliant chest
wall in the birth canal during the birth process.18 The rest will
be absorbed into the pulmonary vascular system and removed
by the pulmonary lymphatic system.5 This process may require
several hours in the normal infant and transient tachypnea of
the newborn may be seen if there is ineffective removal of this
fluid. This is generally a benign process which resolves during
the first day of life. Therapy may include the administration of
supplemental oxygen or continuous positive airway pressure
(CPAP). The first breath may require a very high negative intrathoracic pressures to inflate the lung tissue and fill the alveoli with
air. This may result in a pulmonary air leak, which may cause a
pneumothorax or pneumomediastinum.19 Asymptomatic infants
generally do not require invasive therapy such as tube thoracostomy. However, ongoing observation and monitoring for signs of
respiratory deterioration are necessary.5
The respiratory rate is highest in the newborn period and
gradually falls to adult values by adolescence (Table 23). Young,
especially premature, infants may normally show an irregular
respiratory pattern. Even term infants may normally display
periodic breathing, which is characterized by a period of apnea
lasting from 3 to 10 seconds followed by a period of ventilation

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TABLE 2-3. Mean Respiratory Rates, by Age


Age

Respiratory Rate, breaths/min

Premature
03 months
36 months
612 months
13 years
36 years
612 years
Adult

4070
3555
3045
2540
2030
2025
1422
1218

Adapted from reference 23.

for 10 to 18 seconds. It is rarely seen during the first 24 hours


after birth and disappears by 38 to 40 weeks of gestational age.20 It
is therefore important to count the respiration rate for a full
minute in this age group when performing an assessment.
This normal variation in respiration must be distinguished
from apnea of prematurity, which may require mechanical or
pharmacological therapy. Apnea in infancy is defined as an
unexplained episode of interruption of breathing for 20 seconds or
longer, or a shorter respiratory pause of any duration associated
with symptoms such as bradycardia, cyanosis, pallor, and/or
significant muscular hypotonia.21 Respiratory pauses of up to
20 seconds during sleep are considered to be normal in a healthy
infant.22 As the lungs in an infant are noncompliant and the
chest wall elastic, mild intercostal restractions may be a normal
occurrence and not necessarily indicative of intrathoracic or
pulmonary parenchymal disease. However, this finding must be
considered pathologic in the context of other signs of respiratory
distress such as tachypnea, cyanosis, stridor, wheezing, grunting,
nasal flaring, or retractions.18 Additionally, neonates and infants
are more dependent on the diaphragm for normal ventilatory
function. As such, they may normally display paradoxical or
abdominal breathing where the abdomen moves out while the
chest wall moves in and vice versa.
The larynx in neonates and young infants differs from older
children, adolescents and adults not only in size, but also in
relative dimensions and location.23 An infants glottis is relatively
small compared with an adult glottis, whereas the epiglottis is
proportionately larger. This relative difference in size and the
position of the larynx high in the neck are crucial in allowing
infants to simultaneously suck, swallow, and breath. Therefore,
most newborn infants are obligate nasal breathers. Significant
nasal obstruction presenting at birth such as bilateral choanal
atresia may be a life-threatening situation. The descent of the
larynx to a lower position in the neck begins around 2 years of
age. This change in position results in a confluence of the digestive
and the respiratory tract. Although the ability of breathing and
suckling simultaneously is lost, this change is necessary to elongate
the vocal tract, which in turn is crucial for the development of
complex speech and articulation.23

Cardiovascular System
The development of the cardiovascular system is essentially
complete by 8 weeks of gestation, the most critical period being
day 20 to 50.24 During fetal life, the placenta is providing the
function that the lungs provide after birth. This includes removal

of carbon dioxide and almost full oxygenation of blood, which


then returns to the fetus via the umbilical vein.25 There are three
shunts bypassing organs, which during fetal life do not have a
major function. First is the ductus venosus, serving as a connection
from the umbilical vein to the inferior vena cava, permitting half
of the umbilical venous (oxygenated) blood to bypass the hepatic
microcirculation. Second is the foramen ovale, a direct connection
between the right and the left atrium, allowing blood of the highest
possible O2 concentration (from the umbilical vein into the right
atrium to the left atrium) to perfuse the cerebral circulation.
Finally, the ductus arteriosus, which directs blood from the
right ventricle to the descending aorta, thereby bypassing
the pulmonary circulation. Only approximately 10% of the blood
flowing through the right ventricle circulates through the lungs,
which in utero do not participate in gas exchange. As the rightsided pressures are higher than left-sided pressures in the fetus
due to the high pulmonary vascular resistance, the right ventricle
is more muscular than the left ventricle.
At birth, the fetal circulation begins to transition to the
postnatal circulation. The critical event during this transition is
the establishment of lung inflation. With the first breath, the lungs
become aerated. The contact with air containing oxygen results
in vasodilatation of the pulmonary resistance vessels, which is
accompanied by a tremendous increase of the pulmonary blood
flow as pulmonary vascular resistance acutely falls. Left atrial
pressure becomes immediately higher than right atrial pressure,
causing the foramen ovale to functionally close. Increased
arterial oxygen tension causes constriction and closure of the
ductus arteriosus. The ductus venosus and the umbilical vessels,
which are no longer needed, also constrict and obliterate. These
changes occur gradually over the first few days of life. Therefore,
establishing vascular access through umbilical veins and arteries
for the administration of fluids and medications, or monitoring
in severely sick neonates is only possible for a short period of time
after birth.
The higher affinity of fetal hemoglobin (HbF) for oxygen is
crucial in utero, allowing O2 to be extracted from the maternal
blood. Placental oxygen transfer occurs at a much lower oxygen
tension than does alveolar oxygen transfer after birth. However,
ex utero, this higher affinity is a disadvantage, as it impairs oxygen
delivery at the tissue level. Resting cardiac output in the neonate
is high compared with that of the older child and adult.26 This
allows the infant to meet oxygen demands in the periphery, but as
a result, the ability of the newborn to further increase cardiac
output in conditions of stress is limited.
Accurate blood pressure measurement in children depends
on the selection of an appropriate sized cuff. As is the case with
adults, it is now generally agreed that diastolic blood pressure
corresponds with the disappearance of Korotkoff sounds, also
referred to as the fifth Korotkoff sound.27 In some children,
Korotkoff sounds may be heard down to 0 mmHg. Normal blood
pressure in newborns correlates with gestational age and
birthweight.28 Blood pressure curves for infants are provided in
Figures 212 and 213. Tables 24 and 25 summarize blood
pressure levels for boys and girls from 1 to 17 years of age. Table
26 shows the normal range of heart rate in relationship to the age
of the infant or child.
Electrocardiographic (ECG) findings in neonates and children
are different from that of adults.29 Because of the right-sided
predominance of the fetal heart, the neonatal ECG shows a
marked right axis deviation (30 to 180 degrees) compared

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Figure 2-12. Percentiles for blood


pressure in boys.
Adapted from reference 33.
with that of adults (30 to 105 degrees). The electrocardiogram
also shows tall R waves in the right-sided leads and deep S waves
in the left-sided leads. There is a gradual shift toward the normal
left axis orientation over the course of childhood. This occurs most
rapidly in the first month of life. QRS duration is shorter in
children, ranging from an average of 50 ms in neonates to 80 ms
in adults. The PR interval is shorter, increasing from about 90
100 ms (upper limits of normal is 120 ms) in neonates to 150170
ms (upper limit of normal is 210 ms) in adults. T waves may be
inverted further toward the left in the precordial leads in children
than in adults.
Innocent (or functional) heart murmurs are common in
childhood and may be heard in 80% of children at some point in
life.29 They emanate from cardiovascular structures in the absence
of anatomic abnormalities and are accentuated or brought out in
a high-output state such as fever or feeding. Innocent heart
murmurs can be difficult to diagnose and have to be differentiated
from pathologic heart murmurs. If 1 or more of the following
criteria are present, cardiology consultation is suggested:
1) Symptoms or physical signs of heart failure on examination
(e.g., cyanosis, dyspnea, abnormal strong or weak pulses,
hepatomegaly)

2) Abnormal cardiac size or silhouette or abnormal pulmonary


vascularity on chest x-ray
3) Abnormal ECG
4) Diastolic murmur
5) A systolic murmur that is loud (more than 3/6 or with a thrill),
long in duration and transmits well to other parts of the body
6) Abnormal heart sounds
Innocent systolic murmurs include the vibratory Stills
murmur, the basal systolic ejection murmur, cardiorespiratory
murmur, and the murmur of physiologic peripheral pulmonary
stenosis. The venous hum is a continuous murmur heard
throughout the cardiac cycle. Other innocent heart sounds that
may be present in childhood include the carotid bruit and third
heart sound (S3).

Gastrointestinal System
At birth the gastrointestinal system is almost fully capable of
taking over its functions which include digestion, absorption,
and secretion, as well as endocrine and immunologic activities.
Meconium, the first bowel movement after birth, is of greenishblack color and with a sticky consistency. It is normally discharged

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Figure 2-13. Percentiles for blood


pressure in girls.
Adapted from reference 33.
TABLE 2-4. Blood Pressure Levels for Boys Aged
1 to 17 Years
Age, Years
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17

Systolic Blood Pressure, Diastolic Blood Pressure,


mm Hg (2 SD)
mmHg (2 SD)
98 (94102)
102 (98106)
105 (100109)
107 (102111)
108 (104112)
110 (105114)
111 (106115)
112 (107116)
113 (109117)
115 (110119)
117 (112121)
119 (115123)
122 (117126)
125 (120128)
127 (123131)
130 (125134)
133 (128136)

Adapted from reference 33.

53 (5055)
57 (5559)
61 ( 5963)
64 (6266)
67 (6569)
70 (6772)
72 (6974)
73 (7175)
74 (7277)
75 (7378)
76 (7478)
77 (7579)
77 (7580)
78 (7680)
79 (7781)
81 (7983)
87 (8589)

TABLE 2-5. Blood Pressure Levels for Girls Aged


1 to 17 Years
Age
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17

Systolic Blood Pressure, Diastolic Blood Pressure,


mmHg (2 SD)
mmHg (2 SD)
100 (97104)
102 (99105)
103 (100106)
104 (101108)
106 (103109)
107 (104111)
109 (106112)
111 (108114)
113 (110116)
115 (112118)
117 (114120)
119 (116122)
121 (118124)
122 (119126)
124 (121127)
125 (122128)
125 (122128)

Adapted from reference 33.

54 (5356)
58 (5761)
62 (6164)
65 (6367)
67 (6569)
69 (6771)
70 (6972)
71 (7074)
73 (7175)
74 (7376)
75 (7477)
76 (7578)
78 (7680)
79 (7781)
79 (7882)
80 (7982)
80 (7982)

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TABLE 2-6. Mean Heart Rate, by Age


Age
Premature
03 months
36 months
612 months
13 years
36 years
612 years
Adult

Heart Rate, beats/min


120170*
100150*
90120
80120
70110
65110
6095
5585

Adapted from reference 23.


*In sleep, infant heart rates may drop significantly lower, but if perfusion is
maintained, no intervention is required

within the first 24 to 48 hours of life. Overall, the gastrointestinal


transit time in the infant is shorter than that of an adult and
increases with increasing age. The normal physiologic range of
stool frequency varies greatly (from 10 times a day to 12 times a
week30). Breast-fed infants usually have stools more often than
do their formula-fed counterparts. The frequency of bowel
movements gradually declines over the first years of life, reaching
adult habits at about 4 years of age. The abdomen of the infant and
younger child is protuberant because of the relatively large volume
of the abdominal viscera. In infants the edge of the liver is
normally felt 12 cm below the right costal margin.31 The spleen
should be no more than 1 cm below the rib margin. In young
infants, an umbilical hernia is common, usually of no clinical
concern, and generally closes spontaneously as the muscles
develop toward the end of the first year.
In neonates and younger infants, the lower esophageal sphincter
tone is physiologically decreased and may lead to gastroesophageal
reflux. Other predisposing factors include a short esophagus,
large meals in relation to gastric capacity, frequent feeding
regimen, supine position, and Valsalva maneuvers during bowel
movements.32 Daily vomiting or spitting up may be seen in one
half of all infants between 0 and 3 months of age and up to two
thirds of 4- to 6-month-old infants.33 Most of these infants suffer
no ill effect (happy spitter) and grow well.31 This condition
usually begins in the first weeks of life and resolves spontaneously
by 9 to 24 months of age as solid food has been introduced and the
child becomes more upright. Only between 1:300 and 1:1000
infants have reflux significant enough to cause complications.34
Neonatal jaundice (physiologic hyperbilirubinemia) is a
common condition, which generally begins during the second
24 hours of life, has its peak around the third day of life, and
resolves itself by the end of the first week.35 It is caused by a high
rate of bilirubin production due to the shorter lifespan of the
newborns red blood cells and by a limited ability to effectively
eliminate bilirubin due to immaturity of the hepatic microsomal
enzyme systems. Typical physiologic newborn jaundice is an
unconjugated, or indirect-reacting hyperbilirubinemia. Preterm
and breast-fed newborn babies may show a protracted form of
this condition. Although it is generally a benign, self-limiting
condition, its course should be monitored to prevent missing an
indication for treatment (e.g., phototherapy). It should also be
differentiated from pathologic causes of jaundice such as those
related to blood type incompatibility or hepatic problems such as
biliary atresia.

Colic, an episodic pattern of seemingly inconsolable crying that


tends to occur in the evenings, may be seen in babies less than
3 months of age. The cause of this phenomenon is not completely
understood. Although it resolves spontaneously around the end
of the third month of life, it must be differentiated from organic
causes. It may represent a source of considerable concern and
frustration for parents and caregivers.
Although tooth formation begins in utero during the 4th
month of gestation, the first primary (deciduous) tooth does not
erupt until approximately 6 to 7 months of age.36 Deciduous
dentition (with 20 teeth) is complete between the age of 2 and
3 years. The permanent teeth begin to erupt around the age of
6 years, starting after the loss of the primary central incisors. The
last primary tooth is shed around the age of 12 to 14 years. The
anesthesiologist must be aware of the possibility of loose teeth at
any age during childhood when managing the airway. The set of
permanent teeth (32 teeth) may not be complete until the third
decade of life. The timing of appearance of the dentition is shown
in Table 27.

Renal System
Urine production begins at approximately 12 weeks of gestation
and continues throughout fetal life.1 The urine is excreted into the
amniotic cavity and forms the major part of the amniotic fluid.
However, because the elimination of fetal metabolic waste is a
function of the placenta, there is no need for the kidneys to work

TABLE 2-7. Chronology of Human Dentition


Average Age
of Eruption

Tooth
Deciduous Dentition
Maxillary

Mandibular

Permanent Dentition
Maxillary

Mandibular

Adapted from reference 41.

Central Incisor
Lateral Incisor
Cuspid
First Molar
Second Molar
Central Incisor
Lateral Incisor
Cuspid
First Molar
Second Molar

7.5 months
9 months
18 months
14 months
24 months
6 months
7 months
16 months
12 months
20 months

Central Incisor
Lateral Incisor
Cuspid
First Bicuspid
Second Bicuspid
Second Molar
Third Molar
Central Incisor
Lateral Incisor
Cuspid
First Bicuspid
Second Bicuspid
Second Molar
Third Molar

78 years
89 years
1112 years
1011 years
1012 years
1213 years
1721 years
67 years
78 years
910 years
1012 years
1112 years
1113 years
1721 years

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General Growth and Tissue Development Throughout Childhood 37

before birth. The fetal kidneys receive only 2% of the cardiac


output, compared with 20% for the mature kidney.37 One of the
major functions of the kidney is to maintain extracellular
homeostasis. Although the adult kidneys maintain precise balance
matching fluid and electrolyte excretion to intake, in growing
children this balance must be positive for a number of solutes to
make growth possible. This conveys a great challenge for the
kidneys during this period of life. Although the kidneys are
morphologically fully developed at 34 weeks of gestation, the
functional development is far from complete at birth. Postnatal
functional changes occur in renal blood flow, glomerular filtration
rate (GFR), and tubular function. The glomerular filtration rate is
low in newborn, increases dramatically during the first month of
life, and reaches adult values, corrected to body surface area, by
the age of 2 years. At birth, the serum creatinine concentration
reflects the maternal level and declines during the first days of life.
Since the serum creatinine at birth is a result of the placental
creatinine transfer, it does not reflect the neonatal renal function. Over the course of early childhood, creatinine clearance
increases, reaching adult values between 2 and 3 years. Due to the
rapid growth and increase in muscular mass, normal serum
creatinine values increase with age and are higher in men. In the
newborn the ability to concentrate urine is limited compared
with adults. A maximum urine concentration of 600 mOsm/kg
can be achieved in newborns versus 1200 mOsm/kg in adult
counterparts. In young children, the relative inability to handle
high solute loads is offset by the low solute content of breast milk
and infant formula.

Hematological System
The first blood cells produced by the embryo belong to the red
cell line, followed by granulocytes, platelets and lymphocytes.38
The anatomic site of hematogenesis undergoes developmental
changes during fetal life. At about 3 to 5 months of gestation, the
liver is the chief organ of hematopoiesis and continues to produce
red cells into the first postnatal week. During the last 3 months
of gestation, the bone marrow becomes the chief site of blood
cell formation. The term neonate has a higher hemoglobin

and hematocrit compared to the older child. At birth the infants


hemoglobin is primarily HbF, which has a higher affinity for
oxygen than the adult type (HbA). The initially high hematocrit
drops dramatically during the first days of life, due to decreased
production of hemoglobin and red blood cells combined with the
shorter lifespan of fetal erythrocytes.39 The more immature the
neonate, the shorter is the lifespan of red cells. This and a lower
total body iron store result in a more exaggerated neonatal
anemia in preterm infants compared to their term counterparts.
The nadir of the hemoglobin level is reached at approximately 8 to
12 weeks of age in term infants and 4 to 8 weeks in premature
infants. This physiologic drop of hemoglobin concentration
stimulates erythropoiesis. Hemoglobin produced postnatal is of
the adult type, which has largely replaced HbF by approximately
4 months of age. Besides blood loss, there are two major types of
anemia including the hypo- or aregenerative anemia, where the
production of red blood cells is decreased and hemolytic anemia
with an increased destruction of red blood cells. Table 28 shows
the normal hematologic values during childhood.
The white blood cell count is highest in the first days of life and
drops steadily throughout childhood to finally reach adult values
during adolescence. Leucocytosis is a sign of a possible infectious
process. The younger the child, the more limited is the ability
to react with leucocytosis to an infectious agent. In neonates,
leukopenia is generally more indicative of an infectious process.
This age group is also more likely to develop hypothermia rather
than a fever as a reaction to an infection. Table 29 illustrates
normal leukocytosis counts at different ages. The production of
platelets is regulated by thrombopoietin, which maintains a
normal blood platelet count of 150400  109/L with no age
related differences. Table 210 lists normal platelet counts and
Table 211 gives normal values for selected coagulation tests.
After the initial adjustment during the first hours of life, blood
volume maintains a relatively constant relationship to body weight
throughout most of the life. The average blood volume in term
newborns is 85 mL/kg and 90 mL/kg in preterm newborns. It
increases to an average of 105 mL/kg during the first days of life
and then decreases again over the course of the next few months.
At approximately 6 months of age, the average blood volume is

TABLE 2-8. Normal Hematologic Values in Children


Age
Birth (cord blood)
13 days (capillary)
1 week
2 weeks
1 month
2 months
36 months
0.52 years
26 years
612 years
1218 years:
Female
Male
1849 years:
Female
Male
Adapted from reference 45.

Red Cell Count, 1012/L (2 SD)

Hemoglobin, g/dL (2 SD)

Hematocrit, % (2 SD)

16.5 (13.519.5)
18.5 (14.522.5)
17.5 (13.521.5)
16.5 (12.520.5)
14.0 (10.018.0)
11.5 (9.014.0)
11.5 (9.513.5)
12.0 (10.513.5)
12.5 (11.513.5)
13.5 (11.515.5)

51 (4260)
56 (4567)
54 (4266)
51 (3963)
43 (3155)
35 ( 2842)
35 (2941)
36 (3339)
37 (3440)
40 (3545)

4.7 (3.95.5)
5.3 (4.06.6)
5.1 (3.96.3)
4.9 (3.66.2)
4.2 (3.05.4)
3.8 (2.74.9)
3.8 (3.14.5)
4.5 (3.75.3)
4.6 (3.95.3)
4.6 (4.05.2)

14.0 (12.016.0)
14.5 (13.016.5)

41 (3646)
43 (3749)

4.6 (4.15.1)
4.9 (4.55.3)

14.0 (12.016.0)
15.5 (13.517.5)

41 (3646)
47 (4153)

4.6 (4.05.2)
5.2 (4.55.9)

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TABLE 2-9. Reference Ranges for Leukocyte Counts in Children


Age

Leukocytes, 103/mm3 (2 SD)

Neutrophils, 103/mm3 (2 SD) [%*:

18.1 (9.030.0)
22.8 (13.038.0)
18.9 (9.434.0)
12.2 (5.021.0)
11.4 (5.0(20.0)
10.8 (5.019.5)
11.9 (6.017.5)
11.4 (6.017.5)
10.6 (6.017.0)
9.1 (5.515.5)
8.5 (5.014.5)
8.3 (4.513.5)
8.1 (4.513.5)
7.8 (4.513.0)
7.4 (4.511.0)

11.0 (6.026.0) [61:


15.5 (6.028.0) [68:
11.5 (5.021.0) [61:
5.5 (1.510.0) [45:
4.5 (1.09.5) [40:
3.8 (1.09.0) [35:
3.8 (1.08.5) [32:
3.5 (1.58.5) [31:
3.5 (1.58.5) [33:
3.8 (1.58.5) [42:
4.3 (1.58.0) [51:
4.4 (1.58.0) [53:
4.4 (1.88.0) [54:
4.4 (1.88.0) [57:
4.4 (1.87.7) [59:

Birth
12 hours
24 hours
1 week
2 weeks
1 month
6 months
1 year
2 years
4 years
6 years
8 years
10 years
16 years
21 years

Lymphocytes, 103/mm3 (2 SD) [%*:


5.5 (2.011.0) [31:
5.5 (2.011.0) [24:
5.8 (2.011.5) [31:
5.0 (2.017.0) [41:
5.5 (2.017.0) [48:
6.0 (2.516.5) [56:
7.3 (4.013.5) [61:
7.0 (4.010.5) [61:
6.3 (3.09.5) [59:
4.5 (2.08.0) [50:
3.5 (1.57.0) [42:
3.3 (1.56.8) [39:
3.1 (1.56.5) [38:
2.8 (1.25.2) [35:
2.5 (1.04.8) [34:

Adapted from reference 46.


*Percentages are proportion of leukocytes.

TABLE 2-10. Circulating Platelet Counts in Children


Platelet Count, 109/L

Age

288 53
303 48
338 59
343 72
365 49
314 78
304 66
303 65
295 58
251 40
234 48

Cord blood
2 days
5 days
1 month
211 months
12 years
34 years
56 years
710 years
1115 years
Adult
Adapted from reference 47.

approximately 7577 mL/kg, similar to that of older children and


adults.40

Pharmacology and Therapeutics


Maturational changes in body size and composition, as well
as changes in metabolic, gastrointestinal, hepatic, and renal
function may affect the way pharmacologic agents perform in
infants and general and therefore how they should be prescribed
and administered. In different age groups, divergences may be

seen in absorption, distribution, and clearance of xenobiotics.


These factors should be kept in mind when calculating and
adjusting drug dosages in children, particularly in infants. As a
general rule, on a per kilogram body weight basis, drug doses are
lower in younger infants and higher in children (preadolescents)
than in adults.

Neurological System
Although the nervous system is anatomicly complete at birth,
functionally it remains immature with the continuation of
myelination and synaptogenesis.41 At birth, the cranial sutures are
still open and are easily palpable. There may be some overlapping
of skull bones for the first few days of life, caused by compression
of the head in the birth canal. This should be differentiated from
craniosynostosis (premature closure of 1 or more sutures). The
anterior fontanel is diamond shaped, less than 3.5 cm in diameter
at birth, soft and easily palpable. Its size gradually decreases
following birth, but is still palpable during the first year of life. It
closes at anywhere from 12 to 18 months of age. A bulging or tense
anterior fontanel with or without separation of the sutures may be
an indication of increased intracranial pressure. A sunken fontanel
may be a sign of severe hypovolemia from any of many causes
including dehydration. The posterior fontanel is triangular and
much smaller in size (fingertip). It may be difficult to palpate at
birth and is usually closed by 6 weeks of age. The sutures need to
stay open to allow the brain to grow. (The growth of the head

TABLE 2-11. Reference Values for Selected Coagulation Tests in Children


Age

PT, sec (2 SD)

INR(2 SD)

APTT,
sec (2 SD)

Fibrinogen,
g/L (2 SD)

Bleeding Time,
min (2 SD)

15 years
610 years
1116 years
Adult

11 (10.611.4)
11.1 (10.112.1)
11.2 (10.212.0)
12 (11.014.0)

1.0 (0.961.04)
1.01 (0.91 1.11)
1.02 (0.931.10)
1.10 (1.01.3)

30 (2436)
31 (2636)
32 (2637)
33 (2740)

2.76 (1.704.05)
2.79 (1.574.0)
3.0 (1.544.48)
2.78 (1.564.0)

6 (2.510)
7 (2.513)
5 (38)
4 (17)

PT  prothrombin time; INR  international normalized ratio; APPT  activated partial thromboplastin time. Adapted from reference 48.

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General Growth and Tissue Development Throughout Childhood 39

circumference is presented in Figure 26 for boys and Figure 27


for girls.) Further maturation of the nervous system (myelination
and synaptogenesis) continues rapidly during the first 2 years of
life and is accompanied by rapid development of motor and
behavioral skills. These advances occur in a rostrocaudal pattern.
Myelination is complete by 7 years of age.
Primitive reflexes such as the grasp, rooting, sucking, Moro,
and asymmetric tonic neck reflex are present in the neonate infant
and fade during the latter part of the first year of life in the course
of normal development. Tendon reflexes (biceps, patellar, ankle
jerks) are present at birth. They may be exaggerated with a
tendency to clonus in newborn infants; however, they should be
symmetric. Absent or asymmetric tendon reflexes may be an
indication of a significant central or peripheral nervous system
abnormality. In the newborn, flexor tone predominates, giving the
infant the typical flexed posture.

DEVELOPMENTAL PEDIATRICS
So far this chapter has listed the chronology of anatomic and
physiologic changes that occur in childhood. Of equal importance
are the developmental and behavioral changes featured during
growth of the human organism. The developmental stage of a
child has a remarkable influence on the general approach to
the patient, as well as specific issues related to assessment and
treatment. For example, knowledge of a childs level of cognitive
maturity helps to determine which pain rating scale is most
appropriate. Patient safety may also depend on knowledge of
child development. For instance, adequately high bed rails are
needed for children who might pull themselves to the standing
position. Child development involves several areas including
motor (fine and gross motor), communication, and socialization
skills. Some of the major developmental milestones during
childhood are illustrated in Table 212. It should be kept in mind
that these are only guidelines since children show considerable
variation in timing and succession of stages during normal
development. Chronic illness or frequent hospitalizations as well
as environmental factors, such as psychosocial issues, may delay
achievements of developmental milestones.
Newborn infants do not have predictable sleep schedules. Naps
are interspersed with feedings and periods of crying and quiet
wakefulness. Over time, naps coalesce and episodes of wakefulness
become longer. In general, by 18 months of age, children are only
taking one daytime nap and by 4 years of age children no longer
sleep during the day. Toilet training is a learned behavior whose
timing of onset is extremely variable. The ability to achieve
continence develops by about 20 months of age, so attempting toilet
training before this time is often fruitless. Most children are fully
toilet trained between the ages of 2 and 3 years. Daytime control is
generally achieved before nighttime control, so even children who
are continent during the day may require diapers at night. Primary
nocturnal enuresis, or bedwetting of unknown etiology, may occur
in 15% to 20% of children 5 years of age or more. Thereafter, the
incidence decreases by about 15% of the initial rate per year and
becomes stable at 1% by 15 years of age.42 It is believed to be related
to physiologic immaturity. A positive family history following
mainly the male lineage can often be observed. Primary nocturnal
enuresis may be a source of considerable anxiety for some children,
particularly when they must sleep in an environment other than
their own home, such as in a hospital.

TABLE 2-12. Developmental Milestones


Age
Gross Motor
Rolls from prone to supine
Sits without support
Rolls from supine to prone
Gets to sitting
Pulls self to stand
Stands without support
Walks well
Up and down stairs without support
Runs

45 months
7 months
56 months
8 months
9 months
12 months
15 months
2 years
2 years

Fine Motor
Brings hands together
Grasps object
Reaches for object
Transfers object from one hand to the other
Pincer (thumb-forefinger) grasp
Turns page
Scribbles
Tower of 2 cubes

3 months
3.5 months
4 months
6 months
8 months
12 months
13 months
14 months

Communication and Language


Cooing
Monosyllabic babbling
Imitates sounds made by others
Polysyllabic babbling
Follows 1-step commands
First words other than mama or dada
10-word vocabulary
2-word sentences
Complete sentences
Almost completely intelligible to strangers

24 months
58 months
912 months
912 months
1015 months
12 months
1518 months
1824 months
23 years
35 years

Social skills
Social smile
Separation anxiety / stranger awareness
Interactive games: e.g., peek-a-boo
Feeds self with cup and spoon
Recognizes self in mirror
Dresses self (except for buttons, etc.)
Parallel play
Cooperative play
Able to distinguish fantasy from reality

12 months
612 months
912 months
1518 months
2 years
3 years
12 years
34 years
5 years

Adapted from reference 50.

Although the cognitive development during childhood is a


continuous process, it has been divided into a number of discrete
stages described by Freud, Erikson, Piaget and others. Table 213
offers an overview of the major schools of developmental theories,
including those proposed by Freud, Erikson, and Piaget. Piaget
believed that children perceive the world differently than adults
and that their perception is different in each stage. This thesis can
aid in the understanding the actions and reactions seen in different
age groups. Piaget postulated that children learn through active
interaction with the environment not only through their success,
but also by analyzing their mistakes.43 During the first stage of
Piagets theory of cognitive development (Sensorimotor stage: 0 to

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Developmental Considerations

TABLE 2-13. Theories of Developmental Psychology


Age

Freud

Erikson

Piaget

Acquired Skills

Birth18 months

Oral phase

Basic trust vs.


mistrust

Sensorimotor

18 months3 years

Anal phase

Symbolic
preoperational

36 years

Oedipal phase

Autonomy vs.
shame,
doubt
Initiative vs.
guilt

612 years

Latency

1217 years

Adolescence

Industry vs.
inferiority
Identity vs. role
confusion

Concrete
operational
Formal
operational

Basic trust as feature for later bonding capacity;


Object permanence; Differentiation between
self and world
Verbal communication more sophisticated;
Predominant egocentricity; Control over body
function
Rich imagination and creativity; Symbolic
functioning; Confrontation with societys moral
values
Higher level of social skills in peer interaction;
Development of reasoning
Moving out of family core to gain autonomy and
independence; Abstract reasoning and thinking

Intuitive
preoperational

Adapted from reference 52.

2 years of age), a childs view of the world is shaped by physical


interaction with the environment. Infants may use their mouths
for this purpose and their safety needs to be considered at all
times. It is the stage of establishment of basic trust between the
child and the primary caregiver, which eventually will be a basic
feature for the capacity of bonding and building relationships later
in life. At around 9 months of age, a phenomenon known as
stranger anxiety may be seen when babies are confronted with
unfamiliar individuals. As the preoperative stage approaches, the
concept of object permanence is achieved whereby a child learns
that an object exists even though it is no longer present or visible.
In the preoperative stage (2 to 6 years of age), thought is dominated
by egocentricity and symbolism. Fantasy play is common.
Although toddlers have some appreciation of cause and effect,
they exhibit magical thinking. They may believe that a bad deed
or thought has caused illness in themselves or in others.
This stage also sees the development and subsequent disappearance of temper tantrums, episodes of loss of control over the
environment that leads to loss of internal control. These may be
aggravated if the child is tired or in physical discomfort. As the
third stage approaches the child starts to identify with his parents
and their societys values and to develop an inner voice of selfobservation and self-guidance, the conscience as the cornerstone
of morality. In the third stage of concrete operations (6 to 11 years
of age), children develop the ability to consider different points of
view and to elaborate explanations based on observations.
However, thinking still tends to be dogmatic. The child can
understand causality beyond himself and his own perception.
They move out of egocentricity enough to understand that others
may have ideas, feelings and desires different from their own.
Through social interactions with peers, the child develops ways
to maintain self-esteem while developing increased ability to
tolerate frustration. In the final stage of formal operations (11 years
to adulthood), the ability to think about the world in abstract
terms evolves. Older children can weigh options and consider the
consequences of different courses of action. Adolescents display
an increasing need for autonomy and independence. If not met,
their need to participate in their own medical decision making
may lead to problems in patient compliance. Typical in this
age group are feelings of grandiosity and invulnerability, which

often leads to behaviors with unreasonable risk taking. A childs


understanding for the concept of illness and medical treatment is
influenced by sociocultural and religious factors, as well as by his
cognitive developmental stage. Table 214 illustrates the agerelated development of spirituality and concept of illness and death
and accordingly the adjustment of interventions.44

APPROACH TO HISTORY AND


PHYSICAL EXAMINATION
The approach to history taking in pediatrics varies according to
the age of the child. It is important for the consultant to be aware
of which historical features are of greatest interest in each age
group to avoid missing vital information and to streamline the
information-gathering process. In neonates, the history will of
course be heavily weighted toward pregnancy and delivery. During
infancy, attainment of developmental milestones provides valuable
information on the health status of the infant. As the child ages, his
own past medical history assumes greater and greater importance.
Issues such as medication, allergies, past surgical procedures, and
chronic conditions must be considered. Obviously, in the very
young child, the history will be obtained entirely from a parent or
caregiver. The older child will be able to provide information and
should be allowed to become involved in the process. They should
be given an opportunity to ask questions and raise concerns.
Preadolescents and adolescents may feel uncomfortable discussing
certain issues in front of their parents and therefore should
also be interviewed on their own to make sure a full history is
obtained (e.g., drug abuse, sexual activity, potential for pregnancy,
piercings). Confidentiality must be respected in these situations.
Children, particularly toddlers, are less able to localize symptoms
than are adults. Consequently, a wide range of complaints
including pharyngitis and pneumonia may present as nonspecific
abdominal pain or discomfort. Care must be taken not to miss the
true diagnosis in such cases. Toddlers are also suggestible and may
nod agreeably when asked about specific symptoms. It is usually
preferable to use open-ended questions such as Where does it
hurt? as opposed to leading questions such as Does it hurt
there? Whereas organization of the physical examination by

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TABLE 114 Spirituality and concepts of illness and death in children, and conclusions for interventions. Adapted from53
Age

Characteristics

Spiritual Development

Concept of Illness and Death

Interventions

0 2 years

Sensory and motor


relationship with
environment, Limited
language skills, Object
permanence,
Magical and animistic
thinking, egocentricity,
Thinking is irreversible,
Engages in symbolic
play

Faith reflects trust and


hope in others, Need for
sense of self-worth, love
and containment

None

Faith is magical and


imaginative,
Participation in rituals,
Need for courage

Concrete thinking,
Reasoning about
Causality

Faith concerns right and


wrong, Accepts external
interpretations as truth,

Believes illness and death


can be caused by thoughts
and actions, Death is
temporary and reversible
like sleep, Not
personalizing death
Interested in physiology and
details of illness,
Personalizes illness and
death,
Explores nonphysical
explanations for illness
and death

Provide maximal physical


comfort, familiar
persons and transitional
objects, consistency,
Use simple language
Correct perceptions of
illness as punishment,
Evaluate for sense of
guilt, Use precise
language

2 6 years

6 12 years

12 18 years Generality of thinking,


Reality becomes
objective, Body-image
and self-esteem
paramount, Sense of
invulnerability and
omnipotence

Accepts inner
interpretations as truth,
Searches for meaning,
purpose, and value of
life, Evolution of
relationship with Higher
power

system or by anatomy (head to toe examination) may be


appropriate in adults and older children, some adaptations are
required in infants and toddlers. An opportunistic approach is
usually the most effective strategy in these groups. For example, if
an infant is quiet, it usually makes sense to begin by auscultating
the chest and examining the abdomen and to leave other aspects
such as examination of the extremities until later. Distraction,
either by the parent or by the examiner, is often quite useful.
The value of observation in providing important data should not
be underestimated. The laying on of hands should be the last
part of any assessment. Whenever possible, children should be
examined in the presence of a parent or caregiver. Infants and
toddlers can often be examined in a parents lap. Finally, infants
should not be left exposed any longer than is absolutely necessary to prevent hypothermia. During the neonatal period, an
overhead warmer may be indicated. In older children, especially
adolescents, modesty becomes an important consideration and
should be respected. For the physical examination of adolescents
in the absence of a parent, a nurse as a third person should be
present. Children of all ages should have height, weight, and head
circumference measured, recorded, and plotted on standard
growth curves. These data may provide clues to an underlying
disease and they are needed for appropriate selection of equipment
and calculation of drug doses.

CONCLUSION
The challenges of childhood growth involve anatomic,
physiologic, and cognitive-behavioral developmental changes.
These changes may have a profound influence on a wide variety
of aspects of anesthetic and perioperative care including choice
of medications and equipment, pre- and postoperative evalu-

Provide concrete info, Be


truthful, Allow child to
participate in decision
making
Allow child privacy,
Promote childs
independence, Be
truthful, Allow child to
participate in decision
making

ation, intraoperative care, postoperative management, and patient


safety. A synopsis has been provided to assist the pediatric
anesthesiologist in providing exemplary care to all infants and
children. With a sound knowledge of general growth and
development, supplemented as appropriate with consultation from
other pediatric specialists, this goal is eminently achievable.

REFERENCES
1. Moore K, Persaud T. The Developing Human: Clinically Oriented
Embryology, Philadelphia: Saunders 2003.
2. Shepard TH, Brent RL, Friedman JM, et al. Update on new developments
in the study of human teratogens. Teratology, 2002;65:15361.
3. Feigelman S. Overview and Assessmentt of Variability. In Nelson Textbook
of Pediatrics ed. Kliegman R, Behrman R, Jenson H, et al. Philadelphia:
Saunders, 2007, 3341.
4. Bechard L, Puig M. Body Composition and Growth. In Nutrition in
pediatrics: Basic science and clinical applications, ed. Walker W, Watkins J,
Duggan C . Hamilton, BC: Decker Inc, 2003, 3251.
5. Martin R, Fanaroff A, Walsh M. Neonatal - postnatal medicine: Diseases
of the fetus and infant, Philadelphia: Mosby, 2006.
6. Pesce M. Reference Ranges for Laboratory Tests and Procedures. In
Nelson Textbook of Pediatrics, ed. Kliegman R, Behrman R, Jenson H, et
al. Philadelphia: Saunders 2007, 293954.
7. Delemarre-van de Waal HA. Regulation of puberty. Best Pract Res Clin
Endocrinol Metab, 2002;16:112.
8. Marcell A. Adolescence. In Nelson Textbook of Pediatrics, ed. Kliegman
R, Behrman R, Jenson H, et al. Philadelphia: Saunders, 2007, 6065.
9. Tanner J. Growth at adolescence. Oxford: Blackwell Scientific, 1962.
10. Nottelmann ED, Susman EJ, Dorn LD, et al. Developmental processes in
early adolescence. Relations among chronologic age, pubertal stage,
height, weight, and serum levels of gonadotropins, sex steroids, and
adrenal androgens. J Adolesc Health Care, 1987;8:24660.
11. Heird W. Nutrition. In Nelson Textbook of Pediatrics, ed. Kliegman R,
Behrman R, Jenson H, et al. Philadelphia: Saunders, 2007, 20914.
12. Kramer M, Kokuma R. The optimal duration of exclusive breastfeeding:
A systematic review. World Health Organization, 2001,

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13. Gidding SS, Dennison BA, Birch LL, et al. Dietary recommendations for
children and adolescents: A guide for practitioners. Pediatrics,
2006;117:54459.
14. Kleinman R. Pediatric Nutrition Handbook. American Academy of
Pediatrics, 2004.
15. Cannolly MV. Nutritional assesment. In Nutrition in pediatrics: Basic
science and clinical applications, Walker W, Watkins J, Duggan C.
Hamilton, BC: Decker Inc, 2003, 817.
16. Samour P, King K. Handbook of pediatric nutrition, Sudbury
(Massachusetts) Jones & Barlett Publishers, 2005.
17. Schwartz RM, Luby AM, Scanlon JW, et al. Effect of surfactant on
morbidity, mortality, and resource use in newborn infants weighing 500
to 1500 g. N Engl J Med, 1994;330:47680.
18. Sarnaik A, Heidemann S. Respiratory Pathology and Regulation. In
Nelson Textbook of Pediatrics, ed. Kliegman R, Behrman R, Jenson H,
et al. Philadelphia: Saunders, 2007, 171931.
19. Steele RW, Metz JR, Bass JW, et al. Pneumothorax and
pneumomediastinum in the newborn. Radiology, 1971; 98:62932.
20. Greenough A. Respiratory Disorders in the Newborn. In Kendigs
Disorders of the Respiratory Tract in Children, ed. V. Chernick, T. Boat, R.
Wilmott, et al. Philadelphia: Saunders, 2006, 31741.
21. Herzinger R. Apnea. In Oskis Pediatrics: Principles and Practice, ed.
McMillan J, Feigin R, De Angelis C, et al. Philadelphia: Lippincott
Wlliams & Wilkins, 2006, 31820.
22. Loughlin G, Carroll J. Apparent Life-Threatening Event. In Oskis
Pediatrics: Principles and Practice, ed. McMillan J, Feigin R, De Angelis C,
et al. Philadelphia: Lippincott Williams & Wilkins, 2006, 71422.
23. Smith R, Cable B. Laryngeal Disorders. In Oskis Pediatrics: Principles and
Practice, ed. McMillan J, Feigin R, De Angelis C, et al. Philadelphia:
Lippincott Williams & Wilkins, 2006, 141121.
24. Bezold L. Cardiovascular Embryology. In Oskis Pediatrics: Principles and
Practice, ed. McMillan J, Feigin R, De Angelis C, et al. Philadelphia:
Lippincott Williams & Wilkins, 2006, 32534.
25. Valente A, Fleishman C, Talner N. Cardiovascular Disease in the
Newborn. In Oskis Pediatrics: Principles and Practice, ed. McMillan J,
Feigin R, De Angelis C, et al. Philadelphia: Lippincott Williams & Wilkins,
2006, 33960.
26. Rudolph A. Fetal Circulation and Cardiovascular Adjustments after Birth.
In Rudolphs Pediatrics, ed. Rudolph C, Rudolph A, Hostetter M, et al. New
York: McGrawHill, 2002, 174953.
27. Update on the 1987 task force report on high blood pressure in children
and adolescents: A working group report from the national high blood
pressure education program. National high blood pressure education
program working group on hypertension control in children and
adolescents. Pediatrics, 1996;98:64958.
28. Zubrow AB, Hulman S, Kushner H, et al. Determinants of blood pressure
in infants admitted to neonatal intensive care units: A prospective

29.
30.
31.
32.

33.
34.
35.
36.
37.
38.
39.
40.

41.
42.
43.
44.

multicenter study. Philadelphia neonatal blood pressure study group.


J Perinatol, 1995;15:4709.
Park M. Pediatric Cardiology for Practioners. (St. Louis: Mosby Year Book,
2008).
Klish W. Functional Constipation and Encopresis. In Oskis Pediatrics:
Principles and practice, ed. McMillan J, Feigin R, De Angelis C, et al.
Philadelphia: Lippincott Williams & Wilkins, 2006, 192023.
Wilkinson A, Charlton V, Phibbs R, et al. Examination of the Newborn
Infant. In Rudolphs Pediatrics, ed. Rudolph C, Rudolph A, Hostetter M, et
al. New York: McGrawHill, 2002, 8391.
McEvoy C. Sucking and Swallowing Disorders and Gastroesophageal
Reflux. In Oskis Pediatrics: Principles and Practice, ed. McMillan J, Feigin
R, De Angelis C, et al. Philadelphia: Lippincott Williams & Wilkins, 2006,
38284.
Rudolph C. Disorders of Esophageal Motility. In Rudolphs Pediatrics, ed.
Rudolph C, Rudolph A, Hostetter M, et al. New York: McGrawHill, 2002,
138894.
Orenstein S, Peters J, Kahn S, et al. Gastroesophageal Reflux. In Nelson
Textbook of Pediatrics, ed. Kliegman R, Behrman R, Jenson H, et al.
Philadelphia: Saunders, 2007, 154749.
Stevenson D, Madan A. Jaundice in the Newborn. In Rudolphs Pediatrics,
ed. Rudolph C, Rudolph A, Hostetter M, et al. New York: McGrawHill,
2002, 16469.
Kula K, Josell S. Oral Problems. In Oskis Pediatrics: Principles and Practice,
ed. McMillan J, Feigin R, De Angelis C, et al. Philadelphia: Lippincott
Williams & Wilkins, 2006, 781800.
Baum M. Development of Renal Function. In Rudolphs Pediatrics, ed.
Rudolph C, Rudolph A, Hostetter M, et al. New York: McGrawHill, 2002,
163238.
Quinn C, Buchanan G. Hematopoiesis and Hematologic Disease. In Oskis
Pediatrics: Principles and Practice, ed. McMillan J, Feigin R, De Angelis C,
et al. Philadelphia: Lippincott Williams & Wilkins, 2006, 44050.
OBrien RT, Pearson HA. Physiologic anemia of the newborn infant.
J Pediatr, 1971;79:1328.
Dallman P, Shannon K, Pearson HA. Developmental Changes in
Red Blood Cell Production and Function. In Rudolphs Pediatrics, ed.
Rudolph C, Rudolph A, Hostetter M, et al. New York: McGrawHill, 2002,
151923.
Nelson C. Brain Development and Behavior. In Rudolphs Pediatrics, ed.
Rudolph C, Rudolph A, Hostetter M, et al. New York: McGrawHill, 2002,
40810.
Wan J, Greenfield S. Enuresis and common voiding abnormalities. Pediatr
Clin North Am, 1997;44:111731.
Dixon S. In Encounter with Children: Pediatric Behavior and Development,
ed. S. Dixon S, Stein M. Philadelphia: Mosby, 2006, 1343.
Himelstein BP, Hilden JM, Boldt AM, et al. Pediatric palliative care. N
Engl J Med, 2004;350:175262.

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Anesthesia and the


Developing Brain
Laszlo Vutskits

INTRODUCTION
The normal development of the central nervous system (CNS)
relies on the precise temporal and spatial orchestration of several
molecular pathways that guide the proliferation, migration, differentiation, and survival of neuronal cells. Interference with these
finely tuned developmental mechanisms can disrupt physiologic
developmental patterns and may, ultimately, lead to permanent
impairment of CNS functions. Anesthetics primarily operate via
ligand-gated ionotropic neurotransmitter receptors and, thus,
modulate the activity of different neurotransmitter systems.1 In
turn, it is now well established that, in addition to their role in
synaptic transmission in the CNS, neurotransmitters act during
development as epigenetic factors to control important biologic
processes including progenitor cell proliferation, neuroblast
migration, and neuronal differentiation.2,3 In addition, a delicate
balance between excitatory and inhibitory signals also has a key
role in the functional assembly of neuronal networks.4 Because
even small changes in the relative amounts of excitation and
inhibition can markedly alter information processing, the impact
of anesthesia on neuronal and CNS development is an intriguing
question. This chapter aims to provide a brief synopsis of the
ontogeny of the human CNS and to describe how neurotransmitter signaling contributes to shape the maturing brain and
reviews the accumulating evidence suggesting that anesthetic
agents may indeed interfere with neural development.

ONTOGENY OF THE HUMAN BRAIN


Cell Proliferation, Neurogenesis,
and Neuronal Migration
In the earliest phase of neural development, starting on the 15th
postconceptional day of human embryonic life, neural tissue is
induced and begins to form within the ectodermal layer of the
embryo.5 As a consequence of neural induction, the ectoderm
subsequently divides into three different regions: the neural
ectoderm or neural plate, which will give rise to the CNS; the
nonneural ectoderm, which will form the epidermis; and the cells
at the border between neural and nonneural ectoderm, which for
the most part will become the neural crest tissue. After the
ectoderm differentiates, the neural plate border cells bend to form
the neural folds. Before the closure of the neural tube, the neural
folds expand considerably in the cephalad region (head) as the
first indication of the future brain. In humans, the neural tube
closes at around embryonic day (E) 30.6 At this stage, its wall
consists of a single layer of columnar neuroepithelial cells (also

3
C H A P T E R

called neural stem cells), the direct descendants of cells of the


neural plate. Subsequent to the closure of the neural tube, intense
symmetrical proliferation of these neuroepithelial cells will give
rise to a homogenous pseudostratified epithelium, which is called
the ventricular zone (VZ).6 Early proliferation increases the surface
area and the thickness of the VZ. Consequently, the neural tube
starts to differentiate along several axes. Regional expansions
along its anteroposterior axis will shape the major subdivisions of
the CNS: (1) the spinal cord; (2) the rhombencephalon or hindbrain; (3) the mesencephalon or midbrain; and (4) the prosencephalon or forebrain. The vertical axis determines the dorsal and
ventral sides, whereas the horizontal axis establishes medial and
lateral structural growth. Appropriate differentiation of the axes
of the neural tube is dependent on the precise temporal and spatial
gradients of highly complex gene expression during the early
embryonic period. Defective patterns of gene expression are
known to induce major developmental anomalies in the fetal
nervous system.5
During the early embryonic stages, the first neurons of the
human brain are generated in the rostral part of the neural plate.7
However, the vast majority of neuronal cells are eventually derived
from neuroepithelial stem cells of the VZ. At the start of
neurogenesis, occurring approximately at E33 in the lateral part
of the cortical wall in humans,7 these stem cells down-regulate
their epithelial characteristics and switch from a symmetrical to an
asymmetrical mode of cell division. One daughter remains a
progenitor to give rise to future neuronal cells whereas the other
is a postmitotic cell that is destined to become a neuron. By
gestational weeks (GWs) 5 and 6, the VZ is the only proliferative
zone. In the developing hindbrain and midbrain, the majority of
neurons are generated during this period.8 In the developing
telencephalon, the first postmitotic neurons migrate in a radial
fashion out of the VZ and form the first recognizable cortical layer
(the preplate). Around the seventh and eighth GW, accumulating
postmigratory cells within the preplate form the cortical plate
(CP). This is divided into the marginal zone on the superficial side
and the subplate on the inner side. Parallel to the formation of the
CP, a secondary proliferative region, the subventricular zone
(SVZ) appears above the basal border of the VZ.6 By GWs 25 to 27,
when the SVZ is still proliferating, the human VZ has reduced in
size to a one-cell-thick ependymal layer. The subsequent development of the cerebral cortex during the second half of gestation in
primates is mainly related to cell proliferation in the SVZ. In
addition, whereas the VZ gives rise only to neurons, dividing
progenitors of the SVZ generate both neurons and glial cells.6
During GWs 10 to 25, there is a major wave of generation and
subsequent migration of cortical neurons in the human brain. Two

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major kinds of neurons can be distinguished in the cerebral cortex:


(1) projection neurons with pyramidal morphology, containing
the excitatory neurotransmitter glutamate; and (2) local circuit
neurons with extremely diverse morphology, containing gammaaminobutyric acid (GABA). Projection neurons are all derived
from the neocortical VZ and SVZ of the telecephalon. These cells
migrate radially to accumulate in the CP in an inside-out manner.
The earliest-born neurons are destined to become the future layer
6, and the last-born neurons will become layer 2. In humans, the
majority (~65%) of local circuit neurons are also born in the VZ
and SVZ and migrate radially to populate the CP. A significant
portion (~35%) of local circuit neurons are born in the VZ and
SVZ of the subcortical ganglionic eminence of the ventral
telencephalon from which they migrate tangentially above the
SVZ into the cerebral cortex.9 Peak migratory activity of both
projection and local circuit neurons is thought to occur between
the third and the fifth months of gestation. Migration is competed
during the third trimester. The period after GW 22 is the most
significant time for spatial, laminar, and cytologic differentiation
of the CP. By the seventh month of gestation, the cerebral cortex
is clearly divided into six layers.6 In humans, neurogenesis ceases
in most cerebral regions by the third trimester of pregnancy.
However, newly generated neurons are still continuously added
into discrete regions of the adult brain, such as the hippocampus10
and the olfactory bulb.11 The functional significance of this adult
neurogenesis is still a matter of debate, but it is thought to be
important for hippocampus- and olfaction-related memory
processing.12

Neuronal Differentiation and Synaptogenesis


Neuronal differentiation starts early during fetal life. By GW 8 to
9, neurons in the CP display a fusiform cell body, a descending
axon, and an apical dendrite with a dense terminal tuft in the
marginal zone. Using a variety of chemoattractor or chemorepellent axonal guidance cues, the growth cones of developing
axonal pathways navigate to their intermediate and final targets.
For example, corticospinal axons reach the lower cervical spinal
cord by GW 26. Thereafter, they progressively and extensively
innervate spinal neurons.13 Neuronal dendrites represent the
primary sites of synaptic contacts in developing neurons. It is now
well established that interference with the finely tuned molecular
mechanisms, guiding the formation of neuronal dendritic arbors
in the developing brain, can lead to persistent dysfunctions of the
CNS.14 Although the type-specific morphology of CNS neurons
appears to be specified genetically,15 these intrinsic programs act
in concert with extracellular signals during the differentiation of
the dendritic arbor.16 Dendritic development accelerates from the
third trimester of gestation, remains very active till the end of the
first postnatal year, and continues up to 5 years of age.1719 From
the very early stages of differentiation, neurons establish synaptic
contacts with neighboring neurons. In the spinal cord, the first
synaptic contacts are established around GW 8, whereas synapses
in the cerebral cortex can be detected beginning at GW 9 to 10.20,21
After the formation of the CP, synaptic density steadily increases
with a rate of about 4% per week in all cortical regions until GW
24 to 26.21 Synaptogenesis then considerably accelerates from GW
28, resulting in an approximately sixfold increase in the number
of cortical synapses between this period and the first few months
of postnatal life.22 Peak synaptic density is reached at the age of

3 months (postterm) in primary sensory areas, such as the


auditory and visual cortex, and at the age of 15 months in the
prefrontal cortex.22
Compared with the rodent brain, a distinctive feature of the
primate CNS is the intricate folds of the cerebral cortex. In fact,
during the last trimester of pregnancy, the human cerebral cortex
expands tangentially and folds to accommodate a large surface
area, measuring 1600 to 2000 cm2 in humans, three times larger
than the inner surface of the skull.23,24 Although several hypotheses
have been proposed to explain the folding process during development, the potential influence of genetic, epigenetic, and environmental factors is still poorly understood.

Glial Cell Development


and Myelin Formation
Glial cells in the CNS are from two ontogenetically different
categories. Microglia cells are macrophages residing in the CNS.
These cells are immigrants of the hematopoietic system that enter
the CNS during the early stages of development. Macroglia cells
(astrocytes and oligodendrocytes) are derived from precursors cells
of the SVZ.25 In humans, the majority of glial cells are produced
between GWs 20 and 40.26 Astrocytes have diverse functions
ranging from the regulation of extracellular matrix composition to
the regulation of energy metabolism in the brain.27 Oligodendrocytes are destined to form the myelin sheet around neuronal
axons in the CNS. Although myelination starts at GW 12 in the
spinal cord28 and around GW 14 in the telencephalon,29 it becomes
a vigorously active process only during the first year after term.30
Following the first year of life, myelination continues at a slower
rate and becomes completed only during the fourth decade of life.31

Regressive Phenomena During Development


In addition to progressive biologic events, such as neurogenesis
and differentiation, regressive phenomena also play a major role in
determining the form of the mature CNS.32 Among these regressive phenomena is programmed cell death or apoptosis, which
plays a fundamental role in the control of the final number of
neurons and glial cells during development.33 Two apoptogenic
periods take place during CNS development. The first wave,
observed between GWs 7 and 13 in the proliferative zones of the
human telencephalon, consists of an early neuronal death of
proliferating precursors and young postmitotic neuroblasts.33,34
The second wave affects postmitotic neurons at later stages and is
linked to cell differentiation and synaptogenesis. In the cerebral
cortex, this type of cell death peaks between GWs 19 and 33.
However, apoptosis in sensorimotor, prefrontal, and cingulated
cortices continues until the first month of postnatal life34,35
Axonal retraction without accompanying cell death is another
prominent regressive process in the CNS. Although little is known
about the extent of this phenomenon in humans, data from
primates indicate a considerable postnatal reduction in the
number of projection axonal fibers within the corticospinal,
thalamocortical, and callosal pathways during the first few months
of postnatal life.3638 Physiologic data of children with congenital
hemiplegia suggest that axonal elimination in the corticospinal
tract may be activity-dependent, because in these children, major
parts of the ipsilateral corticospinal projections are conserved.39

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CHAPTER 3
Intense synaptogenesis during the third trimester of pregnancy
and the first 2 years of postnatal life is followed by a period of
synapse elimination during which synaptic density and number
significantly decrease. In the rhesus monkey, synaptic density in
the primary visual and the motor cortex decline to 50 to 60% of
peak values following sexual maturity, whereas the extent of
synapse elimination is significantly lower in the prefrontal and
cingulated cortex of these animals.4043 Human data indicate that
there is a region-specific first phase of decline in synaptic density
between 3 and 5 years of age followed by a plateau phase during
which synaptic density remains relatively constant. This plateau
phase ends around the time of puberty, and then the number of
synapses further declines to reach adult values.22

NEUROTRANSMITTERS AS SIGNALS
FOR CNS DEVELOPMENT
Neurotransmitters are primarily considered as the main actors of
synaptic transmission. However, it is important to note that these
molecules are also present in the chemical microenvironment of
neural cells beginning at the very early stages of CNS development.44,45 Furthermore, neural stem cells, migrating neuroblasts,
and immature neurons express specific receptors for neurotransmitters.45,46 Thus, in addition to their role in neurotransmission in
mature neuronal circuits, these same molecules can also serve as
chemical signals to orchestrate a variety of morphogenetic events
during brain development.47,48 These effects appear to be, at least
partially, mediated through a paracrine mode of action in which
neurotransmitters are nonsynaptically released into the early differentiating cortical environment and activate their cogent receptors.48 This type of early neurotransmitter signaling may mediate
a wide range of developmental effects including proliferation,
differentiation, and synapse formation. This is in contrast with the
more focused, rapid mode of operation at the synapse within the
developed CNS.

Ontogeny of Ligand-Gated Ion Channels


During development, the expression of ligand-gated ion channel
receptors follows a precise spatial and temporal pattern in the
CNS.4446 The specific ontogenic progression in the expression of
different receptor subunit genes characterizes the subunit assembly
of the majority of ionotropic receptors, suggesting that these
protein complexes might respond differently to endogenous and
exogenous ligands at distinct stages of neural development.4446
Several GABAA receptor subunits are expressed from the early
stages of embryonic development, and anatomic mapping of these
subunits in the developing rodent CNS reveals a complex, transient, and region-specific expression pattern of these proteins.4951
In fact, it is now well established that embryonic and early postnatal
GABAA receptors differ markedly from those expressed in the adult
brain.4952 For example, in most brain areas, the 3 subunits, along
with the 2, 3, and 2 subunits are the most prominent
components of the GABAA receptor complex throughout the preand early postnatal development.50 The 3 subunit content then
decreases, and this is accompanied by a concomitant increase in
the expression of the 1 subunit. For detailed region-specific and
temporal expression patterns of GABAA receptor subunit mRNAs
in the brain, the reader is referred to references 49 and 50.

Anesthesia and the Developing Brain 45

The GABAergic signaling system has the unique property of


ionic plasticity, which is based on short-term and long-term
changes in the Cl and HCO3 ion concentrations in the postsynaptic neurons. Although short-term ionic plasticity is caused by
activity-dependent, channel-mediated anion shifts, long-term
ionic plasticity depends on changes in the expression patterns and
kinetic regulation of molecules involved in anion homeostasis.53
During development in immature neurons, activation of GABAA
receptors leads to the depolarization of these cells because of the
high intracellular Cl concentrations. Thus, in addition to glutamate, GABA also acts as an excitatory neurotransmitter during
brain development. The functional switch toward the hyperpolarizing actions of this neurotransmitter and its subsequent
inhibitory properties is linked to the developmental expression of
the K+/Cl cotransporter (KCC2), which actively extrudes intracellular Cl from neurons.53 KCC2 appears in the early postnatal
period in rodents, although no data about the expression pattern
of this protein exist in humans yet.
Among the ionotropic glutamate receptors, AMPA and kainate
receptors are the first to be expressed during early mammalian
CNS ontogenesis.5456 In rodents, these receptors are expressed
from E10 in the neural tube57 and as early as the fifth gestational
week in human embryos.54 Spatiotemporal changes in the expression pattern of subunits (GluR14) forming the AMPA receptor
complex also occur during CNS development.46,5861 GluR1
subunit levels increase progressively during late embryonic and
early postnatal days with varying levels of expression according to
specific brain areas.62 The GluR2/3 subunits are also expressed in
embryonic development, whereas the presence of GluR4 is mainly
restricted to the late postnatal development and adult.46 Concerning the isoforms of AMPA receptors, expression of the flip variants
dominates before birth and continues to be expressed in adulthood, whereas flop variants are in low concentration before the
postnatal period and reach the same level as the flip form by
adulthood.63
Changes in receptor subunit composition affect the functional
properties of the receptor complex, such as Ca2+ permeability,
single-channel conductance, desensitization, and affinity for
agonists.64,65 For example, a developmental switch during the
postnatal period, due to the expression of the GluR2 subunit of
the AMPA receptor complex in neocortical layer V pyramidal
neurons, substantially modifies the Ca2+ permeability of these
cells.65 Similarly to AMPA receptors, kainate receptors also show
a spatial and temporal expression pattern during CNS development with a peak in their expression in the late embryonic and
early postnatal period.46,66,67
In the human embryo, functional N-methyl-D-aspartic acid
(NMDA) receptors can be detected from around the 10th
gestational week.56 The functional NR1 subunit is ubiquitously
present in the brain throughout pre- and postnatal development,
although the modulatory subunits (NR2A-D) are differentially
expressed.46,68,69 The NR2A subunit is expressed mainly during the
postnatal time, whereas the NR2B subunit is detected throughout
the embryonic period with a restricted expression to the forebrain
at the postnatal stages. The NR2C subunit appears postnatally and
is prominent in the cerebellum; the NR2D subunit is mainly
present in the diencephalons and the brainstem at embryonic and
neonatal stages. The NR3 subunit is abundant within late prenatal
and early postnatal brain development.70

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Glycine receptor subunits are expressed at high levels during


early cortical development.71 In newborn rats, the GlyR is 2homomeric and differs from the adult form, which includes three
1 and two subunits.72 As with prenatal GABA signaling,
activation of nonsynaptic Gly receptors during the embryonic
period is excitatory.73 In the developing brain, glycine is found at
very low concentrations,74 and Gly receptors are mainly activated
by another endogenous ligand, taurine.73
Neuronal nicotinic acetylcholine (nACh) receptors are widely
distributed in both the developing and the adult mammalian
CNS.75,76 In rats, functional receptors are present as early as E12,77
and it is now well established that, similar to the previously
mentioned ionotropic receptor complexes, nACh receptor subunit
expression is also developmentally regulated.7880 For example, in
the case of the cerebral cortex, a pair of subunit mRNAs (32)
is initially (E1213) expressed followed by a repression of the 3
subunit (E15) and the subsequent (E17E19) induction of the 4
subunit.80
Serotonin (5-HT3) acts through several different receptors,81
but only the 5-HT3 receptor is ionotropic and mediates rapid
excitatory responses through a ligand-gated ion channel that is
mainly permeable to Na+ and K+, with a variable permeability for
Ca2+ according to the receptor subunit assembly.8284 Both serotonin and the 5-HT3 receptors appear during early prenatal development.85,86 In the rat embryonic brain, 5-HT3 receptors are detected
in a number of proliferative regions as early as E12.5.86 Although
5-HT3 receptor subunits (5-HT3AE) have now been described,87
the developmental expression pattern of these subunits remains
to be determined.

Neurotransmitters and Cell Proliferation


GABAA receptor subunits 4, 1, and 1 are expressed in the rat
VZ during periods of neurogenesis, indicating that GABA may
directly regulate proliferation of CNS progenitors.88 Although the
impact of GABAA receptor activation on cell proliferation remains
to be determined in vivo, activation of this receptor complex can
control cell cycle kinetics in neuronal progenitors. GABA has been
shown to depolarize and decrease the proliferation rate of neuronal
progenitors isolated from the developing rat telencephalon during
the peak period of cortical neurogenesis (E16E19), whereas the
administration of GABAA receptor antagonists displayed opposite
effects.89 The actions of growth factors and GABA are heavily
interconnected, thereby providing a major feedback mechanism.2
In vitro, exposure of proliferating neuroepithelial cells to basic
fibroblast growth factor (bFGF) increased the expression of the 1
subunit on the cell surface. In turn, exposure of these cells to GABA
inhibited the proliferative effects of bFGF on neural progenitors,
suggesting that GABA regulates cell production by providing a
feedback signal that terminates cell division.90 Trophic factors can
also decrease GABA production.91 Accumulating evidence suggests
that the modulatory effect of GABA on cell proliferation depends
on the brain region.44,92 For example, in embryonic neocortical slice
cultures from mice, GABA increases cell proliferation in the VZ
but decreases it in the SVZ.92 This differential modulation of cell
proliferation could regulate the relative contribution of VZ and
SVZ progenitors to neocortical growth and, thus, could be of
significant importance for proper CNS development.92,93 Recent
results further extend our understanding regarding the regulatory
role of GABA on cell proliferation during development by

demonstrating the existence of nonsynaptic GABAergic signaling


between neuroblasts and glial progenitors in the postnatal SVZ.94
According to these data, spontaneous depolarization-induced
nonsynaptic GABA release in neuroblasts activates GABAA
receptors on adjacent astrocytes leading to a decreased proliferation
of these latter cell types. Functional ionotropic glutamate receptors
emerge during terminal cell division and the early neuronal
differentiation of rat neuroepithelial cells.95 Activation of AMPA/
kainite, but not of NMDA receptors, has been shown to shorten
the cell cycle of isolated cortical neuroblasts89 and to differentially
alter cell proliferation in the ventricular and subventricular cortical
germinal zones.92 A similar effect of non-NMDA receptor agonists
has also been observed in O-2A cells in culture.96 By contrast,
proliferation of striatal neuronal progenitors is promoted by an
NMDA-dependent mechanism, but not through AMPA/kainate
receptors in the ventral telencephalon.97 NMDA receptors are also
involved in the regulation of cell proliferation in the hippocampal
dentate gyrus throughout life.98 A single treatment with NMDA
receptor antagonists increases granule cell proliferation approximately twofold within 3 hours, although activation of this receptor
leads to a decrease in the proliferation rate.99 By contrast to what is
known about the importance of GABAA and ionotropic glutamate
receptors in neural progenitor proliferation, the involvement of
Gly, nACh, and 5-HT3 receptors in this process remains to be
determined.

Neurotransmitters and Cell Migration


Once generated, immature postmitotic cells leave the germinative
zones and migrate toward their final destination. The complex
cyto-architectural organization of the mature CNS reflects this
highly precise pattern of cell migration. Deficiency in migration
patterns, caused by genetic disorders, toxins, pharmacological
interventions, or other environmental insults, can result in major
brain malformations.100 There are two major modes of neuronal
migration in the cerebral cortex: (1) a radial mode for the principal
pyramidal cells and (2) a tangential mode for the interneurons.101
A growing body of evidence indicates that neurotransmitters and
their specific receptors are involved in the complex molecular
machinery that orchestrates the migration of immature neurons in
the brain during development and adulthood.102 The GABA
system, via various receptors, is involved at distinct phases of
radial migration of projection neurons. GABAAC receptors are
required for ventricular to intermediate zone migration, GABAB
receptors are required for intermediate zone to cortical plate
migration, and GABAA receptor activation is required for proper
termination of migration within the cortical plate.103105 GABAminergic interneurons, originating in the median ganglionic
eminence, also require GABAA receptor signaling to migrate
tangentially toward the cerebral cortex.106 Although GABA is
present at micromolar concentrations throughout their migratory
route, tangentially migrating interneurons show little response to
GABA stimulation upon leaving the median ganglionic eminence.
However, when these cells reach the proximity of the neocortex,
they change the number and the subunit composition of the
GABAA receptor complex on the cell surface. Changes in the 13subunit composition of the GABAA receptor correlates with the
ability of migrating interneurons to cross the corticostriatal
junction, indicating that these cells require a specific GABAA
receptordependent signal for entry into the cortex.106 GABA,

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through activation of the GABAA receptor, also promotes the
migration of young CA1 pyramidal cells and interneurons in the
developing hippocampus.107,108 Migrating cells, in either the radial
or the tangential pathways, also express functional ionotropic
glutamate receptors on the cell surface.102 Micromolar concentrations of glutamate have been shown to stimulate the chemotaxis of
immature embryonic neurons through an NMDA-dependent and
AMPA/kainate-independent mechanism.109 Conversely, glutamate
released within the hippocampus by glutamatergic neurons
modulates the tangential migration of hippocampal interneurons
through AMPA receptor activation108 and promotes the migration
of young pyramidal neurons via NMDA receptordependent
signaling.107 These latter results suggest that glutamatergic and
GABAminergic neurons could modulate their migration in a
synergistic and cooperative manner through the release of specific
neurotransmitters. Paracrine, nonsynaptic signaling by glutamate
and presumably other neurotransmitters, are also responsible to
shape hindbrain development. The pharmacologic blockade of
the NMDA receptors results in a reduced radial migration of
granule cells.110 The role of Gly, nACh, and 5-HT3 receptors in
neural progenitor proliferation remains to be determined.

Neurotransmitters and Early


Neuronal Differentiation
The initial formation of neuronal axons and dendrites is an important developmental step preceding the assembly of differentiating neurons into functional networks. Axons carry efferent
information from neurons, whereas dendrites represent the
primary sites of synaptic contacts for developing and mature
neurons. Elaboration of a highly complex and organized dendritic
arbor is a prerequisite for the establishment of neuronal circuitry.16
In turn, substantial evidence supports the view that afferent
synaptic and network activity plays a fundamental role in shaping
neuronal arbor development.111113 Although the particular morphology of CNS neurons appears to be specified genetically,15 these
intrinsic programs act in concert with extracellular signals during
the differentiation of the dendritic arbor.16 In several in vitro and
in vivo experimental models, exposure to GABA leads to an
increased dendritic length with increased branching and density
of synapses, whereas antagonism of the GABAA receptor, using
the selective GABAA receptor antagonist bicucullin, has opposite
effects.2 Importantly, blockers of the Ca2+/calmodulin kinase II
(CaMKII) or mitogen-activated protein kinase (MAPK) reduce
the trophic effects of GABA, suggesting that GABA exerts its
effects via activation of Ca2+-dependent kinases.114 Glycine has also
been shown to enhance neuritic outgrowth.115,116 However, these
effects do not seem to be mediated via Gly receptors, but rather
through the activation of the GABAA receptor complex.116 Among
the ionotropic glutamate receptors, activation of the NMDA
receptor has been shown to promote neurite elongation of immature cerebellar granule neurons117 as well as to enhance dendritic outgrowth and branching in differentiating hippocampal
neurons.44,118 By contrast, in embryonic spinal motoneurons,
AMPA and kainite, but not NMDA receptors, mediate dendritic
growth.119 Activation of the nACh receptor promotes neuritogenesis of immature, newly formed neurons in the rat olfactory
bulb and pharmacologic blockade of the 7 subunit of the receptor
complex abolishes this effect.120 Conversely, in cultured embryonic
mouse spinal cord, acetylcholine decreased both growth cone

Anesthesia and the Developing Brain 47

motility and neurite outgrowth via the activation of nACh


receptors.121 Little is known about the effects of 5-HT3 receptor
mediated serotonin signaling during early phases of neuronal
differentiation. Recently, nerve growth factor (NGF)induced
neurite outgrowth in PC12 cells has been shown to be enhanced
by serotonin and this effect was abolished by pharmacologic
blockade of the 5-HT3 receptor.122 The biologic significance of
these data remains to be determined.

Neurotransmitters and Activity-Dependent


Neuronal Network Formation
The establishment of neuronal networks begins with growing
axons recognizing their postsynaptic targets with the formation of
synaptic contacts. The most active phase of neuronal differentiation, synaptogenesis and functional network formation in
the rodent brain take place between the first and the third postnatal
weeks (corresponding to a period extending from the last trimester
of pregnancy up to the first few years of life in humans), which
closely parallels to the onset of sensory input to the cortex.123,124
GABA and glutamate, as synaptically released neurotransmitters, are confirmed regulators of the activity-dependent
development of functional neuronal networks during critical
periods of early postnatal life.125,126 These critical periods represent
developmental time windows in which brain circuits are particularly receptive to acquiring certain types of information or even
need instructive signals for their continued development.45 A
delicate balance between excitatory and inhibitory signals has a
key importance in appropriate network development. In addition
to drastic pharmacologic perturbations of neuronal activity, even
small changes in the relative amounts of excitation and inhibition
can markedly alter information processing.4
Immature or developing neurons and neuronal circuits are
particularly sensitive to external stimuli during the synaptogenetic
period. As discussed in the section on Neurotransmitters and Cell
Migration, endogenous GABA and glutamate are clearly key
factors guiding CNS morphogenesis. Exogenous stimulation or
blockade of GABAminergic and glutamatergic signaling pathways
can also trigger cell death in the developing brain.127 It was shown
during the 1970s that subcutaneous injection of high doses of
glutamate induces acute neuronal necrosis in several brain regions
in newborn mice and monkeys.128,129 Blockade of the NMDA
receptor during synaptogenesis triggers widespread apoptosis in
the developing brain.129
Generation of transgenic mice presenting deficient GABAminergic or glutamatergic signaling pathways further improved
the understanding regarding the role of these molecules during
the critical periods of neuronal network development. GABA is
synthesized by glutamic acid decarboxylase, which is the product
of two distinct genes, Gad65 and Gad67. Although genetic
deletion of the GAD67 enzyme is lethal and eliminates most
cortical GABA content,130 Gad65-knockout mice are viable and
show poor GABA release upon stimulation from synaptic
vesicles.131 This decrease in GABA-mediated synaptic neurotransmission results in an impairment of activity-dependent refinement
of functional connections in the developing visual cortex, thereby
demonstrating the important role of GABAergic neurotransmission in synaptic plasticity.131
In transgenic animals lacking the NR1 subunit of the NMDA
receptor, thus, having no functional NMDA receptors, there is

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increased apoptosis in several brain areas during the period of


naturally occurring cell death and synaptogenesis132 and these
animals die soon after birth.133 Generation of region-specific
knockouts in which nonfunctional NMDA receptors are present
only in the cerebral cortex has allowed the study of the role of this
receptor in the formation of cortical circuits during the early
postnatal life.134 These experiments have revealed the important
role of NMDA receptors during the critical period in several
cortical systems including the formation of the somatosensory
barrel cortex134 and the shaping of ocular dominance columns in
the visual cortex.125
The mammalian neocortex is densely innervated by cholinergic
and serotoninergic fibers, suggesting roles for these neurotransmitters in synaptogenesis and neural circuit formation. Both
acetylcholine and serotonin have been shown to mediate fast
synaptic transmission in the visual cortex, and the early onset of
these mechanisms suggests a role during initial stages of circuit
formation and during subsequent experience-dependent remodeling of cortical connections.135 5-HT3 receptor activation decreases
the amplitude and lateral extent of excitation throughout postnatal
development. This effect peaks after eye opening, which indicates
a function for serotonergic modulation of circuit responses during
the period of refinement of cortical connections.136 nACh receptors are transiently up-regulated during the early postnatal period
in several brain areas.137 Synergistic actions mediated by 7 nACh
receptors and NMDA receptors may contribute to experiencedependent synaptic plasticity in the sensory neocortex during
early postnatal life, although nicotine-induced desensitization of
presynaptic 7 nACh receptors would allow an increased glutamate release onto postsynaptic NMDA receptors.138 Importantly,
altered stimulation of nACh receptors specifically during the
second postnatal week disrupts the development of glutamate
synapses in the rat auditory cortex.139
The fetal alcohol syndrome is a dramatic clinical demonstration of how exogenous perturbations of GABAminergic and glutamatergic signaling can affect brain development. Administration
of ethanol, having both NMDA antagonist and GABA-mimetic
properties, to pregnant rodents provokes disturbances of cortical
lamination and neuronal ectopia, and reduces the thickness of the
cortical mantle in the offspring.140 In fact, ethanol has been shown
to inhibit proliferation of neuronal precursors, to impair their
migration, and to induce neuronal death thereby providing the
potential neurobiologic bases for the reduced brain mass and
lifelong neurobehavioral disturbances associated with the human
fetal alcohol syndrome.140 By contrast to immature cells, differentiated neurons are less sensitive to pharmacologic modulation of
GABAminergic and glutamatergic signaling.127 These findings
suggest that the increased vulnerability of neurons is mainly
confined to the synaptogenetic period, and once this period is
over, transient pharmacologic manipulation of neuronal activity
will not affect neuronal survival and optimal network function.

EFFECTS OF ANESTHETICS
ON CNS DEVELOPMENT
On the basis of our increased understanding regarding the
important developmental role of the neurotransmitter systems, it
is not surprising that the past few years have yielded a veritable
explosion of publications claiming the potential for adverse effects
of anesthetic agents on the immature brain. The following section

reviews the existing laboratory data regarding this phenomenon


with a focus on drugs that have been clearly shown to affect some
aspects of CNS development either in vitro or in vivo.

Specific Anesthetic Agents


Ketamine
Ketamine is a noncompetitive antagonist to the phencyclidine
(PCP) site of the NMDA receptor. By preventing excitotoxic
actions of endogenous excitatory amino acids such as glutamate
and aspartate, it may have a neuroprotective role in ischemiainduced and seizure-related brain damage.141143 The first indications that, in addition to its potential benefits, ketamine can also
induce pathologic changes in the CNS came from the observations
that subcutaneous administration of PCP to adult rats induced
cytopathologic changes (vacuolization of neuronal cytoplasm) in
cerebrocortical neurons.144 These effects were detectable as soon as
2 hours after drug exposure; however, neuronal morphology
returned to normal when only a single dose of PCP was applied.
In this same work, ketamine mimicked the effect of PCP when
administered subcutaneously at 40 mg/kg, although lower doses of
this anesthetic did not induce vacuolar neurodegeneration.144
These observations were further extended to the developing brain
in a subsequent study in which a series of seven subcutaneous
injections of ketamine (20 mg/kg at each dose) spaced evenly over
9 hours induced extensive apoptotic neurodegeneration in 7-dayold rat pups.129 The potential relevance of these rodent data has
recently been confirmed in primates, in which ketamine induced
extensive neuronal cell death in the cerebral cortex of rhesus
monkey fetuses when the pregnant mother was exposed to this
anesthetic for 24 hours.145 These experiments thus support the
contention that long-term exposure to ketamine at anesthetic
concentrations could indeed exert neurotoxic effects on the
developing CNS.
Whether short-term ketamine exposure, as may be used in
current pediatric anesthesia practice, can induce cell death in the
developing brain is a controversial issue. Several independent
observations indicate that, by contrast to repeated injections of
ketamine aimed to produce long-term anesthesia, a single anesthetic dose of this drug does not induce neuronal apoptosis.144147
However, these results were challenged by other experiments
demonstrating that even relatively mild exposure to ketamine can
trigger apoptosis in the developing mouse brain.148 In this latter
study, using immunocytochemical labeling with a specific antibody against the early apoptotic marker, caspase 3; apoptotic cell
bodies could be detected in several brain areas as soon as 4 hours
after a single subcutaneous injection of ketamine to 7-day-old
mice at anesthetic and subanesthetic concentrations (40 mg/kg
and 10 mg/kg, respectively). Although clearly further experiments
are needed to elucidate the impact of a single-dose ketamine administration on neuronal responses, these results raise the intriguing possibility that even a brief apoptogenic stimulus might alter
neuronal development during the peak synaptogenetic period.
An important point of concern in terms of neurotoxicity is that
neuronal apoptosis is not the only parameter to be considered in
evaluating the potential adverse effects of ketamine or other
anesthetics on neuronal development. It is now well established
that interference with the finely tuned molecular mechanisms,
which guides the formation of neuronal dendritic arbors in the
developing brain, can lead to persistent dysfunctions of the CNS.14

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Thus, understanding whether anesthetics modify dendritic arbor
expansion during CNS development is of utmost interest. To
investigate this issue, we have developed an in vitro model in which
immature neuroblasts are isolated from the SVZ of newborn rats.149
This purified cell population develops into GABAminergic
interneurons in low-density cultures with a dendritic arbor. On the
basis of previous experimental and clinical studies measuring
ketamine plasma concentrations following single-shot or repeated
administration in rodents and humans,147,150,151 we have recently
explored the dose- and exposure timedependent effects of
ketamine on the differentiation and survival of GABAminergic
neurons in these cultures.152 We found that ketamine, but not the
noncompetititve NMDA receptor antagonist MK801, rapidly
induced apoptosis of developing neurons when administered at
concentrations previously reported to induce cell death in vivo
(10 mg/mL).147 Neither survival nor long-term dendritic development was altered when differentiating neurons were exposed to
lower, subanesthetic concentrations (2 mg/mL) of this anesthetic
for up to 8 hours. By contrast, long-term exposure (>24 h) of
neurons to ketamine at concentrations as low as 0.01 mg/mL
severely impaired dendritic arbor development. These new data
suggest that long-term use of even low concentrations of ketamine,
such as an adjuvant to postoperative sedation and pain control,
could potentially interfere with the dendritic development of
immature neurons.
Little is known about the molecular mechanisms involved in
ketamine-induced neurotoxicity. Recently, ketamine has been
shown to reduce phosphatidylinositol-3 kinase/Akt phosphorylation and, thus, increase glycogen synthase kinase-3 (GSK-3) levels
in neurons.153 In turn, GSK-3 phosphorylates Bax, a proapoptotic
Bcl-2 family member that stimulates the intrinsic (mitochondrial)
death pathway by eliciting cytochrome C release from the mitochondria, promotes its mitochondrial localization.154 In fact,
application of Akt phosphorylation-activating growth factors, such
as insulin-like growth factor-1 (IGF-1), as well as inhibitors of
GSK-3 has been shown to protect against ketamine-induced
apoptosis.153 In this context, it is important to note that blockade
of the NMDA receptor during the peak synaptogenetic period,
using ethanol, delays the developmental switch from NR2B to
NR2A subunits, thereby altering the function of NMDA signaling
in maturing neural networks.155,156 Another important issue to be
addressed in the future is whether neuronal sensitivity to ketamine
is dependent on the subunit composition of the NMDA receptor
complex. Ketamine-induced neurotoxicity is primarily confined
to the brain growth spurt period when NR1 and NR2B subunits
predominate and the proapoptotic effects of this drug decrease
with the progressive increase in the amount of the NR2A subunit
during this period.68,157
Little is known about the potential adverse effects of ketamine
on neuronal progenitor proliferation and cell migration. Some
observations indicate a possible role for ketamine in progenitor
proliferation in postnatal neurogenic zones. In adult rats receiving
subanesthetic concentrations of ketamine for 5 consecutive days,
the proliferation marker, bromodeoxyuridine, demonstrates enhanced neurogenesis in the hippocampal subgranular zone.158 To
our knowledge, there are no other studies regarding the role of
ketamine exposure on the immature brain before the synaptogenetic period. Given the important role of these earlier developmental stages in the proper formation of the CNS, further research
is needed to clarify these issues.

Anesthesia and the Developing Brain 49

Propofol
Propofol (2,6-diisopropyl phenol) is an alkyl phenol that potentiates the effect of GABA in the CNS by inducing tyrosine kinase
mediated phosphorylation of the subunits of the GABAA
receptor complex.159 Selective toxicity of propofol for GABAminergic neurons, but not for astroglial cells, has been demonstrated in aggregated cell cultures of the fetal rat telencephalon.160
Propofol has also been shown to induce growth cone collapse and
to inhibit neurite outgrowth in immature peripheral, retinal, and
autonomic neurons in vitro.161 In line with these results, we have
shown that even low concentrations of this drug can impair
dendritic differentiation of GABAminergic neurons in vitro.162
Finally, recent in vivo experiments indicate that the intraperitoneal
injection of propofol (60 mg/kg) to 10-day-old mice pups induces
neuronal apoptosis in several brain areas and that these changes
were accompanied by persistent behavioral deficits.163

Benzodiazepines
Benzodiazepines bind selectively to the subunits of the GABAA
receptor and exert agonistic activity on this receptor complex.164
GABA is among the first neurotransmitters to appear in the
developing brain, and signaling through the GABAA receptor is
present from the very early developmental stages.165,166 Chronic
prenatal exposure of rat fetuses to diazepam results in long-term
functional deficits as well as alterations of stress-induced behavioral patterns in these animals.167169 Prolonged diazepam treatment during both the prenatal and the postnatal period induces
long-lasting changes in GABAA receptor as well as neurosteroid
levels.170 In turn, diazepam-induced alterations in GABAA receptor
function result in the impaired modulation of norepinephrine release from brain synaptosomes in response to stressful
stimuli.171,172 In addition to the effects of chronic benzodiazepine
exposure, results indicate that, as with ketamine,148,173 a single,
subanesthetic dose of midazolam can induce a significant neuroapoptotic response in the cerebral cortex as well as in the basal
ganglia of young mice.148 Whether this treatment paradigm also
induces long-term behavioral or cognitive deficits remains to be
determined.

Barbiturates
Barbiturates are also potent agonists of the GABAA receptor. In
line with reports using midazolam or propofol, exposure of 7-dayold rats to barbiturates for 5 hours has been shown to induce
widespread neuronal apoptosis in numerous brain regions.174 In
these experiments, neuronal death was associated with reduced
expression of neurotrophins and decreased concentrations of
survival-promoting proteins in the brain.174

Volatile Anesthetic Agents


Although the exact mechanisms of action of the volatile anesthetic
agents remain to be determined, all of these anesthetics have
GABAmimetic and/or NMDA antagonistic properties. During the
mid-1980s, halothane was among the first of the anesthetics
reported to alter brain development. When rats were chronically
exposed to halothane anesthesia during the entire gestational
period, dendritic length and branching as well as cerebral synaptic
density were severely impaired.175 The effect of halothane on
dendritic growth appeared to be enduring, and the delay in initial

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dendritic growth caused by halothane was not compensated for


by an increased rate of dendritic growth once the drug had been
withdrawn. The effect of halothane treatment on dendritic growth
was associated with learning impairment, decreased exploratory
behavior, and decreased nociceptive reactivity.176
Isoflurane (1.5%) has been shown to induce neuronal degeneration in organotypic hippocampal slice cultures.177 In these
experiments, isoflurane-induced cell death occurred in cultures
obtained from postnatal 7-day-old rats (PND7) but not in those
from PND4 or PND14 rat pups. Moreover, this effect was
observed only with an isoflurane exposure of at least 5 hours.
Recent in vivo data also point to the dose, exposure time, and agedependent toxicity of this volatile anesthetic agent.178,179 Altogether,
these studies further support the notion of both an age- and a
duration-dependent relationship between anesthesia administration and perinatal neuronal death. Interesting new data show that
even shorter exposure time (4 h) to isoflurane in neonatal rat pups,
although not affecting survival, can induce a significant decrease
in hippocampal stem cell proliferation, leading to the long-term
impairment of neurocognitive function revealed by the fear
conditioning test.180
Nitrous oxide (N2O) is a potent antagonist of the NMDA type
of glutamate receptor. When pregnant rats were exposed to 75%
N2O-25% O2 mixtures on gestational days 14 and 15 for 8 hours
per day, permanently altered behavioral deficits could be detected
in the offspring without any accompanying physical abnormalities.181 In line with results observed following ketamine administration, there is now evidence that a 3-hour exposure to N2O
can also trigger apoptosis in the developing brain.182

Opioid Analgesics
Opioid analgesics primarily act on -, -, and -types of opioid
receptors on the cell surface. Upon binding, these opioid receptor
subtypes recruit inhibitory G proteins (Gi/o) and thereby initiate
the activation of multiple intracellular signaling cascades.183,184 In
addition to inducing potent analgesic effects, these signaling
pathways are also implicated in a variety of other biologic events
including the modulation of proliferation, survival, and differentiation of cells expressing opioid receptors.184 In the developing rodent CNS, opioid receptors are expressed from early
developmental stages,185,186 suggesting a role for opioid receptor
mediated signaling in the developmental processes. In rats, chronic morphine exposure during the embryonic and the early
postnatal period induces significant reduction in brain volume,
neuronal packing density, and dendritic growth.187191 Animals
subjected to this treatment paradigm show long-term impairments in learning abilities and motor activity.192,193 By contrast to
the effects of exogenous opioid exposure, pharmacologic blockade
of endogenous opioid signaling by naltrexone induces an increase
in brain size, suggesting a modulator role for the endorphin and
opioid receptor system during development.194
It is now well established that opioids modulate cell proliferation in germinative zones of the developing brain in a receptor-,
brain region, and cell typespecific manner. Activation of the
and opioid receptors increases proliferation rate, whereas
agonists of the receptor decrease cell division in the germinal
zone of the late embryonic neocortex.195 Conversely, morphineinduced receptor activation inhibits DNA synthesis in the
developing cerebellum.196 Finally, signaling through the receptor

increases cell proliferation in oligodendrocytes197 but inhibits


mitosis in astrocytes and neuronal precursors.196,198
Although morphine has been reported to reduce chemotactic
responses in leukocytes199 and increase chemotaxis in microglia,200
the role of opioid signaling in neuronal cell migration in the
developing brain remains to be established. In this context, recent
observations reveal that by contrast to proliferative neural progenitors, migrating neuroblasts do not express opioid receptors
on the cell surface.198 Further work is needed to determine whether
opioids affect the migration of other cell types such as astroglial
cells during development.
Naltrexone-induced chronic pharmacologic blockade of opioid
signaling in the early postnatal period induces a significant
increase in the extent of dendritic arborization as well as in the
number of dendritic spines, indicating that endogenous opioid
systems are critical regulators of neuronal differentiation and that
they control growth through an inhibitory mechanism.201,202 In
vitro observations indicate a dual role for opioid signaling in
neurite growth. Although high-dose (1 mM) morphine inhibits
neurite elongation, low concentrations (<10 nM) of this drug
enhance neurite-promoting activity of NGF.203,204 Although no
data are available on whether pharmacologic blockade or enhancement of opioid signaling induces cell death or survival during CNS
development, application of selective receptor agonists increases
NGF-dependent survival of embryonic chick dorsal root ganglion
neurons, suggesting that growth factormediated neuronal survival might be modulated by opioid signaling.205,206 Conversely, in
the adult rat brain, high doses of opioid have been shown to induce
electoencephalographic seizure activity and cell death in several
brain regions.20,207

Combined Use of Anesthetic Agents


During the perioperative period, patients are usually exposed to a
combination of different anesthetic agents either simultaneously
or in a timely order. As the majority of these drugs have GABAmimetic and/or NMDA antagonistic properties, the question as to
whether combined use of anesthetic agents could act additively or
synergistically in terms of neurotoxicity is of great clinical
significance. Although one of the major arguments for providing
multimodal anesthesia or balanced anesthesia is to diminish
potential side effects linked to higher concentrations of individual
drugs, recent laboratory results would suggest the need for a risk/
benefit reevaluation of this practice.208 Indeed, a large amount of
experimental evidence suggests that concurrent use of several anesthetic agents can potentiate CNS damage. The co-administration of
even low concentrations of ketamine and N2O enhances the
neurotoxic reaction to a much greater degree that can be explained
by the simple additive effects of these agents.182 Recently, the coadministration of sedative concentrations of midazolam and
ketamine to the infant mouse brain was shown to be more effective
in inducing apoptosis than either of these drugs alone.148 The coadministration of ketamine with propofol or thiopental also
potentiates apoptotic neurodegeneration in young rodents.163
Importantly, exposure of 7-day-old rats to a combined midazolamN2O-isoflurane anesthesia for 6 hours led to widespread neurodegeneration in the developing brain and this was accompanied by
persistent learning deficits.209 Interesting new data from this same
research group provide some insights into the molecular mechanisms of anesthesia-induced activation of apoptotic pathways in

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immature neurons.210 Midazolam-N2O-isoflurane rapidly induced
significant changes in the expression pattern of brain-derived
neurotrophic factor (BDNF) in the brain of rat pups. BDNF is a
member of the neurotrophin family of growth factors and is
implicated in neuronal survival, differentiation, and synaptic
plasticity via activation of its high-affinity receptor, TrkB.211 This
neurotrophin also binds to the so-called low-affinity neurotrophin
receptor, p75NTR, leading to the activation of apoptotic cascades.211 In the cerebral cortex of 7-day-old rats, as little as a 2-hourlong anesthetic exposure significantly increased the amounts of
BDNF. This was accompanied by an increase in the expression of
the p75NTR receptor. By contrast, the anesthetic induced an
important decrease in BDNF levels without affecting p75NTR
receptor expression in the thalamus, leading to a reduced BDNFdependent activation of the TrkB receptor. These results suggest
that general anesthesia can perturb CNS development by interacting with the multifaceted molecular pathways of neurotrophin
signaling.

Protection Against AnesthesiaInduced Neurotoxicity


Deciphering the molecular pathways involved in anestheticinduced adverse effects on the developing CNS would allow us to
develop therapeutic strategies to prevent these unwanted complications. In this context, administration of -estradiol has been
shown to reduce anesthesia-induced apoptosis in the developing
brain.210 This sex hormone is known to activate the Akt serine/
threonine kinase, which is an important factor for neuronal
survival pathways. The midazolam-N2O-isoflurane anesthesiainduced apoptotic neurodegeneration has been reported to be
reduced in a dose-dependent manner by the co-administration of
melatonin. Melatonin, in addition to its sleep-promoting activity,
exerts antioxidant effects by improving mitochondrial homeostasis and stabilizing the inner mitochondrial membrane.212 Recent
data indicate that co-administration of L-carnitine, a quaternary
ammonium compound involved in fatty acid metabolism, also
protects against N2O-isoflurane-induced neuroapoptosis.213 In
vitro, ketamine-induced neurotoxicity is prevented by the coadministration of IGF-1, a growth factor known to activate the
phosphatidylinositol-3 kinase/Akt signaling pathway.153 Recently,
co-application of xenon during isoflurane and isoflurane-N2O
anesthesia has been shown to attenuate the neurotoxic effects of
these latter two agents during the early postnatal period.214 These
encouraging observations open a whole new line of research
aimed to counteract anesthesia-induced neurotoxicity. Further
studies should be conducted to address this important issue.

Extrapolation of Laboratory Results to


Clinical Practice
It is of course extremely difficult to evaluate the clinical relevance
of experimental observations claiming the possibility of anesthesiainduced neurotoxicity in the developing brain. A first important
question concerns the possibility of interspecies differences in
terms of drug effects.215 In this context, it is important to note that,
in addition to rodents, anesthetic and subanesthetic doses of
currently used anesthetics have now been shown to induce
apoptosis in other species such as pigs and monkeys.145,216 Another

Anesthesia and the Developing Brain 51

essential criticism concerning the significance of animal


experiments in comparison with human anesthesia practice
concerns the relatively long exposure time needed to produce
detectable neurotoxic effects in the majority of laboratory
studies.217 In fact, from a developmental perspective, several hourlong exposures to anesthetics in rodents would be equivalent to
producing general anesthesia for days or even weeks in the human
neonate.8 However, recent results somewhat counteract these
arguments, showing that even a single exposure to subanesthetic
doses of anesthetics could trigger a two- to fourfold increases in
neuronal apoptosis in the mouse brain during the synaptogenetic
period.148 In addition, in vitro data indicate that short-term exposure to anesthetic agents can also impair neuronal development
by interfering with dendritic growth and branching without
inducing cell death.152,162 Given the utmost importance of neuronal
dendritic architecture in appropriate information processing, one
essential next step will be to determine how neuronal dendritic
arbor development is influenced by anesthetic agents in a more
complex and physiologic environment, using organotypic slice
cultures and in vivo animal experiments. These experiments,
combined with long-term assessment of behavioral outcome
following short-term anesthesia, may help us to better understand
the impact of anesthetic agents on CNS development.
Differences in concentrations of drugs needed to produce
anesthesia across different species further complicate the issue of
anesthesia-induced developmental neurotoxicity. Subanesthetic
plasma concentrations of ketamine in humans vary from 0.1 to
0.5 g/mL,218,219 whereas intravenous administration to children
at doses of 3 mg/kg to induce anesthesia results in blood levels
of 1 to 2 g/mL.150,151 Although no direct comparison in terms of
plasma concentrations exists with rodents; as much as 40 mg/kg of
subcutaneously injected ketamine is insufficient to produce
anesthesia in young mice.148 In laboratory animals, plasma levels
of ketamine are approximately 6 g/mL following a single 20 mg/
kg subcutaneous dose.147 These studies suggest that effective
plasma concentrations and probably on-site brain concentrations
of ketamine needed to produce anesthesia are significantly higher
in rodents than in humans, raising further difficulties in the
extrapolation of these experiments to human infants.
Finally, one can argue that experimental conditions in these
animal experiments are very different from those associated with
surgical anesthesia and complex perioperative management.217
First, based on the neuronal stimulation hypothesis,220 preoperative stress and painful stimuli during surgery can activate NMDA
and other excitatory receptors in the immature brain and anesthetic drugs could, thus, reduce extreme degrees of neuronal
excitation.221 In line with this hypothesis, application of ketamine
has been shown to reduce cell death following inflammatory pain
in the newborn rat brain.222 The average clinical situation is
by contrast to experimental settings in which anesthesia was
administered without painful stimuli and, consequently, the
effect of anesthetics on the suppression of basal neural activity is
evaluated. Second, human neonates and children routinely receive
nutritional support and metabolic monitoring in the perioperative period, thereby minimizing the risk for hypoglycemia and
impaired nutrition. By contrast, although this issue is controversial, rodent pups do not suckle well after general anesthesia,
resulting in a prolonged decrease in weight gain compared
with nonanesthetized littermates.146,223 Given that the role of
malnutrition in decreased brain growth and learning disabilities is

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well established,224,225 one cannot fully exclude the possibility that


the neurotoxic effects of anesthetic agents are, at least partially,
related to impaired nutrition in the perioperative period in these
animal studies.

Anesthesia-Related Neurotoxicity and


Clinical Evidence
Several human cohort studies have demonstrated an association
between surgery in the neonatal period and poor neurodevelopmental outcome. Neurodevelopmental outcome in extremely low
birthweight (ELBW) infants undergoing laparotomy for necrotizing enterocolitis (NEC) has been shown to be significantly
worse than in ELBW infants, with or without NEC, in the absence
of anesthesia and surgery.226 Children who required major neonatal surgery performed significantly less well at 1 year of age and
in early adolescence than with their peers.227,228 Children who
underwent surgical correction for congenital diaphragmatic
hernia or esophageal atresia during the neonatal period have more
learning, emotional, and behavioral problems than children in the
general population.229,230 Recent clinical observations indicate that
surgical closure of patent ductus arteriosus (PDA) in ELBW
infants is associated with significantly worse neurodevelopmental
and neurosensory outcome than indomethacin-induced successful closure without a need for surgery.231 Unfortunately, given the
high number of potentially confounding factors, none of these
studies provides evidence for an association between anesthesia
per se and poor outcome. In fact, the majority of infants included
in these studies have coexisting malformations, prematurity,
sepsis, and associated cardiovascular instability. Also, it is virtually
impossible to distinguish between the effects of anesthetic agents,
surgical stress, and postoperative issues in the clinical setting.
Upcoming clinical trials, attempting to focus on a specific neonatal
population that presents with limited comorbidity but requires
surgery, are necessary to further investigate this issue.232
One should not forget that multiple lines of evidence suggest
the necessity of providing anesthesia in infants. In preterm babies
undergoing surgery, perioperative stress hormone levels as well as
postoperative complications were significantly higher when only
N2O and curare were administered peroperatively compared with
infants who also received fentanyl or halothane.233,234 In neonates
undergoing cardiac surgery, deeper levels of anesthesia decreased
the incidence of postoperative sepsis, disseminated intravascular
coagulation, and mortality.235 Repetitive painful stimuli have been
shown to persistently alter pain processing in humans,217,236 and
epidemiologic studies reveal an association between perinatal
and neonatal complications and behavioral/emotional problems
in childhood, such as anxiety, depression, and even suicidal
tendencies.237241

CONCLUSIONS
Anesthesia-induced neurotoxicity remains a highly debated and
controversial issue. The important role of neurotransmitter
signaling in shaping CNS development raises the intriguing
possibility that interference with these signaling pathways, such
as exposing the developing organism to anesthetic agents, could
potentially alter physiologic developmental patterns during brain
maturation. However, the functional impact of anesthetic agents
on developing humans remains to be determined. At the current

state of our knowledge, we believe that no recommendations can


be made to change clinical practice. Nevertheless, in light of
accumulating experimental data, one should systematically
consider whether elective surgical procedures in infants could be
safely postponed to later periods. Also, when surgery or a
procedure is unavoidable, every effort should be made to limit the
duration of the intervention. Finally, it is important to note that
there is no evidence whether one anesthetic agents is better or
worse that the others in terms of potential for toxicity to the CNS.
Clearly, given the large number of human fetuses and infants
receiving anesthesia worldwide, there is no doubt that additional
experimental and clinical studies are needed to elucidate the
impact of anesthesia on the developing brain.

REFERENCES
1. Yamakura T, Bertaccini E, Trudell JR, Harris RA. Anesthetics and ion
channels: molecular models and sites of action. Annu Rev Pharmacol
Toxicol. 2001;41:2351.
2. Represa A, Ben-Ari Y. Trophic actions of GABA on neuronal
development. Trends Neurosci. 2005;28:278283.
3. Waters KA, Machaalani R. NMDA receptors in the developing brain
and effects of noxious insults. Neurosignals. 2004;13:162174.
4. Liu G. Local structural balance and functional interaction of
excitatory and inhibitory synapses in hippocampal dendrites. Nat
Neurosci. 2004:7:373379.
5. Sarnat HB, Flores-Sarnat L. Integrative classification of morphology
and molecular genetics in central nervous system malformations. Am
J Med Genet A. 2004;126:386392.
6. Bystron I, Blakemore C, Rakic P. Development of the human cerebral
cortex: Boulder Committee revisited. Nat Rev Neurosci. 2008;9:
110122.
7. Bystron I, Rakic P, Molnar Z, Blakemore C. The first neurons of the
human cerebral cortex. Nat Neurosci. 2006;9:880886.
8. Clancy B, Darlington RB, Finlay BL. Translating developmental time
across mammalian species. Neuroscience. 2001;105:717.
9. Letinic K, Zoncu R, Rakic P. Origin of GABAergic neurons in the
human neocortex. Nature. 2002;417:645649.
10. Eriksson PS, Perfilieva E, Bjork-Eriksson T, et al. Neurogenesis in the
adult human hippocampus. Nat Med. 1998;4:13131317.
11. Curtis MA, Kam M, Nannmark U, et al. Human neuroblasts migrate
to the olfactory bulb via a lateral ventricular extension. Science.
2007;315:12431249.
12. Ming GL, Song H. Adult neurogenesis in the mammalian central
nervous system. Annu Rev Neurosci. 2005;28:223250.
13. Eyre JA, Miller S, Clowry GJ, et al. Functional corticospinal projections are established prenatally in the human foetus permitting
involvement in the development of spinal motor centres. Brain.
2000;123:5164.
14. Webb SJ, Monk CS, Nelson CA. Mechanisms of postnatal
neurobiological development: implications for human development.
Dev Neuropsychol. 2001;19:147171.
15. Jan YN, Jan LY. The control of dendrite development. Neuron. 2003;
40:229242.
16. Chen Y, Ghosh A. Regulation of dendritic development by neuronal
activity. J Neurobiol. 2005;64:410.
17. Koenderink MJ, Uylings HB. Postnatal maturation of layer V
pyramidal neurons in the human prefrontal cortex. A quantitative
Golgi analysis. Brain Res. 1995;678:233243.
18. Koenderink MJ, Uylings HB, Mrzljak L. Postnatal maturation of the
layer III pyramidal neurons in the human prefrontal cortex: a
quantitative Golgi analysis. Brain Res. 1994;653:173182.
19. Mrzljak L, Uylings HB, Kostovic I, van Eden CG. Prenatal development of neurons in the human prefrontal cortex. II. A quantitative
Golgi study. J Comp Neurol. 1992;316:485496.

Bissonette-003-(F)

4/5/11

5:29 PM

Page 53

CHAPTER 3
20. Molliver ME, Kostovic I, van der Loos H. The development of
synapses in cerebral cortex of the human fetus. Brain Res. 1973;50:
403407.
21. Zecevic N. Synaptogenesis in layer I of the human cerebral cortex in
the first half of gestation. Cereb Cortex. 1998;8:245252.
22. Huttenlocher PR, Dabholkar AS. Regional differences in synaptogenesis in human cerebral cortex. J Comp Neurol. 1997;387:167178.
23. Hilgetag CC, Barbas H. Role of mechanical factors in the morphology
of the primate cerebral cortex. PLoS Comput Biol. 2006;2:e22.
24. Dubois J, Benders M, Cachia A, et al. Mapping the early cortical folding process in the preterm newborn brain. Cereb Cortex. 2007;18:
14441454.
25. Liu Y, Rao MS. Glial progenitors in the CNS and possible lineage
relationships among them. Biol Cell. 2004;96:279290.
26. de Graaf-Peters VB, Hadders-Algra M. Ontogeny of the human
central nervous system: what is happening when? Early Hum Dev.
2006;82:257266.
27. Pellerin L, Bouzier-Sore AK, Aubert A, et al. Activity-dependent
regulation of energy metabolism by astrocytes: an update. Glia.
2007;55:12511262.
28. Weidenheim KM, Bodhireddy SR, Rashbaum WK, Lyman WD.
Temporal and spatial expression of major myelin proteins in the
human fetal spinal cord during the second trimester. J Neuropathol
Exp Neurol. 1996;55:734745.
29. Zecevic N, Andjelkovic A, Matthieu JM, Tosic M. Myelin basic
protein immunoreactivity in the human embryonic CNS. Brain Res
Dev Brain Res. 1998;105:97108.
30. Brody BA, Kinney HC, Kloman AS, Gilles FH. Sequence of central
nervous system myelination in human infancy. I. An autopsy study of
myelination. J Neuropathol Exp Neurol. 1987;46:283301.
31. Paus T, Zijdenbos A, Worsley K, et al. Structural maturation of neural
pathways in children and adolescents: in vivo study. Science.
1999;283:19081911.
32. Cowan WM, Fawcett JW, OLeary DD, Stanfield BB. Regressive
events in neurogenesis. Science. 1984;225:12581265.
33. Lossi L, Merighi A. In vivo cellular and molecular mechanisms of
neuronal apoptosis in the mammalian CNS. Prog Neurobiol. 2003;
69:287312.
34. Rakic S, Zecevic N. Programmed cell death in the developing human
telencephalon. Eur J Neurosci. 2000;12:27212734.
35. Rabinowicz T, de Courten-Myers GM, Petetot JM, et al. Human
cortex development: estimates of neuronal numbers indicate major
loss late during gestation. J Neuropathol Exp Neurol. 1996;55:
320328.
36. Galea MP, Darian-Smith I. Postnatal maturation of the direct
corticospinal projections in the macaque monkey. Cereb Cortex.
1995;5:518540.
37. Darian-Smith C, Darian-Smith I, Cheema SS. Thalamic projections
to sensorimotor cortex in the newborn macaque. J Comp Neurol.
1990;299:4763.
38. LaMantia AS, Rakic P. Axon overproduction and elimination in the
corpus callosum of the developing rhesus monkey. J Neurosci.
1990;10:21562175.
39. Eyre JA, Taylor JP, Villagra F, et al. Evidence of activity-dependent
withdrawal of corticospinal projections during human development.
Neurology. 2001;57:15431554.
40. Zecevic N, Bourgeois JP, Rakic P. Changes in synaptic density in
motor cortex of rhesus monkey during fetal and postnatal life. Brain
Res Dev Brain Res. 1989;50:1132.
41. Bourgeois JP, Rakic P. Changes of synaptic density in the primary
visual cortex of the macaque monkey from fetal to adult stage.
J Neurosci. 1993;13:28012820.
42. Bourgeois JP, Goldman-Rakic PS, Rakic P. Synaptogenesis in the
prefrontal cortex of rhesus monkeys. Cereb Cortex. 1994;4:7896.
43. Granger B, Tekaia F, Le Sourd AM, et al. Tempo of neurogenesis and
synaptogenesis in the primate cingulate mesocortex: comparison with
the neocortex. J Comp Neurol. 1995;360:363376.

Anesthesia and the Developing Brain 53

44. Nguyen L, Rigo JM, Rocher V, et al. Neurotransmitters as early signals


for central nervous system development. Cell Tissue Res. 2001;305:
187202.
45. Herlenius E, Lagercrantz H. Development of neurotransmitter
systems during critical periods. Exp Neurol. 2004;190(Suppl 1):
S8-S21.
46. Lujan R, Shigemoto R, Lopez-Bendito G. Glutamate and GABA
receptor signalling in the developing brain. Neuroscience. 2005;130:
567580.
47. McMahon D. Chemical messengers in development: a hypothesis.
Science. 1974;185:10121021.
48. Owens DF, Kriegstein AR. Developmental neurotransmitters?
Neuron. 2002;36:989991.
49. Poulter MO, Barker JL, OCarroll AM, et al. Differential and transient
expression of GABAA receptor alpha-subunit mRNAs in the developing rat CNS. J Neurosci. 1992;12:28882900.
50. Laurie DJ, Wisden W, Seeburg PH. The distribution of thirteen
GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and
postnatal development. J Neurosci. 1992;12:41514172.
51. Yu ZY, Wang W, Fritschy JM, et al. Changes in neocortical and
hippocampal GABAA receptor subunit distribution during brain
maturation and aging. Brain Res. 2006;1099:7381.
52. Hutcheon B, Fritschy JM, Poulter MO. Organization of GABA
receptor alpha-subunit clustering in the developing rat neocortex and
hippocampus. Eur J Neurosci. 2004;19:24752487.
53. Rivera C, Voipio J, Kaila K. Two developmental switches in
GABAergic signalling: the K+-Cl cotransporter KCC2 and carbonic
anhydrase CAVII; J Physiol. 2005;562:2736.
54. Bardoul M, Levallois C, Konig N. Functional AMPA/kainate
receptors in human embryonic and foetal central nervous system.
J Chem Neuroanat. 1998;14:7985.
55. Gallo V, Pende M, Scherer S, et al. Expression and regulation of
kainate and AMPA receptors in uncommitted and committed neural
progenitors. Neurochem Res. 1995;20:549560.
56. Ritter LM, Unis AS, Meador-Woodruff JH. Ontogeny of ionotropic
glutamate receptor expression in human fetal brain. Brain Res Dev
Brain Res. 2001;127:123133.
57. Scherer SE, Gallo V. Expression and regulation of kainate and
AMPA receptors in the rat neural tube. J Neurosci Res. 1998;52:
356368.
58. Pellegrini-Giampietro DE, Bennett MV, Zukin RS. Differential
expression of three glutamate receptor genes in developing rat brain:
an in situ hybridization study. Proc Natl Acad Sci U S A. 1991;88:
41574161.
59. Gallo V, Upson LM, Hayes WP, et al. Molecular cloning and development analysis of a new glutamate receptor subunit isoform in
cerebellum. J Neurosci. 1992;12:10101023.
60. Ripellino JA, Neve RL, Howe JR. Expression and heteromeric interactions of non-N-methyl-D-aspartate glutamate receptor subunits
in the developing and adult cerebellum. Neuroscience. 1998;82:
485497.
61. Migues PV, Cammarota M, Kavanagh J, et al. Maturational changes
in the subunit composition of AMPA receptors and the functional
consequences of their activation in chicken forebrain. Dev Neurosci.
2007;29:232240.
62. Martin LJ, Furuta A, Blackstone CD. AMPA receptor protein in
developing rat brain: glutamate receptor-1 expression and localization
change at regional, cellular, and subcellular levels with maturation.
Neuroscience. 1998;83:917928.
63. Hollmann M, Heinemann S. Cloned glutamate receptors. Annu Rev
Neurosci. 1994;17:31108.
64. Swanson GT, Kamboj SK, Cull-Candy SG. Single-channel properties
of recombinant AMPA receptors depend on RNA editing, splice
variation, and subunit composition. J Neurosci. 1997;17:5869.
65. Kumar SS, Bacci A, Kharazia V, Huguenard JR. A developmental
switch of AMPA receptor subunits in neocortical pyramidal neurons.
J Neurosci. 2002;22:30053015.

Bissonette-003-(F)

54

PART 1

4/5/11

5:29 PM

Page 54

Developmental Considerations

66. Lilliu V, Perrone-Capano C, Pernas-Alonso R, et al. Ontogeny of


kainate receptor gene expression in the developing rat midbrain and
striatum. Brain Res Mol Brain Res. 2002;104:110.
67. Bahn S, Volk B, Wisden W. Kainate receptor gene expression in the
developing rat brain. J Neurosci. 1994;14:55255547.
68. Watanabe M, Inoue Y, Sakimura K, Mishina M. Distinct spatiotemporal distributions of the NMDA receptor channel subunit
mRNAs in the brain. Ann N Y Acad Sci. 1993;707: 463466.
69. Takai H, Katayama K, Uetsuka K, et al. Distribution of N-methyl-Daspartate receptors (NMDARs) in the developing rat brain. Exp Mol
Pathol. 2003;75:8994.
70. Sun L, Margolis FL, Shipley MT, Lidow MS. Identification of a long
variant of mRNA encoding the NR3 subunit of the NMDA receptor:
its regional distribution and developmental expression in the rat
brain. FEBS Lett. 1998;441:392396.
71. Malosio ML, Marqueze-Pouey B, Kuhse J, Betz H. Widespread
expression of glycine receptor subunit mRNAs in the adult and
developing rat brain. EMBO J. 1991;10:24012409.
72. Langosch D, Thomas L, Betz H. Conserved quaternary structure of
ligand-gated ion channels: the postsynaptic glycine receptor is a
pentamer. Proc Natl Acad Sci U S A. 1988;85:73947398.
73. Flint AC, Liu X, Kriegstein AR. Nonsynaptic glycine receptor activation during early neocortical development. Neuron. 1998;20:
4353.
74. Aprison MH, Shank RP, Davidoff RA. A comparison of the concentration of glycine, a transmitter suspect, in different areas of the
brain and spinal cord in seven different vertebrates. Comp Biochem
Physiol. 1969;28:13451355.
75. Court JA, Lloyd S, Johnson M, et al. Nicotinic and muscarinic cholinergic receptor binding in the human hippocampal formation during
development and aging. Brain Res Dev Brain Res. 1997;101:93105.
76. Paterson D, Nordberg A. Neuronal nicotinic receptors in the human
brain. Prog Neurobiol. 2000;61:75111.
77. Naeff B, Schlumpf M, Lichtensteiger W. Pre- and postnatal development of high-affinity [3H]nicotine binding sites in rat brain regions:
an autoradiographic study. Brain Res Dev Brain Res. 1992;68:
163174.
78. Schuetze SM, Role LW. Developmental regulation of nicotinic acetylcholine receptors. Annu Rev Neurosci. 1987;10:403457.
79. Winzer-Serhan UH, Leslie FM. Codistribution of nicotinic
acetylcholine receptor subunit alpha3 and beta4 mRNAs during rat
brain development. J Comp Neurol. 1997;386:540554.
80. Zoli M, Le Novere N, Hill JAJ, Changeux JP. Developmental regulation of nicotinic ACh receptor subunit mRNAs in the rat central and
peripheral nervous systems. J Neurosci. 1995;15: 1912-1939.
81. Barnes NM, Sharp T. A review of central 5-HT receptors and their
function. Neuropharmacology. 1999;38:10831152.
82. Le Novere N, Changeux JP. LGICdb: the ligand-gated ion channel
database. Nucleic Acids Res. 2001;29:294295.
83. Derkach V, Surprenant A, North RA. 5-HT3 receptors are membrane
ion channels. Nature. 1989;339:706709.
84. Ronde P, Nichols RA. High calcium permeability of serotonin 5-HT3
receptors on presynaptic nerve terminals from rat striatum.
J Neurochem. 1998;70:10941103.
85. Lauder JM, Wallace JA, Krebs H. Roles for serotonin in neuroembryogenesis. Adv Exp Med Biol. 1981;133: 477506.
86. Tecott L, Shtrom S, Julius D. Expression of a serotonin-gated ion
channel in embryonic neural and nonneural tissues. Mol Cell
Neurosci. 1995;6:4355.
87. Niesler B, Walstab J, Combrink S, et al. Characterization of the novel
human serotonin receptor subunits 5-HT3C,5-HT3D, and 5-HT3E. Mol
Pharmacol. 2007;72:817.
88. Ma W, Barker JL. Complementary expressions of transcripts encoding
GAD67 and GABAA receptor alpha 4, beta 1, and gamma 1 subunits
in the proliferative zone of the embryonic rat central nervous system.
J Neurosci. 1995;15:25472560.

89. LoTurco JJ, Owens DF, Heath MJ, et al. GABA and glutamate
depolarize cortical progenitor cells and inhibit DNA synthesis.
Neuron. 1995;15:12871298.
90. Antonopoulos J, Pappas IS, Parnavelas JG. Activation of the GABAA
receptor inhibits the proliferative effects of bFGF in cortical
progenitor cells. Eur J Neurosci. 1997;9:291298.
91. Nguyen L, Malgrange B, Breuskin I, et al. Autocrine/paracrine
activation of the GABA(A) receptor inhibits the proliferation of
neurogenic polysialylated neural cell adhesion molecule-positive
(PSA-NCAM+) precursor cells from postnatal striatum. J Neurosci.
2003;23:32783294.
92. Haydar TF, Wang F, Schwartz ML, Rakic P. Differential modulation
of proliferation in the neocortical ventricular and subventricular
zones. J Neurosci. 2000;20:57645774.
93. Kornack DR, Rakic P. Changes in cell-cycle kinetics during the
development and evolution of primate neocortex. Proc Natl Acad
Sci U S A. 1998;95:12421246.
94. Liu X, Wang Q, Haydar TF, Bordey A. Nonsynaptic GABA signaling
in postnatal subventricular zone controls proliferation of GFAPexpressing progenitors. Nat Neurosci. 2005;8:11791187.
95. Maric D, Liu QY, Grant GM, et al. Functional ionotropic glutamate
receptors emerge during terminal cell division and early neuronal
differentiation of rat neuroepithelial cells. J Neurosci Res. 2000;
61:652662.
96. Steinhauser C, Gallo V. News on glutamate receptors in glial cells.
Trends Neurosci. 1996;19:339345.
97. Luk KC, Kennedy TE, Sadikot AF. Glutamate promotes proliferation
of striatal neuronal progenitors by an NMDA receptor-mediated
mechanism. J Neurosci. 2003;23:22392250.
98. Cameron HA, Hazel TG, McKay RD. Regulation of neurogenesis by
growth factors and neurotransmitters. J Neurobiol. 1998;36:287306.
99. Cameron HA, McEwen BS, Gould E. Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the
dentate gyrus. J Neurosci. 1995;15:46874692.
100. Kato M, Dobyns WB. Lissencephaly and the molecular basis
of neuronal migration. Hum Mol Genet. 2003;12(Spec No 1):
R89R96.
101. Nadarajah B, Parnavelas JG. Modes of neuronal migration in the
developing cerebral cortex. Nat Rev Neurosci. 2002;3:423432.
102. Heng JI, Moonen G, Nguyen L. Neurotransmitters regulate cell
migration in the telencephalon. Eur J Neurosci. 2007;26:537546.
103. Behar TN, Li YX, Tran HT, et al. GABA stimulates chemotaxis and
chemokinesis of embryonic cortical neurons via calcium-dependent
mechanisms. J Neurosci. 1996;16:18081818.
104. Behar TN, Schaffner AE, Scott CA, et al. Differential response of
cortical plate and ventricular zone cells to GABA as a migration
stimulus. J Neurosci. 1998;18:63786387.
105. Behar TN, Schaffner AE, Scott CA, et al. GABA receptor antagonists
modulate postmitotic cell migration in slice cultures of embryonic
rat cortex. Cereb Cortex. 2000;10:899909.
106. Cuzon VC, Yeh PW, Cheng Q, Yeh HH. Ambient GABA promotes
cortical entry of tangentially migrating cells derived from the medial
ganglionic eminence. Cereb Cortex. 2006;16:13771388.
107. Manent JB, Demarque M, Jorquera I, et al. A noncanonical release
of GABA and glutamate modulates neuronal migration. J Neurosci.
2005;25:47554765.
108. Manent JB, Jorquera I, Ben-Ari Y, et al. Glutamate acting on AMPA
but not NMDA receptors modulates the migration of hippocampal
interneurons. J Neurosci. 2006;26:59015909.
109. Behar TN, Scott CA, Greene CL, et al. Glutamate acting at NMDA
receptors stimulates embryonic cortical neuronal migration.
J Neurosci. 1999;19:44494461.
110. Komuro H, Rakic P. Modulation of neuronal migration by NMDA
receptors, Science. 1993;260:9597.
111. McAllister AK. Cellular and molecular mechanisms of dendrite
growth. Cereb Cortex. 2000;10:963973.

Bissonette-003-(F)

4/5/11

5:29 PM

Page 55

CHAPTER 3
112. Cline HT. Dendritic arbor development and synaptogenesis. Curr
Opin Neurobiol. 2001;11:118126.
113. Wong RO, Ghosh A. Activity-dependent regulation of dendritic
growth and patterning. Nat Rev Neurosci. 2002;3:803812.
114. Borodinsky LN, OLeary D, Neale JH, et al. GABA-induced neurite
outgrowth of cerebellar granule cells is mediated by GABA(A) receptor activation, calcium influx and CaMKII and erk1/2 pathways.
J Neurochem. 2003;84:14111420.
115. Furuya S, Tabata T, Mitoma J, et al. L-Serine and glycine serve as
major astroglia-derived trophic factors for cerebellar Purkinje
neurons. Proc Natl Acad Sci U S A. 2000;97:1152811533.
116. Tapia JC, Mentis GZ, Navarrete R, et al. Early expression of glycine
and GABA(A) receptors in developing spinal cord neurons. Effects
on neurite outgrowth. Neuroscience. 2001;108:493506.
117. Pearce IA, Cambray-Deakin MA, Burgoyne RD. Glutamate acting
on NMDA receptors stimulates neurite outgrowth from cerebellar
granule cells. FEBS Lett. 1987;223:143147.
118. Wilson MT, Kisaalita WS, Keith CH. Glutamate-induced changes
in the pattern of hippocampal dendrite outgrowth: a role for
calcium-dependent pathways and the microtubule cytoskeleton.
J Neurobiol. 2000;43:159172.
119. Metzger F, Wiese S, Sendtner M. Effect of glutamate on dendritic
growth in embryonic rat motoneurons. J Neurosci. 1998;18:1735
1742.
120. Coronas V, Durand M, Chabot JG, et al. Acetylcholine induces
neuritic outgrowth in rat primary olfactory bulb cultures. Neuroscience. 2000;98:213219.
121. Owen A, Bird M. Acetylcholine as a regulator of neurite outgrowth
and motility in cultured embryonic mouse spinal cord. Neuroreport.
1995;6:22692272.
122. Homma K, Kitamura Y, Ogawa H, Oka K. Serotonin induces the
increase in intracellular Ca2+ that enhances neurite outgrowth in
PC12 cells via activation of 5-HT3 receptors and voltage-gated
calcium channels. J Neurosci Res. 2006;84:316325.
123. Miller M. Maturation of rat visual cortex. I. A quantitative study
of Golgi-impregnated pyramidal neurons. J Neurocytol. 1981;10:
859878.
124. Miller M, Peters A. Maturation of rat visual cortex. II. A combined
Golgi-electron microscope study of pyramidal neurons. J Comp
Neurol. 1981;203:555573.
125. Hensch TK. Critical period regulation. Annu Rev Neurosci. 2004;
27:549579.
126. Hensch TK. Critical period plasticity in local cortical circuits. Nat
Rev Neurosci. 2005;6:877888.
127. Olney JW. New insights and new issues in developmental
neurotoxicology. Neurotoxicology. 2002;23:659668.
128. Olney JW, Sharpe LG. Brain lesions in an infant Rhesus monkey
treated with monsodium glutamate. Science. 1969;166:386388.
129. Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain.
Science. 1999;283:7074.
130. Asada H, Kawamura Y, Maruyama K, et al. Cleft palate and decreased brain gamma-aminobutyric acid in mice lacking the 67-kDa
isoform of glutamic acid decarboxylase. Proc Natl Acad Sci U S A.
1997;94:64966499.
131. Hensch TK, Fagiolini M, Mataga N, et al. Local GABA circuit
control of experience-dependent plasticity in developing visual
cortex. Science. 1998;282:15041508.
132. Adams SM, de Rivero Vaccari JC, Corriveau RA. Pronounced cell
death in the absence of NMDA receptors in the developing
somatosensory thalamus. J Neurosci. 2004;24:94419450.
133. Li Y, Erzurumlu RS, Chen C, et al. Whisker-related neuronal
patterns fail to develop in the trigeminal brainstem nuclei of
NMDAR1 knockout mice. Cell. 1994;76:427437.
134. Iwasato T, Datwani A, Wolf AM, et al. Cortex-restricted disruption
of NMDAR1 impairs neuronal patterns in the barrel cortex. Nature.
2000;406:726731.

Anesthesia and the Developing Brain 55

135. Roerig B, Nelson DA, Katz LC. Fast synaptic signaling by nicotinic
acetylcholine and serotonin 5-HT3 receptors in developing visual
cortex. J Neurosci. 1997;17:83538362.
136. Roerig B, Katz LC. Modulation of intrinsic circuits by serotonin
5-HT3 receptors in developing ferret visual cortex. J Neurosci. 1997;
17:83248338.
137. Broide RS, Robertson RT, Leslie FM. Regulation of alpha7 nicotinic
acetylcholine receptors in the developing rat somatosensory cortex
by thalamocortical afferents. J Neurosci. 1996;16:29562971.
138. Aramakis VB, Metherate R. Nicotine selectively enhances NMDA
receptormediated synaptic transmission during postnatal development in sensory neocortex. J Neurosci. 1998;18:84858495.
139. Aramakis VB, Hsieh CY, Leslie FM, Metherate R. A critical period
for nicotine-induced disruption of synaptic development in rat
auditory cortex. J Neurosci. 2000;20:61066116.
140. Ikonomidou C, Bittigau P, Ishimaru MJ, et al. Ethanol-induced
apoptotic neurodegeneration and fetal alcohol syndrome. Science.
2000;287:10561060.
141. Albers GW, Goldberg MP, Choi DW. N-Methyl-D-aspartate antagonists: ready for clinical trial in brain ischemia? Ann Neurol. 1989;
25:398403.
142. Bullock R. Strategies for neuroprotection with glutamate antagonists. Extrapolating from evidence taken from the first stroke and
head injury studies. Ann N Y Acad Sci. 1995;765:272278; discussion 298.
143. Himmelseher S, Durieux ME. Revising a dogma: ketamine for
patients with neurological injury? Anesth Analg. 2005;101:524534,
table of contents.
144. Olney JW, Labruyere J, Price MT. Pathological changes induced in
cerebrocortical neurons by phencyclidine and related drugs. Science.
1989;244:13601362.
145. Slikker WJ, Zou X, Hotchkiss CE, et al. Ketamine-induced neuronal
cell death in the perinatal rhesus monkey. Toxicol Sci. 2007;98:
145158.
146. Hayashi H, Dikkes P, Soriano SG. Repeated administration of
ketamine may lead to neuronal degeneration in the developing rat
brain. Paediatr Anaesth. 2002;12:770774.
147. Scallet AC, Schmued LC, Slikker W Jr, et al. Developmental
neurotoxicity of ketamine: morphometric confirmation, exposure
parameters, and multiple fluorescent labeling of apoptotic neurons.
Toxicol Sci. 2004;81:364370.
148. Young C, Jevtovic-Todorovic V, Qin YQ, et al. Potential of ketamine
and midazolam, individually or in combination, to induce apoptotic
neurodegeneration in the infant mouse brain. Br J Pharmacol.
2005;146:189197.
149. Gascon E, Vutskits L, Zhang H, et al. Z. Sequential activation of p75
and TrkB is involved in dendritic development of subventricular
zone-derived neuronal progenitors in vitro. Eur J Neurosci.
2005;21:6980.
150. Malinovsky JM, Servin F, Cozian A, et al. Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth. 1996;77:203207.
151. Weber F, Wulf H, Gruber M, Biallas R. S-Setamine and Snorketamine plasma concentrations after nasal and i.v. administration in anesthetized children. Paediatr Anaesth. 2004;14:983988.
152. Vutskits L, Gascon E, Tassonyi E, Kiss JZ. Effect of ketamine on
dendritic arbor development and survival of immature GABAergic
neurons in vitro. Toxicol Sci. 2006;91:540549.
153. Takadera T, Ishida A, Ohyashiki T. Ketamine-induced apoptosis in
cultured rat cortical neurons. Toxicol Appl Pharmacol. 2006;210:
100107.
154. Linseman DA, Butts BD, Precht TA, et al. Glycogen synthase
kinase-3beta phosphorylates Bax and promotes its mitochondrial
localization during neuronal apoptosis, J Neurosci. 2004;24: 9993
10002.

Bissonette-003-(F)

56

PART 1

4/5/11

5:29 PM

Page 56

Developmental Considerations

155. Nixon K, Hughes PD, Amsel A, Leslie SW. NMDA receptor subunit
expression following early postnatal exposure to ethanol. Brain Res
Dev Brain Res. 2002;139:295299.
156. Nixon K, Hughes PD, Amsel A, Leslie SW. NMDA receptor subunit
expression after combined prenatal and postnatal exposure to
ethanol. Alcohol Clin Exp Res. 2004;28:105112.
157. Li JH, Wang YH, Wolfe BB, et al. Developmental changes in localization of NMDA receptor subunits in primary cultures of cortical
neurons. Eur J Neurosci. 1998;10:17041715.
158. Keilhoff G, Bernstein HG, Becker A, et al. Increased neurogenesis
in a rat ketamine model of schizophrenia. Biol Psychiatry. 2004;
56:317322.
159. Bjornstrom K, Sjolander A, Schippert A, Eintrei C. A tyrosine kinase
regulates propofol-induced modulation of the beta-subunit of the
GABA(A) receptor and release of intracellular calcium in cortical
rat neurones. Acta Physiol Scand. 2002;175:227235.
160. Honegger P, Matthieu JM. Selective toxicity of the general anesthetic
propofol for GABAergic neurons in rat brain cell cultures. J Neurosci
Res. 1996;45:631636.
161. Al-Jahdari WS, Saito S, Nakano T, Goto F. Propofol induces growth
cone collapse and neurite retractions in chick explant culture. Can
J Anaesth. 2006;53:10781085.
162. Vutskits L, Gascon E, Tassonyi E, Kiss JZ. Clinically relevant concentrations of propofol but not midazolam alter in vitro dendritic
development of isolated gamma-aminobutyric acid-positive interneurons. Anesthesiology. 2005;102:970976.
163. Fredriksson A, Ponten E, Gordh T, Eriksson P. Neonatal exposure to
a combination of N-methyl-D-aspartate and gamma-aminobutyric
acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits. Anesthesiology.
2007;107:427436.
164. Rudolph U, Antkowiak B. Molecular and neuronal substrates for
general anaesthetics. Nat Rev Neurosci. 2004;5:709720.
165. Fiszman ML, Behar T, Lange GD, et al. GABAergic cells and signals
appear together in the early post-mitotic period of telencephalic and
striatal development. Brain Res Dev Brain Res. 1993;73:243251.
166. Lauder JM, Han VK, Henderson P, et al. Prenatal ontogeny of the
GABAergic system in the rat brain: an immunocytochemical study.
Neuroscience. 1986;19:465493.
167. Kellogg C, Tervo D, Ison J, et al. Prenatal exposure to diazepam
alters behavioral development in rats. Science. 1980;207:205207.
168. Kellogg CK, Simmons RD, Miller RK, Ison JR. Prenatal diazepam
exposure in rats: long-lasting functional changes in the offspring.
Neurobehav Toxicol Teratol. 1985;7:483488.
169. Simmons RD, Miller RK, Kellogg CK. Prenatal exposure to
diazepam alters central and peripheral responses to stress in adult
rat offspring. Brain Res. 1984;307:3946.
170. Roberts AA, Pleger GL, Kellogg CK. Effect of prenatal exposure to
diazepam on brain GABA(A) receptor mRNA levels in rats examined at late fetal or adult ages. Dev Neurosci. 2001;23:135144.
171. Raol YH, Zhang G, Budreck EC, Brooks-Kayal AR. Long-term
effects of diazepam and phenobarbital treatment during development on GABA receptors, transporters and glutamic acid decarboxylase. Neuroscience. 2005;132, 399407.
172. Martire M, Altobelli D, Cannizzaro C, et al. Prenatal diazepam
exposure functionally alters the GABA(A) receptor that modulates
[3H]noradrenaline release from rat hippocampal synaptosomes.
Dev Neurosci. 2002;24 7178.
173. Rudin M, Ben-Abraham R, Gazit V, et al. Single-dose ketamine
administration induces apoptosis in neonatal mouse brain. J Basic
Clin Physiol Pharmacol. 2005;16:231243.
174. Bittigau P, Sifringer M, Genz K, et al. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad
Sci U S A. 2002;99:1508915094.
175. Uemura E, Levin ED, Bowman RE. Effects of halothane on synaptogenesis and learning behavior in rats. Exp Neurol. 1985;89:520529.

176. Levin ED, Uemura E, Bowman RE. Neurobehavioral toxicology of


halothane in rats. Neurotoxicol Teratol. 1991;13:461470.
177. Wise-Faberowski L, Zhang H, Ing R, et al. Isoflurane-induced
neuronal degeneration: an evaluation in organotypic hippocampal
slice cultures. Anesth Analg. 2005;101:651657.
178. Li Y, Liang G, Wang S, et al. Effects of fetal exposure to isoflurane on
postnatal memory and learning in rats. Neuropharmacology. 2007;
53:942950.
179. Johnson SA, Young C, Olney JW. Isoflurane-induced neuroapoptosis in the developing brain of nonhypoglycemic mice. J Neurosurg
Anesthesiol. 2008;20:2128.
180. Stratmann G, Bouchra H, Arora K, et al. Isoflurane increases stem
cell proliferation in adult but not in neonatal rat hippocampi. Soc
Neurosci Abst. 2005;826:829.
181. Mullenix PJ, Moore PA, Tassinari MS. Behavioral toxicity of nitrous
oxide in rats following prenatal exposure. Toxicol Ind Health. 1986;
2:273287.
182. Jevtovic-Todorovic V, Benshoff N, Olney JW. Ketamine potentiates
cerebrocortical damage induced by the common anaesthetic agent
nitrous oxide in adult rats. Br J Pharmacol. 2000;130:16921698.
183. Milligan G. Opioid receptors and their interacting proteins.
Neuromolecular Med. 2005;7:5159.
184. Tegeder I, Geisslinger G. Opioids as modulators of cell death and
survivalunraveling mechanisms and revealing new indications.
Pharmacol Rev. 2004;56:351369.
185. Zhu Y, Hsu MS, Pintar JE. Developmental expression of the mu,
kappa, and delta opioid receptor mRNAs in mouse. J Neurosci.
1998;18:25382549.
186. Georges F, Normand E, Bloch B, Le Moine C. Opioid receptor gene
expression in the rat brain during ontogeny, with special reference
to the mesostriatal system: an in situ hybridization study. Brain Res
Dev Brain Res. 1998;109:187199.
187. Zagon IS, McLaughlin PJ. Morphine and brain growth retardation
in the rat. Pharmacology. 1977;15:276282.
188. Ford DH, Rhines RK. Prenatal exposure to methadone HCl in
relationship to body and brain growth in the rat. Acta Neurol Scand.
1979;59:248262.
189. Hammer RPJ, Ricalde AA, Seatriz JV. Effects of opiates on brain
development. Neurotoxicology. 1989;10:475483.
190. Ricalde AA, Hammer RPJ. Perinatal opiate treatment delays growth
of cortical dendrites. Neurosci Lett. 1990;115:137143.
191. Seatriz JV, Hammer RPJ. Effects of opiates on neuronal development
in the rat cerebral cortex. Brain Res Bull. 1993;30:523527.
192. Zagon IS, McLaughlin PJ, Thompson CI. Development of motor
activity in young rats following perinatal methadone exposure.
Pharmacol Biochem Behav. 1979;10:743749.
193. Zagon IS, McLaughlin PJ, Thompson CI. Learning ability in adult
female rats perinatally exposed to methadone. Pharmacol Biochem
Behav. 1979;10:889894.
194. Zagon IS, McLaughlin PJ. Increased brain size and cellular content
in infant rats treated with an opiate antagonist. Science. 1983;221:
11791180.
195. Reznikov K, Hauser KF, Nazarevskaja G, et al. Opioids modulate
cell division in the germinal zone of the late embryonic neocortex.
Eur J Neurosci. 1999;11:27112719.
196. Hauser KF, Houdi AA, Turbek CS, et al. Opioids intrinsically inhibit
the genesis of mouse cerebellar granule neuron precursors in vitro:
differential impact of mu and delta receptor activation on proliferation and neurite elongation. Eur J Neurosci. 2000;12:12811293.
197. Knapp PE, Maderspach K, Hauser KF. Endogenous opioid system in
developing normal and jimpy oligodendrocytes: mu and kappa
opioid receptors mediate differential mitogenic and growth
responses. Glia. 1998;22:189201.
198. Sargeant T.J, Day DJ, Mrkusich EM, et al. Mu opioid receptors are
expressed on radial glia but not migrating neuroblasts in the late
embryonic mouse brain. Brain Res. 2007;1175:2838.

Bissonette-003-(F)

4/5/11

5:29 PM

Page 57

CHAPTER 3
199. Grimm MC, Ben-Baruch A, Taub DD, et al. Opiate inhibition of
chemokine-induced chemotaxis. Ann N Y Acad Sci. 1998;840:920.
200. Takayama N, Ueda H. Morphine-induced chemotaxis and brainderived neurotrophic factor expression in microglia. J Neurosci.
2005;25:430435.
201. Hauser KF, McLaughlin PJ, Zagon IS. Endogenous opioids regulate
dendritic growth and spine formation in developing rat brain. Brain
Res. 1987;416:157161.
202. Hauser KF, McLaughlin PJ, Zagon IS. Endogenous opioid systems
and the regulation of dendritic growth and spine formation. J Comp
Neurol. 1989;281:1322.
203. Tenconi B, Lesma E, DiGiulio AM, Gorio A. High opioid doses
inhibit whereas low doses enhance neuritogenesis in PC12 cells.
Brain Res Dev Brain Res. 1996;94:175181.
204. Brailoiu E, Hoard J, Brailoiu GC, et al. Ultra low concentrations of
morphine increase neurite outgrowth in cultured rat spinal cord and
cerebral cortical neurons. Neurosci Lett. 2004;365:1013.
205. Sakaguchi M, Fujimori T, Satoh T, et al. Effects of opioids on
neuronal survival in culture of embryonic chick dorsal root ganglion
neurons. Neurosci Lett. 1999;262:1720.
206. Kofke WA, Garman RH, Stiller RL, et al. Opioid neurotoxicity:
fentanyl dose-response effects in rats. Anesth Analg. 1996;83:1298
1306.
207. Kofke WA, Garman RH, Garman R, Rose M. Opioid neurotoxicity:
role of neurotransmitter systems. Neurol Res. 2000;22:733737.
208. Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in
neonates and young children. Anesth Analg. 2007;104:509520.
209. Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure
to common anesthetic agents causes widespread neurodegeneration
in the developing rat brain and persistent learning deficits.
J Neurosci. 2003;23:876882.
210. Lu LX, Yon JH, Carter LB, Jevtovic-Todorovic V. General anesthesia
activates BDNF-dependent neuroapoptosis in the developing rat
brain. Apoptosis. 2006;11:16031615.
211. Teng KK, Hempstead BL. Neurotrophins and their receptors:
signaling trios in complex biological systems. Cell Mol Life Sci.
2004;61:3548.
212. Yon JH, Carter LB, Reiter RJ, Jevtovic-Todorovic V. Melatonin
reduces the severity of anesthesia-induced apoptotic neurodegeneration in the developing rat brain. Neurobiol Dis. 2006;21:
522530.
213. Zou X, Sadovova N, Patterson TA, et al. The effects of l-carnitine
on the combination of, inhalation anesthetic-induced developmental, neuronal apoptosis in the rat frontal cortex. Neuroscience.
2008;151:10531065.
214. Ma D, Williamson P, Januszewski A, et al. Xenon mitigates
isoflurane-induced neuronal apoptosis in the developing rodent
brain. Anesthesiology. 2007;106:746753.
215. Berde C, Cairns B. Developmental pharmacology across species:
promise and problems. Anesth Analg. 2000;91:15.
216. Rizzi S, Carter LB, Ori C, Jevtovic-Todorovic V. Clinical anesthesia
causes permanent damage to the fetal guinea pig brain. Brain Pathol.
2008;18:198210.
217. Anand KJ, Soriano SG. Anesthetic agents and the immature
brain: are these toxic or therapeutic? Anesthesiology. 2004;101:
527530.
218. Roytblat L, Talmor D, Rachinsky M, et al. Ketamine attenuates the
interleukin-6 response after cardiopulmonary bypass. Anesth Analg.
1998;87:266271.
219. Zilberstein G, Levy R, Rachinsky M, et al. Ketamine attenuates
neutrophil activation after cardiopulmonary bypass. Anesth Analg.
2002;95:531536, table of contents.
220. Lipton SA, Nakanishi N. Shakespeare in lovewith NMDA
receptors? Nat Med. 1999;5:270271.
221. Bhutta AT, Anand KJ. Vulnerability of the developing brain.
Neuronal mechanisms. Clin Perinatol. 2002;29:357372.

Anesthesia and the Developing Brain 57

222. Anand KJ, Garg S, Rovnaghi CR, et al. Ketamine reduces the cell
death following inflammatory pain in newborn rat brai. Pediatr Res.
2007;62:283290.
223. Olney JW, Young C, Wozniak DF, et al. Anesthesia-induced developmental neuroapoptosis. Does it happen in humans? Anesthesiology.
2004;101: 273275.
224. Dobbing J. Undernutrition and the developing brain. The relevance
of animal models to the human problem. Am J Dis Child. 1970;
120:411415.
225. Lucas A, Morley R, Cole TJ. Randomised trial of early diet
in preterm babies and later intelligence quotient. BMJ. 1998;317:
14811487.
226. Chacko J, Ford WD, Haslam R. Growth and neurodevelopmental
outcome in extremely-low-birth-weight infants after laparotomy.
Pediatr Surg Int. 1999;15:496499.
227. Ludman L, Spitz L, Lansdown R. Developmental progress of
newborns undergoing neonatal surgery. J Pediatr Surg. 1990;25:
469471.
228. Ludman L, Spitz L, Wade A. Educational attainments in early
adolescence of infants who required major neonatal surgery.
J Pediatr Surg. 2001;36:858862.
229. Bouman NH, Koot HM, Hazebroek FW. Long-term physical,
psychological, and social functioning of children with esophageal
atresia. J Pediatr Surg. 1999;34:399404.
230. Bouman NH, Koot HM, Tibboel D, Hazebroek FW. Children with
congenital diaphragmatic hernia are at risk for lower levels of
cognitive functioning and increased emotional and behavioral
problems. Eur J Pediatr Surg. 2000;10:37.
231. Kabra NS, Schmidt B, Roberts RS, et al. Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants: results from the Trial of
Indomethacin Prophylaxis in Preterms. J Pediatr. 2007;150:229234,
234.e1.
232. Davidson A, McCann ME, Morton N. Anesthesia neurotoxicity
in neonates: the need for clinical research. Anesth Analg. 2007;105:
881882.
233. Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of
fentanyl anaesthesia in preterm babies undergoing surgery: effects
on the stress response. Lancet. 1987;1:6266.
234. Anand KJ, Sippell WG, Schofield NM, Aynsley-Green A. Does
halothane anaesthesia decrease the metabolic and endocrine stress
responses of newborn infants undergoing operation? Br Med J (Clin
Res Ed). 1988;296:668672.
235. Anand KJ, Hickey PR. Halothane-morphine compared with highdose sufentanil for anesthesia and postoperative analgesia in
neonatal cardiac surgery. N Engl J Med. 1992;326:19.
236. Peters JW, Schouw R, Anand KJ, et al. Does neonatal surgery lead
to increased pain sensitivity in later childhood? Pain. 2005;114:
444454.
237. Botting N, Powls A, Cooke RW, Marlow N. Attention deficit hyperactivity disorders and other psychiatric outcomes in very low
birthweight children at 12 years. J Child Psychol Psychiatry. 1997;38:
931941.
238. Whitfield MF, Grunau RE. Behavior, pain perception, and the
extremely low-birth weight survivor. Clin Perinatol. 2000;27:
363379.
239. Coplan JD, Andrews MW, Rosenblum LA, et al. Persistent elevations
of cerebrospinal fluid concentrations of corticotropin-releasing
factor in adult nonhuman primates exposed to early-life stressors:
implications for the pathophysiology of mood and anxiety disorders.
Proc Natl Acad Sci U S A. 1996;93:16191623.
240. Jacobson B, Bygdeman M. Obstetric care and proneness of offspring
to suicide as adults: case-control study. BMJ. 1998;317:13461349.
241. Salk L, Lipsitt LP, Sturner WQ, et al. Relationship of maternal and
perinatal conditions to eventual adolescent suicide. Lancet.
1985;1:624627.

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Nociception and Pain Perception


in Infants and Children
Suzanne Wiener and Joseph D. Tobias

INTRODUCTION
The study of pediatric pain from the underlying neurobiologic
mechanisms to its effective management has grown since the early
1990s into an extremely active and important field. A crucial
change has been the realization that infants experience pain and
demonstrate dramatic and robust pain behaviors. Before that
realization, there was the misconception that the immaturity of
the central and peripheral nervous systems was such that infants
did not feel pain, and consequently, analgesia for painful interventions was unnecessary. However, it is now fully accepted not
only that infants are capable of experiencing pain but that there
are potential acute and long-term adverse effects from the undertreatment of pain.1
Pain sensation involves a multilayered network of nociceptors,
nerve fibers, neurons, and glial cells distributed in multiple
peripheral, spinal, and supraspinal areas, forming diverse feedback
and feed-forward loops. The participation, function, and neurochemical profiles of these cellular elements are constantly modified by external and internal cues.2,3 Signaling of pain at any stage
of development depends not only on the context and characteristics of the painful stimulus but also on the behavioral state and
cognitive demands at that time.2
Current pain research shows that the neonate or infant is not a
merely a little adult. Structures and mechanisms used for pain
processing during early development are unique and different
from those used in adult pain processing. Many of these structures
or mechanisms are not maintained beyond specific periods of
early development.4,5 Thus, the immature pain system plays a
signaling role during each stage of development and uses neural
elements available at that time to fulfill this role.6 This plasticity of
the developing nervous system may allow for the greatest impact
of pain to occur in the most premature infants.5
To better understand the tremendous impact of pain on the
developing nervous system and its pervasive long-term effects, we
review the uniqueness of the nocioceptive pathway including

4
C H A P T E R

specific receptors, transduction, peripheral sensitization, phenotypic switches, transmission, ascending projections, supraspinal
centers, and the descending modulation systems. In addition
to the complex nervous pathways involved in nociception, the
sensing of pain, which occurs only after the integration of the
noxious message into supraspinal centers, can be affected by
numerous factors. These include psychological factors (sex,
age, cognitive level, previous pain experiences, family learning,
culture), situational factors (expectations, control, relevance), and
emotional factors (fear, anger, frustration). Furthermore, this
chapter reviews how chronic pain syndromes develop and how
painful procedures, at an early age, can have deleterious long-term
consequences.

THE NOCICEPTIVE PATHWAY


Nociceptors
A nociceptor is a sensory receptor that sends signals that cause the
perception of pain in response to potentially damaging stimulus.
These receptors are found in any area of the body that can sense
pain either externally (skin, cornea, mucosa) or internally (muscles, joint, bladder, gut, digestive tract). They have four major
functional components (Figure 41): (1) the peripheral terminal
that transduces external stimuli and initiates action potentials;
(2) the axon that conducts action potentials; (3) the cell body that
controls the identity and integrity of the neuron, and (4) the
central terminal that forms the presynaptic element of the first
synapse in the sensory pathway in the central nervous system
(CNS).7 The cell bodies of the first-order neurons are located in
either the dorsal root ganglia (DRGs) or the trigeminal ganglia.
The trigeminal ganglia are specialized nerves for the face, whereas
the dorsal root ganglia are associated with the rest of the body.
Nociceptors are silent receptors and do not sense normal stimuli.
Only when activated by a threatening response (high-threshold
receptors) do they invoke a reflex.

Figure 4-1. Operational components of the nocioceptor including the peripheral terminal that innervates the tissue,
the axon that conducts the impulse toward the central nervous system, the cell body that lies in the dorsal root ganglia, and a central terminal that conducts information to the synapse with the second-order neuron.

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Nociceptors develop from neural crest stem cells. The neural
crest is responsible for a large part of the early development in
vertebrates and, more specifically, for neuronal development. The
neural crest stem cells form the neural tube, and nociceptors grow
from the dorsal part of this tube in a rostrocaudal progression.
They form late during neurogenesis when compared with
proprioceptors (A) or low-threshold mechanoreceptors (A),
which form during the early stages of gestation.5,8 These are non
pain-sensing receptors, so the development of nociceptors late in
neurogenesis allows for their different sensing capabilities. All
embryonic nociceptors express the TrkA nerve growth factor
(NGF) receptor.8 The formation of most TrkA+ neurons is dependent on the proneural transcripition factor neurogenin 1
(Ngn1). The homebox gene Brn3a and the zinc finger gene Klf7
are required for maintenance of TrkA expression. However, these
transcription factors are not specific for nociceptors.911 Following
sensory neurogenesis, differentiation occurs and two different
types of nociceptors are formed. They are classified as either
peptidergic or nonpeptidergic nociceptors. These two sets of receptors express distinct ion channels and receptors. This specialization allows the receptors to innervate different peripheral and
central targets. This differentiation occurs in both the perinatal
and the postnatal periods.
Early embryonic nociceptors share similar molecular identity,
co-expressing both TrkA and Runx1.11 The nonpeptidergic
nociceptors switch off the TrkA NGF and begin expressing Ret.
Ret is a transmembrane signaling component that allows for the
expression of another growth factor, the glial cellderived growth
factor (GDNF). Most of these neurons bind isolectin B4 (IB4).
This transition is assisted by Runx1, which has proved to be vital
in the development of nonpeptidergic nociceptors and in the
coordination of afferent targeting to the spinal cord. The signals
that trigger Runx1 down-regulation in the peptidergic neurons
remain unclear. The peptidergic nociceptors continue to use TrkA,
after the loss of Runx1 in the DRGs. They express a completely
different type of growth factor (calcitonin generelated peptide
[CGRP], Substance P [SP])11,12 and they do not bind IB4. Ongoing
research is attempting to determine more specifically what creates
the differences between these nociceptors.7
Nociceptors sensory channels/receptors can be divided into
Runx1-dependent and Runx1-independent subgroups. Runx1dependent genes are further divided into three groups: (1) Retdependent, (2) Ret-independent and TrkA-dependent, and
(3) Ret-independent and TrkA-independent.1314 Runx1 is selectively required for thermal, but not mechanical pain sensitivity in
vivo, supporting the idea that development of nociceptive mechanical and thermal sensitivity is subject to separate genetic control.
The sensory specificity of nociceptors is established by their
high threshold to particular stimuli. Only when the high threshold
has been reached by either chemical, thermal, or mechanical
stimuli are the nociceptors triggered. The majority of nociceptors
are classified by the type of stimulus to which they respond. Some
nociceptors respond to more than one stimulus and are consequently designated polymodal nociceptors. Other nociceptors respond to none of these modalities and yet may respond to
stimulation under conditions of inflammation after tissue damage
or after sensitization. This latter group is known as sleeping or
silent nociceptors.
Nociceptors have two different types of axons. The first are the
A fiber axons. They are myelinated and allow a fast action
potential to be carried to the spinal cord and CNS. The other type

Nociception and Pain Perception in Infants and Children

59

is the C fiber axon, which has slower conduction because of the


light or nonmyelination of the axon. Therefore, pain comes in two
phases. The first phase (first, sharp pain) is mediated by the fastconducting A fibers and the second (second, dull pain) by
C fibers. If there is massive, repetitive, or prolonged input to a
C fiber, there is progressive buildup in the spinal cord dorsal horn.
This phenomenon is called wind-up, which may increase sensitivity to pain.14

Transduction
Transduction is the first stage of the nociceptive pathway and
involves the process of converting a noxious or painful stimulus,
which can be mechanical, thermal, or chemical, into a nervous
impulse. Specific nociceptor transducers are responsible for how
and whether the specific nerve ending responds to stimulus.
Members of the TRP channel family (transient receptor potential;
cation channels; TRPV1, TRPV2, TRPV3, TRPV4),15 all expressing a particular C-terminal domain, detect noxious heat.16 The
extent to which all of these TRPs are involved in heat-responsive
nociceptor neurons remains uncertain. Heat-evoked activity in
nociceptors may also be modulated by co-expression of heatsensitive potassium channels like TREK-1, whose activity is reduced by increased heat. Cool stimuli are sensed by the TRPM8
channel, whereas the molecular transducers for noxious cold
remain unclear, perhaps involving TRPM8, TRPA1, and others.
Interestingly, although tactile sensibility and motor function
deteriorate in the cold, pain perception persists. This is achieved
by expression in nociceptor peripheral terminals of the TTX-R
Nav 1.8 voltage-gated sodium channel (VGSC), whose inactivation, unlike TTX-S channels, is cold resistant.17 The ENaC/DEG
channel family (degenerin/epithelial sodium channel) detects
mechanical stimuli. Although there are several candidates for the
high-threshold (pinch) mechanotransducers, as of today, all of
those appear to be invalid. These include TRPs (TRPA1), ASICs,
and potassium channels.18 Noxious chemicals, such as capsaicin
or acid (extracellular protons, spider toxins), may be detected
through a common transducer (TRPV1). TRPV1 appears to be a
major intergrator of diverse chemical (wasabie, mustard, raw
garlic, bradykinin) and perhaps even of thermal and mechanical
noxious stimuli.19,20
A single type of stimulus can interact with multiple detectors,
as seen by the ability of extracellular protons to activate not only
TRPV1, but also ASICs, which are also members of the ENaC/
DEG channel family.21 Furthermore, some nociceptors have quite
low thresholds with maximal responses in the noxious range
(TRPV3-4); others have thresholds so high that they do not
normally respond to noninjurious stimuli (TRPV2) and are called
sleeping or silent nociceptors because they wake and become responsive only in the presence of inflammation.7 Thus, transduction
is mediated by high-threshold transducer ion channels that
depolarize the peripheral terminal activating voltage-dependent
sodium channels.
Mutations in the NGF TrkA receptor that result in a failure of
nociceptor survival in the embryo22 lead to loss of nociceptor
neurons in patients with hereditary sensory and autonomic
neuropathy type 4, producing congenital pain hyposensitivity.
A congenital indifference to pain without loss of nociceptor
neurons has been shown recently to occur with loss of functional
mutations in the SCN9A gene encoding the alpha subunit of

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Nav 1.7 VGSC.23,24 These two examples of mutations reveal the


crucial importance of nociceptors as a warning device.

Peripheral Sensitization
Peripheral sensitization represents a form of stimulus-evoked
functional plasticity of the nociceptor. The stimulus is the sustained presence of inflammatory mediators released from injured
and inflammatory cells that sensitize the nociceptor, reducing the
threshold and increasing the responsiveness (primary hyperalgesia). The peripheral nociceptive hyperexcitability is induced
through increased receptor (autosensitization) or cell membrane
(heterosensitization) reactivity to stimuli. As a result of the change
in the chemical milieu produced by the disruption of cells, degranulation of mast cells, secretion by inflammatory cells, and
induction of enzymes like cycloxygenase-2 (COX-2), nociceptors
are no longer exclusively noxious stimuli detectors. They also
become detectors of innocuous inputs. Thus, low-intensity stimuli
gain access to the nociceptive pathway and begin to produce pain.
Various sensitizers (kinins, amines, prostanoids, growth factors,
chemokines, cytokines) combined with protons and adenosine
triphosphate (ATP), forming an inflammatory soup, are detected
by the nociceptor terminal and, as a result, change the properties
of the transducer and sodium channels, mainly as a result of
phosphorylation. Transducer channel activity is, thus, heightened
by the diverse inflammatory agents that bind to their cell-surface
receptors to stimulate phospholipase C (PLC- or PLC-) signaling
pathways. This, in turn, leads to hydrolysis of plasma membrane
lipids and the subsequent stimulation of protein kinase C subforms
(PKC-). Both of these actions have been proposed to potentiate
TRPV1 receptor function. Prostaglandins (PGE2) and other inflammatory products that activate adenylyl cyclase (AC) through
G-coupled receptors also enhance nociceptor excitability. This
occurs, in part, by cyclic adenosine monophosphatedependent
protein kinase (cAMP-PKA)dependent phosphorylation of Na,
1.8, and/or 1.9. Furthermore, substance P and CGRP dilate blood
vessels, increasing the local inflammatory response and contributing to peripheral sensitization. Several new products have also
been identified as peripheral sensitizers including the transforming
growth factor- (TGF-) member activin,25 TNF,26 the chemokine CCL3,27 prokineticins,28 proteases that activate proteaseactivated GPCR receptors,29,30 and GDNF.31
From multiple knockout studies, it has been shown that both
TRPV1 and TRPA1 contribute to peripheral sensitization as do
the VGSCs, Nav1.8, Nav1.7, and Nav1.9. TRP receptor antagonists and sodium channel selective blockers may be a useful
approach for reducing peripheral sensitization and thereby inflammatory pain.32

Phenotypic Switches
In addition to driving peripheral sensitization, peripheral inflammation produces retrograde signals in nociceptor neurons that
increase the transcription of neuropeptides, brain-derived neurotrophic factor (BDNF), and sodium channels in the cell body as
well as increase the translation of TRP channels to augment both
central transmission and peripheral sensitization. Furthermore,
the expression of -opioid receptors is increased by inflammation
via NGF enhancing sensitivity to opioids. Transport of NGFactivated Trk receptors and perhaps those of other growth factors

from the periphery appears to be a major means whereby nociceptor cell bodies change in response to peripheral inflammation.
Inflammation tends to cause an increase in the expression of specific nociceptive ion channels/receptors. The underlying transcriptional mechanisms are unclear and may involve axonal transport
of transcripts and local translation.7
If the peripheral axon of nociceptors is severely injured, disrupting contact of the cell body with its terminal and its peripheral
target, profound changes in transcription are induced. Negative
signals such as a loss of target-derived growth factors and positive
signals like retrograde protein kinase G or a vimentin-dependent
translocation of activated ERK drive activation of multiple signaltransduction pathways in the cell body that alter transcription in
more than 1000 genes. These molecular reactions are attempts
either by the neuron to survive the major insult or for the axon to
regrow. However, many axotomy-induced transcriptional changes
are maladaptive and produce alterations in function that can result
in neuropathic pain. Injured neurons lose some normal nociceptor
features (a down-regulation of TRP and sodium channels),
although at the same time gaining a new molecular identity. One
example of this is the up-regulation in DRG neurons of enzymes
involved in the synthesis and recycling of tetrahydrobiopterin
(BH4) after peripheral axonal injury. BH4 is an essential cofactor
for aromatic amine hydroxylases and nitric oxide synthetases. Its
increase drives NO production in DRG neurons, which in turn
increases calcium influx in the neurons. Inhibition of BH4 synthesis produces analgesia, whereas increased synthesis of BH4
produces painlike behavior. A human variant of the rate-limiting
enzyme in the BH4 pathway (guanosine triphosphate [GTP]
cyclohydrolase, which produces less BH4 in response to stress or
injury), is associated with decreased chronic pain in patients after
surgery. Although changes in the injured DRG neurons show a
major phenotypic shift, alterations are also seen in their spared,
noninjured neighbors. These cells may also be involved in the
genesis of chronic pain.

Presynaptic Terminal and Transmission


Stimuli from the periphery are transmitted to the spinal cord
through the sensory afferent nerves (Figure 42). Afferent
nociceptive fibers travel back to the spinal cord where they form
synapses in its superficial dorsal horn (gray matter) for somatic
neurons and in the spinal nucleus of the trigeminal nerve for those
neurons innervating the face. The nociceptive fiber located in the
periphery is known as a first-order neuron. The first-order neuron
carries the sensory input to the dorsal horn of the spinal cord
where they synapse with second-order neurons. This synapse
transfers information carried by action potentials regarding the
intensity and duration of the peripheral noxious stimuli. The
rostrocaudal and mediolateral topography of the central terminal
reflects the spatial location of the peripheral nociceptor, whereas
their dorsoventral location reflects the identity of the nociceptor.
Thus, they evoke fast and slow excitatory postsynaptic potentials
that exhibit significant spatial and temporal summation.7 Unlike
low-threshold primary sensory neurons that use glutamate as their
unique neurotransmitter, nociceptors use various compounds
including glutamate, neuropeptides (substance P), acetylcholine
(ACh)_, CGRP, and proteins like BDNF as transmitters and
synaptic modulators.
N-Type (CaV2.2) voltage-gated calcium channels are key
mediators of nociceptive signaling. These channels control the

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Figure 4-2. Schematic representation of the central regulation of pain and nocioceptive transmission.

release in the spinal cord of glutamate and neuropeptides such as


substance P. Consequently, inhibition of N-type channels via
activation of opioid receptors or by N-type channel antagonists
mediates analgesia. CaV2.2 RNA undergoes alternative splicing,
producing multiple CaV2.2 channel isoforms with distinct
electrophysiologic properties, distribution, and physiologic role.
CaV2.2 e37a variant is responsible for thermal and mechanical
nociception in undamaged tissues and thermal and mechanical
hyperalgesia during both inflammatory and neuropathic pain.
Both N-type channel CaV2.2 e37a and e37b isoforms, differing by
their proximal C terminus, contribute to tactile neuropathic
allodynia. N-Type channels and its alternative splicing of CaV2.2
are, thus, significantly involved in chronic pain. The elucidation
and better understanding of the molecular complexity in splice
variants and their respective locations and roles in different pain
pathways will allow for the development of better therapeutic
strategies for the treatment of chronic pain.33,34
Transmitter-modulated reductions in transmitter release from
nociceptors are a prominent control mechanism in nociceptor
input to the CNS. Chemicals involved in this modulation include
endogenous opioids acting on - and -opioid receptors (DOR),
gamma-aminobutyric acid (GABA) acting on GABAB receptors,
glycine, serotonin, norepinephrine (NE), and endogenous cannabinoids acting on CB1 receptors. The density of these receptors
changes based on several dynamic factors. In the case of the opioid receptor, there is an increase after inflammation and a
decrease after axonal injury. The DOR has another form of
regulation. Very little of the receptor is normally inserted in the
nociceptor terminal membrane. The majority of DORs are located
within the membrane in peptide-containing, large dense-core
vesicles. Following nociceptor activation, fusion of the vesicles to
the terminal membrane during synaptic release results in
stimulus-triggered exocytosis and the introduction of the receptor
into the terminal. Therefore, DOR-mediated analgesia requires
previous activation of the nociceptor before analgesia can be
achieved. Cannabinoids exert their analgesic action primarily on
CB1 receptors expressed on the peripheral terminals of nocicep-

tors. This mechanism of action of the cannabinoids may enable


the development of peripherally acting cannabinoid analgesics
without central side effects.
Other agents act to increase nociceptor input to the CNS. PGE2
and bradykinin act to increase transmitter release at the central
terminal. PGE2 is produced following induction of the COX-2
enzyme in dorsal horn neurons in response to peripheral inflammation, whereas bradykinin is released in the spinal cord within
minutes of nociceptor input. Both agents act via their G protein
coupled receptors to increase transmitter release.

Ascending Pathway
Following a painful stimulus, if sufficient numbers of a particular
type or types of nociceptors are activated, an afferent volley will be
produced. This ascending pathway initiates the conscious sensation of pain. A fibers, conveying fast, spontaneous pain, form
synapses in lamina I of the dorsal horn of the spinal cord
(Hematopoietic Progenitor Cells [HPC], which are reactive to
heat, pinch, and cold) and lamina V (WDR cells [wide-dynamicrange] neurons, which have large receptive fields and receive input
from mechanoreceptors in addition to nociceptors). In these
laminae, a synapse is formed with a second-order neuron. After
being activated by mainly glutamate-activated AMPA (-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) type of
glutamate receptors, the second-order neurons crosses the midline
through the anterior white commissure and travel cephalad
through the lateral spinothalamic tracts (STTs) or the neospinothalamic tracts, located in the anterolateral quadrant of the
controlateral spinal cord white matter. The second-order neurons,
without making connections elsewhere, terminate in the ventroposterior nucleus of the thalamus. The ventroposterior nucleus
includes the ventral posterolateral (VPL), the ventral posteromedial (VPM) and the posterior (PO) nuclei of the thalamus.
Third-order neurons project from the thalamus to the cortex and
synapse with the dendrites of the primary somatosensory cortex
(S1) in the postcentral gyrus.

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S1 is organized somatotopically and is subdivided into four


parallel strips: Brodmanns areas 3a, 3b, 1, and 2. In each area,
different receptor types predominate. In area 3a, afferents from
muscle predominate, whereas in area 3b, afferents from the skin
predominate. From area 3b, information is sent to areas 1 and 2,
which are important in recognizing the texture and the size/shape
of objects, respectively. The body representation (homunculus) in
S1 is distorted because some body parts are overrepresented
(hand, face) whereas other body parts are underrepresented
(trunk, leg). The distorsion is related to discriminative properties
that are more prominent in some territories (hand, face) than in
others. From S1, somatosensory information is then sent to
areas 5 and 7 in the posterior parietal associative somatosensory
cortex (S2) where stereognosis takes place. Fast pain is felt within
0.1 sec from the application of the painful stimulus and is sharp
and acute. Pain is detected as soon as it reaches the thalamus,
yet physical awareness of the location, quality, intensity, and extent
of the painful stimulus becomes possible only when the somatosensory cortex is activated. This ascending path is responsible for the discriminative aspect of nociception. Because it has
mainly controlateral projections, the body representation is
contralateral.
Conveying slow, increasing pain, C fibers enter the spinal cord
and connect with interneurons in laminae I, II, and possibly III.
The interneurons that receive this input express different subtypes
of glutaminergic receptors, namely N-methyl-D-aspartic acid
(NMDA) and AMPA. High levels of afferent input depolarize the
interneuron first through the AMPA then through the NMDA
receptors. The interneurons then transmit the signal, mainly
by the release of substance P (essential for wind-up), to the STT
cells (second-order neurons) that reside mainly in laminae I
(nociceptive-specific [NS] neurons), IV, and V. The axons of the
STT cells project across the spinal cord to the STT, joining fibers
from the fast pathway. Whereas fast-pain fibers travel through the
neospinothalamic tract (lateral), slow-pain fibers travel through
the paleospinothalamic tract (anterior). Both neospinothalamic
tract and paleospinothalamic tract convey ascending monosynaptic tracts and constitute the anterolateral extralemniscal system.
The paleospinothalamic neurons terminate in the ventrolateral
medulla, in various areas throughout the brainstem (reticular
formation), in the periaqueductal gray matter (mesencephalon), in
the parabrachial nucleus (pons), and in the thalamus (intralaminar
nucleus and other midline nuclei), where they synapse with thirdorder neurons. However, C fiber impulses are not relayed to the
somatosensory cortex, but rather to the frontal association cortex.
Their impulses are responsible for the affect that accompanies pain
and, thus, allows a cognitive appraisal of the nociceptive input.
The appraisal of pain is likely closely linked to ones pain tolerance.
Slow pain is different from acute pain because it is poorly localized
(non-discriminative), has a bilateral body representation, and is
described as an aching, throbbing, or burning pain.
The paleospinothalamic neurons include several ascending
monosynaptic tracts involved in the nociceptive process. The
neurons of the spinoreticular tract (SRT) originate mainly in
laminae V, VII, and VIII, and also in laminae I and X, mostly from
NS and WDR neurons, although also involving nonnociceptive
(N-NOC) neurons. These neurons propagate noxious and
innocuous stimuli from skin, viscera, and muscles. The SRT has
two projections to the brainstem. The first of these is directed to
the precerebellar nucleus in the lateral reticular formation and is

involved in motor control. The other is directed to the medial


pontobulbar reticular formation and is involved in the mechanisms of nociception. Few branches project to the centromedian
and intralaminar nuclei of the thalamus. Most fibers project
ipsilaterally, unlike the STTs. The afferents of the SRT are involved
in the motivational and affective characteristics as well as the
neurovegetative responses to pain. This tract is an important
pathway for the modulation of the nociceptive segmental pathways by activating brainstem structures responsible for descending
suppression.
The neurons of the spinomesencephalic tract (SMT) originate
in the WDR, substantia nigra (SN), and N-NOC neurons mainly
in laminae I, II, IV, V, VI, but also in laminae VII and X and in the
ventral horn. They terminate in several structures of the midbrain,
especially the periaqueductal gray (PAG) matter and the deep
layers of the superior colliculus. The projections to the PAG matter
originate from WDR and SN and are functionally distinct. Those
that reach the PAG in the portion more dorsal to the limiting
sulcus have an excitatory characteristic in afferent nociceptive
transmission, and those that project more ventral to the limiting
sulcus activate inhibitory mechanisms responsible for the
inhibition of the afferents of this same pathway. This suggests
an autoregulatory function of the medulla and midbrain. Stimulation of regions innervated by the SMT produces different responses involved in nociceptive processing. Responses include
aversive behaviors in the presence of noxious stimuli as well as
motor, autonomic, cardiovascular, motivational, and affective
responses.
The parabrachial nucleus (PN), constituting the spinoparabrachial tract (SPBT), receives direct and indirect afferents from
nociceptive pathways. The lateral parabrachial region receives
projection from nociceptive SN neurons originating in lamina I.
This area in turn projects primarily to the amygdala and hypothalamus. The patterns of nociceptive connectivity suggest that
the parabrachial area plays an important role in the motivational
and affective components of pain sensation and/or autonomic and
endocrine responses to noxious stimulation. Neurons in the internal lateral parabrachial nucleus also respond to noxious stimulation. By contrast to the lateral parabrachial region, nociceptive
input to the internal lateral parabrachial nucleus is derived from
the deep dorsal horn (laminae V and VI). Its neurons send their
axons to the medial thalamus, to the paracentral nucleus.
The spinohypothalamic tract (SHT) originates from laminae I,
V, X and some other regions around the central medullary canal.
It is composed of SN, WDR, and N-NOC neurons. These neurons
respond to noxious and innocuous stimulation coming from
muscles, tendons, joints, skin, and viscera. Its projections contribute to the neuroendocrine, autonomic, motivational-affective,
and alertness responses of pain of both somatic and visceral
origin.35 Two polysynaptic tracts, the spinocervicothalamic and
the dorsal horn postsynaptic tracts, are also involved in ascending
nociception. The spinocervicothalamic tract originates mainly
from laminae III and IV and, to a lesser extent, from laminae I,
II, and V. Its neurons receive afferents from peripheral A and
A fibers, consisting mostly of WDR and N-NOC fibers, although
SN neurons have also been described. Projections ascend in
the ipsilateral lateral cervical nucleus (LCN) where they
synapse. LCN neurons project to the controlateral thalamus via
the medial lemniscus. The functions related to this tract concern
the sensory-discriminative, motivational-affective, and autonomic

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characteristics of pain, as well as playing a role as in sensory
integration and modulation of afferent inputs in the spinal cord.
The dorsal horn postsynaptic tracts originate mainly from
laminae III and V as well as laminae VI and VII. The input is composed mainly of WDR and N-NOC neurons with a few SN neurons. Ascending fibers are organized along two distinct pathways,
close to the midline of the spinal cord and at the junction of the
gracile and cuneiform bundles, originating from the lumbar sacral
region and the thoracic column, respectively. The gracile nucleus,
with extensive direct and indirect projections, plays an important
role in sensory integration of the projections from abdominal
organs and from the skin. After crossing completely, fibers form
the medial lemniscus, which in turn, projects to the ventrobasal
nuclear complex of the thalamus. The postsynaptic pathway of the
dorsal column represents the largest afferent pathway for information of visceral origin. This has been revealed in studies demonstrating the control of visceral cancer pain by means of
myelotomy techniques. Lesions in this region are more effective
in the control of visceral pain than in interruption of the pathway
of the anterolateral quadrant of the spinal cord. This pathway also
has functions related to proprioception, tactile discrimination, and
graphesthesia. Given its projections to various thalamic regions,
the postsynaptic pathway of the dorsal column is considered to be
involved in the sensory-discriminative and motivational-affective
components of pain.35

Supraspinal Centers of Nociception


It is now clear that there is no single pain center in the brain.
Ascending pain pathways are relayed either directly or indirectly
to cortical and subcortical brain regions. The regions that are
commonly activated by nociceptive stimulation are often referred
to as the pain matrix. The pain matrix is subdivided into a medial
and a lateral pain system. This distinction, which is based on the
projection sites from either medial or lateral thalamic structures to
the cortex, is an oversimplification of the networks involved but is
a useful means for grouping brain regions that appear to have
similar roles in pain processing.36 The lateral pain system is
primarily thought to have a sensory-discriminative function, comprising spatial, temporal, and intensity properties. The medial pain
system has an affective-motivational dimension, related to the
unpleasantness of the stimulus as well as the behavioral and autonomic reactions it evokes. Some regions encode both sensorydiscriminative and affective pain processing. All of these areas
communicate extensively and reciprocally with the prefrontal
cortex, which brings the situational and memory context to the
experience (cognitive-evaluative function). We present a more
detailed description of supraspinal centers of nociception,
subdivided according to their main function.

Lateral Pain System (Sensory-Discriminative)


The lateral thalamic nuclei function as a relay station by conveying
sensory information from the spinal cord and brainstem to
sensory-discriminatve processing regions. The VPM and the VPL
project to the primary somatosensory (SI) cortex and send minor
projections to the secondary somatosensory (SII) areas of the
cortex. The ventral posterior inferior (VPI) nucleus sends axons
mainly to the SII. Reaching the somatosensory cortex, physical
awareness of pain becomes possible. The posterior insular cortex
as well as its thalamic relay nucleus, the ventromedial nucleus

Nociception and Pain Perception in Infants and Children

63

(VMpo) are also involved in the sensory-discriminative dimension. The insula, being a component of the limbic system, is also
involved in affective processing.36

Medial Pain System (AffectiveBehavioral-Autonomic)


The medial thalamic nuclei are the relay station for ascending
pathways, conveying essentially affective-motivational components
of pain. The limbic system (amygdala, cingulated gyrus, hippocampus, hypothalamus, thalamus) plays a crucial role in emotional behavior during painful experiences. The cingulate gyrus is
a major part of the anatomic limbic system and, thus, is involved in
emotion related to pain. The cingulate cortex also participates in
sensory, motor, and cognitive processes related to pain. The
anterior cingulate cortex (ACC), consisting of areas 25 and 24, has
been implicated in a wide variety of autonomic functions including
visceromotor, skeletomotor, and endocrine outflow. These processes include responses to the painful stimuli. Because all of these
activities have an affective component, it is likely that connections
with the amygdala are essential.37 ACC is also involved in rational
cognitive functions, such as anticipation and decision-making. By
contrast, the posterior cingulate cortex (PCC), consisting of areas
29, 30, 23, and 31, contains neurons that monitor eye movements
and respond to sensory stimuli. It is involved in spatial orientation
and memory. It is likely that connections between the PCC and the
parahippocampal cortex contribute to these processes.
The hypothalamus coordinates behaviors necessary for survival, including the emotional homeostasis and responses to pain.
It regulates the autonomic and humoral responses to pain, stress,
and emotional expression. Many other areas in the brainstem
mediate homeostatic changes in bodily functions associated with
pain while receiving active regulatory inputs from cortical,
subcortical, and thalamic areas. The reticular activating system
(reticular formation) is involved in the arousal effects of the
painful stimuli. The arousal may activate noradrenergic neurons
in the locus coeruleus (LC) and, thus, decrease the upward pain
transmission (see the section on Descending Inhibitory Systems
(Endogenous Pain Modulation)). The cathecholaminergic nuclei
of the brainstem receive input from lamina 1 (pain-specific)
pathways and regulate vigilance and attention through cortical
projections. Furthermore, they regulate bodily functions via the
autonomic nervous system and are involved in the descending
modulation of the spinal nociceptive afferents. The parabrachial
nucleus is involved in cardiovascular regulation. It has connections
to the ventral medial nucleus of the hippocampus and the central
nucleus of the amygdala. Both of these areas of the CNS are involved in the affective response to pain. The PAG area is involved
in endogenous analgesia and in automatic coping behavior such as
the fight or flight reaction. The superior colliculus may play a role
in pain-related visuomotor orientating, a reflex function that
allows turning of the upper body, head, and eyes in the direction
of a painful stimulus. The pretectal nuclei are involved in the
regulation of endogenous analgesia. The red nucleus is involved in
pain-related motor functions.

Cognitive-Evaluative Function
The intralaminar and reticular thalamic nuclei, the prefrontal
cortex, and the ACC are involved in the cognitive dimension of
pain.

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Descending Inhibitory Systems


(Endogenous Pain Modulation)
Modulation of nociceptive transmission occurs at multiple
(peripheral, spinal, supraspinal) levels. Endogenous opioids, found
at the peripheral, spinal, and supraspinal levels, act at G-coupled
protein opioid receptors by increasing potassium channel activity
(hyperpolarization) and by inhibiting the Ca2+ voltage-gated
channel, thereby inhbiting substance P release. These endogenous
opioids include -selective enkephalins, -selective dynorphins,
and -selective endomorphins. Endogenous opioids play an
important role in pain modulation and are found in the cerebral
cortex, hypothalamus, thalamus, hippocampus, basal ganglia,
amygdala, PAG, LC, reticular formation, and parabrachial nucleus.
At the spinal level, modulation of the pain input has been
viewed as the attenuation of dorsal horn transmission. Melzack
and Walls Gate Control Theory first suggested this theory in 1965.
Gate control regulation of pain occurs in the gelatinous substance
(lamina II) of the dorsal horn. The selective stimulation of large
cutaneous afferent A fibers from an injured area blocks activation
of the second-order neurons, which are stimulated by the
nociceptive A and C fibers. The nociceptive input will be sensed
as painful only if it can subtract itself from the inhibitory influence
of enkephalin interneurons activated by A fibers. This type of
control modulates the pain intensity (sensory-discriminative
modulation).
At the supraspinal level, multiple brain regions contribute to
the escending inhibitory pathways. These descending pain
inhibitory controls are immature at birth and do not become
functionally effective until postnatal day 10 in the rat, although all
descending projections are already present at birth. They may have
gender-specific and genetic-specific differences contributing to
individual variability in pain sensitivity. Each of the descending
inhibitory system has different neurochemistry (endogenous
opioids, serotonin, NE, GABA) and different neuroanatomic connections. Both the PAG, the RVM (nucleus raphe magnus), and
adjacent reticular formation including the nucleus gigantocellularis pars alpha and paragigantocellularis ventralis receive direct
projections from the spinal dorsal horn and control the ascending
nociceptive input by a feedback mechanism, thereby modulating
pain intensity (sensory-discriminative modulation). On the basis
of their physiologic response properties, spinally projecting RVM
neurons can be classified into three types. The on-cells give an
excitatory response to a noxious stimulus starting just before a
spinal nocifensive reflex (withdrawal reflex). The off-cells give an
inhibitory response to a noxious stimulus starting just before a
spinal nocifensive reflex. The neutral cells give variable responses
or are unresponsive to noxious stimuli. Morphine suppresses oncell activity, increases indirectly off-cell activity through a
GABAergic mechanism within the RVM, and has little effect on
neutral cell activity. A subgroup of neutral cells are serotoninergic
and project to the spinal cord where its receptor contributes to
descending antinociceptive action by modulating the effects induced by on- and off-cells.
At the spinal cord level, the dorsolateral funiculus is the main
descending pathway mediating antinocieptive effects from the
RVM to the spinal dorsal horn. The noradrenergic neuronal cell
groups of the brainstem, particularly the LC (LC-A6) as well as
pontine noradrenergic cell groups A5 and A7, receive projections
from the PAG. Descending axons originating in these noradrenergic neuronal cell groups, conveyed by the ventrolateral pathway,

are the source of spinal NE. NE is known to have a significant


antinociceptive influence through action on spinal presynaptic 2adrenergic receptors (subtype 2A, 2C). NE also exerts its
descending inhibition by direct catecholaminergic postsynaptic
innervation of STT neurons and by activating, in the superficial
laminae, a population of small, low-threshold units, likely to be
inhibitory interneurons. The latter enhance GABAergic and glycinergic inhibitory synaptic transmsission in the substantia gelatinosa. The LC also receives projections from the central nucleus
of the amydgala, preoptic area, paraventricular nucleus of the
hypothalamus, and lateral hypothalamus. NE systems have little
influence on baseline pain sensitivity; however, in persistent pain,
these systems have an important role. In conditions that cause
persistant pain (inflammation, injury), the function of descending
pathways may change considerably. These changes may enhance
the efficacy of descending inhibition by increasing turnover of NE
and by increasing the number of 2-adrenergic receptors in the
spinal cord. Increased efficacy of glutamatergic receptors of the
medulla, accompanied by a phenotypic switch of medullary
neurons, has also been observed following inflammation. In the
presence of sustained pain stimulation, a decrease of descending
inhibition or an increase of descending facilitation of pain may
also be seen.
Other brainstem, diencephalic, and telencephalic structures
modulate pain. The hypothalamus is involved in stress-induced
analgesia either by endocrine mechanisms (Corticotropin releasing
factor (CRF) released after activation of the hypothalamicpituitary-adrenal axis) or by spinal antinociception through axonal
projections from the hypothalamus to the PAG-RVM circuitry. The
limbic system and the frontal cortex are closely associated with
memory and emotions. With other brain structures, they have an
important impact on pain modulation and perception (emotiveaffective modulation).
Another inhibitory system is the diffuse noxious inhibitory
controls (DNICs). Some neurones in the dorsal horn of the spinal
cord are strongly inhibited when a nociceptive stimulus is applied
to any part of the body, distinct from their excitatory receptive
fields. DNICs influence only convergent neurones. The other cell
types that are found in the dorsal horn, including specific nociceptive neurones, are not affected by this type of control. In normal
conditions, these inhibitions can be triggered only by conditioning
stimuli, which are nociceptive. The inhibitions are extremely
potent, affect all the activities of the convergent neurones, and
persist, sometimes for several minutes, after the removal of the
conditioning stimulus. In fact, only activity of A or C peripheral
fibers can trigger DNICs. DNICs are sustained by a complex loop
that involves supraspinal structures because, unlike segmental
inhibitions, they are not observed in animals in which the cord
has previously been transsected at the cervical level. The ascending
and descending limbs of this loop travel, respectively through the
ventrolateral and dorsolateral funiculi, respectively. DNICs result
from the physiologic activation of the subnucleus reticularis
dorsalis (SRD) in the caudal medulla.

Perception and Chronic Pain


Perception is how pain actually feels to someone rather than pain
as a sensation. It is the cerebral cortical response to nociceptive
signals that are projected by third-order neurons to the brain. The
relief of nociception, the antinociception, is simply the blockade
of nociceptive inputs. This notion should be differentiated

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from analgesia, the relief of perception of noxious stimulus. The
relationship between the reported pain intensity and the peripheral stimulus that evokes it depends on many factors such as
past pain experience, depression, distraction, expectation or
anticipation, anxiety, the level of arousal, gender, and genetics.
Therefore, people have different pain thresholds. The prefrontal
cortex and the limbic system are responsible for learning and
memorization of painful experiences and the way an individual,
who coped with pain in the past, will cope with subsequent
episodes of pain. Individuals who are already suffering from an
illness or experience depression or insomnia are more likely to
have a lower pain threshold than healthy people. In reality, the
experience of pain is nothing more than the interpretation of
nociceptive inputs. If a dissociation between nociception and pain
appraisal occurred, the experience of pain would not influence
behavior because the affect is missing. This affect accounts for the
variability of pain tolerance among individuals.
Supraspinally mediated factors that fall into the cognitive domain may account for a significant amount of the interindividual
differences in the subjective experience of pain. For example,
distractions main effect appears to be increased activity within the
medial pain systems via the descending pain modulatory system
and a corresponding reduction in activation in the lateral pain
system. Other experiments have investigated the effect of anticipation of an impending painful stimulus on regional brain activity. The main effects of anticipation were found to be activation
of rostral anterior insula and medial prefrontal cortices during the
anticipation of pain, whereas during pain itself, insular activity
was more caudal and the prefrontal focus was replaced by activity
within the ACC. The hippocampal formation (entorhinal complex) is responsible for producing anxiety-induced increased pain
perception.
A few genes have been identified that are associated with the
perception of pain in humans. Single nucleotide polymorphisms
(SNPs) in genes that code for the melanocortin-1 receptor and
neuronal cytochrome P450 (PY2D6) are associated with alteration
in opioid analgesia. Congenital insensitivity to pain (CIP) type I
has been linked to the gene encoding a subunit of serine palmitoyltransferase, and type IV has been linked to the gene encoding
for a NGF-specific tyrosine kinase receptor. Furthermore, a
common SNP in codon 158 (val138met) of the gene that codes for
catecholamine-O-methyltransferase (COMT) has been proposed
to contribute to differences in the human experience of pain.
Recent studies have identified three genetic haplotypes of the gene
encoding COMT, designated low pain sensitivity (LPS), average
pain sensitivity (APS), and high pain sensitivity (HPS). These
haplotypes encompass 96% of the human population, and five
combinations of these haplotypes are strongly associated with
variation38 in the sensitivity to experimental pain. The presence
of even a single LPS haplotype diminishes, by as much as two to
three times, the risk of developing a chronic pain condition. The
LPS haplotype produces much higher levels of COMT enzymatic
activity than the APS or the HPS haplotypes. As shown in rat
studies, inhibition of COMT results in a profound increase in pain
sensitivity.38
The threshold for eliciting pain has to be high enough that it
does not interfere with normal activites but low enough that is can
be evoked before frank tissue damage occurs. This threshold is not
fixed and can be shifted either up or down, which may be either
adaptative or maladaptive. Shifts in pain threshold and responsiveness are an expression of neural plasticity, the neurobiologic

Nociception and Pain Perception in Infants and Children

65

means by which changes in the nervous system can modulate the


response to any stimulus. Such plasticity or modifiability of the
sensory system characterizes pain syndromes.3,39
Chronic pain is not just a prolonged acute pain; it is a distinct
entity, with many functional and structural alterations of the
peripheral nervous system (peripheral sensitization or primary
hyperalgesia) and CNS (central sensitization or secondary hyperalgesia). Ongoing nociceptive input from the periphery is needed
to maintain central hyperexcitability, the key process in the
generation of chronic pain. Repetitive and intense activation of the
high-threshold C fibers and AMPA postsynaptic receptors results
in release of excitatory substances such as glutamate and substance
P. Early changes also include elimination of the voltage-dependent
magnesium blockade of NMDA receptors and Na channel
stimulation. These changes permit glutamate to activate NMDA
and non-NMDA postsynaptic receptors and cause a gradual
increase in the frequency of dorsal horn neurons firing, known as
the NMDA-mediated wind-up phenomenon. Activated receptors
increase intracellular calcium levels with subsequent activation of
calcium-dependent intracellular kinase and phosphorylation of ion
channels and NMDA receptors. Potential consequences of these
changes include altered synaptic transfer and transcriptional
changes with c-fos production in the second-order dorsal horn
projection neurons (marker of central sensitization).
Activation of the NMDA receptors represents the first step in
central sensitization (the transition from acute to chronic pain). As
such, adequate treatment of physiologic, nociceptive pain is the
most important goal of acute pain management because it may
prevent subsequent central sensitization. Other neurochemical
changes involved in central sensitization include sensitization of
WDR neurons to nonnociceptive stimuli and expression of
substance P by A fiber presynaptic terminals. Neuroanatomic
modifications include sprouting of A fiber terminals into the
superficial layers of the dorsal horn with synapses onto the
nociceptive second -order neurons. Additional modifications
include extensive reorganization of the somatosensory cortical
maps and remodeling in the brainstem, cerebellum, basal ganglia,
and motor cortical areas with subsequent dysfunctional descending inhibition. This central sensitization and neuroplastic remodeling are responsible for all the main features of chronic pain
including hypersensitivity to nociceptive stimuli (hyperalgesia),
perception of pain upon nonnociceptive stimulation (allodynia),
expansion of the pain-receptive fields to uninjured tissue (referred
pain), and prolonged pain after a transient stimulus (persistant
pain).

DEVELOPMENT OF
NOCICEPTIVE CIRCUITRY
Somatosensory processing comprises a fine balance of sensory
afferent input, local inhibitory and excitatory control on dorsal
horn projection neurons, and descending inhibitory and facilitatory modulation. The development and maturation of each of
these components will affect the nociceptive responsivity.

Primary Sensory Afferents


Development of primary sensory neurons is the first stage in the
development of the somatosensory pathways that will transmit
sensory stimuli from the periphery to the higher areas of the CNS.

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Nociceptive neurons develop without influence from either central


or peripheral targets.40 Primary sensory neurons that make up the
DRG appear at embryonic day 12 (E12). The future, cutaneous,
nonnociceptive A fibers expressing the neurotrophin receptors
TrkB and TrkC appear first, followed by the C fiber cells that
express TrkA. The development of these two populations is under
the control of separate transcription factors of the neurogenin
family. Ngn1) is required for small C fiber neurons and Ngn2 for
the larger A fibre cells.41 The number of neurons increases until the
time of birth and is followed by a 15 to 20% loss over the first few
postnatal weeks,42 coinciding with the final innervation of the skin
by the peripheral afferents of the DRG neurons. The survival of
the neurons is dependent upon the presence of neurotrophic
factors produced by both the peripheral (skin) and the central
targets.43

Growth of Axons Toward Peripheral


and Central Targets
Toward the periphery, outgrowth of axons from DRG sensory
neurons occurs before birth. Large-diameter A fibers form an
initial nerve plexus and are followed by the smaller-diameter C
fibers.44 This growth is extremely precise with each DRG innervating somatotopically appropriate dermatomes. There is an initial
hyperinnervation of the skin, extending beyond the dermis into
the epidermal surface. These projections subsequently withdraw,
resulting in a pattern of innervations similar to that found in the
adult.45 The first sensory neuronderived afferents to penetrate
the spinal cord are the A fibers at E15 to E17, followed by C fiber
projections at E18 to E20. Although the peripheral target skin
influences the pattern of projections in the CNS, it does not direct
cutaneous axons to specific populations of neurons in the dorsal
horn. The inhibitory growth cone collapsing molecule semaphorin
3A and the homeodomain protein, DRG11, seem to play an
important role in the specific growth of sensory axons.45
Spontaneous action potentials of fetal dorsal horn ganglia cells
during this period may also be responsible for appropriate
synaptic connections.

Functional Development of Nociceptors


Determinant characteristics of C fibers such as the expression
of the neurotrophin receptor TrkA and selective binding of IB4
can be seen at an early embryonic age. The sodium canal TTXresistant Nav 1.8 (SNS/PN3) that regulates the neuronal hyperexcitability is expressed in C fibers from E17 with adult levels
present from the seventh day of life.46 Within days of birth,
the receptor for the capsaicin TRPV1, which has a predominant
role in the detection of thermal and chemical stimuli, is expressed
in the dorsal ganglia at a percentage similar to that found in adults.
The ATP-gated P2X3 receptor, important for thermal and
mechanical hyperalgesia following inflammation or nerve injury,
is also expressed from an early age by cells of the DRG.

Cell Determination in the Dorsal Horn


The expression of the gene homeobox Lbx1 is required for both
the correct specification of substantia gelatinosa neurons and the
appropriate sensory afferent innervation of the dorsal horn.47 The
selection of postmitotic genes Tlx1 and Tlx3 seals the destiny of

embryonic dorsal horn cell, resulting in excitatory glutamatergic


or inhibitory GABA cells.48 It is interesting to note that the genesis
of projecting neurons of lamina I is completed before the local
interneuron circuitry,49 implying that direct transmission of
nociceptive activity from the spinal cord to the CNS may appear
before the development of the local modulation circuitry. At
postnatal days 18 to 27, the miniature excitatory postsynaptic
current (mEPSC) frequencies of lamina I are five times higher
than those in the interneurons. The relatively late maturation of
interneurons means that their axodendritic growth takes place
postnatally, which may be important for the activity-dependent
shaping of nociceptive circuits (see Section on Growth of Axons
Toward Peripheral and Central Targets).

Functional Maturation of
Nociceptive Circuitry
The appearance of connections between the afferent sensory and
the spinal neuronal cells leads to the first functional reflex
response to tactile and nociceptive stimluli. Although these spinal
reflexes are not proof of the consciousness of pain, they confirm
the presence of a functional connectivity of somatosensory circuitry, a prerequisite of any behavioral response to a peripheral
sensory stimulus. The study of pain behaviors in fetal and neonatal
animal is restricted to examination of reflex responses that can be
elicited only once the primary afferent, dorsal horn neuron, and
motor neuron circuitry synaptic connections are complete. Reflex
responses can be elicited to both tactile and noxious stimuli. The
presence of these responses is not evidence of pain perception, rather, it is an indication of the degree of maturation of
somatosensory ciruitry and sensitivity to peripheral stimuli. Even
though prevalent in rats at E15 to E-17,50 cutaneous reflex
responses, at birth, are diffuse and exaggerated with lowered
thresholds. Receptive fields of hind limb flexor muscles are large
and disorganized in younger animals, resulting in inappropriate
limb withdrawal responses to noxious stimuli.51 Despite their
importance in early behavior, reflex responses cannot be equated
with a true pain experience, which must involve the cortex and
cognitive brain function. These reflexes are likely to reflect the
absence of the normal inhibitory control that higher brain
structures exert at more mature stages of development to dampen
spinal excitability. These reflex responses decrease as the rat
matures, becoming more restricted to an isolated leg or foot
movement. The fine-tuning of both excitatory and inhibitory
synaptic connections with interneurons within lamina II during
the postnatal period allows a progressive modification and
adaptation of these behaviors. The early presence and maturation
of A fiber terminations witin lamina II during the first weeks of
postnatal life seem to influence considerably the neuronal responses of the dorsal horn, contributing to the high level of
cutaneous reflexes excitability. On the contrary, the activity
triggered in the dorsal horn by C fibers appears gradually during
the postnatal period with a lower percentage of neurons conveying
a nocicepive signal during the first weeks of life compared with
those in an adult.52

Balance Between Excitation and Inhibition


The dorsal horn cells of newborn animals are more excitable than
those of adults. A painful cutaneous stimulation at an early

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postnatal age (P03) frequently results in action potentials with a
prolonged activity of 30 to 90 sec beyond the end of the stimulus.
This effect diminishes with age in both amplitude and duration.53
The newborn dorsal horn cells high-response capacity demonstrates the immaturity of excitatory and inhibitory synaptic
transmission in the spinal cord of the newborn. The elimination
of some synapses (such as the A fiber input to lamina II) and the
strengthening of others (such as C fiber inputs) alter the balance
of postnatal transmission. This process may be linked to the
number of silent synapses which express only NMDA receptors
in neonatal superficial dorsal horn neurons.54 Repeated afferent
stimulation may convert silent synapses to functional ones by
rapid insertion of AMPA receptors. The parallel development of
inhibitory, organized synapses is crucial to the development of a
functional nociceptive system. The subtle equilibrium between
excitation and inhibition within the CNS determines the functionality of the system. The presence of inhibitory synpases can
determine the impact of adjacent excitatory synapses only if they
are localized on the same dentritic branch and are activated
simultaneously.55 As with the excitatory synapses, the inhibitory
GABA and glycinergic synapses are regulated in the dorsal horn
and go through important functional modifications during the
postnatal period.

The Development of Descending


Pain Pathways
Descending activity from the brainstem is another factor contributing to the balance between excitation and inhibition in spinal
nociceptive circuits. Brainstem fibers containing serotonin
innervate the PAG at birth, yet the pattern and the density of adult
terminals are not achieved in the lumbar spine until P21. This
observation explains why stimulus-produced analgesia from the
PAG is not effective until P21 in rats. The dorsolateral funiculus of
the spinal cord, which transmits the descending inhibitory
pathways, grows down the spinal cord early in fetal life but does
not extend collateral branches into the dorsal horn until P10.56 The
lack of descending inhibition in the neonatal dorsal horn means
that there is no endogenous analgesic system to dampen noxious
inputs as they enter the CNS, and their effects may, therefore, be
more profound than in the adult. The late functional maturation
of this system is due to either low serotonin levels in the synaptic
terminals or a delay in receptor maturation in the early postnatal
period. Although the low levels of serotonin may limit synaptic
transmission, they may still influence synaptic maturation, as the
exposure to serotonin causes rapid insertion of AMPA receptors
into the synaptic membrane of neonatal substantia gelatinosa
neurons. The descending noradrenergic inhibitory system seems
to mature earlier because the administration of a 2-adrenergic
receptor agonist produces analgesia following nociceptive mechanical or thermal stimuli in the newborn rat. Also, the intrathecal
administration of dexmedetomidine, a potent and selective 2adrenergic agonist, reverses inflammatory hyperalgesia at all
postnatal ages at doses that have no effect on baseline sensory
processing and that are lower than those needed in the adult.57

Early and Late Consequences of Pain


Nociceptive activity is not a normal physiologic event during the
neonatal period. After tissue injury, a strong and prolonged

Nociception and Pain Perception in Infants and Children

67

activation of C fibers is observed. Nociceptive C fibers can be


sensitized by inflammatory chemicals even before birth. As soon
as the stimulation of peripheral C fibers begins to trigger cells of
the dorsal horn, a repeated stimulus creates a wind-up NMDA
receptordependent phenomenon.58 Hyperalgesia can be triggered
in the young animal from age P3 or even before, although its
magnitude may not be as great as in adults.59 The postnatal maturation of hyperalgesia may follow the development of signaling
by substance P, which has been shown to be important for this
form of central sensitization.
Whereas many of the nervous system responses to local tissue
damage resolve after the injury is healed, tissue damage during a
critical period in newborn rodents can cause prolonged alterations
in somatosensory function that persist into adult life. The
consequences of neonatal injury depend on the type of injury and
the modality of sensation.6062 The early-onset inflammatory
hyperalgesia and the later-onset basal hypoalgesia extend into
adulthood and appear only if the original inflammatory stimulus
is applied during the first 10 days of life. Although it is not known
how these long-term changes in pain signaling develop, potential
mechanisms include alterations in synaptic connectivity and
signaling in postnatal nociceptive pathways as well as changes in
the balance of inhibition versus excitation. In addition, tissue
injury in the newborn triggers the secretion of higher concentrations of growth factors, which may have various effects on the
development of peripheral nociceptors.63 The permanent expansion of the dorsal horn receptor field in the neonatal injured area
is evidence for the failed development of a directed inhibitory
system within the nociceptive circuitry.

SUMMARY
This chapter has concentrated on nociceptive processing and its
maturation at the peripheral and spinal level, the importance of
functional higher brain centers in the pain experience on the
early and late consequences of pain, and issues related to the
development of chronic pain. Neuroanatomic evidence demonstrates that pain and its perception are complex entities involving
multiple ascending pathways, different functional projections to
the thalamic area, a cortical circuit, and a crucial excitatory and
inhibitory synaptic transmission system. Clinical and laboratory
research has elucidated many of the physiologic, pharmacologic,
and neurobiologic/immune complex mechanisms involved in the
immature pain pathways. Research has also shown how the
developing pain circuitry depends on nonnoxious sensory activity
in the healthy newborn and how early injury can permanently
alter pain processing. The demonstration of interactions between
the nervous and the immune systems and the discovery of the
synthesis and release of immune chemical messengers secondary
to a noxious stimulus have been crucial in our understanding of
the pathophysiology of the nervous and nocioceptive systems.
These messengers are involved in the regulation of the activity of
CNS neurons (mainly those in the dorsal horn of the spinal cord)
in certain pathologic situations leading to inflammatory and
chronic neuropathic pain. Questions related to the affective and
cognitive aspects of the pain experience among different chronic
pain conditions in later ages still remain to be more extensively
explored. These studies should not only help us to better prevent
and assess pain but also contribute to rational design of analgesic
regimes that are specific to young infants.

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REFERENCES
1. Fitzgerald M, Howard R. The neurobiologic basis of pediatric pain.
In: Schechter N, Berde C, Yaster M, editors. Pain in Children and
Adolescents. Philadelphia: Lippincott Williams & Wilkins; 2003.
pp. 1942.
2. Price DD. Psychological and neural mechanisms of the affective
dimension of pain. Science. 2000;288:17691772.
3. Woolf CI, Salter MW. Neuronal plasticity:increasing the gain in pain.
Science. 2000;288:17651768.
4. Narsinghani U, Anand KJS. Developmental neurobiology of pain in
neonatal rats. Lab Animal. 2000;29:2739.
5. Fitzgerald M. The development of nociceptive circuits. Nat Rev
Neurosci. 2005;6:507520.
6. Glover V, Fisk N. We dont know: better to err on the safe side from
mid-gestation. BMJ. 1996;313:796800.
7. Woolf CJ, Ma Q. Nociceptorsnoxious stimulus detectors. Neuron.
2007;55:353364.
8. Marmigere F, Ernfors P. Specification and connectivity of neuronal
subtypes in the sensory lineage. Nat Rev Neurosci. 2007;8:114127.
9. Ma Q, Chen Z, del Barco Barrantes I, et al. Neurogenin1 is essential
for the determination of neuronal precursors for proximal cranial
sensory ganglia. Neuron. 1998;20:469482.
10. Ma Q, Fode C, Guillemot F, et al. Neurogenin1 and neurogenin2
control two distinct waves of neurogenesis in developing dorsal root
ganglia. Genes Dev. 1999;13:17171728.
11. Chen CL, Broom DC, LiuY, et al. Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic
pain. Neuron. 2006;49:365377.
12. Yoshikawa M, Senzaki K, Yokomizo T, et al. Runx1 selectively
regulates cell fate specification and axonal projections of dorsal root
ganglion neurons. Dev Biol. 2007;303:663674.
13. Luo W, Wickramasinghe SR, Savitt JM, et al. A hierarchical NGF
signaling cascade controls Ret-dependent and Ret-independent
events during development of nonpeptidergic DRG neurons. Neuron.
2007;54:739754.
14. Fields HL, Rowbotham M, Baron R. Postherpetic neuralgia: irritable
nociceptors and deafferentation. Neurobiol Dis. 1998;5:209227.
15. Dhaka A, Viswanath V, Patapoutian A. Trp ion channels and temperature sensation. Annu Rev Neurosci. 2006;29:135161.
16. Brauchi S, Orta G, Salazar M, et al. A hot-sensing cold receptor: Cterminal domain determines thermosensation in transient receptor
potential channels. J Neurosci. 2006;26:48354840.
17. Alloui A, Zimmermann K, Mamet J, et al. TREK-1, a K+ channel
involved in polymodal pain perception. EMBO J. 2006;25:23682376.
18. Zimmermann K, Leffler A, Babes A, et al. Sensory neuron sodium
channel Nav1.8 is essential for pain at low temperatures. Nature.
2007;447:856859.
19. Hu J, Milenkovic N, Lewin GR. The high threshold mechanotransducer: a status report. Pain. 2006;120:37.
20. Bandell M, Story GM, Hwang, SW, et al. Noxious cold ion channel
TRPA1 is activated by pungent compounds and bradykinin. Neuron.
2004; 41:849857.
21. Kwan KY, Allchorne AJ, Vollrath MA, et al. TRPA1 contributes to
cold, mechanical, and chemical nociception but is not essential for
hair-cell transduction. Neuron. 2006;50:277289.
22. Julius D, Basbaum AL. Molecular mechanisms of nociception.
Nature. 2001;413:203210.
23. Verpoorten N, Claeys KG, Deprez L, et al. Novel frameshift and splice
site mutations in the neurotrophic tyrosine kinase receptor type 1
gene (NTRK1) associated with hereditary sensory neuropathy type
IV. Neuromuscul Disord. 2006;16:1925.
24. Cox JJ, Reimann F, Nicholas AK, et al. An SCN9A channelopathy
causes congenital inability to experience pain. Nature. 2006;444:
894898.

25. Goldberg YP, MacFarlane J, MacDonald ML, et al. Loss-of-function


mutations in the Nav1.7 gene underlie congenital indifference to pain
in multiple human populations. Clin Genet. 2007;71:311319.
26. Xu P, Hall AK. The role of activin in neuropeptide induction and pain
sensation. Dev Biol. 2006;299:303309.
27. Jin X, Gereau RW. Acute p38-mediated modulation of tetrodotoxinresistant sodium channels in mouse sensory neurons by tumor
necrosis factor-. J Neurosci. 2006;26:246255.
28. Zhang N, Inan S, Cowan A, et al. A proinflammatory chemokine,
CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1.
Proc Natl Acad Sci U S A. 2005;102:45364541.
29. Vellani V, Colucci M, Lattanzi R, et al. Sensitization of transient
receptor potential vanilloid 1 by the prokineticin receptor agonist
Bv8. J Neurosci. 2006;26:51095116.
30. Grant AD, Cottrell GS, Amadesi S, et al. Protease-activated receptor
2 sensitizes the transient receptor potential vanilloid 4 ion channel
to cause mechanical hyperalgesia in mice. J Physiol. 2007;578:
715733.
31. Dai Y, Wang S, Tominaga M, et al. Sensitization of TRPA1 by PAR2
contributes to the sensation of inflammatory pain. J Clin Invest.
2007;117:19791987.
32. Malin SA, Molliver DC, Koerber HR, et al. Glial cell linederived
neurotrophic factor family members sensitize nociceptors in vitro
and produce thermal hyperalgesia in vivo. J Neurosci. 2006;26:8588
8599.
33. Woolf CJ, Ma Q. Nociceptorsnoxious stimulus detectors. Neuron.
2007;55:353364.
34. Jarvis MF, Honore P, Shieh CC, et al. A-803467, a potent and selective
Nav1.8 sodium channel blocker, attenuates neuropathic and
inflammatory pain in the rat. Proc Natl Acad Sci U S A. 2007;104:
85208525.
35. Ji RR, Samad TA, Jin SX, et al. MAPK activation by NGF in primary
sensory neurons after inflammation increases TRPV1 levels and
maintains heat hyperalgesia. Neuron. 2002;36:5768.
36. Puehler W, Zollner C, Brack A, et al. Rapid upregulation of mu opioid
receptor mRNA in dorsal root ganglia in response to peripheral
inflammation depends on neuronal conduction. Neuroscience. 2004;
129:473479.
37. Delcroix JD, Valletta JS, Wu C, et al. NGF signaling in sensory
neurons: evidence that early endosomes carry NGF retrograde
signals. Neuron. 2003;39:6984.
38. Sung YJ, Chiu DT, Ambron RT. Activation and retrograde transport
of protein kinase G in rat nociceptive neurons after nerve injury and
inflammation. Neuroscience. 2006;141:697709.
39. Perlson E, Michaelevski I, Kowalsman N, et al. Vimentin binding to
phosphorylated Erk sterically hinders enzymatic dephosphorylation
of the kinase. J Mol Biol. 2006;364:938944.
40. Xiao HS, Huang QH, Zhang FX, et al. Identification of gene
expression profile of dorsal root ganglion in the rat peripheral
axotomy model of neuropathic pain. Proc Natl Acad Sci U S A. 2002;
99:83608365.
41. Tegeder I, Costigan M, Griffin RS, et al. GTP cyclohydrolase and
tetrahydrobiopterin regulate pain sensitivity and persistence. Nat
Med. 2006;12:12691277.
42. Raingo J, Castiglioni AJ, and Lipscombe D. Alternative splicing
controls G proteindependent inhibition of N-type calcium channels
in nociceptors. Nat Neurosci. 2007;10:285292.
43. Swayne LA, Bourinet E. Voltage-gated calcium channels in chronic
pain: emerging role of alternative splicing. Eur J Physiol. 2008;456:
459466.
44. Altier C, Dale CS, Kisilevsky AE, et al. Differential role of N-type
calcium channel splice isoforms in pain. J Neurosci. 2007;27:6363
6373.
45. Mannion RJ, Costigan M, Decosterd I, et al. Neurotrophins: peripherally and centrally acting modulators of tactile stimulusinduced
inflammatory pain hypersensitivity. Proc Natl Acad Sci U S A. 1999;
96:93859390.

Bissonette-004-(F)

4/5/11

5:30 PM

Page 69

CHAPTER 4
46. Kohno T, Ji RR, Ito N, et al. Peripheral axonal injury results in
reduced mu opioid receptor pre- and post-synaptic action in the
spinal cord. Pain. 2005;117:7787.
47. Guan JS, Xu ZZ, Gao H, et al. Interaction with vesicle luminal
protachykinin regulates surface expression of delta-opioid receptors
and opioid analgesia. Cell. 2005;122:619631.
48. Agarwal N, Pacher P, Tegeder I, et al. Cannabinoids mediate analgesia
largely via peripheral type 1 cannabinoid receptors in nociceptors.
Nat Neurosci. 2007;10:870879.
49. Vasko MR. Prostaglandin-induced neuropeptide release from spinal
cord. Prog Brain Res. 1995;104:367380.
50. Wang H, Kohno T, Amaya F, et al. Bradykinin produces pain
hypersensitivity by potentiating spinal cord glutamatergic synaptic
transmission. J Neurosci. 2005;25:79867992.
51. Samad TA, Moore KA, Sapirstein A, et al. Interleukin-1bmediated
induction of Cox-2 in the CNS contributes to inflammatory pain
hypersensitivity. Nature. 2001;410:471475.
52. Almeida TF, Roizenblatt S, Tufik S. Afferent pain pathways: a
neuroanatomical review. Brain Res. 2004;1000:4056.
53. Raij TT. Pain Processing in the Hhumain BrainViews From
Magnetoencephalography and Functional Magnetic Resonance
Imaging [thesis]. Helsinki, Finland : Brain Research Unit of Low
Temperature Laboratory and Advanced Magnetic Imaging Centre.
Helsinki University of Technology. Department of Psychiatry,
University of Helsinki ; 2005.
54. Brooks J, Tracey I. From nociception to pain perception: imaging the
spinal and supraspinal pathways. J Anat. 2005;207:1933.

Nociception and Pain Perception in Infants and Children

69

55. Bromm B. Brain images of pain. News Physiol Science. 2001;16:


244.
56. Fitzgerald M, Koltzenburg M. The functional development of
descending inhibitory pathways in the dorsolateral funiculus of the
newborn rat spinal cord. J Neurophysiol. 1986;56:555571.
57. Leong SK, Shieh JY, Wong WC. Localizing spinal-cord-projecting
neurons in neonatal and immature albino rats. J Comp Neurol.
1984;228:1823.
58. Staud R, Cannon RC, Mauderli AP, et al. Temporal summation
of pain from mechanical stimulation of muscle tissue in normal
controls and subjects with fibromyalgia syndrome. Pain. 2003;102:
8795.
59. Jasmin L, Tien D, Weinshenker D, et al. The NK1 receptor mediates
both the hyperalgesia and the resistance to morphine in mice lacking
noradrenaline. Proc Natl Acad Sci U S A. 2002;99:10291034.
60. Ren K, Hylden JL, Williams GM, et al. The effects of a noncompetitive NMDA receptor antagonist, MK-801, on behavioral
hyperalgesia and dorsal horn neuronal activity in rats with unilateral
inflammation. Pain. 1992;50:331344.
61. Bantick SJ, Wise RG, Ploghaus A, et al. Imaging how attention
modulates pain in humans using functional MRI. Brain. 2002;125:
310319.
62. Porro CA, Baraldi P, Pagnoni G, et al. Does anticipation of pain affect
cortical nociceptive systems? J Neurosci. 2002;22:32063214.
63. Ploghaus A, Narain C, Beckmann CF, et al. Exacerbation of pain by
anxiety is associated with activity in a hippocampal network.
J Neurosci. 2001;21:98969903.

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Central Nervous System:


Neurotransmitters and Anesthesia
Thomas Engelhardt and William Wisden

INTRODUCTION
The conduct of general anesthesia has become safer. The incidence
of anesthesia-related mortality has decreased dramatically since
the 1970s and is now estimated at much less than 1 in 10,000.
However, the progress in safety has not been matched by the
understanding of the molecular basis of general anesthesia.
Despite considerable research efforts, the exact mechanisms of
general anesthesia remain to be elucidated. This chapter reviews
central nervous system (CNS) neurotransmitters and their role in
sleep-awake states and considers aspects of neurodevelopment
relevant to anesthesia.

ANESTHETICS AND THEIR


INTERACTION WITH CNS
NEUROTRANSMITTERS
The commonly used general anesthetic agents include both
inhalational and intravenous agents. The inhalational agents
include both gases such as nitrous oxide (N2O) and xenon as well
as the vapors of volatile liquids such as halothane, isoflurane,
sevoflurane, or desflurane. The intravenous agents include the
barbiturates (thiopental and methohexital), propofol, ketamine,
etomidate, and benzodiazepines. Although the clinically relevant
anesthetic agents are often small, highly lipid-soluble molecules,
the previously held hypothesis that these agents act by dissolving
within the membrane of nerve cells inducing structural changes of
the lipid bilayer has now been discarded.15 Current thinking
hypothesizes that anesthetic agents amplify and modulate neurotransmitter signals within the CNS. In addition, some anesthetic
agents (the volatile or inhalational agents) directly open ion
channels such as two pore domain K+ channels or, in the case of
propofol, inhibit cyclic nucleotidegated (HCN) channels.5
Although these latter effects on ion channels are important
anesthetic targets, this chapter focuses on how anesthetic agents
interact directly with neurotransmitter receptors. Because of the
huge diversity in molecular structure of the different classes of
anesthetic agents, it is not surprising that these drugs interact with
a variety of protein targets (i.e., receptors and ion channels).
Therefore, the concurrent use of anesthetic agents, analgesic
agents, and neuromuscular blocking agents results in the simultaneous modulation of multiple receptors and ion channels systems
during general anesthesia.
Neurotransmitters are small molecules that relay, amplify, and
modulate signals between neurons and other cells. In addition,
as discussed in Chapter 3, these agents may also control or regulate

5
C H A P T E R

the development of the CNS. Quanta of neurotransmitters


are released after membrane depolarization via an exocytotic
process. Following diffusion across the synaptic cleft and binding
to a transmembrane receptor, binding to the specific ligandreceptor complex then determines the subsequent effect. The
majority of neurotransmitters are removed from the synaptic
cleft via re-uptake processes, degradation, or diffusion. There
may also be neuromodulators that change the sensitivity of the
receptor to its (natural) ligand and are not re-absorbed by the
presynaptic neuron. The receptors in biochemistry terms
are proteins on the cell membrane or within the cytoplasm that
bind specific factors (ligands) and initiate a cellular response to
the ligand. They are divided into transmembrane and intracellular
receptors. Only the transmembrane receptors are relevant to
anesthesia. Transmembrane receptors are integral membrane
proteins and are normally composed of two or more subunits. In
general, transmembrane receptors are classified according to their
function (metabotropic or ionotropic) or structure (domains)
(Figure 51).

Ionotropic Receptors
The activity of ionotropic receptors is regulated by changes of
either the membrane potential (voltage-gated) or the ligands
(ligand-gated). Voltage-gated ion channels are normally closed at
resting membrane potential, and a change in the membrane potential of the cell causes conformational changes that result in the
opening of the pore and the transmembrane movement of ions. A
transitional change leads to an inactivated state. Ligand-gated ion
channels are primary targets for general anesthetic agents. These
ligand-gated ion channels contain an intrinsic ion channel and an
extracellular binding site(s) for the ligand(s). Ligand binding
causes a conformational change with an increase of opening
probability of the ion pore. Ligand-gated ion channels fall into two
families: (1) the Cys loop family, which includes the nicotinic,
serotonin (5-HT3), gamma-aminobutyric acid A (GABAA), and
glycine receptors; and (2) the glutamate-gated ionotropic receptors, which comprise the -amino-3-hydroxy-5-methylisoxazole4-propionic acid (AMPA), kainite, and N-methyl-D-aspartic acid
(NMDA) receptor subtypes. The Cys loop family is characterized
by a pentameric arrangement of subunits and can be subdivided
into excitatory (nicotinic, 5-HT3) and inhibitory (GABAA, glycine)
ligand-gated channels. The ionotropic glutamate receptors are
encoded from an entirely different gene family that encodes subunits with a different membrane topology from those of the Cys
loop family. Ionotropic glutamate receptors assemble as heteromeric tetramers.

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Figure 5-1. Classification of transmembrane


receptors. Only receptors potentially relevant
to anesthesia are displayed. GABAB =
gamma-aminobutyric acid B; 5-HT1A =
5-hydroxytryptamine; NMDA = N-methylD-aspartic acid.

Metabotropic Receptors
Metabotropic receptors constitute the largest family of cell-surface
receptors and are a subclass of transmembrane receptors that
amplify their signal through G proteins linked to the receptor.
Metabotropic receptors have seven membrane-spanning domains
and the signaling unit is referred to as G proteinlinked receptors
(GPLRs). G proteins comprise three subunits, , and and
are molecular switches that transduce a signal to an amplifying
enzyme whose activity produces a second messenger, resulting in
the activation or inhibition of an enzyme or ion channel. Agonists
bind to GPLRs that activate G proteins through the release of
guanosine 5 diphosphate (GDP) bound to the subunit initiating
the G protein cycle (Figure 52).
All subunits transduce signals and regulate a range of second
messenger production or destruction. G Proteins are traditionally
classified according to their subunits: s, i, q, and 12/13. In
general, Gs stimulates adenylate cyclase activity and regulates
calcium ion channels whereas Gi inhibits adenylate cyclase, activates cyclic guanosine monophosphate (cGMP)specific phosphodiesterases, and regulates potassium and calcium channels.
The family of Gq G proteins activates phospholipase C (PLC-),
and the function of G12/13 is likely to regulate chloride ion
channels. Individual receptors can activate more than one G protein, and variation in different stages of G protein activation and
deactivation can affect the regulation of intracellular signaling.
The guanosine triphosphate (GTP) hydrolysis and binding properties vary for individual G subunits, and accessory and regulatory proteins affect these processes. It is likely that anesthetic
agents interfere with GPLR and dependent enzyme systems;
however, evidence so far has been inconclusive.

ROLE OF NEUROTRANSMITTERS
IN SLEEP-AWAKE STATES
The principal mechanisms of natural sleep and the neurotransmitters involved are helpful in furthering our understanding of
the mechanisms of general anesthetic agents.5,6 The natural states
of consciousness include wakefulness and sleep. The latter is
commonly divided into two phases: rapid eye movement (REM)

sleep, often associated with high level of brain activity and vivid
dreaming, and nonrapid eye movement (NREM) sleep, with a
reduced level of brain activity.7,8 Although not universally accepted, it is likely that anesthetic agents interfere with the neuronal
circuitry underlying these processes.5

Wakefulness
The ascending reticular activating system projects from the
midbrain to the thalamus, hypothalamus, and neocortex. The
cholinergic neurons that project to the thalamus originate from
the pedunculopontine and laterodorsal tegmental nuclei and fire

Figure 5-2. G protein cycle. Following agonist binding and release


of guanosine diphosphate (GDP), subsequent binding of guanosine
triphosphate (GTP) leads to dissociation of the heterotrimer into its
component subunits. The GTPase activity of the subunit determines
the lifetime of this dissociated, now active G protein. Hydrolysis of GTP
back to GDP leads to re-association of the heterotrimer and completion
of the G protein cycle.

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rapidly during wakefulness and REM sleep.9 Other neuronal types
involved in stimulating arousal include noradrenergic, serotinergic, and histaminergic, and/or exinergic neurons. The monoaminergic neurons from the locus ceruleus (LC; norepinephrine),
dorsal raphe nuclei (DRN; serotonin), and tuberomamillary
nucleus (TMN; histamine) fire rapidly during wakefulness, but
only infrequently during sleep. Orexins (also named hypocretins)
are peptide neurotransmitters originating in the perifornical
region of the lateral hypothalamus (PFLH) and are thought to be
involved in the pathogenesis of narcolepsy. The orexinergic
neurons display maximal activity during wakefulness and are only
minimally active during REM and NREM sleep.10,11 These neurotransmitters promote wakefulness and can be considered potential
targets for general anesthetic agents.6,12,13

Central Nervous System: Neurotransmitters and Anesthesia

73

thesis is supported by the reciprocal neuronal activity in POA on


one side and the LC, DRN, TMN, and PFLH on the other side18
(Figure 54).

CURRENT AND POTENTIAL TARGETS


FOR GENERAL ANESTHESIA
Ligand-activated receptor systems are important targets for general anesthetic agents. Their functional classification has been
previously discussed in the section on Ionotropic and Metabotropic
Receptors in this chapter. It is likely that only a very few subtypes
might be sensitive to general anesthetic agents when used at clinical
concentrations. The principal neurotransmitter systems relevant
to anesthesia are the inhibitory GABA and the excitatory glutamate
systems. Other receptor types may make a smaller contribution.12

REM and NREM Sleep


REM sleep time depends on the maturity of the nervous system.7
REM sleep time declines rapidly in early childhood from 50% at
birth to approximately 20% after 6 years.14,15 Characteristics of REM
sleep include irregular heart rate and breathing pattern as well as
muscle atonia. Transsection and pharmacologic studies on animals
suggest that the pons and caudal midbrain are fundamental for
REM activity, with cholinergic neurons acting as promoters and
monoaminergic neurons as suppressors of REM sleep.8 The
switching between NREM and REM sleep is poorly understood,
but may be regulated by REM-on/REM-off areas in the mesopontine tegmentum (Figure 53). Both areas contain inhibitory
GABAergic neurons heavily innervating each other. The REM-on
side also contains excitatory glutamatergic neurons projecting into
the basal forebrain, medulla, and spinal cord, which regulates electroencephalographic components and muscle atonia, respectively.16
The existence of NREM sleeppromoting structures in the
rostral hypothalamus as opposed to wake-promoting systems in
the posterior hypothalamus was postulated almost 80 years ago.17
Sleep-active neurons are located in several regions of the preoptic
area (POA) and are concentrated in the ventrolateral POA
(vlPOA) and the median preoptic nucleus (MnPN).18 Anatomic,
electrophysiologic, and immunohistochemical (c-FOS; surrogate
marker of neuronal activity) evidence supports a role of these
neurons in promoting NREM sleep onset and maintenance by
inhibiting and modulating multiple arousal systems.19 This hypo-

Figure 5-3. Reciprocal interaction model of


rapid eye movement (REM) sleep. 1: Positive
feedback of the REM-on neuronal population
results in gradual increased excitation of
REM-off neurons. 2: The REM-off neurons
inhibit the REM-on neurons, terminating
REM sleep (3). 4: The REM-off neurons are
self-inhibiting, terminating inhibition of
REM-on neurons and completing the cycle.
Adapted from reference 8.

Cys Loop Receptors (GABAA,


Glycine, Nicotinic, and 5-HT3)
GABA is the major inhibitory neurotransmitter and is involved in
all aspects of brain function including the regulation of wakefulness, anxiety, memory, and motor output. GABAA receptors are
hetero-oligomeric chloride channels. The subunits are selected
from four principle families (, , , and ) (Figure 55), although
others have been identified. The receptors are important targets
for many classes of drugs in clinical use including anesthetic
agents. The most common mammalian CNS GABAA receptor
(60%) comprises two 1, two 2, and a single 2 subunit. Each
GABAA receptor isoform displays a distinct distribution in the
brain, suggesting specific physiologic functions.20,21
Binding of GABA to the GABAA receptor complex leads to the
movement of chloride ions into the postsynaptic neuron, resulting
in hyperpolarization of the cell membrane and inhibition.22 In the
developing nervous system, the Cl gradient is reversed, being
higher on the inside than on the outside of the neurons. Thus, in
young neurons (probably fetal stage in humans), GABAA receptors
produce depolarizing actions by opening of voltage-gated Ca2+
channels and excitation. GABAA receptors produce fast (phasic)
inhibition at central synapses and tonic inhibition (from ambient
GABA) at extrasynaptic sites.23 The 2 type receptors are
localized at synapses, and the 4 and 6 receptors are

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Figure 5-4. Simplified sleep switch. Reciprocal relationship between sleep-promoting area (POA) and
arousal systems (locus ceruleus [LC], dorsal raphe nucleus [DRN], tuberomamillary nucleus [TMN],
and perifornical region of the lateral hypothalamus [PFLH]). The flip-flop mechanisms prevent intermediate states. The cholinergic system contributes to arousal as well as rapid eye movement (REM) sleep.
GABA = gamma-aminobutyric acid; 5-HT = serotonin; IL-1b = interleukin-1; LDT = laterodorsal
tegmental nucleus; MnPN = median preoptic nucleus; NE = norepinephrine; PGD2 = prostaglandin D2;
PPT = pedunculopontine tegmental nucleus; VLPO = ventrolateral preoptic hypothalamic area.
Adapted from reference 19 and modified after references 18 and 7.

Figure 5-5. A: Subunit arrangement in 2 (synaptic) and (extrasynaptic) containing gamma-aminobutyric acid A (GABAA) receptors. B:
Schematic of an individual subunit topology. The pore-lining domain,
TM2, is shown in blue. Pink triangles represent GABA. The blue circle
represents a benzodiazepine ligand. C = cysteine; TM = transmembrane
domain. Reproduced with permission from reference 22.

extrasynaptic.23 The functional GABAA receptor system can be


probed with selective drugs.24 Drug specificity in vivo was established using knockin mice with point mutations in the GABAA
receptor subunit genes and from gene knockouts.24 Zolpidem acts
preferentially at 12 receptors (producing sedation and hypnosis); benzodiazepines act on 12/32 (producing sedation and
hypnosis), 22/32 (producing anxyliolysis and myorelaxation),
32 (producing anxyiolysis and myorelaxation), and 52
receptors (reducing memory). The latter receptor subtype is
mainly expressed in the hippocampus. Propofol and etomidate act
largely at 2- and 3-containing GABAA receptors.24 Point mutant
mice show that 2- and 3-containing GABAA receptors are largely responsible for the anesthetic actions of these two intravenous
anesthetic agents.
Other GABAA drugs are potent sleep inducers and act mostly
at extrasynaptic GABAA receptors. The GABAmimetic agent
gaboxodol exerts most of its effects (sleep induction) via 4
receptors.25 The extrasynaptic receptors remain a potentially
important target for new drug development. Steroids, including
steroid anesthetics, activate and modulate many GABAA receptor
subtypes.26 Recombinant GABAA receptors are activated potently
by inhalational anesthetic agents,27 and GABAA receptor modulation provides some component of the inhalational-induced
anesthesia. However, the in vivo contribution of these receptors
to the actions of inhalational anesthetic agents requires more
clarification.
GABAC receptors appear to represent a relatively simple form
of ligand-gated chloride channel made up of subunits. Many
argue that they are really a specialized GABAA receptor subtype
and that they should be reclassified as this. GABAC receptors are
insensitive to bicuculline and baclofen and are most prominent in

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the retina. They are not modulated by barbiturates or benzodiazepines. The superior colliculi also use GABAC receptors at some
synapses.
Together with GABA, glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem. Very closely related to the
GABAA receptors, glycine receptors (GlyRs) are hetero-oligomeric
ligand-gated chloride channels and consist of three and two
subunits. Four subunit genes (14) are expressed, and coexpression of the subunits is essential for targeting the receptor
to the synapse. Strychnine is a major GlyR antagonist, whereas alanine and taurine are full or partial agonists. Glycine and GABA
are coreleased from interneuron terminals in the spinal cord and
the brainstem.2831 GlyRs may mediate some of the actions of
volatile anesthetic agents in the spinal cord and brainstem.5 Similar
to GABAA receptors, GlyRs undergo developmental changes in
their expression. As with GABAA receptors, the activation of GlyRs
in immature neurons induces the outflow of chloride ions,
membrane depolarization, neuronal excitation, calcium influx,
and transmitter release. This is in contrast to the inhibitory effects
these receptors have on mature neurons.32 The effect of anesthetic
agents on the GlyRs in the developing human brain is unclear.
The neurotransmitter acetylcholine exerts its pre- and postsynaptic effects on muscarinic and nicotinic receptors. Neuronal
nicotinic acetylcholine receptors (nAChRs) are principally ligandoperated cation channels (calcium, sodium, and potassium) and
modulate the activity of various transmitter systems. They are
widely distributed in various regions of the brain potentially
relevant to general anesthesia. In the brain, the pentameric
channels are formed from (210) and (24) subunits,
whereas the , , and subunits are present in muscle. The
subunit contains the acetylcholine binding site. In addition to the
acetylcholine binding site, nAChRs have associated modulatory
sites for neurosteroids and acetylcholine esterase inhibitors. The
predominant neuronal nAChRs are composed of the subunits
(4)2(2)3 and (7)5. Both receptor subtypes can be pre- or
postsynaptic. The 7 receptors are fast-inactivating nonselective
cation channels with high Ca2+ permeability. The (4)2(2)3
receptors are mainly permeable to Na+ and K+. The nAChRs may
be involved in Parkinson and Alzheimer diseases and the
pathophysiology of schizophrenia. The main interest of nAChRs
for the anesthesiologist is the potential as a target for analgesic
agents and neuropathic pain research. However, a narrow therapeutic window between analgesic efficacy and toxicity has hindered the development of nicotinic agonists as novel analgesics.33
An exciting new development is the potential neuroprotective
effect of nicotine following spinal cord injury.34
Very closely related to the neuronal nicotinic receptors,
the 5-HT3s are ligand-gated cation channels and targets for
commonly used antiemetics in anesthesia.35 The receptors are
expressed throughout the brain, especially on GABAergic interneurons.

Glutamate-Gated Ionotropic Receptors:


AMPA, Kainate, and NMDA
The glutamate receptor family mediates fast excitatory neurotransmission at the majority of synapses in mammals. Glutamate
receptors are widespread in the brain and are divided based on
their pharmacology into three major subtypes: NMDA, AMPA,
and kainate. AMPA receptors are responsible for most fast excitatory synaptic currents at glutamatergic synapses. AMPA recep-

Central Nervous System: Neurotransmitters and Anesthesia

75

tors are permeable only to Na+ and K+, although a specialized


AMPA receptor subtype also alters Ca2+ permeability. NMDA
receptors carry slower integrative excitatory currents and gate
calcium ions in addition to sodium and potassium ions. The
primary target for general anesthetic agents is the NMDA subtype,
which is a heterotetramer consisting of an NR1 subunit combined
with one or more NR2 (AD) subunits and, in some subtypes, an
NR3 subunit. The NR1 subunit is obligatory. Two ligand recognition sites must be occupied for channel opening; one for
glutamate and one for glycine. The channel is blocked by Mg2+
ions. The Mg2+ block is removed by membrane depolarization.
This property, together with the selective Ca2+ permeability of the
channel, means that NMDA receptors can, in some contexts,
function as coincidence detectors used in the formation of
memories. However, the slow integrative currents produced by
NMDA receptor activation is also used in other types of circuits
(e.g., those producing rhythm in breathing). Most inhalational
anesthetic agents variably inhibit NMDA receptors; ketamine is
an NMDA receptor antagonist, and the gases nitrous oxide and
xenon inhibit NMDA receptor currents.5
The intracellular C termini of the NMDA receptor subunits
couples the receptor to a huge complex of proteins termed the
postsynaptic density (PSD), a structure unique to glutamaterigic
synapses. The PSD comprises thousands of proteins, most of
whose function is uncharacterized. Nevertheless, some proteins
have been characterized. For example, the neuronal form of nitric
oxide synthase (nNOS or type I NOS) is coupled to the NMDA
receptor via the PSD protein 95 (PSD 95), which allows tight
regulation of calcium influx and regulation of type I NOS activity.36 The hippocampus is particularly rich in NMDA synapses
and appears to play a central role in learning and memory.
Plasticity within the hippocampus is mediated in part through
changes in synaptic strength and revealed by long-term potentiation and long-term depression. NMDA receptors are crucial for
inducing these plastic changes, and blocking these receptors
reduces plasticity and impairs learning. Intravenous and volatile
anesthetic agents appear to impair long-term potentiation and
enhance long-term depression development.37 One of the downstream effectors of the NMDA receptor is the second messenger
cGMP. General anesthetic agents interact with the receptor, cGMP
formation, and degradation (Figure 56).
cGMP has long been recognized as a secondary messenger, but
its importance in signal transduction was not been recognised
until the identification of the first messenger, now identified as
nitric oxide (NO). Low intracellular concentrations of cGMP
when compared with cyclic adenosine monophosphate (cAMP)
further challenge investigations into its biologic role. cGMP is
formed from GTP through the action of the enzyme guanylyl
cyclase (GC), which exists in either soluble or particulate forms,
with the soluble form being located within the cytosol and the
particulate form within the cell membrane. The particulate form
of GCs is activated through cell membranebound receptors such
as the natriuretic peptide receptors or intestinal peptidebinding
receptors. Binding of the ligand at the extracellular domain of
these receptors results in the production of intracellular cGMP.
Soluble GC is the most abundant form in the CNS. It exists as a
heterodimer consisting of and subunits and is activated by the
interaction with NO resulting in an up to 400-fold activation.
Clinically used activators of soluble GC are described as NO
donors and include pharmacologic agents such as glycerol trinitrate (nitroglycerin), sodium nitroprusside, or S-nitrosothiol

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Figure 5-6. Simplified pathways of formation and degradation of cyclic guanosine


3,5- monophosphate (cGMP) within the
brain. Anesthetic agents have been shown
to interact with the process of the formation of cGMP, namely nitric oxide synthase
(NOS-1) and N-methyl-D-aspartic acid
(NMDA) receptors (NMDAr). GC-s =
soluble guanylyl cyclase; NO = nitric oxide;
PDE = phosphodiesterase; PSD95 =
postsynaptic density protein 95. Adapted
from reference 38.

agents. Methylene blue is a direct inhibitor of soluble GC but has


also been shown to inhibit NOS directly.
The release of cGMP has effects at three levels by affecting
cGMP kinases (protein kinase G [PKG]), cGMP-regulated ion
channels, and phosphodiesterase (PDE) activity. The duration of
cyclic nucleotide signaling is dependent on the rate of cyclic nucleotide formation and on its rate of breakdown. The cyclic nucleotides, cAMP and cGMP, are hydrolyzed by PDE, of which 11
isoforms are currently described. Clinically relevant human PDE
isoforms and their distributions are summarized in Table 51.
Apart from the selective PDE inhibitors for PDE3 (milrinone),
PDE 4, (rolipram) and PDE 5 (sildenafil), there are several wellknown nonisoform specific inhibitors such as caffeine, theophylline, and pentoxifylline. PDE isoforms 1, 2, and 3 utilize both
cyclic nucleotides as secondary messengers, whereas PDE5 and 6
are specific for cGMP. PDE5 is cGMP-specific and is a wellestablished and important regulator of cGMP function. The
activity of the PDE enzymes is regulated by cAMP and cGMP and
is subject to feedback activation and inhibition.
The AMPA receptor subtype is a hetero-oligomer formed from
combinations of GluR14 subunits. When glutamate binds to the
receptor, the channels open to gate the movement of Na+ and K+
TABLE 5-1. Human Phosphodiesterase Characteristics,
Tissue Distribution, and Selective Inhibitors
Family

Main Characteristics

Primary Tissue Distribution

PDE 1

Calcium/calmodulinstimulated
cGMP-stimulated
cGMP-inhibited,
cAMP-selective
cAMP-specific,
cGMP-insensitive
cGMP-specific
cGMP-specific

Heart, brain, lung, smooth


muscle
Adrenal gland, heart, lung
Heart, lung, liver, platelets

PDE 2
PDE 3
PDE 4
PDE 5
PDE 6

Sertoli cells, kidney, brain


Lung, brain, smooth muscle
Photoreceptors

cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine


monophosphate.

ions. Nearly all AMPA receptors contain GluR2 subunits. AMPA


receptors that do not contain GluR2 are permeable to Ca2+ in
addition to Na+ and K+. These specialized Ca2+ permeable AMPA
receptors are mostly found on GABAergic interneurons. AMPA
receptors show little anesthetic sensitivity.5
The kainate receptor subtype consists of hetero-oligomers
comprising the GluR5-7 and KA1 and KA2 subunits. The relevance of the kainate receptor complex for general anesthesia is
unclear, but there is evidence for a presynaptic location in the
hippocampus. Antagonists of kainate, NMDA, and AMPA receptors are thought to be of therapeutic benefit in stroke, head
injuries, epilepsy, and pain.

Metabotropic Receptors
2-Adrenoreceptors are members of the G proteincoupled family
of membrane receptors and mediate the actions of the endogenous
catecholamines, epinephrine, and norepinephrine. Their distribution is widespread, and they are located at pre- and postsynaptic
sites. Three 2-adrenoceptor proteins have been identified,
designated 2a, 2b, and 2c, with the 2a being responsible for most
of the 2-adrenoceptormediated actions. The 2 adrenoreceptor
agonists exert their effects via coupled Gi proteins by inhibiting
adenylyl cyclase and modifying K+/Ca2+ channel activity. 2Adrenoreceptor agonists such as clonidine and dexmedetomidine
are used for the treatment of hypertension, sedation, and analgesia.
There are currently no in vitro selective agonists for the 2adrenoceptor subtypes.39
Serotonin (5-hydroxytryptamine [5-HT]) is a major neurotransmitter in the CNS, being involved in wakefulness (see Role of
Neurotransmitters in Sleep-Awake States). 5-HT is synthesized
from L-Tryptophan in serotonergic neurons and enterochromaffin
cells. To date, 13 human subtypes of the serotonin receptor have
been identified and are subdivided into seven different classes (5HT1 to 5-HT7). Serotonin transduces its effects via G protein
coupled receptors, with 5-HT1 utilizing Gi-mediated adenylyl
cyclase modulation and 5-HT2 signaling via Gq and phospholipase (PLC-). The 5-HT1A receptors are involved in depression
and anxiety, and selective serotonin re-uptake inhibitors (SSRIs)

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77

are widely used, whereas the 5-HT1B/D receptors have emerged as


targets for migraine treatment (sumatriptan). 5-HT2 receptors may
present future targets for treatment of schizophrenia and obesity,
whereas 5-HT3 receptors are targets for the control of perioperative nausea and vomiting.

DEVELOPMENTAL CONSIDERATIONS
The effects of general anesthesia on neuronal development in
humans are controversial. Some rodent animal studies have
suggested that prolonged exposure to anesthetic agents leads to
widespread apoptotic neurodegeneration in the developing brain,
deficits in hippocampal synaptic function, and persistent memory
and learning impairments.40,41 These studies need to be balanced
against evidence that withholding anesthesia during the perioperative period increases the incidence of intraoperative and
postoperative complications.42,43 The brain growth, synaptic differentiation, and cellular proliferation period occurs at different
times in different species. In humans, it is both a pre- and a
postnatal phenomenon (from the 6th mo of gestation to 24 mo
after birth), whereas in rats, mice, and other primates, it is mainly
a postnatal phenomenon, thereby suggesting that application of
the rodent model to human CNS development may not be appropriate.44
Neuronal cell death occurs via two2 mechanisms: apoptosis
and necrosis. Apoptosis, programmed cell death or cellular suicide,
is a kinetic event that can be triggered by a variety of stimuli such
as cytokines, hormones, viruses, and toxic neurologic insults.
Necrosis, in contrast to apoptosis, can affect a number of contiguous cells and trigger an inflammatory reaction and/or death of
cellular structures in the surrounding tissue. Necrosis, which
typically occurs as a result of neuronal injury or cytotoxic exposure, is a pathologic or an accidental mode of cellular death. It is
characterized by irreversible swelling of the cytoplasm and the
mitochondria (Table 52).
The mechanism of apoptosis is a highly complex network of
energy-dependent cascades. Characteristic morphologic features
that define apoptosis are dependent on caspase activation and
cleavage of specific cellular proteins or the liberation of death
provoking substrates within the cell. Apoptosis is, therefore,
considered a caspase-mediated form of cell death.45 There are
two main pathways of caspase-mediated cell death: the extrinsic
or death receptormediated pathway and the intrinsic or
mitochondria-dependent pathway.46 Apoptosis is induced in the
TABLE 5-2. Comparison of Contrasting Morphologic
Features of Apoptosis and Necrosis
Apoptosis

Necrosis

Chromatin condensation
Cell shrinkage
Preservation of organelles
and cell membranes
Rapid engulfment by
neighbouring cells
preventing pericellular
inflammation
Maintenance of integrity

Nuclear swelling
Cell swelling
Disruption of organelles
Rupture of cell membrane and
release of cellular contents
Inflammatory response
Ingested by phagocytes

Figure 5-7. Simplified illustration of the extrinsic apoptotic pathway.


The ligation or binding of CD95L (FasL) to its receptor CD95 (Fas)
leads to the recruitment of an adapter protein (Fas-associated death
domain [FADD]). The FADD recruits the procaspase-8, a deathinducing signaling complex (DISC). A high local concentration of
active caspase 8 activates the main downstream effector, caspase 3.
Caspase 3 triggers the characteristic cellular changes associated with
apoptosis. Courtesy of Dr. Morgan Blaylock.

extrinsic pathway through specialized death surface receptors,


whereas in the intrinsic pathway, apoptosis is induced from within
the cell, mainly through mitochondrial activation in response to
extracellular cues and internal insults such as DNA damage. The
extrinsic pathway plays a fundamental role in the maintenance of
tissue homeostasis, especially in the immune system. The extrinsic
signaling pathway initiates apoptosis by triggering a transmembrane receptormediated interaction (Figure 57). The
intrinsic apoptosis pathway is induced from within the cell, mainly
through activation of mitochondria in response to extracellular
stimuli and internal insults such as DNA damage.47,48
One of the first processes involved in the mitochondrial apoptotic pathway is increased permeability of the outer mitochondrial membrane releasing mitochondrial molecules, most
importantly cytochrome C, into the cytoplasm. The primary mechanism of the increased permeability of the outer mitochondrial
membrane during apoptosis involves members of the Bcl-2 family
of proteins such as Bax and Bid. Once released, cytochrome C binds
to an adaptor molecule termed Apaf-1, which recruits procaspase9, then designated the apoptosome. This is required for the cleavage
and activation of caspase-3, the main effector caspase, by caspase9 (Figure 58). It remains to be determined whether general
anesthesia demonstrates a preference to a particular pathway,
which may then influence the choice of general anesthetic agents.

FUTURE DEVELOPMENTS
The better understanding of the physiology of sleep and wakefulness, neurotransmitters, and neuronal networks has led to new
insights into possible targets of general anesthesia.5 Further
research will undoubtedly lead to the development of anesthetic
agents targeting specific neurotransmitter systems and potentially
allow real-time monitoring of its effects. If the current concern
regarding the impact of general anesthesia on neurodevelopment

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Figure 5-8. Simplified illustration of the intrinsic apoptotic pathway. Cytochrome C is


released from the mitochondria as a result of
Bax or of caspase 2 activation. The released
cytochrome C binds to an adapter molecule
termed Apaf-1, which via oligomerization of
procaspase 9 forms the apoptosome, ultimately
leading to caspase 3 activation and apoptosis.
Courtesy of Dr. Morgan Blaylock.

is verified, it remains to be seen whether this will change the current standard practice in pediatric anesthesiology. The integration
and translation of emerging evidence in basic neuroscience
research into clinical studies will guarantee an exciting future for
basic research in the field of pediatric anesthesiology.

REFERENCES
1. Meyer H. Welche Eigenschaft der Anaesthetica bedingt ihre narkotische Wirkung? Arch Exp Pathol Pharmakol (Nauyn-Schmiedebergs).
1899;42:109118.
2. Overton CE. Studien ber die Narkose zugleich ein Beitrag zur
allgemeinen Pharmakologie. Gustav Fischer, Jena, Germany. 1901
3. Franks NP, Lieb WR Do general anesthetics act by competitive
binding to specific receptors? Nature. 1984;310:599601.
4. Franks NP, Lieb WR. Volatile general anesthetics activate a novel
neuronal K+ current. Nature. 1988;333:662664.
5. Franks NP. General anaesthesia: from molecular targets to neuronal
pathways of sleep and arousal. Nat Rev Neurosci. 2008;9:370386.
6. Nelson LE, Guo TZ, Lu J, et al. The sedative component of anesthesia
is mediated by GABAA receptors in an endogenous sleep pathway.
Nat Neurosci. 2002;5:979984.
7. McCarley RW. Mechanisms and models of REM sleep control. Arch
Ital Biol. 2004;142:429467.
8. McCarley RW. Neurobiology of REM and NREM sleep. Sleep Med.
2007;8:302330.
9. Hallanger AE, Wainer BH. Ascending projections from the pedunculopontine tegmental nucleus and the adjacent mesopontine
tegmentum in the rat. J Comp Neurol. 1988;274:483515.
10. Alam MN, Gong H, Alam T, et al. Sleep-waking discharge patterns of
neurons recorded in the rat perifornical lateral hypothalamic area.
J Physiol. 2002;538:619631.
11. Lee MG, Hassani OK, Jones BE. Discharge of identified orexin/
hypocretin neurons across the sleep-waking cycle. J Neurosci. 2005;
25:67166720.
12. Sonner JM, Antognini JF, Dutton RC, et al. Inhaled anesthetics and
immobility: mechanisms, mysteries, and minimum alveolar anesthetic concentration. Anesth Analg. 2003;97:718740.

13. Kelz MB, Sun Y, Chen J, et al. An essential role for orexins in emergence from general anesthesia. Proc Natl Acad Sci U S A. 2008;105:
13091314.
14. Kohyama J, Shimohira M, Iwakawa Y. Maturation of motility and
motor inhibition in rapid-eye-movement sleep. J Pediatr. 1997;130:
1171122.
15. Iglowstein I, Jenni OG, Molinari L, Largo RH. Sleep duration from
infancy to adolescence: reference values and generational trends.
Pediatrics. 2003;111:302307.
16. Lu J, Sherman D, Devor M, Saper CB. A putative flip-flop switch for
control of REM sleep. Nature. 2006;441:589594.
17. Von Economo C. Sleep as a problem of localization. J Nerv Ment Dis.
1930;71:249259.
18. Szymusiak R, Gvilia I, McGinty D. Hypothalamic control of sleep.
Sleep Med. 2007;8:291301.
19. Saper CB, Chou TC, Scammell TE. The sleep switch: hypothalamic
control of sleep and wakefulness. Trends Neurosci. 2001;24:726731.
20. Rudolph U, Antkowiak B. Molecular and neuronal substrates for
general anaesthetics. Nat Rev Neurosci. 2004;5:709720.
21. Wisden W, Laurie DJ, Monyer H, Seeburg PH. The distribution of 13
GABAA receptor subunits in the rat brain. I. Telencephalon,
diencephalons, mesencephalon. J Neurosci. 1992;12:10401062.
22. Goetz T, Wulff P, Wisden W. GABAA receptorsmolecular biology,
cell biology, and pharmacology. In: Squire LR, editor. Encyclopedia
of Neuroscience. Oxford: Academic Press; June 2009.
23. Farrant M, Nusser Z. Variations on an inhibitory theme: phasic and
tonic activation of GABAA receptors. Nat Rev Neurosci. 2005;6:
215229.
24. Rudolph U, Mohler H. Analysis of GABAA receptor function and
dissection of the pharmacology of benzodiazepines and general
anesthetics through mouse genetics. Annu Rev Pharmacol Toxicol.
2004;44:475498.
25. Chandra D, Jia F, Liang J, et al. GABAA receptor alpha 4 subunits
mediate extrasynaptic inhibition in thalamus and dentate gyrus and
the action of gaboxadol. Proc Natl Acad Sci U S A. 2006;103:15230
15235.
26. Belelli D, Lambert JJ. Neurosteroids: endogenous regulators of the
GABAA receptor. Nat Rev Neurosci. 2005;6:565575.
27. Mihic SJ, Ye Q, Wick MJ, et al. Sites of alcohol and volatile anaesthetic
action on GABAA and glycine receptors. Nature. 1997;389:385389.

Bissonette-005-(F)

4/5/11

5:24 PM

Page 79

CHAPTER 5
28. Song W, Chattipakorn SC, McMahon LL. Glycine-gated chloride
channels depress synaptic transmission in rat hippocampus.
J Neurophysiol. 2006;95:23662379.
29. Chry N, de Koninck Y. Junctional versus extrajunctional glycine and
GABA(A) receptor-mediated IPSCs in identified lamina I neurons
of the adult rat spinal cord. J Neurosci. 1999;19:73427355.
30. Jonas P, Bischofberger J, Sandkhler J. Corelease of two fast neurotransmitters at a central synapse. Science. 1998;281:419424.
31. OBrien JA, Berger AJ. Cotransmission of GABA and glycine to brain
stem motoneurons. J Neurophysiol. 1999;82:16381641.
32. Ye JH. Regulation of excitation by glycine receptors. Results Probl Cell
Differ. 2008;44:123143.
33. Vincler M. Neuronal nicotinic receptors as targets for novel analgesics. Expert Opin Investig Drugs. 2005;14:11911198.
34. Garrido R, Springer JE, Hennig B, Toborek M. Apoptosis of spinal
cord neurons by preventing depletion nicotine attenuates arachidonic
acid-induced of neurotrophic factors. J Neurotrauma. 2003;20:
12011213.
35. Tramr MR. [Postoperative nausea and vomiting] (German). Anaesthesist. 2007;56:679685.
36. Tao F, Johns RA. Effect of disrupting N-methyl-D-aspartate receptor
postsynaptic density protein-95 interactions on the threshold for
halothane anesthesia in mice. Anesthesiology. 2008;108:882887.
37. MacDonald JF, Jackson MF, Beazely MA. G proteincoupled receptors control NMDARs and metaplasticity in the hippocampus.
Biochim Biophys Acta. 2007;1768:941951.
38. Engelhardt T, Chan MK, McCheyne AJ, et al. The effect of varying
continuous propofol infusions on plasma cyclic guanosine 3,5monophosphate concentrations in anesthetized children. Anesth
Analg. 2007;105:616619.

Central Nervous System: Neurotransmitters and Anesthesia

79

39. Tobias JD. Dexmedetomidine: applications in pediatric critical care


and pediatric anesthesiology. Pediatr Crit Care Med. 2007;8:115131.
40. Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to
common anesthetic agents causes widespread neurodegeneration in
the developing rat brain and persistent learning deficits. J Neurosci.
2003;23:876882.
41. Fredriksson A, Pontn E, Gordh T, Eriksson P. Neonatal exposure to
a combination of N-methyl-D-aspartate and gamma-aminobutyric
acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits. Anesthesiology.
2007;107:427436.
42. Anand KJ, Sippell WG, Aynesley-Green A. Randomised trial of
fentanyl anaesthesia in preterm babies undergoing surgery: effects
on the stress response. Lancet. 1987;1:6266.
43. Anand KJ, Sippell WG, Schofield NM, Aynsley-Green A. Does
halothane anaesthesia decrease the metabolic and endocrine stress
responses of newborn infants undergoing operation? Br Med J (Clin
Res Ed). 1988;296:668672.
44. Dobbing J, Sands J. Comparative aspects of the brain growth spurt.
Early Hum Dev. 1979;3:7983.
45. Samali A, Zhivotovsky B, Jones D, et al. Apoptosis: cell death defined
by caspase activation. Cell Death Differ. 1999;6:495496.
46. Hengartner MO. The biochemistry of apoptosis. Nature. 2000;407:
770776.
47. Li P, Nijhawan D, Budihardjo I, et al. Cytochrome c and dATPdependent formation of Apaf-1/caspase-9 complex initiates an
apoptotic protease cascade. Cell. 1997;91:479489.
48. Zou H, Henzel WJ, Liu X, et al. Apaf-1, a human protein homologous
to C. elegans CED-4, participates in cytochrome cdependent activation of caspase-3. Cell. 1997;90:405413.

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Anatomy and Physiology
Bruno Bissonnette

6
C H A P T E R

INTRODUCTION
It is important for anesthesiologists to understand the anatomic
and psychological differences between an adult and a newborn,
an infant, and a growing child.1 It is even more important when
the brain is involved. Challenges in neuroanesthesia are most often
the result of the lack of knowledge of the disturbances caused by
a pathologic process affecting the central nervous system (CNS).
These alterations can be significant in the anesthesia preparation
and perioperative management.
The CNS does not reach maturity until the end of the first year
of life. Many pathologic processes result from abnormal neuroembryologic development, which may affect the physiology of the
brain as a whole. The understanding of cerebral physiology is an
important part of both neuroanesthesia and intensive care in order
to reduce both the neuromorbidity and the mortality. It is essential
to know the embryology, anatomy, and physiology of this vital
system in order to provide good clinical care of the child with
intracranial or spinal pathology.

NEUROEMBRYOLOGY
AND DEVELOPMENT
The three major processes by which the CNS develops are
(1) neurulation, (2) canalization, and (3) retrogressive differentiation (Table 61).

Neurulation
Early Stage
Neural tube development occurs in the first 56 to 60 days after
fertilization25 (see Table 61). During stage 6 (second wk of development), the nervous system begins to appear with the
TABLE 6-1. Phases and Stages of Neural Development
During Gestation
Phases

Stages

Age, d

Outcome

1. Neurulation

1628

2. Canalization

1320

3052

Brain, spinal cord


through L24
Sacral, coccygeal
segments
Filum terminale

3. Retrogressive 18Birth 46after


differentiation
birth
Modified from reference 6, with permission.

development of the primitive streak and Hensens node. The


notochord extends rostrally from Hensens node (stage 7), and
during the next 48 hours, fusion of the neural folds occurs at the
level of the third or fourth somite (of which there are six or seven
by this stage). The rhombencephalon or hindbrain corresponds
to this area.6 By stage 11, neural folds extend to the level of the
colliculi. The terminal hole is distorted by the primordia of the
thalamus and the corpus striatum. The neuroectoderm is connected to the amniotic cavity through the posterior neuropore at
this stage.

Later Stage
After closure of the anterior neuropore (stage 11), an interval
occurs before differentiation of the telencephalon or forebrain.
Bilateral cerebral vesicles appear in stage 15; they connect later to
the neural tube, thus, creating the foramina of Monro. As these
structures enlarge, areas that will later develop into the lobes of
the brain become identifiable: frontal and parietal areas (stage 17),
occipital area (stage 19), and temporal pole (stage 23). The main
differentiation of the cerebral cortex occurs during the third
trimester.7 However, even at this stage of development, the CNS
bears no resemblance to its final anatomic configuration. As the
brain develops, the external appearance changes. The surface of
the brain begins to develop fissures and sulci. As gyri develop,
most of the surface of the cortex becomes buried. During stage 22,
a layer of neuroblasts derived from pyramidal cells migrates to the
marginal zone, forming the primordium of the cortical gray
matter. During stage 23, the caudate nucleus is divided from the
putamen and globus pallidus by the progressive development of
upper and lower fibers. The early development of the cerebellum
occurs mainly about 1 month after the embryonic period begins
even though, at this stage, the paired cerebellar primordia have
not developed an identifiable pattern. The anlage of the cerebellum may be found when the pontine and cervical flexures begin
to form (stage 13). The cerebral nuclei derived from the diencephalon or midbrain appear at various stages, with the thalamic
structure appearing at stage 15. As the embryo makes the transition to fetus, the CNS is still relatively primitive, with the
development of the brain occurring during the later phases of
gestation and into the postnatal period.

Canalization and Retrogressive


Differentiation
Canalization is the process of development of the neural tube
caudal to that created by neurulation, which forms the lower

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lumbar, sacral, and coccygeal segments. During this process, a
secondary phase of caudal neural tube development occurs with a
proliferation of cells in the wall of the neural tube. This leads to an
excess of segments. Retrogressive differentiation is the process by
which these excess segments are remodeled to form the cauda
equina and the filum terminale.8 Eventually, the conus medullaris
is brought to its adult level opposite L12.

Neural Tube Defects and Embryology


Any defect in the development of the CNS may be referred to as a
neural tube defect. These may be classified by the extent of
involvement of the CNS: (1) those involving the brain and spinal
cord, (2) those involving the brain alone, and (3) those involving
the spinal cord alone. If both the brain and the spinal cord fail to
undergo complete neurulation, a condition of total dysraphism or
craniorachischis occurs. Anencephaly results when the brain alone
fails to close. Many abnormalities associated with the later stages
of development of the nervous system may be of significance to
the pediatric neuroanesthetist. Migrational abnormalities are
associated with schizencephaly (clefts in the cerebral wall),
pachygyri (sparse, broad gyri), and polymicrogyria. Lissencephaly
(smooth brain) may result from migrational abnormalities or
earlier defects in development. Agenesis of the corpus callosum is
often associated with migrational abnormalities, although it is not
considered to be a migrational abnormality in itself. Myeloceles
result from caudally defective neurulation. If an enlarged subarachnoid space is present dorsally to the defective cord, the
condition of meningomyelocele is present.

The Ventricular and Cerebrospinal


Fluid Systems
During stage 12, the posterior neuropore closes and, at that point,
the ventricular system is closed. It now consists of the systems
within the prosencephalon, diencephalon, mesencephalon, rhombencephalon (metencephalon, nyencephalon), and central canal
of the spinal cord. The roof of the rhombencephalon thins during
stage 14 and evaginations of the cerebral hemispheres develop
(stage 15). The anlage of the lateral ventricles, third ventricle, and
the foramen of Monro become demarcated, and by stage 20, the
cerebral hemispheres have overlapped the diencephalons, with the
lateral ventricles becoming the largest of the ventricular system.
The foramen of Magendie is created from a perforation in the roof
of the fourth ventricle. About 10 weeks later in the development of
the CNS, the foramina of Luschka develop. As the tectum and
tegmentum enlarge, the aqueduct of Sylvius narrows. The choroid
plexuses differentiate and the brain mass increases, reducing the
volume of the ventricular system. The ventricular system normally
terminates after birth at the level of the obex of the caudal floor of
the fourth ventricle as the spinal canal is obliterated by cellular
proliferation within the spinal cord. In the Arnold-Chiari malformation complex, the embryologic development of the caudal cerebellum is abnormal; the central canal remains enlarged, causing
hydrosyringomyelia.

Cerebrovascular Development
There are five periods of development of the cerebral vasculature.9
Initially (up to stage 8 or 9), there are no arteries or veins. As the

Central Nervous System: Anatomy and Physiology 81

embryo develops, primordial endothelium-lined channels form a


plexiform network from which arteries and veins develop (second
period, stages 1013). Thus, circulation to the CNS is established.
In the third period, direct connections between the arterial side
and the primitive aorta and between the venous side and the
jugular system are formed. The arterial and venous systems are
divided in the fourth period (stage 19) and extend into fetal
development. The fifth and final stage extends into the postnatal
period and is characterized by late histologic changes in the vascular walls as they become adult in form. Most vascular malformations are believed to occur before the arterial walls thicken when
the embryo is about 40 mm long and represents a structural defect
in the primitive arteriolar-capillary network.10

NEUROANATOMY
Gross Anatomy
In order to understand the complex nature of the CNS, it is
essential to have a working knowledge of its anatomy. The
neuroanesthetist should have a clear understanding of the
effects of trauma and other pathologic processes on the function
of the brain and spinal cord in order to introduce management strategies to minimize the disruption to the functioning of
the CNS.
The CNS is protected by the calvarium and vertebral column.
At birth, the calvarium is composed of ossified plates covering the
dura mater, separated by fibrous sutures and the fontanelles
(Figure 61). Two fontanelles are present at birth. The posterior
fontanelle closes at 2 to 3 months, whereas the anterior fontanelle
closes between 10 to 18 months. This fibrous membrane will
normally become ossified during adolescence.11 The single
continuous space within the calvarium and the vertebral column
contains the brain parenchyma (neurons, glial tissue, and
interstitial fluid), cerebrospinal fluid (CSF; 10%), and the cerebral
blood volume (CBV). An increase in the volume of any of these
compartments results in compression and displacement of vital
components of the CNS because of a lack of extensibility (e.g.,
impedance) within the subdural space and low compliance of the
system as a whole. Any process that causes an increase in the
volume of the tissue compartments within the craniospinal system
(tumor growth, hydrocephalus, hemorrhage) may cause a rapid
rise in intracranial pressure (ICP). It is essential to note that the
ability to compensate for an acute rise in ICP even in presence of
an open fontanelle is virtually nonexistent because of the lack of
distensibility of the dura mater. The dura mater offers high resistance to a rapid rise in volume of any of the tissue compartments
enclosed within it.12 Conversely, a slow rise in ICP may allow a
more progressive expansion of the nonfused fontanelles and
separation of the fibrous sutures.13 It is possible to use the anterior
fontanelle to assess the ICP in the infant either by clinical
palpation or with the use of skin transducers.14,15
At birth, the brain weighs about 335 g (1015% of body weight)
and grows rapidly throughout the first year of life, doubling
its weight by 6 months. At 1 year of age, the brain weighs 900 g;
at 2 years, 1000 g; finally reaching its adult weight by 12 years
(12001400 g). At this point it makes up about 2 % of the bodys
weight.11 The intracranial space may be separated into two compartments by a layer of dura mater and the tentorium cerebelli.
These are the supratentorial compartment and the infratentorial
compartment.

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Figure 6-2. Midsagittal nuclear magnetic resonance imaging (MRI)


scan shows the supratentorial (A) and posterior fossa (B) structures.
The white arrow shows the tentoria cerebelli and the straight sinus.

Figure 6-1. Three-dimensional image constructed from a computed


tomography scan of a 7-month-old infant showing the craniofacial
contours. The face is smaller than the cranium. The V shape downward
of the face helps us to understand why the mouth of the infant is small.
The open anterior fontanelle is easily seen. The coronal and metopic
sutures are also visualized.

structures. Obstruction of the anterior cerebral artery may lead to


ischemia. As the pressure within the supratentorial compartment
increases, the diencephalon, cerebral peduncle, oculomotor nerves, posterior communicating artery, and uncus of the temporal
lobe, which sits in the middle cranial fossa adjacent to the incisura,
will herniated, leading to contralateral hemiplegia, ipsilateral large
irregular pupil, and abnormal posturing.

The Infratentorial Compartment


The Supratentorial Compartment
The supratentorial compartment is the larger compartment of the
craniospinal space and includes the anterior and middle cranial
fossae. It contains the cerebral hemispheres, which consist of three
lobes (frontal, parietal, and parieto-occipital) and the diencephalon, which comprises the thalamus, hypothalamus, epithalamus, and subthalamus. The diencephalon (rostral end of the
brainstem) occupies the central part of the supratentorial compartment, the size of which is determined by the calvaria and
tentorium cerebelli (Figure 62). The tentorium is a tent-shaped
dural septum forming a roof over the posterior cranial fossa
between the supratentorial compartment and the cerebellum. It
has an oval opening (tentorial incisura) between the anteromedial
aspects of the right and the left leafs through which the brainstem
passes from the middle to the posterior cranial fossa. The cerebral
hemispheres are separated by the falx cerebri, a sickle-shaped
portion of dura in the longitudinal fissure separating the hemispheres. If there is a primary brain injury severe enough to cause
major hemorrhage or edema, both the inferior edge of the falx
cerebri and the tentoria incisura become important sites of
secondary injury. A differential pressure may occur across the
incisura, leading to herniation of the brainstem and other vital

The infratentorial compartment, often described as the posterior


cranial fossa, comprises the cerebellum, the pons, and the medulla
oblongata. It is delineated by the anterior and posterior occipital
portions of the skull. The consequences of lesions in this area can
be very severe because of compression of many vital structures
such as the reticular activating system, the cardiac and respiratory
control centers, and the cranial nerves. The cerebellum, which is
the largest structure in the infratentorial compartment, is mainly
associated with the regulation of posture, muscle tone, and coordination. Hence, lesions to the cerebellum may lead to an unsteady
gait, hypotonia, and tremor. Increased pressure within the posterior fossa may lead to a pressure differential across the foramen
magnum, the pressure cone phenomenon. This leads to herniation
of the cerebellar tonsils (posteroinferior prolongations of the
cerebellum) through the foramen magnum. This condition is
commonly fatal and may be preceded by relatively subtle clinical
signs.

The Spinal Canal Compartment


The spinal canal compartment contains the spinal cord and the
CSF. The spinal cord is the continuation of the medulla oblongata

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Central Nervous System: Anatomy and Physiology 83

Figure 6-3. Position of the distal end of the spinal cord in relation to the vertebral column and meninges according to
the age of development of the patient. The sacral nerve (S1) root must stretch upward significantly to accommodate the
upward change in position of the spinal cord. A: 24 Weeks. B: Newborn. C: 8-Year-old child. D: Adult.

and is a cylindrical object, flattened slightly anteriorly and


posteriorly where the vascularization occurs. Following retrogressive differentiation at birth, the spinal cord ends at the intervertebral level of L34, reaching the usual adult level of L12 at the
age of 8 (Figure 63). The adult spinal cord is 42 to 45 cm in length
and may actually terminate anywhere between T12 and L3. The
spinal cord occupies approximately 66% of the entire vertebral
space, the rest being occupied by the CSF. The intradural space
extends to the level of S2, and therefore, the segment of L2 to S2
consists of a reservoir of CSF. This may act as a mechanism to
compensate for increases in ICP. However, acute decompression of
the spinal compartment by lumbar puncture may lead to transforaminal herniation, because the spinal compartment is larger
than the posterior fossa and has greater compliance secondary to
the slight distensibility of the spinal dura mater and the compressibility of the venous plexuses.

The venous sinuses of the dura mater are the most important
components of the venous drainage of the brain. They are valveless
channels between the dura mater and the cranial periosteum.
Their endothelium is continuous with that of the veins draining

Vascular Anatomy
Blood flow to the brain is supplied by two sets of paired arteries,
the internal carotid and the vertebral arteries. Each of these four
arteries contributes to the circle of Willis or circulus arteriosus
cerebri formed by the posterior cerebral artery, the posterior
communicating artery, the internal carotid siphon, the anterior
cerebral artery, and the anterior communicating artery (Figure
64). The circle of Willis prevents cerebral ischemia and infarction
in the event of failure of one of these blood supplies to the brain;
however, this protective mechanism is incomplete. In most cases
of occlusion to one of the vessels of the circle of Willis, insufficient
blood is supplied by the collateral routes. Up to 28% of individuals
lack at least one anastigmatic component of the arterial circle, the
most commonly absent part being the anterior communicating
artery.

Figure 6-4. The cerebral arterial circle of Willis and its principal
branches in a 9-month-old child. 1 = Basilar artery; 2 = posterior
cerebral artery; 3 = posterior communicating artery; 4 = middle
cerebral artery; and 5 = anterior cerebral artery. The black arrow
shows the anterior communicating artery.

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into them. There is no muscle in the sinus walls, and hence, tears
to the venous sinuses during surgery may lead to severe hemorrhage. The superior sagittal sinus, situated in the midline, is particularly vulnerable during surgery for correction of craniosynostosis
and during a morcellation craniectomy. Most commonly, this
sinus ends by becoming the right transverse sinus, which runs
above the tentorium cerebelli to the S-shaped sigmoid sinus
laterally. Most of the blood in the venous sinuses of the dura enters
the sigmoid sinuses and then into the venous enlargements or
superior bulbs of the internal jugular veins. The blood of the
inferior petrosal sinuses enters the internal jugular veins directly.
The smallest sinus, the occipital sinus, communicates with the
internal vertebral plexus. The cavernous sinuses situated around
the sella turcica join the inferior petrosal sinuses.

Vascular Anatomy of the Spinal Cord


Blood supply to the spinal cord is separated into anterior and
posterior circulations with no collateral flow between them. Both
circulations arise from the vertebral arteries, supplemented by the
intercostal and lumbar vessels from the descending aorta (Figure
65). A single anterior spinal artery supplies the ventral two thirds
of the spinal cord, which includes the corticospinal tracts and the
motor neurons. The dorsal one third is supplied by paired
posterior spinal arteries that form a plexus on the surface of the
cord.16 The ventral spinal cord is supplied by the anterior spinal
artery and, to a variable extent, by collateral flow from radicular
arteries arising from the aorta. The anterior spinal artery may not
be continuous throughout its length. Its branches run circumferentially on the surface of the spinal cord or penetrate the
parenchyma and divide within the gray matter (sulcal branches).
Radicular arteries arise from intercostal and lumbar arteries on
the left side of the aorta. Of the 62 radicular arteries present during
intrauterine life, only 5 to 8 are still present in the adult. Forty-five
percent of the population has fewer than 5 radicular arteries (12
cervical, 23 thoracic, and 12 lumbar). Hence, there are certain
watershed areas of the cord (upper thoracic and lumbar levels)
that are very vulnerable to ischemia. The great radicular artery of
Adamkiewicz arising from the aorta between the eighth thoracic
and the third lumbar roots provides up to 50% of the entire spinal
cord blood flow and, therefore, is crucial to the blood supply to
the cord. It may be particularly vulnerable to damage during aortic
or spinal surgery and trauma.

Figure 6-5. Arterial blood supply to the spinal cord. 1 = posterior


spinal artery; 2 = radicular artery; and 3 = anterior spinal artery.

Venous drainage from the spinal cord is via two systems, the
internal and the external venous plexuses, which communicate
with each other and with the segmental systemic veins and the
portal system.17 The internal venous plexus surrounds the dura
and the posterior longitudinal ligament in a weavelike pattern of
thin-walled, valveless veins. At each segmental level, the plexus
receives veins from the cord plus a basivertebral vein from the
vertebral body. The occipital and basilar sinuses of the brain
communicate with this system via the foramen magnum. Venous
blood from the internal venous plexus drains into the intervertebral veins passing through the intervertebral and sacral foramina
to the vertebral, intercostal, lumbar, and lateral sacral veins. Veins
draining vertebral bodies form the external venous plexuses,
which join to form the anterior vertebral plexus. Veins draining
the ligamentum flavum form the posterior venous plexus.

NEUROPHYSIOLOGY
Cerebral Metabolism and Ionic Transport
The physiologic structure and function of the human brain
represent one of the most complex structures of all biologic
systems. A young adult has about 100 million neurons each
connected to other neurons through 100 to 1000 synapses. The
two major elements involved in this complex system are the
innumerable synaptic connections and the presence of several
intra- and intercellular messenger, the last ones acting as
interneuronal mediators.18 The energy required to maintain and
regulate these biologic systems is somewhat extensive. After
8 years of age, the human brain weighs only 2% of the total body
mass. However, it consumes more than 20% of all the adenosine
triphosphate (ATP) produced by the entire body. Although
metabolic activity is necessary to sustain the complex interactive
functions of the brain, it also renders the neuronal tissue
particularly vulnerable to any reduction of energetic reserve.
Under normal physiologic conditions, the main substance used
to produce cerebral energy is D-glucose (2-deoxyglucose being the
only molecular form capable of crossing the blood-brain barrier
[BBB] in both directions).19 D-Glucose is the only source of
metabolic energy used by the Krebs cycle to produce ATP. Any
important decrease in the supply of glucose leads to coma and
possibly to cellular and cerebral death. It is interesting to note that
the brain, despite its enormous glucose requirement (6.8 mg
glucose/100 g/min in a child as opposed to 5.5 mg glucose/100 g/
min in an adult), does not store glucose and does not elaborate
any glycogen. The muscular and hepatic reserves of glycogen are,
respectively, 10 and 100 times that of the brain. Thus, with normal
consumption of ATP, the brains glucose reserve secures only
3 minutes of energy supply to maintain normal cerebral function.
The brain depends almost, if not entirely, on blood perfusion for
a daily glucose consumption of 120 g. D-Glucose comes from the
aerobic glucogenesis of the liver and muscles. A minimum
quantity is synthesized de novo through amino acids, glycerol, and
intermediate metabolites of the Krebs cycle. In infants and young
children, the use of ketones (also an important source of energy in
the adult after prolonged starvation) contributes to the supply of
energy to the brain. The use of these metabolic products such as
beta-hydrobutyrate and acetoacetate is normal in the child. The
ability of the CNS to use ketones as substrate to energy is essential
when there is a drop in glucose supply. An adult requires a period
of 12 to 16 hours to increase ketone production and begins to

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utilize them as energy substrate. More than 50% of all oxygen used
by the brain during a period of starvation is used to oxidize ketone
bodies. However, ketones produce only enough energy to maintain vital cellular functions but, do not, for example, allow recovery
from a hypoglycemic coma.
D-Gglucose penetrates the brain through a transport mechanism assisted by a specific membrane transporter having saturability properties (first-order kinetics) and competitive affinity to the
receptor. Aerobic glycolysis and phosphorylative oxidation
produce ATP, CO2, and H2O. Aerobic glycolysis in the internal
membrane of the mitochondria creates 30 ATP directly whereas
6 ATP come from 2 NADH (nicotinamide adenine dinucleotide,
reduced form) generated in the cytosol during glycolysis. Aerobic
mitochondrial oxidative metabolism produces 18 times more ATP
per molecule of glucose than cytoplasmic anaerobic glycolysis in
which NADH cannot be retransformed into NAD (nicotinamide
acid dehydrogenase) because of the lack of O2. In case of anaerobic
metabolism, NAD is regenerated by the transformation of pyruvate into lactate. Basic glucose consumption by the brain is
approximately 0.3 to 0.8 mmol/100 g/min, which is higher than
that reported for the heart (69 mmol/min).20 The combustion of
1 glucose molecule requires 6 molecules of O2. In the presence of
O2, 90 to 95% of all carbohydrates are consumed by the brain
through the phosphor-oxidative pathway. The production of
cerebral lactate represents less than 4% of the glucose metabolized
in presence of O2.
Of all human organs, the brain is the organ that consumes the
second largest amount of O2, after the glomic cells of the carotid
body known as the ultimum moriens (the last cells to die). The
total O2 consumption of the brain or the cerebral metabolic rate
for oxygen (CMRO2) in a young man (average age, 21 y) is 3.5 mL
O2/100 g/min.21 It is almost the same in an elderly person (average
age, 71 y). However, children (average age, 6 y) have a significantly
increased CMRO2 (5.5 mL O2/100 g/min). This increase in O2
consumption is probably related to the energetic requirements of
growth. The brain is the organ most sensitive to lack of O2. For
this reason, it is capable of regulating the use of O2 according to its
needs.
O2 is necessary for the synthesis and maintenance of mitochondrial ATP. The ATP produced by aerobic glycolysis is almost
entirely utilized for maintaining transmembrane electric functions
and ionic gradients. It is also used to supply energy for the biosynthesis, liberation, and capture of synaptic neurotransmitters. The
most costly energetic mechanism is undoubtedly the transmembrane transport of ions. About 60% of ATP produced is used to
maintain the ionic transmembrane potential, mainly the Na+/K+ATPase pump.22 Following a period of depolarization and liberation of synaptic neurotransmitters, much energy is required to
ensure the neuronal recapture of K+ (repolarization) and neurotransmitters. Consequently, even the basic neurologic activity
requires a large O2 supply, which significantly increases during a
period of external stimulation (visual) or voluntary movement. In
the presence of ischemia or anoxia, any interruption of the ionic
pump will cause a loss of cellular regulation and intracellular acidbase balance. The anesthesiologist must try to maintain the energy
balance between cerebral supply and demand. Approximately 50%
of the CMRO2 is used by the astrocytes for the maintenance of
energy production (e.g., ATP-glutamatedependent pumps) and
synthesis of neurotransmitters (the functional metabolism of the
brain). The other 50% is used to maintain the structural characteristics and functional metabolism of the brain cells.18

Central Nervous System: Anatomy and Physiology 85

Cerebral Blood Flow and CBV


The cerebral blood flow (CBF) is one of the variables that can be
modified by the anesthesiologist. It is indirectly linked to the
intracerebral blood volume. Manipulation of the CBF helps to
control ICP. Although the presence of intracranial pathology may
change or even paradoxically inverse the relationship between ICP
and CBF, in most cases, the use of an anesthetic technique to alter
CBF remains an efficient and powerful tool for the anesthesiologist.
An adult brain weighs 1400 g on average and receives about
20% of the cardiac output at rest. It controls its own O2 supply
according to its metabolic requirement for O2 and glucose (metabolism flow coupling). Current techniques used to measure CBF
do not give a precise estimation of global CBF. The use of positron
emission tomography (PET) confirmed that the mean CBF in
the adult is 50 mL/100 g/min with a variability of 30 to 90 mL/
100g/min.23 In the pediatric population, CBF is 42 to 48 mL/min/
100 g in term neonates, 90 mL/100 g/min between the ages of 4
and 6 months, peaks around 110 mL/min/100 g at 3 to 4 years to
subsequently decrease to approximately 78 mL/min100 g at
9 years2426 The global CBF of children from 6 months to 4 years
of age is twice than of the adult. An accelerated cerebral development during this period explains the important increase in CBF.
Nevertheless, it has been reported that CBF in children born
prematurely is much lower than adults, varying significantly from
5 to 23 mL/min/100g in 26 to 28 weeks premature newborns to
approximately 50 mL/100g/min at term.27,28 This reduction of CBF
is associated with the presence of decreased cerebral mass and
metabolism as well as the significant absence of cerebral development in the first few weeks of life. The CBF of gray matter is higher
than that of the corresponding white matter.29 The perfusion of
the cerebral white matter represents about one third of that of the
gray matter, and this ratio remains constant during the entire
lifetime.30 This implies that the age-related reduction of cerebral
metabolism and CBF is mainly because of a loss of synapses or a
drop in their activity rather than to a neuronal anatomic loss.
The interstitial cerebral compartment is maintained constant
by the presence of the astrocytes and the tight junctions (9 ) that
form the BBB (Figure 66). The BBB is impermeable to electrolytes and allows osmotic pressures to equilibrate by a water shift between the blood and the brain compartments. Therefore, normal
brain volume is physiologically controlled by plasma osmotic
pressure. Brain cells are resistant to osmotic variation and possess
powerful adaptation mechanisms that correct neuronal volume
within minutes. When cerebral injury occurs, the BBB can be
injured and water transfer across the BBB is dependent on hydrostatic pressure gradients. The interstitial pressure is high with tight
cell junctions. This also prevents the flux of water toward the
interstitium.

Cerebral Perfusion Pressure


The arteriovenous pressure gradients that are observed are much
more complex in the brain than in other organs because the brain
is confined in a closed cranial vault. The presence of a rigid box
brings about the formation of arteriovenous gradients that are
directly dependent on the variation of ICP, which is normally
higher than the atmospheric pressure and central venous pressure
(CVP).30 Consequently, neither the CVP nor the venous pressure
of the cerebral sinuses affect CBF. The relative absence of pressure

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Figure 6-6. Relevant anatomic characteristics of the brain vessel. The


neural vasculature differs from the peripheral systemic vessels by the
tight junctions, the presence of numerous mitochondria, and rare
pinocytic vesicles. Astrocyte feet surround the vessel and form the
blood-brain barrier.

inside the venous sinuses is a consequence of the very resistant


fibrous wall that protects them from most changes in ICP. The
hydrostatic pressure of the cerebral venous sinuses is determined
almost entirely by the CVP. However, contrary to the venous
sinuses, the pressure of the veins of the cerebral tissue is totally
dependent on ICP. However, this should always be higher than
ICP in order to avoid any extrinsic compression. Direct measurement of their pressure has demonstrated this hypothesis. For that
reason, cerebral perfusion pressure (CPP) is equal to the mean
arterial pressure (MAP) less CVP or ICP (the greater of the two):
CPP = MAP ICP (or CVP)

Cerebral Autoregulation
The term autoregulation is used to describe the phenomenon by
which the CBF is maintained constant despite important changes
in CPP (Figure 67). This control is limited in the adult to CPP
range between 50 and 150 mmHg of CPP.31 The lower and higher
thresholds of cerebral autoregulation in the infant and the young
child are not known. Animal models suggest that the lower and
higher limits of the autoregulation mechanism are lower than
those observed in the adult, 40 to 90 mmHg, respectively.32,33 It
has been shown in infants and young children undergoing balloon
dilation of coarctation of the aorta that the cerebral autoregulation
mechanism is present and capable of rapid response.34 However,
the effect of systemic arterial hypotension on cerebral autoregulation of the newborn remains unknown. It is reasonable to think
that CBF is rather well maintained despite low perfusion pressures.
CBF is matched to CMRO2. At rest, it is maintained at a
constant level of about 50 mL/min/100 g for a large range of MAP.
With decreasing MAP, cerebral vasodilatation occurs and CBV
increases. With hypertension, vasoconstriction leads to a decrease
in CBV and ICP. This autoregulation process is necessary to
maintain local tissue PCO2 (carbon dioxide pressure) constant.
Three mechanismsmyogenic, metabolic, and neurogenicare
involved in cerebral autoregulation.35 The rapid component (i.e.,

Figure 6-7. The effect of cerebral perfusion pressure (CPP) on cerebral


blood flow (CBF). CBF is autoregulated between 50 and 150 mmHg in
the adult. In the child aged 6 months to 12 years, CBF is maintained
constant to higher values than those in the adult, whereas for the premature baby and infant younger than 6 months of age, mean CBF is lower
and the inferior and superior limits of autoregulation are different.

the myogenic response) takes from 30 seconds up to 3 minutes to


respond. The myogenic mechanism is probably the most efficient
against severe and rapid changes in CPP, whereas the metabolic
control system is associated with slower changes caused by modification of the metabolic flow balance.34 The myogenic theory rests
on the concept that smooth endovascular muscles have an
intrinsic property capable of reacting to changes in CPP. The
presence of stretching receptors capable of recognizing changes in
transmural pressure rather than the locoregional variation of flow
has been confirmed (the Bayliss effect described in 1902).36 In
children, the myogenic response seems even faster than described
in adults. It is activated within the first 10 seconds after an abrupt
change in CPP and completed under 2 minutes.34,37 The second
component of this cerebrovascular autoregulatory control is the
fine-tuning response based on neurogenic and metabolic mediators. The control of CBF by direct innervation of the autonomous
nervous system remains a complex phenomenon.35 Several neurotransmitters have been identified as having a direct contribution
to the cerebral autoregulation mechanism. The presence of an
important sympathetic innervation, mainly noradrenergic, on the
major cranial vessels and the small arteries cannot be neglected,
1-, 2-, and -adrenergic receptors having been identified on
the cortical microcirculation.38 Scientific evidence suggests that
the microcirculation is mainly responsible for the fine-tuning of
the cerebral autoregulation.
The metabolic factors involved in this system are the levels of
CO2, K+, and adenosine.35 CO2 is the most powerful vasodilator of
the cerebral vessels. An increase in CO2 produces cerebral vasodilatation and causes an increase in CBF and CBV. When CO2
doubles from 40 to 80 mmHg, CBF also doubles and is the same
for a reduction in CO2, halving from 40 to 20 mmHg when CBF
is reduced by as much. In the adult, CBF varies in a linear way
with any change in PaCO2 (arterial pressure of carbon dioxide)
between 20 and 80 mmHg (Figure 68). A 1-mmHg fall in PaCO2
results in a 4% decrease in CBF. As PaCO2 falls, CSF pH rises and
periarteriolar changes in pH are reflected in vasoconstriction. The
use of prolonged hyperventilation to control ICP is effective only
for a period of 6 to 8 hours, after which, unless the CO2 has
dropped again, CBF will return to its prehyperventilation value.
The clinical implication for this physiologic observation is that, if

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Figure 6-8. Hypocapnia widens the autoregulation plateau, whereas


hypercapnia reduces it. Young WL. Clinical Neuroscience Lectures, Cathenart Publishing, Munster, IN 1993.

hyperventilation is maintained for a certain period and then


normoventilation and, thus, normocapnia are then restored
rapidly, the pH of the interstitial space will drop. This decrease in
pH will be linked to the increase in PaCO2 and CBF and CBV will
increase dramatically, which will cause an increase in ICP. Chronic
hyperventilation will result in slow movement of bicarbonate ions
out of the CSF with normalization of CSF pH and CBF within 24
hours.39 However, sudden increases in PaCO2 after chronic hyperventilation of more than 24 hours can result in cerebral vasodilatation and increases in ICP.40 Previous studies have suggested that
the immature brain is relatively unresponsive to small changes in
PaCO2,41 but investigations on fetal rabbit brain have demonstrated that CBF responds to changes in PaCO2.42 In the child, a
study using transcranial Doppler has shown that the mathematical
relationship, describing the relationship between CBF when CO2
varies between 20 and 80 mmHg, is a logarithmic curve, which
suggests that the maximum vasodilatation effect of CO2 is rapidly
reached at around 50 mmHg.43
Cerebrovascular reactivity to CO2 represents the first therapeutic line used by emergency physicians, anesthetists, and intensivists
to control ICP. However, the effect of CO2 on the cerebral vasculature seems to be transient. A sustained modification in the
CO2 level for 6 to 8 hours causes a resetting of CBF to its initial
value. This suggests that the cerebrovascular effect of CO2 is
mediated via changes in H+ concentration in the extracellular
space. The vascular effect of CO2 is about 6 hours because the
extracellular HCO3 needs 6 to 8 hours to reset the acid-base
balance and, thus, the extracellular pH. It is important to stress
the importance of mild hypocapnia, which widens the autoregulation plateau, whereas hypercapnia decreases this plateau (Figure
69). Hypotension (MAP decreases) impairs CO2 reactivity of the
cerebral vasculature, whereas normotension maintains its effect
(see Figure 69). Blood viscosity may also have a major impact on
cerebral autoregulation. A decrease in blood viscosity will cause a
temporary increase in CBF, which will be rapidly corrected by
metabolic adjustment.44
Cerebral O2 and glucose demands also directly influence cerebral vasoreactivity and CBF. The cerebral vascular response to
hypoxia is not well studied in children. Even in the presence of

Central Nervous System: Anatomy and Physiology 87

Figure 6-9. Hypotension impairs CO2 reactivity of the cerebral vasculature when compared with normotension. With permission from W. L.
Young, 1993, USA.

adequate autoregulation, the global distribution of CBF is not


uniform, which implies the presence of a regional vascular regulation linked to the regional CMRO2. Adults show no change in CBF
until PaO2 (arterial oxygen pressure) falls below 50 mmHg, at
which time, CBF begins to increase exponentially. The CBF seems
to depend on the quantity of oxygen available for the mitochondrial phosphorylative oxidation mechanisms. However, hyperoxia
does not modify CBF. Below a certain autoregulation limit, the
CBF varies in parallel with changes in CPP. When CPP is lower
than the inferior limit of autoregulation, the regions most vulnerable to ischemia are the vascular transition zones between the gray
and the white matters as well as the vital subcortical structures and
the basal nuclei. When CPP is greater than the superior autoregulation limit, CBF increases and the hydrostatic force transmitted
on the vasculature already dilated to a maximum could cause
edema, thrombotic occlusion, and/or intracerebral (mainly of the
germinal matrix) and intraventricular hemorrhage. Occlusive
thrombosis seems to result from fibrinoid necrosis of the vascular
endothelium causing the formation of platelet aggregates.
The controlled hypertension concept is based on intact cerebral
autoregulation.45 In the case of brain injury, a decreased CPP leads
to cerebral vasodilatation, increasing CBV and further increasing
ICP. To counteract this process, increasing MAP leads to an increased CPP and reflex cerebral vasoconstriction. This vasoconstriction decreases CBF and CBV, thus, further decreasing ICP and
increasing CPP. This therapeutic approach, by vasoconstriction in
uninjured areas, leads to increased perfusion in injured areas
(Robin Hood effect).46,47 Clinically, it is achieved by expanding
plasma volume and the use of vasopressor agents if needed.
However, it must be stressed that controlled hypertension must be
progressive to allow autoregulation to occur and must stay within
the patients autoregulation range of 80 to 100 mmHg. Cerebral
autoregulation can be impaired in the newborn, presenting a state
of severe respiratory distress in the presence of an anoxic or a hypoxic episode48 or simply during the administration of vasodilator
agents such as CO2, nitroprusside, or inhalational anesthetic
agents. Abrupt MAP changes will transiently lead to changes in
CBF. The autoregulation window ranges from a mean CPP of 50

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to 150 mmHg in normal subjects and is shifted to higher values in


hypertensive patients and to lower values in hypotensive patients
or in the brain surrounding an arteriovenous malformation.
Several factors impair cerebral vasoregulation. The two of primary
concern are PaCO2 and volatile anesthetic agents. Intravenous
agents like thiopental, etomidate, and propofol are cerebral vasoconstrictors. When cerebral vasoreactivity is uneven, vasodilating
agents can increase blood flow to uninjured areas, thus decreasing
blood flow to injured areas (vascular steel effect), whereas vasoconstricting agents increase blood flow to injured areas (Robin
Hood effect).

Not surprisingly, medications such as acetazolamide and


furosemide, which can reduce the production of CSF, have a
minimal effect on ICP. Only patients with an marked decrease in
intracerebral compliance with a very high ICP may benefit from
this pharmacologic effect. In patients with ICP issues, it is
important to avoid using certain anesthetic agents such as
enflurane, which can increase the secretion of CSF, or alfentanil,
which can hinder its reabsorption. Finally, resorption rate depends
on the CSFtovenous pressure gradient and resorption resistance. The pressure gradient between the CSF and the venous
compartment is called effective CSF pressure.

CSF

Spinal Cord Blood Flow

The brain is highly sensitive to environmental changes, and any


change in the extracellular ionic concentration can modify its
activity. The CSF composition is controlled very strictly, which
differentiates CSF from other fluids in the body (Table 62). The
brain is protected by two barriers, the BBB and the blood-CSF
barrier, which is responsible for maintaining ionic homeostasis
between blood and CSF and, moreover, between blood and the
respiratory control centers. The CSF is largely secreted by the choroidian plexi (80%), which are located in the cerebral ventricles.
The capillaries of the choroidian plexi are equipped with openings
and intercellular spaces allowing the free passage of molecules
through this special endothelium that is responsible for the
secretion of CSF. The presence of an extrachoroidian site involved
in the production of CSF has not been clearly identified. However,
it has been suggested that the surface of the ependyma as well as
the cerebral parenchyma are potentially able to participate in the
production of CSF. In the adult, normal CSF volume varies
between 100 and 150 mL or 1.5 to 2.0 mL/kg. Under normal
conditions, the production and reabsorption of CSF are balanced.
The production of CSF in the adult is 0.35 mL/min or 500 mL/
day.49 In the child, it is slightly less or about 0.3 mL/min. Because
the total CSF reserve is lower in the child, the effect on cerebral
compliance is more pronounced, and because the total quantity is
lower, the total CSF volume can be replaced entirely three to four
times a day. CSF is mainly formed by the passive transport of Na
, Cl, and HCO3, which follows a simple concentration gradient
with water passively following these ions, whereas active transport
is necessary for glucose and amino acids. There are virtually no
proteins in the CSF (see Table 62). Arachnoidian villi are
responsible for the passive reabsorption process of CSF through
their endovenous outgrowth. This reabsorption mechanism has
not yet been fully understood. A reduction of 35% in the
production of CSF causes a reduction of only 1.1 mmHg in ICP.50

The use of the Doppler technology has simplified the noninvasive


evaluation of CBF. In the child, it has opened up the study of the
pathophysiology of the cerebral circulation and the circulation in
the spinal cord. Previously, almost all scientific data linked to the
circulation of the spinal cord came from animal studies.51 Despite
the fact that blood flow is evaluated in velocity rather than in
milliliters per minute, the studies on blood flow in the spinal cord
carried out on cats demonstrate an excellent statistical correlation
with the measurements obtained by Doppler velocimetry. Animal
studies confirm that the physiology of the blood flow in the spinal
cord is comparable with that of CBF. However, because the spinal
cord metabolism is proportionally lower than that of the brain,
blood flow in the spinal cord is lower. Blood flow in the gray spinal
matter is 50% of blood flow at the level of the gray matter of the
brain, whereas blood flow in the white matter represents only one
third of the perfusion of the white cerebral matter.
The equation of the perfusion pressure of the spinal cord
(PPSP) is: PPSP = MAP extrinsic pressure. At the spinal cord
level, it is the equivalent of the CPP at the brain level. This concept
is clinically useful because it highlights the factors influencing
blood flow at the spinal cord level. Extrinsic pressure can be the
result of a tumor, hematoma, CSF, and/or epidural venous congestion. The presence of autoregulation in the spinal cord secures
a constant flow as occurs in the brain. Although the limit values
are often described as 60 to 150 mmHg, an inferior limit of
45 mmHg and a superior limit of 180 mmHg have also been
reported. It is most difficult to rely on monitoring to evaluate the
impact of an extrinsic compression on the spinal cord. It is, thus,
recommended to maintain the PPSP above 50 mmHg by
maintaining a normal MAP.
Finally, vascular reactivity of the spinal cord to changes in
PaCO2 and PaO2 is very comparable with that of the brain. Thus,
a PaO2 higher than 60 mmHg does not affect spinal blood flow.
However, spinal cord blood flow significantly increases when PaO2
is lowered to below 60 mmHg. Studies suggest that PaCO2 affects
blood flow in a linear fashion between 20 and 80 mmHg, resulting in absolute variation from 0.5 to 1.0 mL/100 g/min.52 It has
been demonstrated that CBF in the adult changes from 1 to 2 mL/
100 g/min.31,53

TABLE 6-2. Composition of the Human Cerebrospinal


Fluid and Plasma
Constituants
1

Sodium (mEq/L )
Potassium (mEq/L1)
Calcium (mEq/L1)
Magnesium (mEq/L1)
Chloride (mEq/L1)
Glucose (mg/dL1)
Protein (g/dL1)
CSF = cerebrospinal fluid.

CSF

Plasma

138.0
2.8
2.4
2.7
124.0
60.0
0.05

140.0
4.0
4.6
1.8
99.0
99.0
7.1

CONCLUSION
Successful anesthesia for infants and children affected with a
neurologic disease depends on a good understanding of the anatomy and physiology of the CNS.54 Application of basic principles
facilitates the clinical management of intracranial or spinal pathologies during neurosurgical procedures. Ischemia and necrosis

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represent the ultimate consequence of physiologic imbalance.
Although the brain does no mechanical work, a substantial
amount of energy is needed to maintain its cellular integrity and
biologic functions. Cerebral protection is possible only if one
anticipates the physiologic changes triggered by a pathologic disturbance and applies fundamental concepts to restore the normal
physiology as soon as possible.55 This clinical management is the
exclusive domain of the anesthesiologist and the neurosurgeon
and will be discussed in Chapters 93 and 92.

REFERENCES
1. Kleinman S, Bissonnette B: Management of successful pediatric
neuroanesthesia. In: Bissonnette B, editor. Cerebral Protection, Resuscitation and Monitoring: A Look Into the Future of Neuroanesthesia.
Philadelphia: WB Saunders; 1992. p. 537.
2. Streeter G: Developmental horizons in human embryos. Description
of age group XIII, embryos about 4 or 5 millimeters long, and age
group XIV, period of indentation of the lens vesicle. Contrib Embryol.
1942;31:211.
3. Streeter G: Developmental horizons in human embryos. Description
of age group XV, XVI, XVII and XVIII, being the third issue of a
survey on the Carnegie collection. Contrib Embryol. 1948;32:133167.
4. Streeter G: Developmental horizons in human embryos (fourth
issue). A review of the histogenesis of bone and cartilage. Contrib
Embryol. 1949;33:149178.
5. Streeter G: Developmental horizons in human embryos. Description
of age groups XIX, XX, XXi, XXII, XXIII, being the fifth issue of
a survey of the Carnegie collection. Contrib Embryol. 1951;34:
165198.
6. Heuser C, Corner G: Development horizons in human embryos. Description of age group X, 4 to 12 somites. Contrib Embryol. 1975;36:
2942.
7. Lemire R, Loeser JD, (eds). Normal and Abnormal Development of
the Normal Nervous System. New York, Harper & Row; 1975. p 421.
8. Streeter G: Factors involved in the formation of the filum terminale.
Am J Anat. 1919;25:122.
9. Streeter G: The development of the human cerebrospinal fluid
pathway with particular references to the roof of the fourth ventricle.
J Anat. 1918;105:467481.
10. Padget D: The cranial venous system in man in reference to development, adult configuration and relation to the arteries. Am J Anat.
1956;98:307319.
11. Milhorat T: Circulation of the cerebrospinal fluid. In: McLaurin R,
Schut L, Venes J, Epstein F, editors. Pediatric Neurosurgery. Survey of
the Developing Nervous System. Section of Pediatric Neurosurgery of
the American Society of Neurological Surgeons. Philadelphia: WB
Saunders; 1989. pp. 170180.
12. Harris M, Stone D: Anesthesia for increased intracranial pressure in
pediatrics. Probl Anesth. 1980;4:6788.
13. Loefgren J, Zwetnow NN: Cranial and spinal components of the
cerebrospinal fluid pressure-volume curve. Acta Neurol Scand. 1973;
49:575585.
14. Hill A, Volpe J: Measurement of intracranial pressure using the Ladd
intracranial pressure monitor. J Paediatr. 1984;98:974977.
15. Hill A: Intracranial pressure measurements in the newborn. Clin
Perinatol. 1985;12:161178.
16. Ross RT: Spinal cord infarction in disease and surgery of the aorta.
Can J Neurol Sci. 1985;12:289295.
17. Batson O: The vertebral vein system. AJR Am J Roentgenol. 1957;78:
195207.
18. Bickler P: Energetics of cerebral metabolism and ion transport. In:
Bissonnette B, editor. Cerebral Protection, Resuscitation and Monitoring: A Look Into the Future of Neuroanesthesia. Philadelphia: WB
Saunders; 1992. pp. 563575.

Central Nervous System: Anatomy and Physiology 89

19. Bachelard HS: Specificity and kinetic properties of monosaccharide


uptake into guinea pig cerebral cortex in vitro. J Neurochem. 1971;
18:213222.
20. Nishiki K, Erecinska M, Wilson DF: Effect of Amytal on metabolism
of perfused rat heart: relationship between glycolysis and oxidative
phosphorylation. Am J Physiol. 1979;237:C221C230.
21. Sokoloff L: Circulation and energy metabolism of the brain. In: Siegel
G, Agranoff B, Albers R, Molinoff P, editors. Basic Neurochemistry:
Molecular, Cellular and Medical Aspects. New York: Raven Press; 1989.
pp. 565591.
22. Erecinska M, Silver IA: ATP and brain function. J Cereb Blood Flow
Metab. 1989;9:219.
23. Powers WJ, Grubb RJ, Darriet D, et al. Cerebral blood flow and
cerebral metabolic rate of oxygen requirements for cerebral function
and viability in humans. J Cereb Blood Flow Metab. 1985;5:600608.
24. Bucher HU, Edwards AD, Lipp AE, et al. Comparison between near
infrared spectroscopy and 133Xenon clearance for estimation of
cerebral blood flow in critically ill preterm infants. Pediatr Res. 1993;
33:5660.
25. Edwards AD, Wyatt JS, Richardson C, et al. Cotside measurement of
cerebral blood flow in ill newborn infants by near infrared spectroscopy. Lancet. 1988;2:770771.
26. Altman DI, Powers WJ, Perlman JM, et al. Cerebral blood flow
requirement for brain viability in newborn infants is lower than in
adults. Ann Neurol. 1988;24:218226.
27. Younkin DP, Reivich M, Jaggi J, et al. Noninvasive method of
estimating human newborn regional cerebral blood flow. J Cereb
Blood Flow Metab. 1982;2:415420.
28. Cross KW, Dear PR, Hathorn MK, et al. An estimation of intracranial
blood flow in the newborn infant. J Physiol (Lond). 1979;289:
329345.
29. Ogawa A, Sakurai Y, Kayama T, et al. Regional cerebral blood flow
with age: changes in rCBF in childhood. Neurol Res. 1989;11:
173176.
30. Farrar J, Roach M: The effects of increased intracranial pressure
on flow through major cerebral arteries in vitro. Stroke. 1973;4:
795806.
31. Lassen NA, Christensen MS: Physiology of cerebral blood flow. Br J
Anaesth. 1976;48:719.
32. Hernandez MJ, Brennan RW, Bowman GS: Autoregulation of cerebral
blood flow in the newborn dog. Brain Res. 1980;184:199202.
33. Purves MJ, James IM: Observations on the control of cerebral blood
flow in the sheep fetus and newborn lamb. Circ Res. 1969;25:651667.
34. Bissonnette B, Benson L: Does balloon dilatation angioplasty for
coarctation of the aorta affect cerebrovascular circulation in children?
Circulation. 1991;84:545546.
35. Baumbach GL, Heistad DD: Effects of sympathetic stimulation and
changes in arterial pressure on segmental resistance of cerebral vessels
in rabbits and cats. Circ Res. 1983;52:527533.
36. Sparks H: Effect of a quick stretch on isolated vascular smooth
muscle. Circ Res. 1973;20:15381544.
37. Symon L, Held K, Dorsch NW: A study of regional autoregulation in
the cerebral circulation to increased perfusion pressure in normocapnia and hypercapnia. Stroke. 1973;4:139147.
38. Kobayashi H, Magnoni MS, Govoni S, et al. Neuronal control of brain
microvessel function. Experientia. 1985;41:427434.
39. Rosomoff H, Holaday D: Cerebral blood flow and cerebral oxygen
consumption during hypothermia. Am J Physiol. 1954;179:8597.
40. Muizelaar JP, van, der, Poel, Hg, Li ZC, et al. Pial arteriolar vessel
diameter and CO2 reactivity during prolonged hyperventilation in
the rabbit. J Neurosurg. 1988;69:923927.
41. Hidaka A, Suzuki Y, Komatani M, et al. Influence of maternal
hyperoxia or hypercarbia on the hemodynamics of the placenta and
fetal brain. N Sanka Fuj Gak Zas. 1986;38:17541762.
42. Yamashita N, Kamiya K, Nagai H: CO2 reactivity and autoregulation
in fetal brain. Childs Nerv Syst. 1991;7:327331.

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43. Pilato MA, Bissonnette B, Lerman J: Transcranial Doppler: response


of cerebral blood-flow velocity to carbon dioxide in anaesthetized
children. Can J Anaesth. 1991;38:3742.
44. Muizelaar JP, Wei EP, Kontos HA, et al. Cerebral blood flow is regulated by changes in blood pressure and in blood viscosity alone.
Stroke. 1986;17:4448.
45. Rosner MJ, Daughton S: Cerebral perfusion pressure management in
head injury. J Trauma. 1990;30:933940.
46. Drummond J, Oh Y, Cole D, et al. Phenylephrine-induced hypertension reduces ischemia following middle cerebral artery occlusion
in rats. Stroke. 1989;20:15381544.
47. Andrews P: What is the optimal perfusion pressure after brain injury:
a review of the evidence with emphasis on arterial pressure. Acta
Anaesthesiol Scand. 1995;39:112114.
48. Tweed A, Cote J, Lou H, et al. Impairment of cerebral blood flow
autoregulation in the newborn lamb by hypoxia. Pediatr Res. 1986;20:
516519.

49. Ruben RC, Henderson ES, Ommaya AK, et al. The production of
cerebrospinal fluid in man and its modification by acetazolamide.
J Neurosurg. 1966;25:430436.
50. Bissonnette B, Ravussin P. Biomechanics and intracranial hypertension. Ann Fr Anesth Reanim. 1997;16:389394.
51. Goto T, Crosby G: Anesthesia and the spinal cord: In: Bissonnette B,
editor. Cerebral Protection, Resuscitation and Monitoring: A Look
Into the Future of Neuroanesthesia. Philadelphia: WB Saunders;
1992. pp. 493521.
52. Sandler AN, Tator CH: Review of the measurement of normal spinal
cord blood flow. Brain Res. 1976;118:181198.
53. Lassen N: Cerebral and spinal cord blood flow. In: Cottrell J, editor.
Anesthesia and Neurosurgery. St. Louis: CV Mosby; 1986. pp. 122.
54. Bissonnette B. Specificities of neurosurgical anesthesia in the child.
Ann Fr Anesth Reanim. 2003:21:7377
55. Bissonnette B. Cerebral protection. Paediatr Anaesth. 2005,14:
403407.

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Normal and Abnormal Development


of the Heart and the Circulation
Christian Apitz and Andrew N. Redington

INTRODUCTION
The development of the heart reflects a complex interaction of
genes, environment, biomechanical events, and chance. Although
the embryo is growing exponentially, the heart transforms from a
muscle-wrapped tube without valves, septums, conduction system, or coronary circulation into a four-chambered structure that
will pump blood to the lungs and body 60 to 160 times/min for
more than 80 years. In approximately 1% of pregnancies, this
usually well-orchestrated process fails and congenital heart disease
results. Even in the normal heart, important maturational changes
must be taken into account when caring for infants and children.
In this chapter, we explore some of the important issues that are of
clinical relevance to those providing anesthesia care for the
pediatric population.

THE SPECTRUM OF
CONGENITAL HEART DISEASE
AND ITS DESCRIPTION
No matter what the cause, the ability to describe any structural
cardiac abnormality in a cohesive and comprehensive manner
forms the basis of communication, management, and description
of outcomes. There have been two schools of, often hotly debated, nomenclature: (1) the Van-Praaghian and (2) the Andersonian systems, which are eponymously named after their advocates.
Both have evolved and became more aligned since the early 1980s.
They are based on the description of the heart as a series of
segments.14 Without wishing to enter the debate of superiority,
and in the interests of clarity, in this section, we describe the most
widely used system, the Andersonian system of sequential
segmental analysis. Although it is beyond the scope of this chapter
to explore all of this morphologic method in detail, what follows is
a usable synopsis of the main concepts.

7
C H A P T E R

extending between the AV and the ventriculoarterial junctions. In


terms of its own intrinsic morphology, this ventricular mass can be
divided into (1) inlet portions surrounding the AV valves and
extending to the attachments of their papillary muscles, (2) apical
trabecular components, and (3) outlet components supporting
the arterial valves. The atrial and ventricular chambers and the
great arteries are paired structures. Each member of the pair is
distinguishable by its morphologically right or morphologically
left characteristics. Congenitally malformed hearts can then
be analyzed in the way that these morphologically right and left
components are arranged and connected or, in some cases, not
connected.

The Atria
The part of the atrium most uniformly present and most distinctive of rightness and leftness is the appendage. The morphologically right appendage is triangular-shaped with a broad base at its
junction with the smooth-walled atrium, whereas the morphologically left appendage is a finger-like structure having a narrow
junction with the smooth-walled atrial component. The great
veins cannot be used to distinguish accurately between a left and
a right atrium because an anomalous drainage of the great veins is
not uncommon in complex congenital defects.

The Ventricles
The most characteristic pattern to distinguish morphologically
right and morphologically left ventricles is their trabecular components. Characteristically, the right ventricle has coarse apical
trabeculations whereas the left ventricle typically has fine trabeculations. Additional morphologic criteria for the right ventricle
are the moderator band crossing the ventricular cavity (this is an
especially useful feature for echocardiographic diagnosis) and the
presence of tendinous cords attaching the septal leaflet of the
tricuspid valve to the ventricular septum.

The Segments

The Great Arteries

The basis of segmental analysis is the concept that all congenital


heart malformations can be readily analyzed in terms of three
basic segments: (1) the atria, (2) the ventricular mass, and (3) the
great arteries. These segments have uniquely defining features and
discrete anatomic boundaries. The atria are separated from the
ventricles by the fibrous tissue plane of the atrioventricular (AV)
junction. The ventriculoarterial junction is marked by the attachment of the arterial wall to the ventricular mass. The ventricular
segment of the heart is, therefore, defined as the muscle mass

The description of the arterial trunks is made on the basis


of patterns of branching. An aorta can be distinguished as an
arterial trunk giving rise to systemic and coronary arteries. A
pulmonary trunk is one giving rise to pulmonary arteries. A
common arterial trunk is defined as a single arterial vessel from
which systemic, pulmonary, and coronary arteries arise directly.
The second step of the segmental analysis is to describe the
connections between the components of the different segments.
Usually, we start with the description of the arrangement of the

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Figure 7-1. Arrangement of the appendages.

heart. According to the classification of the bodily arrangements,


we distinguish four basic arrangements: (1) the usual arrangement
(situs solitus), (2) the mirror image (situs inversus), (3) right
isomerism, and (4) the left isomerism. Because the appendages
are the most constant component to distinguish between the right
and the left parts of segments, the arrangement of the heart is
defined by the arrangement of the appendages (Figure 71).

ARRANGEMENTS OF THE APPENDAGES: Usually, the morphologically right atrium is right-sided and the morphologically left
atrium is left-sided (situs solitus = usual). In the mirror-image
arrangement (situs inversus), the morphologically right atrium is
left-sided. There are two other atrial arrangements, right or left
isomerism of the atrial appendages, in which both appendages
have morphologically right or morphologically left characteristics.
THE AV JUNCTION:

We have to distinguish the more common


biventricular AV connection, in which each atrium is connected
to its own ventricle, and the univentricular AV connections, in
which the atria are connected to only one ventricle (Figure 72).
This could be seen as a double-inlet ventricle or one with absent
right AV connection or absent left AV connection. In this second
group of hearts, it is always necessary to describe the type and
mode of AV connection together with the ventricular morphology
and the size of a rudimentary ventricle if present.

VENTRICULAR TOPOLOGY: In situs solitus with AV concordance,

the morphologically right ventricle almost always wraps itself

Figure 7-3. Single outlet of the heart with a common arterial trunk.

around the left ventricle in a fashion comparable with the


observers right hand being placed upon the morphologically right
ventricular septal surface, with the palm against the septum, the
thumb in the inlet, the fingers in the outlet, and the wrist in the
trabecular component. This pattern of ventricular topology can
be termed a right-hand pattern, and is also almost always seen in
hearts with situs inversus and AV discordance. The complementary left-handed pattern is usually found in hearts with either situs
inversus and AV concordance or AV discordance in situs solitus.
THE VENTRICULOARTERIAL JUNCTION:

There are four different


types of ventriculoarterial connection. The first two of these are
ventriculoarterial concordance, in which the aorta is connected to
a left ventricle and the pulmonary trunk to a right ventricle, and
ventriculoarterial discordance, in which there is the reverse connection (most commonly referred to as transposition). The other
two connections describe arrangements that are neither concordant nor discordant, including double-outlet ventricle, in which
both great arteries are connected to the same ventricular chamber,
and single outlet of the heart, either with the ventricles draining
via a common arterial trunk or with one ventriculoarterial connection absent, either an atretic aortic or a pulmonary trunk
without connection to the ventricle (Figure 73).

CARDIOVASCULAR EMBRYOLOGY

Figure 7-2. Biventricular (A) and univentricular (B) atrioventricular


junction with usual arrangement of the appendages. B: An absent right
atrioventricular connection (tricuspid atresia).

Cardiovascular embryology offers the basis for understanding the


pathogenesis of many types of congenital heart defects and is
particularly relevant to the abnormal development of the cardiac
segments.5 However, as with sequential segmental analysis
previously addressed in the section The spectrum of congenital
heart disease and its description, a detailed discussion of this

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Normal and Abnormal Development of the Heart and the Circulation 93

complex area is beyond the scope of this chapter. Nonetheless, we


provide a brief overview of the key elements of cardiovascular
development in early fetal life.
Although ultimately becoming a contiguous and integrated
structure, the ventricular myocardium is now known to be derived
from several different embryologic origins. For example, even
though they ultimately come to share myofibers, elements of the
right and left ventricles derive from separate heart fields in very
early embryogenesis. The vascular system of a human embryo
starts to develop in the second and third weeks of gestation. At
this point, diffusion alone is not sufficient to provide oxygen and
other substrates to the developing organs. Consequently, angiogenic cell structures move toward the developing heart at the cranial
end of the embryo, forming the endocardial tubes. These tubes
form the dorsal aorta and the rudimentary venous system. As the
heart tube continues to develop, the dorsal aorta and the vitelloumbilical veins serve as anchors as the heart tube bulges and
loops. The looping of the heart tube serves to form the primordial
heart chambers with a sinus venosus, the paired primitive atria,
the AV sulcus, the primitive ventricle, and its developing interventricular sulcus. On the outflow of the tube, the bulbous cordis
is forming part of the right ventricle and its outflow tract. As the
heart tube forms its bulboventricular loop, a common atrium is
formed. Partitioning of the atrium, by the appearance of the
septum primum, occurs by about the 28th day. The primum septum fuses with the endocardial cushions with superior perforations that ultimately coalesce to form the ostium secundum. If
these perforations are too large, a secundum atrial septal defect
will result. At the same time as atrial septation is occurring, the
left atrium and pulmonary veins are becoming confluent with the
lung buds to allow pulmonary venous return to the left atrium. As
the atrial wall expands, the pulmonary veins become fully incorporated into the posterior wall of the left atrium. Failure of incorporation of the pulmonary veins will lead to forms of total
anomalous pulmonary venous connection (TAPVC) with drainage of the pulmonary veins to other structures. The most common form of TAPVC is supracardiac drainage (usually via
connection of the pulmonary veins to remnants of the left-sided
cardinal venous system, which usually disappears during early
fetal life). Other forms of TAPVC include connection to the splanchnic veins below the diaphragm (infradiaphragmatic TAPVC),
to cardiac veins (TAPVC to coronary sinus), or mixed types.
The formation of the ventricles initially occurs from separate
heart fields, but ultimately develops as a looping of the newly
formed heart tube. The interventricular sulcus grows to separate
the right and left ventricles, which continue to expand until the
seventh week of gestation. The inlet of the ventricles develops from
the AV canal, which gradually shifts to the right in order to allow
communication between the atrial mass and the developing right
ventricle. Fusion of the endocardial cushions is responsible for
completion of both the septation of the atrium and the ventricle
and is integral to the formation of the AV valves. A common AV
canal between the atria and the ventricles is present in the normal
heart as it develops, but may also persist as one of the most
common of all cardiac anomalies. Failure of ventricular septation
in the presence of normal separation of the AV junctions will
account for the remainder of ventricular defects, which can be
classified broadly as perimembranous, muscular, doubly committed,
and juxta-arterial.
The outflow tract of the ventricle is gradually partitioned to
form a separate aorta and pulmonary trunk. The ascending aorta

coalesces to develop continuity with the dorsal aorta and the


pulmonary trunk coalesces with six arch structures to form the
branch pulmonary arteries, supplying the lungs. Abnormal septation can lead to the development of a common arterial trunk
(truncus arteriosus) and other abnormalities such as aortopulmonary window, an anomalous origin of a branch pulmonary
artery from the ascending aorta.

ETIOLOGY OF CONGENITAL
HEART DISEASE
Fundamental to the understanding of the origin of cardiac defects
are the impressive advances in the understanding of developmental mechanisms of cardiac morphogenesis. In the following
section, we address the most important factors contributing to
maldevelopment of the heart.

Genetic Factors
Although there is increasing understanding of the role of genetic
influences on early cardiac development, our understanding
remains incomplete. A substantial part of cardiovascular diseases
is either directly caused by gene mutations (monogenic) or at least
modified by genetic variation (polygenic, multifactorial).6 Among
infants born with associated noncardiac anomalies, chromosomal
anomalies and single-gene disorders are more frequently identified, and conversely, cardiac anomalies are overrepresented in
many definable genetic syndromes. For example, approximately
50% of children with trisomy 21 will have an associated cardiac
anomaly.7 AV septal defect is the most frequent defect, followed
in decreasing order by ventricular septal defect, atrial septal defect,
tetralogy of Fallot, and patent ductus arteriosus.810 Although less
frequently encountered than trisomy 21, almost all infants with
trisomy 18 will have a congenital cardiac defect. Among the sex
chromosome abnormalities, Turners syndrome is the most
frequent, with 10 to 40% of these patients having coarctation of
the aorta and associated bicuspid aortic valve.11 It is likely that
many cardiac diseases will have more subtle genetic origins such
as point mutations or microdeletions. The most frequent microdeletion syndrome associated with congenital heart disease is
22q11 syndrome. The syndrome has a population prevalence of
approximately 1 in 2000 in the United States. It has drawn considerable attention because a number of common psychiatric
illnesses are phenotypic features including attention deficit disorder, schizophrenia, and bipolar disorder.12,13 These children are
born with a spectrum of conotruncal abnormalities including
tetralogy of Fallot, interrupted aortic arch, and common arterial
trunk.

Environmental Factors
It has long been known that maternal factors can modify cardiac
development. Maternal infection with rubella is rare in Western
populations, but it leads to severe abnormalities of the pulmonary
arteries. Maternal viral illness in the third trimester is often associated with myocarditis in the newborn infant, coxsackie being
the most common viral agent. Ingested teratogens can be equally
devastating. The potential risks caused by maternal drug intake
were brought to light by the thalidomide tragedy. Exposure of
mothers who took thalidomide during pregnancy resulted in a

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high risk of cardiac malformations, especially of the conotruncal


type, tetralogy of Fallot, and truncus arteriosus.14 In addition,
various anticonvulsants used by mothers for the treatment of
epilepsy such as barbiturates, valproic acid, or diphenylhydantoin
have been found to cause defects such as pulmonary stenosis and
tetralogy of Fallot. There are also more generic effects of maternal
disease. Maternal diabetes not only may lead to a specific form of
transient hypertrophic cardiomyopathy in the newborn15 but is
also associated with increased risk of structural heart disease via
mechanisms yet to be fully elucidated.16 Maternal phenylketonuria
may also be a cause of congenital heart disease in the offspring, in
which patent ductus arteriosus, coarctation of the aorta, and
tetralogy of Fallot are the most frequently reported lesions.17
Mothers with systemic lupus erythematosus, even if not obviously
ill, have a risk of congenital complete heart block in the offspring
because of isoimmune damage of the fetal cardiac conduction
tissue.18

Abnormalities of Intracardiac Blood Flow


A group of human congenital cardiac malformations are associated with abnormal blood flow patterns in the fetus. The fetal
flow hypothesis of congenital heart disease has long been debated,
because it is very difficult to separate chicken from egg (i.e., is it
a subtle structural abnormality that modifies flow or vice versa?).
However, there does appear to be some evidence that primary
abnormalities of flow can lead to structural defects. A good
example of this is the development of right ventricular outflow
tract abnormalities in the recipient of an in utero twin-to-twin
transfusion.19 The flow hypothesis for the development of left
heart hypoplasia is less well defined. Although experimental
preparations have shown that perturbations in left heart flow
such as closure of the foramen ovale in the developing fetus
can lead to the typical disease, the clinical pathogenesis is less
clear.20 Indeed, hypoplasia of the left ventricle may be present in a
variety of congenital heart defects.21,22 The severity of left
ventricular hypoplasia may range from mild hypoplasia to its most
severe form, hypoplastic left heart syndrome.23 Left ventricular
hypoplasia is not a distinct disorder, but rather represents the
common end point of a wide variety of different pathophysiologic mechanisms, all resulting in diminished flow through the
left ventricle in utero.24 Thus, diminution in flow may be the cause
or the consequence of anatomic obstruction (e.g., restrictive
foramen ovale, mitral or aortic stenosis), intrinsic left ventricular disease (fibroelastosis), or extrinsic compression (congenital
diaphragmatic hernia), genetics, or a combination of several
factors.

Closure of the Foramen Ovale


When the umbilical cord is clamped, the low-resistance placental
circulation is lost and the systemic vascular resistance (SVR)
increases. With the initiation of respiration, the pulmonary vascular resistance (PVR) begins to decrease and the lungs begin to
be perfused with a greater amount of blood. With the increased
flow to the lungs, blood return from the lungs to the left atrium
also increases. Clamping of the umbilical cord decreases return of
systemic blood to the right atrium. These events represent the
reverse of the situation that occurred in the fetus, when right atrial
return from the placenta exceeded left atrial return. Now, with
increased pulmonary blood flow and increased left atrial pressure
relative to right atrial pressure, the flap mechanism of the foramen
ovale results in functional closure.

Closure of the Ductus Arteriosus


In normal term infants, the ductus arteriosus functionally closes
within 24 hours after birth. One factor responsible for ductal
closure is the increase in oxygen tension related to conversion to
the lung as the organ of respiration. Another may be the change in
levels of local circulating prostaglandins. Final anatomic closure of
the ductus ateriosus by way of muscle contraction, thrombosis,
and fibrosis usually occurs within the first few months of life.
Factors that can delay ductal closure include prematurity, hypoxemia, and associated congenital heart disease.

Closure of the Ductus Venosus


The ductus venosus (which in utero is a conduit for oxygenated
blood from the placenta to bypass the liver and go directly to the
heart) functionally closes soon after birth, but there is evidence
that it may remain anatomically open for up to 20 days before
closing secondary to connective tissue proliferation that obliterates
the lumen. With clamping of the umbilical cord, venous return
in the inferior vena cava is composed only of blood returning from
the lower body and the abdominal organs. Reduction of flow
through the ductus venosus allows it to passively collapse and
functionally close. Sphincter-like structures appearing at the
junction of the ductus venosus and the umbilical vein have also
been proposed as mechanisms responsible for regulation of ductus
venosus blood flow and for facilitation of ductus venosus closure.
The practical importance of this is that umbilical vein catheterization is a convenient method of central catheter placement for the
administration of drugs and fluids in the newborn. In addition, it
allows a pathway through which balloon atrial septostomy can be
performed via the umbilicus in the first day or two of life in infants
with transposition of the great arteries.

THE NORMAL CIRCULATION


AT BIRTH

The Transitional Pulmonary Circulation

Even in the normal heart, important maturational changes must


be taken into account when caring for children. At birth, a transformation must be made from having a parallel circulation, a
placenta as a respiratory organ, and a liquid environment in the
lungs, to having a series circulation, a lung as a respiratory organ,
and a gaseous environment. This requires that the shunt pathways,
which were necessary for the placenta to function as the organ of
respiration, abruptly cease to operate and that the lungs quickly
begin their role as organs of gas exchange.

In early gestation, the PVR is very high. Therefore, the lungs


receive only a small portion of the combined ventricular output.
During the last weeks of gestation, pulmonary blood flow begins
to increase, reaching 8 to 10% of combined ventricular output by
term. This period of increased pulmonary blood flow coincides
with a period of growth of the pulmonary vascular bed and with
the beginning of release of surface active material. The immediate
postnatal decrease in PVR results from the independent effects of
mechanical expansion of the lungs and the increase in arterial

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oxygen pressure (PaO2). In the normal state in the human neonate,


the PVR is approximately one half that of the SVR at 24 hours
of age and continues to decrease until it reaches adult values by
6 weeks of age.25

Persistent Pulmonary Hypertension


of the Newborn
PVR will not fall at birth and persistent pulmonary hypertension
will result if the pulmonary vascular bed has not demonstrated
normal pharmacologic maturation or if some perinatal insult such
as hypoxia sustains the vasoconstricted state of the pulmonary
vascular bed. Persistent pulmonary hypertension of the newborn
may also result from structural abnormalities. For example,
following an intrauterine insult, peripheral, normally nonmuscular arteries may be muscularized and muscular arteries may
show medial hypertrophy. In conditions causing pulmonary
hypoplasia such as diaphragmatic hernia, a severe reduction in the
number of alveoli and pulmonary vascular hypoplasia appear to be
the cause of pulmonary hypertension. As a consequence of persistent pulmonary hypertension in the newborn, the ductus arteriosus and foramen ovale do not close after birth. This leads to
intracardiac or great arterial level shunting of blood away from
the lungs and severe hypoxemia unless the PVR can be reduced
relative to the SVR.

The Abnormal Transitional Circulation


Problems occur when fetal pathways that should close during the
transitional period stay open or reopen, as in a premature baby
with a ductus arteriosus. Reopening of the duct, as a result of a
hypoxic stimulus, may cause a large left-to-right shunt and pulmonary edema because of the relatively rapid fall in resistance in
the poorly muscularized pulmonary arteries of the premature
infant. Other potential shunt pathways may exist or remain open
in the full-term newborn, but without causing apparent problems
in early life. This is because the PVR falls more slowly in these
infants. Consequently, symptoms from left-to-right shunting
through a ductus arteriosus or ventricular septal defect may not
become evident for several weeks after birth.

All of the normal physiologic responses that occur immediately


following birth may themselves be modified by the presence of
congenital heart disease. The various shunt pathways present in
the fetus that allow a parallel circulation to exist also permit many
fetuses with congenital cardiac malformations to grow and
develop normally in utero. Problems arise at birth and during the
transitional period only when the shunt pathways begin to close.
For example, a newborn infant with hypoplastic left heart syndrome does well during the transitional period until the ductus
arteriosus closes, leaving the infant with no means for systemic
cardiac output. In the following section we describe common
physiologic variants of transition in the presence of congenital
heart disease.

CONGENITAL HEART DISEASE


Left-to-Right Shunts at the
Ventricular and Arterial Level
The physiologic alterations associated with left-to-right shunt
lesions at the ventricular or great artery level are determined
principally by the size of the defect and the postnatal changes in
SVR and PVR (Figure 74). During fetal life, a large defect at the
ventricular level has no major physiologic effect. This is due
mainly to the presence of a high PVR in the fetus, which limits
any shunting into the pulmonary circulation, and the low
resistance of the placental circuit. However, following birth, the
decrease in PVR at the same time that the SVR is increasing
becomes the major determinant of left-to-right shunt flow. As
discussed in the section on The normal circulation at birth, the
normal decline in PVR to adult levels takes place within the first
6 weeks after birth. In the presence of a large communication, this
decline may be delayed by 1 to 3 months. Nonetheless, there is a
gradual increase in pulmonary blood flow with increasing
symptoms of congestive heart failure and failure to thrive. The
marked volume overload results in left atrial and pulmonary
venous hypertension and dilatation of the left and right ventricles.
The former contributes to the production of pulmonary edema,
and the latter stimulates an increase in ventricular mass. The need
for intervention is governed by symptoms and/or the presence of

Figure 7-4. Examples of left-to-right shunts at the ventricular and arterial levels. Ventricular septal defect (A), aortopulmonary window (B), and
persistent ductus arteriosus (C).

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pulmonary hypertension. For nonlimiting defects (large ventricular septal defect, aortopulmonary window, large patent ductus
arteriosus), the risk of irreversible pulmonary hypertension
(pulmonary vascular disease) rises steeply after the first year of
life. Therefore, elective intervention is usually planned in the first
3 to 6 months of life. The onset of pulmonary vascular disease may
be accelerated in some, and there may be a lack of signs or
symptoms even when the defect is large. Important causes of
accelerated pulmonary hypertension include the coexistence of
pulmonary parenchymal disease or upper airway obstruction, the
latter of which is particularly common in infants with trisomy 21.
For that reason, it is recommended that all children with trisomy
21 undergo echocardiographic screening early in life.26 When
present, pulmonary hypertension with incipient pulmonary
vascular disease represents a risk factor for adverse outcomes after
surgery. The risk of overt pulmonary hypertensive crisis in the
postoperative period has receded with the trend toward earlier
surgical correction, but the degree of postoperative elevation of
PVR still predicts the rate of postoperative recovery.27

Left-to-Right Shunts at the Atrial Level


By contrast with left-to-right shunts at the ventricular or arterial
level, shunting at the atrial level appears to be determined principally by the relative compliances of the right and left ventricles and
not necessarily by the size of the defect, unless the communication
is very small. The direction of blood flow through the defect is
determined by left and right atrial pressure differences during the
cardiac cycle. The latter, in turn, reflect the relative compliances of
the ventricles. In utero, atrial communications permit flow relations that mimic normal shunting across the foramen ovale.
Because the right ventricle is relatively stiff and noncompliant, leftto-right shunting is minimal early in life. As PVR falls and the
right ventricle becomes more compliant, the left-to-right shunt
increases gradually. The development of congestive heart failure
from increases in pulmonary blood flow secondary to atrial level
shunts is relatively rare. Despite large communications, pulmonary
artery pressures and resistances with few exceptions tend to be
low, hence, closure (nowadays, usually by transcatheter device)
can be delayed for several years.

Transposition of the Great Arteries


There appears to be little, if any, effect of transposition of the
great arteries on the fetal flow pathways or circulatory dynamics
(Figure 75). However, soon after birth, transposition of the
great arteries with limited mixing of pulmonary venous and
systemic venous streams is an acutely life-threatening condition
because of the sudden imposition of an extremely low level of
systemic arterial oxygen saturation. Early treatment with prostaglandin E2 therapy to maintain ductal patency is life-saving, but
is ineffective in the absence of an intracardiac shunt. Contrary to
popular belief, the effect of ductal reopening has little to do with
mixing of desaturated and oxygenated blood at the level of the
great arteries, but rather has its effects by increasing pulmonary
venous return, increasing left atrial pressure, and thereby
improving mixing at the atrial level. All of this will be further
improved by the performance of a balloon atrial septostomy,
which is performed in most newborns with transposition before
surgical repair.

Figure 7-5. Transposition of the great arteries with intact ventricular septum. Mixing of blood occurs at the atrial level (arrow) and
is increased by maintaining patency of the ductus arteriosus.

Single-Ventricle Physiology
Single-ventricle physiology is shared by several anatomic substrates. The most common is the hypoplastic left heart syndrome
(in which the systemic ventricle is the right ventricle), but similar
physiology is seen in those with absent right AV connection
(classic tricuspid atresia), unbalanced AV septal defect (in which
either the left or the right ventricle is too small to support the
circulation), and pulmonary atresia with intact ventricular septum. Although the details of the specific management of each of
these conditions are beyond the scope of this chapter, some
general rules are common to each of these conditions.
Some of these lesions manifest ductal-dependent pulmonary
perfusion. In the setting of hypoplastic right heart lesions, the right
ventricle is essentially bypassed with right-to-left shunting at the
atrial level. In the case of tricuspid atresia, pulmonary blood flow
may take place via a ventricular septal defect to the pulmonary
artery or via the ductus arteriosus. In the case of pulmonary atresia
with intact septum, pulmonary blood flow depends totally on
patency of the ductus arteriosus. These lesions appear to have little
effect on fetal growth and development. Postnatally, the dominant
physiologic theme is hypoxemia except where there is unobstructed flow into the pulmonary circulation. Early treatment
includes prostaglandin E2 therapy to maintain patency of the ductus arteriosus and surgical creation of a systemictopulmonary
artery anastomosis usually during the first weeks of life. The longterm palliative strategy is the creation of the so-called Fontan
circulation (see Ductal-dependent systemic perfusion).

Ductal-Dependent Systemic Perfusion


These defects include variations on the theme of hypoplastic
left heart syndrome including aortic atresia, interruption of the
aortic arch, and coarctation of the aorta (Figure 76A). During

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Figure 7-6. Hypoplastic left heart syndrome


before (A) and after (B) Norwood palliation.

intrauterine development, systemic perfusion is not compromised,


being maintained by the ductal flow from right ventricle to aorta.
Postnatally, systemic perfusion falls as the ductus arteriosus
constricts. In the case of aortic atresia, the entire systemic circulation depends on an open duct, whereas with interruption of
the arch and coarctation of the aorta, lower body perfusion is
acutely curtailed. Although coarctation of the aorta and interruption of the aortic arch can usually be surgically corrected
so that the circulation is restored to near-normal during the
first week of life, the classic hypoplastic left heart will be treated
by a series of palliative procedures extending over the first 2 or
3 years of life, starting with the so-called Norwood procedure (see
Figure 76B). Be it with the traditional or the new hybrid
approach,28,29 the goals of the initial Norwood procedure include
providing unobstructed systemic blood flow, unobstructed pulmonary venous return to the single ventricle (usually via atrial
septectomy), and limitation of pulmonary blood flow. An acceptable balance between the pulmonary and the systemic output
provides enough pulmonary flow for adequate oxygen delivery
to prevent acidosis without an excessive volume load to the
single ventricle or physiologic steal of blood away from the
systemic circulation. Assuming a mixed venous oxygen saturation
of 65% and a pulmonary venous oxygen saturation of 95%, arterial
oxygen saturation should be 80%. For the patient with either
excessive cyanosis (oxygen saturation < 75%) or relatively high
(>8588%) systemic oxygen saturations, the postoperative physiology must be carefully evaluated. Excessive cyanosis is caused
mainly by pulmonary issues such as pneumothorax or pleural
effusion, and decreased pulmonary blood flow is caused by
a restrictive systemictopulmonary artery shunt or elevated
PVR. The patient who is too pink typically has low PVR and
pulmonary blood flow far in excess of systemic blood flow. This
may result in inadequate systemic perfusion, renal dysfunction,
and an inability to wean the patient from mechanical ventilation.
The management of such neonates has considerably evolved since
the early 1990s, with a move away from ventilatory maneuvers to
increase PVR (breathing of subatmospheric concentrations of
oxygen or additional inhaled CO2) to pharmacologic therapy to
lower SVR (phenoxybenzamine or milrinone).30,31 Nonetheless,

permissive hypercapnia may increase systemic blood flow and


lower total body oxygen consumption.32
Further surgical intervention in patients with hypoplastic left
heart syndrome is necessary to avoid the chronic volume overload
state of the single ventricle. Following the Glenn procedure, the
superior vena cava venous return passes directly to and through
the lungs, thereby increasing effective pulmonary blood flow and
reducing cardiac work. Thus, the pulmonary blood flow equals
the brachiocephalic arterial flow, which is typically approximately
half of the total
output. The pulmonary to systemic
. ventricular
.
flow ratio (Q p:Q s) ratio is therefore approximately 0.5. This
typically results in a decrease in the ventricular volume load,
improved ventricular function, and improved AV valve function.
Patients with clinical signs of significantly elevated superior vena
cava pressure may have obstruction at the anastomosis, distal
pulmonary artery distortion, or marked elevations in PVR.
Excessive cyanosis (oxygen saturation < 75%) should be
investigated promptly. Etiologies include pulmonary or systemic
venous desaturation or decreased pulmonary blood flow because
of venous collaterals. Transient, or rarely permanent, sinus node
dysfunction is common and responds well to chronotropic agents
or temporary atrial pacing.33
The Glenn procedure is followed by the third state of the repair
of total cavopulmonary anastomosis or the Fontan circulation,
whereby the inferior vena cava is connected to the pulmonary
artery (Figure 77). Postoperative management after the Fontan
operation must be specifically tailored to the preoperative anatomy
and physiology as well as to the specific type of surgical procedure
performed. In general, it is geared toward optimizing cardiac
output at the lowest central venous pressure possible. Low cardiac
output may be caused by inadequate preload due to hypovolemia
(low right atrial and left atrial pressures), elevated PVR (low left
atrial and high right atrial pressures), or anatomic obstruction in
the systemic venous pathway. Alternatively, low cardiac output
in the face of high left atrial pressure is an ominous sign and
may be due to ventricular dysfunction, loss of AV synchrony, AV
valve regurgitation, or ventricular outflow obstruction. Significant
arrhythmias (e.g., junctional ectopic tachycardia) are particularly
poorly tolerated in this patient population. Mechanical positive-

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Figure 7-7. Hypoplastic left heart syndrome after establishment of a


total cavopulmonary anastomosis.

pressure ventilation with increased mean airway pressures may


adversely affect PVR and ventricular filling. Early institution of
spontaneous ventilation may improve hemodynamic function in
the awake state. The duration and frequency of pleural and pericardial effusions, typically the most frequent postoperative problem requiring prolonged hospitalization, have been reduced with
the use of baffle fenestrations and the adjustable atrial septal
defect.34

SUMMARY
The wide spectrum of diseases, resulting physiologic responses,
and modes of treatment make the care of infants with congenital
heart disease particularly challenging. The relationship between
pulmonary physiology, ventilation, and cardiac physiology is
almost ubiquitous and must be taken into account when assessing
and managing these patients. Those providing anesthetic care for
patients with congenital heart disease may be called upon to
provide anesthetic care for surgical correction or palliation directly
related to the congenital heart disease, during diagnostic and
therapeutic cardiac catheterization, or for surgical procedures
unrelated to the congenital heart disease. Given the frequent
occurrence of multiple congenital anomalies, these patients
frequently require anesthetic care at various stages of their lives
for procedures outside of the cardiovascular system. The care of
children with complex abnormalities should be in specialized
units staffed by subspecialty experts, at all levels, in the management of children with congenital heart disease.

REFERENCES
1. Van Praagh R. The segmental approach to diagnosis in congenital
heart disease. The cardiovascular system. Birth Defects Orig Artic Ser.
1972;8:423.
2. Van Praagh R. Terminology of congenital heart disease: glossary and
commentary. Circulation. 1977;56:139143.
3. Anderson RH, Tynan M. Sequential chamber localization. In: Hamer
J, Rowlands DJ, editors. Recent Advances in Cardiology. Vol. 8.
Edinburgh: Churchill Livingstone; 1981. pp. 265285.

4. Anderson RH. Terminology. In: Anderson RH, Baker EJ, Macartney


FJ, et al., editors. Paediatric Cardiology. 2nd ed. London, Toronto:
Churchill Livingstone; 2002. pp. 1936.
5. Wenink ACG. Embryology of the heart. In: Anderson RH, Baker EJ,
Macartney FJ, et al., editors. Paediatric Cardiology. 2nd ed. London,
Toronto: Churchill Livingstone; 2002. pp. 62153.
6. Dahme T, Katus HA, Rottbauer W. Fishing for the genetic basis of
cardiovascular disease. Dis Model Mech. 2009;2:1822.
7. American Academy of Pediatrics. Health supervision for children
with Down syndrome. Pediatrics. 2001;107:442449.
8. Freeman SB, Bean LH, Allen EG, et al. Ethnicity, sex, and the
incidence of congenital heart defects: a report from the National
Down Syndrome Project. Genet Med. 2008;10:173180.
9. Frid C, Drott P, Lundell B, et al. Mortality in Downs syndrome in
relation to congenital malformations. J Intellect Disabil Res. 1999;
43:234241.
10. Vis JC, Duffels MG, Winter MM, et al. Down syndrome: a cardiovascular perspective. J Intellect Disabil Res. 2009;53:419425. [Epub
2009;February 18.]
11. Sachdev V, Matura LA, Sidenko S, et al. Aortic valve disease in Turner
syndrome. J Am Coll Cardiol. 2008;51:19041909.
12. Bassett AS, Chow EWC, Husted J, et al. Clinical features of 78
adults with 22q11 deletion syndrome. Am J Med Genet. 2005;138:
307313.
13. Bassett AS, Chow EWC. Schizophrenia and 22q11.2 deletion
syndrome. Curr Psychiatr Rep. 2008;10:148157.
14. Pexieder T. Teratogens. In: Pierpont ME, Moller JM, editors. The
Genetics of Cardiovascular Disease. Boston: Martinus-Nijhoff; 1986.
pp. 2568.
15. Gutgesell HP, Speer ME, Rosenberg HS. Characterization of the
cardiomyopathy in infants of diabetic mothers. Circulation. 1980;61:
441456.
16. Ferencz C, Rubin JD, McCarter RJ, Clark EB. Maternal diabetes and
cardiovascular malformation: predominance of double outlet right
ventricle and truncus arteriosus. Teratology. 1990;14:313326.
17. Rouse B, Azen C, Koch R, et al. Maternal Phenylketonuria Collaborative Study (MPKUCS) offspring: facial anomalies, malformations,
and early neurological sequelae. Am J Med Genet. 1997;69:8995.
18. Lee LA. The clinical spectrum of neonatal lupus. Arch Dermatol Res.
2009;301:107110.
19. Lougheed J, Sinclair BG, Fung Kee Fung K, et al. Acquired right
ventricular outflow tract obstruction in the recipient twin in twintwin transfusion syndrome. J Am Coll Cardiol. 2001;38:15331538.
20. Schall SA, Dalldorf FG. Premature closure of the foramen ovale and
hypoplasia of the left heart. Int J Cardiol. 1984;5(1):103107.
21. Tchervenkov CI, Jacobs ML, Tahta SA. Congenital Heart Surgery
Nomenclature and Database Project: hypoplastic left heart syndrome.
Ann Thorac Surg. 2000;69:S170S179.
22. Corno AF. Borderline left ventricle. Eur J Cardiothorac Surg. 2005;
27:6773.
23. Tchervenkov CI, Jacobs JP, Weinberg PM, et al. The nomenclature,
definition and classification of hypoplastic left heart syndrome.
Cardiol Young. 2006;16:339368.
24. Cohen MS, Rychik J. The small left ventricle: how small is too small
for biventricular repair? Semin Thorac Cardiovasc Surg Pediatr Card
Surg Annu. 1999;2:189202.
25. Rudolph AM. Fetal and neonatal pulmonary circulation. Am Rev
Respir Dis. 1977;115:1118.
26. Wren C, Richmond S, Donaldson L. Presentation of congenital heart
disease in infancy: implications for routine examination. Arch Dis
Child Fetal Neonatal Ed. 1999;80:F49F53.
27. Schulze-Neick I, Li J, Penny DJ, Redington AN. Pulmonary vascular
resistance after cardiopulmonary bypass in infants: effect on postoperative recovery. J Thorac Cardiovasc Surg. 2001;121:10331039.
28. Calderone CA, Benson L, Holtby H, et al. Initial experience with
hybrid palliation for neonates with single-ventricle physiology. Ann
Thorac Surg. 2007;84:12941300.

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CHAPTER 7

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29. Akinturk H, Michel-Behnke I, Valeske K, et al. Hybrid transcathetersurgical palliation: basis for univentricular or biventricular repair:
the Giessen experience. Pediatr Cardiol. 2007;28:7987.
30. De Oliveira NC, Ashburn DA, Khalid F, et al. Prevention of early
sudden circulatory collapse after the Norwood operation. Circulation.
2004;110(11 Suppl 1):II133II138.
31. Guzzetta NA. Phenoxybenzamine in the treatment of hypoplastic left heart syndrome: a core review. Anesth Analg. 2007;105:
312315.

32. Li J, Zhang G, Holtby H, et al. Carbon dioxidea complex gas in a


complex circulation: its effects on systemic hemodynamics and oxygen transport, cerebral, and splanchnic circulation in neonates after the
Norwood procedure. J Thorac Cardiovasc Surg. 2008;136:12071214.
33. Cohen MI, Wernovsky G, Vetter VL, et alA. Sinus node function after
a systematically staged Fontan procedure. Circulation. 1998;98
(19 Suppl):II352II358.
34. Mott AR, Spray TL, Gaynor JW, et al. Improved early results with
cavopulmonary connections. Cardiol Young. 2001;11:311.

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Airway Development
Pierre Fayoux and Bruno Marciniak

INTRODUCTION
During the course of development, the upper airway undergoes
significant anatomic restructuring from the neonatal period to
adulthood. Anatomic restructuringincluding changes in size
and shape and the anatomic relationship between the various
componentsis particularly prominent during the first few years
of life. Many of the specific anatomic variations and differences of
the newborn and premature airway are important to outline and
consider because of their implications for airway management.
This chapter separates the discussion of airway development into
three parts: the face and the nasal chamber, the oropharynx including the tongue, and the laryngotracheal lumen. For each part,
the embryologic development and the morphologic modification
during the fetal period, infancy, and childhood are detailed.

THE FACE
Embryologic Considerations
The development of the skull can be divided into two major parts:
the development of the neurocranium, which forms the cranial
vault and skull base, and the viscerocranium, which forms the
skeletal part of the face. Most of the structures of the face and neck
originate from the first two branchial (pharyngeal) arches,
consisting of an outer layer of ectodermal tissue and an inner layer
of epithelium of endodermal origin. Both of these enclose the core
of mesenchymal tissue. The mesenchyma for the formation of the
cranial structures is from the para-axial and lateral plate mesoderm, together with a substantial part from neural crest cells.
These neural crest cells of the developing 3- to 4-week embryo,
composed of ectoderm, are found at the junction of the neural
plate and surface ectoderm. Neural crest cells migrate to the
branchial arch mesoderm. The face develops as a result of this
massive cell migration and their interactions with differentiating
cells of mesodermal origin, which contribute to the skeletal
components of the face.
The dorsal portion of the viscerocranium, originating from the
first pharyngeal arch, forms the maxillary process. This process
extends forward and forms the premaxilla, maxilla, zygomatic
bone, and part of the temporal bone. The anterior part also forms
the mandibular process and gives rise to the mandible. The dorsal
part of the mandibular process, together with the structures originating from the second pharyngeal arch, forms the ossicles of the
middle ear.
The caudal boundary of the oral cavity is less complex, consisting of the paired primordium of the mandibular arch. Appearing

8
C H A P T E R

first on either side of the midline are marked local thickenings


resulting from the rapid proliferation of mesenchymal tissue. Until
these thickenings have extended from either side to merge in the
midline, a conspicuous midline notch remains. With their merger,
the arch of the lower jaw is completed.1 The primitive mouth
(stomodeum) appears as a slight depression in the surface ectoderm separated by the oropharyngeal membrane. This membrane
ruptures at 24 to 26 days of gestation. With rupture of the membrane, the primitive gut communicates with the amniotic cavity.2
At 28 days of gestation, the face begins to show its eventual
relationship to the five primordia from which it is derived: the
frontonasal prominence (the cranial boundary of the stomodeum
or primitive mouth); the paired maxillary prominences (first
branchial arch); and the paired mandibular prominences (also
derived from the first branchial arch). The mandibular prominences grow medially and begin to merge with each other by the
end of the fourth week of gestation, forming the lower lip, the chin,
and the mandible.2 The midface is formed through the proliferation of the facial primordial tissue between 4 and 8 weeks of
gestation. The nasomedial prominence expands and displaces the
forebrain prominence from the forming mouth by merging in the
midline. The nasomedial prominences also fuse with the rapidly
elongating maxillary processes to complete the formation of the
tissues that constitute the upper jaw and lip. The segment of the
upper jaw, which is of medial nasal origin, gives rise externally to
the upper lip in the region of the philtrum. A deeper triangular
portion of the fused nasomedial prominence becomes the premaxillary portion of the dental arch as well as the median (primary) part of the palate. The intermaxillary segment in the central
portion of the upper lip area consists of three parts: the labial component, forming the philtrum; a maxillary component associated
with the four upper central incisor teeth; and a palatal component,
which becomes the primary palate. The upper lip is formed by the
merging of the maxillary prominences with the nasomedial
prominences.
During the second month of gestation, the development of the
palate separates the nasomaxillary complex from the oral cavity.
The premaxilla forms from the fusion of the globular processes of
the nasomedian process forming a small triangular median
portion of the palate (primary palate). The main part of the palate
(secondary palate) is derived from the maxillary process. It
develops in a medial direction, fusing in the midline, and unites
with the premaxilla and the developing nasal septum. The soft
palate forms from continued growth of the posterior edge of these
palatal processes, ending with the formation and fusion of the two
halves of the uvula.

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The nose originates in the cranial ectoderm, which subsequently develops into the frontonasal prominence, with the formation of nasal placodes during the third week of development. The
superior portion of the nose is formed from the nasolateral processes, whereas the inferior portion of the nasal cavity is incomplete until the paired maxillary processes of the first branchial arch
grow anteriorly and medially to fuse with the nasomedial processes. The nasomedial processes merge on the midline to form
the upper lip and the septum of the nose, which serves to separate
the two nasal chambers. The nasal chambers extend posteriorly
during development under the influence of the posteriorly directed fusion of the palatal processes. As this occurs, the membrane
that separates the two nasal chambers from the oral cavity thins.
By the 38th day of development, the two-layer oronasal membrane, consisting of nasal and oral epithelium, ruptures, forming
the choanae. The principal stages of craniofacial and nasopharyngeal development are illustrated in Figure 81.

Morphologic Considerations
The development of the face is influenced by the development of
the system of paranasal sinuses. Originally, because the sinuses are
absent, the facial structures are small compared with the neurocranium. The first signs of the development of the maxillary sinus
are evident at approximately the 10th week of gestation as a pouch
in the lateral wall of the ethmoidal infundibulum. The other
paranasal sinuses also begin their formation during the fetal
period as diverticuli of the lateral nasal wall and gradually differentiate inside the cranial bones to form the ethmoid, frontal,
and sphenoid sinuses. The sinuses develop postnatally. Their
maturation is not complete until adolescence or early adulthood.
The maxillary and ethmoidal sinuses are present at birth, whereas
the frontal and sphenoidal sinuses are not clinically detectable at
birth. Development begins around 2 years of age. Frontal sinuses
can usually not be detected radiographically until about 7 years of
age. The paranasal sinuses will not reach their final shape and size
until the end of puberty, giving the final appearance to the face.35
The skull base grows rapidly until 6 years of age, with relatively
slower growth thereafter.6 In addition, the cranial base flexes
postnatally during the rapid growth trajectory that is complete by
2 years of age. Modification of this angulation can occur as a result
of growth within the sphenooccipital, midsphenoidal, and sphenoethmoid synchondroses as well as from differential drift and
rotation of the components of the basioccipital, sphenoid, and
ethmoid relative to each other.7 The depth of the nasopharynx
increases because of remodeling of the palate as well as changes
in the angulation of the skull base.2 The soft tissues of the pharyngeal structures surrounding the upper airway grow proportionally
to the skeletal structures during the chilhood.8 Postnatally, the
dimensions of the nasal cavity increase very quickly. During the
first year of life, the total minimal cross-sectional area increases
by 67%, and the volume of the nasal airways increases by 36%
when measured by acoustic rhinometry.9 Choanal diameter also
undergoes rapid growth until 2 years of age and does not reach
its maximum size until 14 years of age.10 The volume of the
newborn oral cavity is proportionally less than that of an adult,
owing to the significantly shorter mandibular rami. The volume of
the oral cavity increases during the first 12 months of life because
of rapid growth in the height of the mandibular rami and eruption
of the dentition, which leads to enlargement of the lower face
(Figure 82).11

Figure 8-1. Embryologic development of the upper airway. The


principal stages of airway development during the embryologic period
are shown. Right column, Craniofacial development. Left column,
Nasopharyngolaryngeal development.

OROPHARYNX AND TONGUE


Embryologic Considerations
The primordial areas involved in forming the covering of the
tongue appear early during the second month of development.1

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With all of the shiftings of the components that occur as the
tongue develops, a small pit known as the foramen cecum delineates the border between the parts of the tongue that are formed
from the first and second branchial arches. The foramen cecum
is a vestige of the invagination from the floor of the pharynx that
gives rise to the thyroid primordium.

Morphologic Considerations
Compared with the adult tongue, the neonatal tongue12 contains
considerably less fat and soft tissue, a relatively enlarged extrinsic
musculature, and a less-developed superior longitudinal muscle,
resulting in a flatter dorsal surface and a larger tongue than that of
the adult configuration. Attachments between the extrinsic muscles and the transverse muscle, present only in the neonatal
tongue, may explain the poor lateral mobility of this structure.

LARYNX AND TRACHEA


Embryologic Considerations

Figure 8-2. Maturation of craniofacial and mandibular structures,


based on three-dimensional reconstructions of images from a computed tomography (CT) scanner (Osirix software). The volume of the
newborn oral cavity is proportionally lower than that of the adult
because of the significantly shorter mandibular ramus. The volume of
the oral cavity increases significantly during the first 12 months of life
because of rapid growth in the height of the mandibular ramus and
eruption of the dentition, which lead to enlargement of the lower face.

The tongue surface arises primarily from the mesenchyma of the


first arch, with significant contributions from the third and fourth
arches. In 5-week-old embryos, paired lateral thickenings, the
lateral lingual swellings, arise as a result of the rapid proliferation
of the mesenchyma beneath the overlying epithelium. These
structures border a posterior small median elevation known as the
tuberculum impar. Behind the tuberculum impar, the copula,
another median elevation, unites the second and third second
arches into a midventral prominence. The copula extends in a
cephalocaudad direction from the tuberculum impar to the
primordial swelling that marks the beginning of the epiglottis.

The larynx is developed embryologically from ectodermal,


endodermal, and mesodermal tissues that are derived from the
third, fourth, and sixth branchial arches and pouches.1,3,4,13 The
laryngeal cartilages and muscles form from the mesenchyma of
the fourth and sixth pharyngeal arches. Cartilaginous tissues from
these pharyngeal arches fuse to form the cartilaginous structures
of the airway including the arytenoid, thyroid, cricoid, corniculate,
and cuneiform cartilages. The hyoid bone is derived from the
second branchial arch (lesser horn and superior portion of the
body) and the third branchial arch (greater horn and inferior part
of the body). During the fourth week of embryonic life, a ventral
and midline diverticulum arises from the foregut, referred to as
the respiratory primordium. As this primordium deepens, it
becomes the laryngotracheal tube. The laryngotracheal groove
fuses from the caudal to the cephalic end, forming a tracheoesophageal septum that separates the laryngotracheal groove from
the esophagus. In the fifth to sixth embryologic week, three masses
of tissue appear around the primordial glottic slit at the base of
the third and fourth branchial arches.13 At approximately 6 weeks
of embryonic age, with the rapid proliferation of the mesenchyma
at the end of the laryngotracheal tube into the arytenoid prominences, the laryngeal entrance develops from a simple slit to a
T-shaped opening located directly below the epiglottal swelling.
The epiglottis itself develops from the caudal part of the eminentia
hypobranchialis (anterior parts of the third and fourth pharyngeal
arches). Between the arytenoid prominences is the epithelial
lamina, limited cephalad by the vestibulotracheal canal and
caudad by the pharyngotracheal canal. The rapid proliferation of
the laryngeal epithelium leads to temporary occlusion of the
lumen (Figure 83). After recanalization of the lumen at about
10 weeks of gestation, a pair of lateral recesses (laryngeal ventricles) remains. Around the lateral recesses, the true and false
vocal cords can be recognized as mesenchymal bands. During the
next 6 weeks, the larynx develops almost to its definitive appearance with the formation of thyroid, cricoid, and arytenoid
cartilages from the mesenchyma and further differentiation of the
epiglottis.5 At the end of the embryologic period, the larynx
structures are macroscopically differentiated. The fetal period is
characterized by the maturation of laryngeal ultrastructures,
particularly at the glottic level.14

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Morphologic Considerations

Figure 8-3. Median cross-section through the neck of a human embryo at 8 weeks. The laryngeal cartilages can be identified. The epithelial
lamina is limited cephalad by the vestibulotracheal canal and caudad by
the pharyngotracheal canal. At this stage, the glottic lumen is occluded.

Figure 8-4. Evolution of


laryngeal lumen morphology.
The neonatal larynx has a
conical shape, wider at the
supraglottic level and narrower in the subglottic level.
The larynx of an older infant
or adult larynx has a symmetrical cylindrical shape. The
hyolaryngeal descent leads to
a decrease in the pharyngolaryngotracheal angle.

Neonatal laryngeal morphology differs significantly from that of


the adult and major postnatal changes occur during the first year
of life. The larynx has a conical shape in infants and children,
wider at the supraglottic level and narrower at the subglottic level.
The adult larynx has more of a symmetrical cylindrical shape
(Figure 84).15,16 The neonatal supraglottic area has larger ventricular bands, larger arytenoids, and a shorter epiglottis, the latter
frequently configured in a U or an (omega) shape (Figure 85).
The angle between the epiglottis and the glottic plane is more
acute than in the adult. Neonatal vocal cords are shorter than those
of the adult, representing only the anterior half of the glottis, the
posterior half being covered by vocal process of arytenoids (Figure
86).17 The maturational descent of the larynx, considered as an
essential event in the transition from an obligate nasal to oral
breather, results in the further separation of the epiglottis from the
soft palate.
At 23 to 25 weeks of embryonic life, the fetal hyoid and larynx
are high relative to the cervical vertebrae, with the larynx extending from the basioccipital level to the level of the third and fourth
cervical vertebrae (C34).18,19 In the neonate, the hyoid lies opposite the junction between C2 and C3, just inferior to the mandible, with the larynx extending down to C3 to C4.18,20 By 2 years of
age, the hyoid and larynx have attained their adult position relative
to the cervical vertebrae, with the superior margin of the hyoid
body opposite the junction between C3 and C4 (Figure 87).21,22
During the majority of postnatal growth, the hyolaryngeal complex descends relative to the face and cranial base, but not relative
to the vertebral column.11 However, the hyoid descends relative to
the palatal plane during the first year of life, presumably because
of rapid growth in the height of the mandibular ramus. The
maturational position of the tip of the epiglottis relative to the
vertebral level is controversial, with a biphasic pattern according
to Sasaki23 and Westhorpe22 or a gradual linear descent according
to Schwartz and Keller.24 Schwartz and Keller reported that the tip
of the epiglottis is opposite the middle of the body of C2 in
children 1 day to 24 months of age, at the inferior end of the plate
of C2 in children 25 months to 10 years of age, and at the C23
intervertebral disk in adolescents.24 The hyolaryngeal descent

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Figure 8-5. Morphologic changes of the supraglottic structures


Endoscopic views of the supraglottic larynx. The supraglottic area
of a neonate has larger ventricular bands, larger arytenoids, and a
shorter epiglottis, which is frequently U or (omega) shaped.

relative to the craniovertebral structures leads to a decrease in the


orolaryngopharyngeal angle25 and the laryngotracheal angle (see
Figure 84).
Laryngotracheal measurements grow in a quasilinear fashion
during the fetal period, with a linear relationship observed between the laryngotracheal measurements and either body weight
or height.2628 The exception is the glottis, which has a curvilinear
growth pattern.26,28 The cricoid lumen is significantly less than the
tracheal and glottic lumens during perinatal period, thereby
representing the narrowest section of the airway.17,28 Sasaki23 and
Wailoo and Emery29 suggested that there were three phases of
laryngotracheal lumen growth (fetal period, birth to prepubertal
period, and postpubertal period), with the greatest growth occurring during the earliest period and decreasing thereafter.
Litman and colleagues30 and Arens and associates8 reported a
linear growth pattern of the laryngotracheal lumen during childhood. The evolution of cricoid and tracheal luminal dimensions
during childhood reported is outlined in Table 81.10,23,2634

Consequences of Anatomic Differences in


Pediatric Airway Management
Anatomic differences of the neonatal airway suggest the need for
the consideration of modifications of technique and equipment

Figure 8-7. Maturational descent of the larynx. The maturational


descent of the larynx is shown on parasagittal CT images. In the
newborn, the hyoid lies opposite the junction between C2 and C3, and
the glottis lies opposite the junction between C3 and C4. After 2 years
of age, the hyoid and larynx have attained their adult position relative
to the cervical vertebrae, as illustrated by this 13-year-old patient. The
hyoid body projects opposite the junction between C3 and C4 and the
glottis is opposite C5.

during airway management in the premature and neonatal population. The management of the neonatal pediatric airway is
discussed in detail in chapters 43 and 72. However, the specific
implications of some of the anatomic and morphologic differences
are reviewed.
The development of the mandibulofacial skeleton and modifications of the relationship between the soft palate and the tongue
make classic predictive tools of intubation such as the Mallampati
score inappropriate in pediatric population. The high position of
the neonatal larynx leads to a more anterior location of the glottis
during laryngoscopy. Because of the supraglottic morphology,
high position of the larynx, and acute glottoepiglottic angle, the
direct visualization of the glottic plane is more difficult in neonates. As such, the Cormak classification is also not applicable.
Moreover, the frequency of laryngomalacia in this age group may
further decrease the visualization of the glottis. In this case, the
most effective landmark for placement of an endotracheal tube is
the triangle formed by the arytenoid cartilages and the epiglottis.
The more acute laryngotracheal angle, related to the high position
TABLE 8-1. Development of Laryngotracheal Lumen*
Age
<28 GA
2834 GA
3438 GA
3841 GA
1y
3y
5y
10 y

Figure 8-6. Evolution of the glottis. The vocal cords of a neonate make
up only the anterior half of the glottis whereas the posterior half makes
up the vocal process of the arytenoids. This is compared with the glottis
of a 12-year-old in which the vocal cords make up two thirds of the
glottis.

Laryngeal Diameter,
mm
2.23.1
2.93.5
2.75.5
3.76.4
4.510
612
712
716

Tracheal Diameter,
mm
2.55
2.75.5
36
3.76.5
5.27.8
6.39
810
12

*
The growth of the laryngotracheal lumen according to anatomic and radiologic
studies reported from the literature. See references 10, 23, 2634. The mean
diameters reported in studies of Wailoo and Emery29 and Eckel and coworkers17
were recalculated based on the results expressed, respectively, in perimeter and
surface area of the subglottic cross-section.
GA = gestational age in weeks.

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of the neonatal larynx, not only is associated with a higher
incidence of difficulties during endotracheal intubation but also
results in a higher risk of anterior laryngotracheal injury such as
cricotracheal or cricothyroid dislocation.
The laryngeal structures have some degree of elasticity before
36 weeks of gestation, thereby permitting placement of an
endotracheal tube (ETT) that is larger than that predicted by direct
anatomic measurement.35 Therefore, in the premature population,
the risk of injury is greatest to the posterior glottic region. This
elasticity disappears around term, and the site of injury is then
predominantly in the subglottic area. The traumatic risk is correlated to the outer diameter (OD) of the ETT. Therefore, guidelines regarding sizing of the ETT should focus on the OD and not
the inner diameter (ID). The relationship between the OD and the
ID is different according to different manufacturers because of
differences in the thickness of the wall of the ETT. For similar ODs
of various ETTs, the ID may vary up to 1 mm. This is important
when considering the risk of airway trauma related to the OD of
the ETT and the respiratory resistance during spontaneous
ventilation, which is dependent on the ID of the ETT.

REFERENCES
1. Carlson BM. Development of head, neck, and lymphoid system. In:
Pattens Foundations of Embryology. 6th ed. New York: McGraw-Hill;
1996. pp. 513715.
2. Holzman RS. Anatomy and embryology of the pediatric airway.
Anesthesiol Clin North Am. 1998;4:707727.
3. Sadler TW. Langmans Medical Embryology. 7th ed. Baltimore:
Williams & Wilkins; 1995; pp. 1460.
4. Moore KL, Persaud TVN. The Developing Human: Clinically Oriented
Embryology. 6th ed. Philadelphia: WB Saunders; 1998. pp. 1563.
5. Pohunek P. Development, structure and function of the upper
airways. Paediatr Respir Rev. 2004;1:28.
6. Myer CM 3rd. Growth of the pediatric skull base: assessment using
magnetic resonance imaging. Laryngoscope. 1995;105(9 Pt 2 Suppl
75):110.
7. Lieberman DE, McCarthy RC. The ontogeny of cranial base angulation in humans and chimpanzees and its implications for reconstructing pharyngeal dimensions. J Hum Evol. 1999;5:487517.
8. Arens R, McDonough JM, Corbin AM, et al. Linear dimensions of the
upper airway structure during development: assessment by magnetic
resonance imaging. Am J Respir Crit Care Med. 2002;1:117122.
9. Djupesland PG, Lyholm B. Changes in nasal airway dimensions in
infancy. Acta Otolaryngol. 1998;6:852858.
10. Violaris NS, Pahor AL, Chavda S. Objective assessment of posterior
choanae and subglottis. Rhinology. 1994;3:148150.
11. Lieberman DE, McCarthy RC, Hiiemae KM, Palmer JB. Ontogeny of
postnatal hyoid and larynx descent in humans. Arch Oral Biol.
2001;2:117128.
12. Iskander A, Sanders I. Morphological comparison between neonatal
and adult human tongues. Ann Otol Rhinol Laryngol. 2003;9:768776.
13. Tucker HM. The Larynx. New York: Thieme Medical Publishers;
1987. pp. 1819.
14. Fayoux P, Devisme L, Merrot O, et al. Histologic structure and
development of the laryngeal macula flava. Ann Otol Rhinol Laryngol.
2004;6:498504.

Airway Development

105

15. Cotton RT. Management and prevention of subglottic stenosis in


infants and children. In: Bluestone CD, Stool SE, Kenna MA, editors.
Pediatric Otolaryngology. 3rd ed. Philadelphia: WB Saunders; 1996.
pp. 13731389.
16. Hudgins PA, Siegel J, Jacobs I, Abramowsky CR. The normal pediatric larynx on CT and MR. AJNR Am J Neuroradiol. 1997;2:
239245.
17. Eckel HE, Koebke J, Sittel C, et al. Morphology of the human larynx
during the first five years of life studied on whole organ serial
sections. Ann Otol Rhinol Laryngol. 1999;3:232238.
18. Bosma JF (ed). Anatomy of the infant head. 1st edn. Johns Hopkins
University Press, Baltimore, 1986. pp 462.
19. Magriples U, Laitman JT. Developmental change in the position of
the fetal human larynx. Am J Phys Anthropol. 1987;4:463472.
20. Laitman JT, Heimbuch RC, Crelin ES. Developmental change in a
basicranial line and its relationship to the upper respiratory system in
living primates. Am J Anat. 1978;4:467482.
21. Roche AF, Barkla DH. The level of the larynx during childhood. Ann
Otol Rhinol Laryngol. 1965;3:645654.
22. Westhorpe RN. The position of the larynx in children and its relationship to the ease of intubation. Anaesth Intensive Care. 1987;4:
384388.
23. Sasaki CT. Development of laryngeal function: etiologic significance
in the sudden infant death syndrome. Laryngoscope. 1979;12:
19641982.
24. Schwartz DS, Keller MS. Maturational descent of the epiglottis. Arch
Otolaryngol Head Neck Surg. 1997;6:627628.
25. Vorperian HK, Kent RD, Gentry LR, Yandell BS. Magnetic resonance
imaging procedures to study the concurrent anatomic development
of vocal tract structures: preliminary results. Int J Pediatr Otorhinolaryngol. 1999;3:197206.
26. Schild JA. Relationship of laryngeal dimensions to body size and
gestational age in premature neonates and small infants. Laryngoscope.1984;94:12841291.
27. Kalache KD, Franz M, Chaoui R, Bollmann R. Ultrasound measurements of the diameter of the fetal trachea, larynx and pharynx
throughout gestation and applicability to prenatal diagnosis of
obstructive anomalies of the upper respiratory-digestive tract. Prenat
Diagn. 1999;19:211218.
28. Fayoux P, Marciniak B, Devisme L, Storme L. Prenatal and early
postnatal morphogenesis and growth of human laryngotracheal
structures. J Anat. 2008;213:8692.
29. Wailoo MP, Emery JL. Normal growth and development of the
trachea. Thorax. 1982;8:584587.
30. Litman RS, Weissend EE, Shibata D, Westesson PL. Developmental
changes of laryngeal dimensions in unparalyzed, sedated children.
Anesthesiology. 2003;98:4145.
31. Too-Chung MA, Green JR. The rate of growth of the cricoid cartilage.
J Laryngol Otol. 1974;88:6570.
32. Tucker GF, Tucker JA, Vidic B. Anatomy and development of the
cricoid. Serial section whole organ study of perinatal larynges. Ann
Otol Rhinol Laryngol. 1977;86:766769.
33. Fishman RA, Pashley NRT. A study of the premature neonatal airway.
Otolaryngol Head Neck Surg. 1981;89:604607.
34. Sellars I, Keen EN. Laryngeal growth in infancy. J Laryngol Otol.
1990;104:622625.
35. Fayoux P, Devisme L, Merrot O, Marciniak B. Determination of
endotracheal tube size in a perinatal population. An anatomical and
experimental study. Anesthesiology. 2006;104:954960.

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Respiratory Physiology
Etsuro K. Motoyama

INTRODUCTION
Pediatric anesthesia involves perioperative and critical care of
patients of all sizes between preterm infants weighing less than
1 kg and teenagers weighing well over 100 times that of small
infants. Physiologic differences between the two extremes of
pediatric patients may even be more significant than their
differences in body size. In order for an infant to survive in the
extrauterine environment, the circulatory and respiratory systems
must undergo the most drastic changes during the first few
minutes of life. The neonate must exercise the effective neural
drive and respiratory muscles to displace the fluids filling the
airways and pulmonary alveoli and introduce sufficient air into
the lungs against the surface tension to establish sufficient alveolar
surface for pulmonary gas exchange. In response to rapid increases
in blood O2 tensions, pulmonary vascular beds must dilate rapidly
and increase pulmonary blood flow so as to establish regional
alveolar ventilation-pulmonary perfusion balance and maintain
adequate pulmonary gas exchange. Simultaneously, the pattern of
circulation must change from fetal placental circulationin which
the right and left heart outputs function in parallel, perfusing the
lower and upper portions of the body, respectivelyto the adulttype circulation with the circulation of blood through the right
and left sides of the heart in series.
Neonatal adaptation of the medullary respiratory control and
lung mechanics evolves much more slowly than circulatory
adaptation, which takes at least several weeks. Even beyond this
period of adaptation, the maturation of the infants lungs and the
chest wall, which support the stability of lung inflation, continues
during the first year and beyond. These different cardiorespiratory
characteristics in infants and young children make anesthetic
management quite different and extremely challenging for
pediatric anesthesiologists.
In this chapter, we first review the prenatal development of the
lungs and neonatal adaptation. We then review the postnatal
development and growth of the lung and thorax. We also discuss
some essential and practical aspects of respiratory physiology in
infants and children that have direct and indirect relevance to
pediatric anesthesiology. Such information is indispensable for a
better understanding of the complexity of neonatal physiology and
for the proper care of infants and young children during the
perioperative period.

C H A P T E R

DEVELOPMENT OF THE
RESPIRATORY SYSTEM
Prenatal Development of the Lung
The morphologic development of the human lung is seen as early
as several weeks into the embryonic period and continues well into
the first decade and beyond of the postnatal life (Figure 91).1 The
entire endodermal structure of the lung arises from the primitive
foregut as a ventral pouch in the third week of embryonic
development when the fetus is only 3 mm in length. The outgrowth
of the endodermal cavity together with surrounding mesenchymal
tissue projects into the pleuroperitoneal cavity to form lung buds.
The future airway and alveolar membranes including mucous
glands are derived from the endoderm; whereas the smooth
muscle, cartilage, connective tissues, lymph, and blood vessels
originate from the mesenchymal elements surrounding the lung
buds.2 During the pseudoglandular period, which extends into the
17th week of gestation, the budding of bronchi and the growth of
lung tissues progress rapidly. At the end of this period, preacinar
branching of the future airways down to the terminal bronchioles
are all but completed.3 Any disturbance of the free expansion of the
developing lung in this period, as seen in congenital diaphragmatic
hernia, results in hypoplasia of the lung and airway branching.4
The canalicular period, which extends into the 24th week of gestation, is characterized by airway branching into future respiratory
bronchioles, as the relative amount of the connective tissues
diminishes. At the same time, there is increased secretory gland
and capillary formation around the airways.2
At approximately the 24th week of gestation, at the beginning
of the terminal sac (alveolar) period, clusters of terminal air sacs
appear with flattened epithelia.5 These terminal air sacs (saccules)
are larger with relatively thicker walls with fewer capillaries than
future alveoli.6 Type II pneumocytes, which produce pulmonary
surfactant, appear at 24 to 26 weeks of gestation but occasionally
as early as the 20th week.7 At 26 to 28 weeks of gestation, the
proliferation of the capillaries surrounding the saccules becomes
sufficient for pulmonary gas exchange.8 These morphologic and
biochemical developments may occur earlier in some extremely
premature infants born before the 25th week of gestation who
survive with neonatal intensive care.
From the 28th week of gestation onward, the wall thickness of
the saccules decreases rapidly with increasing septal capillary

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Respiratory Physiology 107

Figure 9-1. Stages of human lung development and their timing. Note overlapping between stages, particularly between the alveolar stage and the stage of microvascular maturation. Open-ended bars indicate uncertainty as to exact
timing. From Zeltner TB, Burri PH. The postnatal development and growth of the human lung. II. Morphology. Respir
Physiol. 1987;67:269, with permission.

networks. There is further lengthening of terminal air sacs with


the possible additional development of air spaces. The formation
of alveoli from the terminal saccules occurs in some human fetuses
as early as the 32nd week of gestation. By the 36th week of
gestation, alveoli are consistently present,9 although the majority
of the terminal air sacs are primarily saccules at the time of birth
with further growth of alveoli during the postnatal period.
The lung produces a large quantity of liquid, which expands the
airways while the larynx is closed. This expansion helps to stimulate
lung growth and development. The lung fluid is periodically
expelled into the uterine cavity, contributing approximately one
third of the total amniotic fluid. During the 1990s, prenatal ligation
or occlusion of the trachea was thought to be a potential treatment
of the fetus with congenital diaphragmatic hernia (CDH).10 This
treatment causes the expansion of the fetal airways and results in
accelerated growth of the otherwise hypoplastic lung. Fetal surgery
for the repair of CDH was eventually abandoned.11
Idiopathic respiratory distress syndrome (IRDS) or hyaline
membrane disease (HMD) occurring in prematurely born infants
is the most common cause of neonatal maladaptation and is caused
by the immaturity of the lung, with its insufficient pulmonary
surfactant production and inactivation. Experimental studies in
animals have shown that certain hormones, such as cortisone12,13
and thyroxine,14 enhance lung maturation, as evidenced by the
earlier appearance of type II pneumocytes and surfactant
production. In 1972, Liggins and Howie15 reported the first clinical

study that demonstrated an acceleration of lung maturation in the


fetus after the administration of corticosteroids to mothers 24
to 48 hours before the delivery of premature infants. Prenatal
glucocorticoid therapy has been used routinely since the 1980s to
induce lung maturation and surfactant synthesis in mothers at risk
of premature delivery.

Perinatal Adaptation
At birth, the infant must overcome the high surface tension within
the alveoli with its first several breaths to introduce air into the
liquid-filled lung. Even a normal full-term infant with sufficient
surfactant available must exert a large negative pleural pressure
(80 cmH2O) to overcome the surface force/tension (Figure
92).16 The fluid in the trachea and the rest of the airways is
expelled quickly through the upper airways, whereas residual fluid
leaves the lung more slowly through the lymphatic system and the
pulmonary circulation. With the expansion of the lung, arterial
oxygen tension (PaO2) increases, dramatically reducing pulmonary vascular resistance. The resultant large increase in pulmonary
blood flow and the increase in left atrial pressure and the decrease
in right atrial pressure reverse the pressure gradient across the
atria and functionally close the foramen ovale. The accelerated
production of pulmonary surfactant and its abundant presence on
the alveolar surface is essential for the smooth transition from the
fetal to the neonatal state.

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Figure 9-2. A: A pressure-volume curve of expansion of a gas-free lung. AB represents the initial expansion. In the example,
approximately 13 cmH2O pressure will be necessary to overcome surface forces. C represents deflation to zero pressure with
gas trapping. B: Pressure-volume relationships during the first breath of a newborn weighing 4.3 kg. Here, 60 to 70 cm H2O
pressure was necessary to overcome the surface forces. A and B: From reference 16, with permission.

Postnatal Development of
the Lung and Thorax
The development and growth of the lung and surrounding thorax
continue with amazing speed during the first year of life; the
morphologic development of the lungs, however, continues
throughout the first decade of life. Although the formation of the
airway system, down to the terminal bronchioles, is completed by
the 16th week of gestation,3 alveolar formation in human fetuses
begins only at about the 36th week of gestation. At birth, the
number of terminal air sacs (most of which are saccules) is
between 20 and 50 million, less than one tenth that of adults. The
postnatal development of alveoli from primitive saccules occurs
more rapidly than previously assumed and is essentially completed
by 18 months of age.9
During the early postnatal period, the lung volume of infants is
disproportionately small in relation to body size. In addition,
because of higher metabolic rates in infants (O2 consumption per
unit body weight is twice as high as that of adults), the ventilatory
requirement per unit of lung volume in infants is markedly
increased. Thus, infants have much less reserve of lung surface area
for gas exchange. This is an important reason why infants and
young children develop rapid O2 desaturation with hypoventilation
or apnea of a relatively short duration.
In the neonate, static (elastic) recoil pressure of the lung is very
low (i.e., compliance is high), not unlike that of geriatric or
emphysematous lungs with diminished elastic recoil, because the
development of elastic fibers does not occur until the postnatal
period.1719 Perhaps more important clinically, the elastic recoil
pressure of the thorax (chest wall) is extremely low because of the
infants very compliant cartilaginous rib cage with its limited
thoracic muscle mass (see Control of Breathing). These unique
characteristics make infants more prone to lung collapse and
respiratory insufficiency, especially under general anesthesia (see
Anesthetic Effect on Respiratory Muscles). Throughout infancy
and childhood, static recoil pressure of the lung steadily increases
(compliance, normalized for size, decreases) toward normal values
for young adults.20,21
The actual size of the airway from the larynx to the bronchioles
in infants and children, of course, is much smaller than that in

adolescents and adults, and flow resistance in absolute terms is


higher. However, when normalized for per unit lung volume or
body size, infants airway size as well as airway resistance is
generally lower than in adults.22,23 For example, the upper airway
caliber of a 3.5-kg neonate (3.5 mm endotracheal [ET] tube size)
is relatively larger than that of a 70-kg adult (89 mm ET tube).
These findings do not necessarily conflict with the clinical
evidence that infants and toddlers are more prone to severe
obstruction of upper and lower airways. The absolute (not relative)
airway diameters in infants are much smaller than those in
adults, and young children develop upper airway obstruction
more often and more severely than do adults. Given the smaller
cross-sectional area of the pediatric airway, relatively mild
airway inflammation, edema, or secretions can lead to far-greater
degrees of obstruction in the subglottic (croup) to bronchiolar
(bronchiolitis) airways in infants than in adults.

CONTROL OF BREATHING
Prenatal Development
Respiratory rhythmogenesis occurs long before parturition.
In 1970, Dawes and coworkers24 were the first to demonstrate
breathing activities with rhythmic diaphragmatic contractions in
fetal lambs. Rhythmic movement of the human fetal thorax was
recorded soon afterward by means of ultrasound techniques.25
More recent studies have demonstrated that breathing activities
in human fetuses occur regularly during the last trimester of
pregnancy. Fetal breathing activities naturally occur only during
REM (rapid eye movement) sleep and are most active with
increased levels of maternal blood sugar a few hours after a
maternal meal.26
Hypoxia depresses, rather than stimulates, fetal respiratory
movement. This suppression may be related to decreased REM
sleep with hypoxia.27 Normally, low fetal arterial PaO2 (carotid
PaO2, 1925 mmHg) may be a physiologic mechanism that
suppresses fetal breathing activities.28 Severe hypoxia induces
gasping, which is independent of the peripheral chemoreceptors
and is unrelated to rhythmic fetal breathing. The near-term fetus
is relatively insensitive to arterial carbon dioxide tension (PaCO2)

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changes. In the fetal lamb, however, extreme hypercapnia (PaCO2
> 60 mmHg) can induce rhythmic breathing movement that is
preceded by a sudden activation of inspiratory muscle tone with
expansion of the thorax and inward movement (inhalation) of
amniotic fluid in amounts of up to 30 to 40 mL/kg (an apparent
increase in functional residual capacity [FRC]) (Motoyama,
unpublished observation). When PaCO2 was reduced, breathing
activities ceased, followed by a reversal of the sequence of events
noted above (i.e., relaxation of the thorax and outward flow of
amniotic fluid).

Perinatal Adaptation
Before the 1980s, the traditional view of the mechanism that
triggers the onset of breathing at birth was that transient fetal
asphyxia during labor and delivery stimulates fetal gasping
followed by rhythmic breathing that is maintained by tactile,
auditory, thermal, and other sensory stimuli. However the onset of
breathing activity occurs weeks before parturition and the onset of
air breathing. It is not clear why and how the fetus must breathe
in utero when respiratory gas exchange is handled by the placenta.
One reason may be prenatal practice or exercise of the respiratory
muscles by the fetus suggested by Dawes.29 Another reason is that
the stretching of the airways and lung parenchyma is an important
stimulus for lung development. Experimental blockade of fetal
breathing with bilateral phrenic nerve sections in the fetal lamb
results in hypoplasia of the lung.30
The current concept of the mechanism of continuous neonatal
breathing may be summarized as follows31,32:
1. Neonatal breathing is but a continuation of breathing activity,
which is present weeks before parturition.
2. The clamping of the umbilical cord is an important factor
initiating or restarting rhythmic breathing.
3. Relative hyperoxia (PaO2 > 4060 mmHg) with air breathing
compared with the low fetal PaO2 (2030 mmHg) augments
and maintains rhythmicity.

Figure 9-3. Effect on breathing 14% O2 (hypoxemia)


from room air and then 100% O2 (hyperoxia) in
three newborn infants. Ventilation (mean standard
error of the mean [sem]) is plotted against time.
During acute hypoxia, there was a transient increase
in ventilation followed by depression. Hyperoxia
increased ventilation. Modified from reference 101.

Respiratory Physiology 109

4. Continuous rhythmicity is independent of PaCO2; it is


unaffected by carotid denervation.
5. Hypoxia depresses or abolishes, rather than stimulates,
continuous breathing.

Control of Breathing in Neonates


and Infants
Response to Hypoxemia
During the first several weeks of life, both full-term and preterm
neonates respond to moderate hypoxemia (15% inhaled O2) with
a transient (a few minutes) increase in breathing followed by
sustained respiratory depression33 (Figure 93). However, in cold
environments, the initial period of transient hyperventilation is
abolished in neonates born between 32 and 37 weeks of gestation,
indicating the importance of maintaining a neutral thermal
environment.34,35 By contrast, when 100% O2 is given, a transient
decrease in ventilation is followed by sustained hyperventilation in
neonates. This ventilatory response to hyperoxia, similar to that of
the fetus, is distinctly different from that of the adult, in whom
ventilation continues to be decreased. 36 By 3 weeks after birth,
hypoxemia induces a sustained increase in ventilation, as is seen
in older children and adults.33
The biphasic depression of ventilation in hypoxemic neonates
has been attributed to central depression, rather than to the
depression of the peripheral chemoreceptors.37 Conversely, in the
study of newborn monkeys under hypoxemia, both tracheal
occlusion pressure (an index of central neuronal drive) and
diaphragmatic electromyogram (EMG) studies increased above
the control levels, during both the initial increase in ventilation
and the subsequent sustained ventilatory depression.38 These
findings imply that the biphasic ventilatory response to hypoxemia
in the neonate results from changes in the mechanics of the
respiratory system (such as increased stiffness or fatigue of the
thoracic muscles or upper airway obstruction), rather than
neuronal depression, as has been assumed.39

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at 10 to 12 months of age.41,43 An addition of 2 to 4% CO2 to the
inspired gas mixture abolishes periodic breathing, probably
because of respiratory stimulation.44
Central apnea of infancy is the cessation of breathing activity
lasting longer than 15 to 20 seconds or a shorter period of apnea
associated with bradycardia (heart rate < 100 beats/min), cyanosis,
or pallor.45 The mechanism of apnea in preterm infants is not well
understood but is related to an immature respiratory control
mechanism.46 Central apnea is relatively rare in full-term neonates
but occurs in the majority of premature infants.41,42 In a more
recent study with data on home monitoring involving more than
1000 infants with sudden infant death syndrome (SIDS), their
siblings, and controls who were monitored consecutively for 180
days (Collaborative Home Infant Monitoring Evaluation or
CHME Study), prolonged central apnea among full-term infants
was shown to be less common than was previously thought. Two
to 3% of healthy full-term infants developed central, obstructive,
or mixed apnea lasting more than 30 seconds during sleep. In
addition, prolonged obstructive sleep apnea (OSA) was observed
in a few normal-term infants with a simple upper respiratory
infection (URI), whereas 15 to 30% of preterm infants developed
prolonged apnea and severe desaturation with a URI.47

Figure 9-4. Mean steady-state CO2 response curves at different inspired oxygen concentrations in eight preterm infants. The slope of
the CO2 response curve decreases with decreasing oxygen. The slope increases with increasing oxygen. From Rigatto H, De La Torre Verduzco
R, Cates DB: Effects of O2 on the ventilatory response to CO2 in
preterm infants. J Appl Physiol. 1975;39:8969.

Response to CO2
Both full-term and preterm neonates respond to increased PaCO2
by increasing ventilation, but to lesser extents than in older infants.
The slope of the CO2 response curve is less in preterm than in
full-term neonates. The CO2 response (slope) increases with
postnatal age, independent of postconceptional age.32,40 Although
this increase in CO2 sensitivity may represent an increase in
chemosensitivity, it may also be due to the improved mechanics of
the respiratory system. In adults, the CO2 response curve increases
in slope as well as shifts to the left with the severity of hypoxemia.
By contrast, in neonates breathing a hypoxic mixture, the CO2
response curve is shifted to the right and the slope decreased.
Furthermore, hyperoxia (breathing 100% O2) shifts the curve to
the left and increases the slope (Figure 94).33

Periodic Breathing and Central Apnea


Full-term neonates sleep most of the time and spend 50% of their
sleep time in active (REM) sleep, compared with the 20% of REM
sleep of adults. Premature neonates stay in REM sleep most of
the time.28,32 Both full-term and premature neonates breathe
irregularly. Periodic breathing, in which rhythmic breathing is
interposed with a series of short apneic spells lasting less than
10 seconds without cyanosis or bradycardia, occurs during both
active and quiet (non-REM) sleep and even during wakefulness.
Although breathing is more irregular in REM sleep than in nonREM sleep, periodic breathing occurs mostly during quiet sleep.41
The incidence of periodic breathing in full-term neonates is about
80%, whereas it is nearly 100% in premature neonates.41,42 The
frequency of periodic breathing diminishes after 44 weeks
postconception and thereafter with maturation during the first
year of life. It is still present at sometime in nearly 30% of infants

Postoperative Apnea in Premature Infants


With advances in neonatal intensive care and improved survival
of prematurely born infants since the early 1980s, postoperative
apnea has become an important clinical issue in pediatric
anesthesia. There have been controversies regarding the age
at which these expremature infants can be safely discharged
from the hospital after simple surgical procedures such as inguinal
herniorrhaphy. The classic paper by Liu and colleagues and a
number of subsequent studies have shown that prematurely
born infants less than 44 weeks postconception, especially those
with a history of apnea, are at a high risk (2040%) of developing
postoperative apnea.48 Apnea occurs mostly within 12 hours
postoperatively.49 Conversely, Kurth and associates reported
that postoperative apnea could occur as late as 56 weeks postconception.50
More recent studies indicate that a number of compounding
factors are associated with the development of postoperative
apnea, such as the extent of surgery, anesthetic techniques, anemia,
and postoperative hypoxemia.51 It appears that the probability of
postoperative apnea between 44 and 60 weeks postconception is
less than 5%.52,53 The only important exception is the anemic infant
(hematocrit 30%) in whom the risk of developing apnea remains
high regardless of the postconceptional age.51,53
Most of the patients in these reports of postoperative apnea in
preterm infants were anesthetized with halothane and isoflurane,
agents with relatively high lipid solubility that remain in the
body tissues for a prolonged period of time. In the era of newer
anesthetic agents with a much lower lipid solubility (sevoflurane
and desflurane), increased use of total intravenous anesthesia, as
well as the use of regional block, the incidence of postoperative
apnea in preterm infants seems to have decreased.54 Indeed,
postoperative apnea is reported to be significantly lower with
sevoflurane or desflurane anesthesia than with other inhalational
anesthetic agents.55
Both theophylline and caffeine have been known to be effective
in reducing the incidence of apnea in premature infants.42,56
Caffeine is especially useful for prematurely born infants for the

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Respiratory Physiology 111

prevention of postoperative apnea.57 In addition, xanthine


derivatives, including theophylline and caffeine, are known to
strengthen muscle contractility and prevent fatigue.58 Therefore,
respiratory stimulation in the premature infants may occur by
both central and peripheral mechanisms. It is important to note
that hypoxemia or hypoxia induced by upper airway obstruction
(OSA) can trigger central apnea, because cerebral hypoxia is a
potent respiratory depressant. Indeed, many apneic episodes are
found to be mixed apnea and are often triggered by upper airway
obstruction.47

Postoperative Apnea in Children


Postoperative apnea is not limited to expremature infants. Apnea
or hypoventilation can occur in infants and children of all ages as
well as adults who are predisposed to upper airway obstruction
(OSA), not related to neuronal or central apnea. Surgical
correction of upper airway obstruction caused by obstructive
lesions such as micrognathia, macroglossia, adenotonsillar
hypertrophy, and nasal polyps can improve OSA. Children with
Down syndrome (trisomy 21) have an increased incidence of OSA,
which is often exaggerated during the perioperative period
because of the residual depressant effect of anesthetic agents,
opioids, or sedatives.39 With increasing obesity among adolescents
and even among younger children since the later 1990s, especially
in the United States, perioperative OSA has become a more
frequent and important clinical entity for pediatric anesthesiologists.59

Neural Control of Breathing


The mechanism that regulates and maintains pulmonary gas
exchange is remarkably efficient in healthy individuals in whom
PaCO2 is kept within a very narrow range (40 2 mmHg), whereas
O2 consumption and CO2 production vary greatly between states
of rest and exercise. Breathing is achieved by the coordinated
action of a large number of inspiratory and expiratory muscles.
Inspiration is produced mainly by the contraction of the
diaphragm and, to a lesser extent, the external intercostal muscles
and other thoracic muscles, which generate negative pleural
pressure and draw air through the airways to the lung. Expiration
is primarily produced by the elastic recoil of the lung and
the thorax while the sustained contraction (with diminishing
intensity) of the diaphragm and the upper airway muscles
(expiratory braking) impedes and smoothens the expiratory
phase of breathing. Rhythmic contraction and relaxation of the
respiratory muscles are governed by the respiratory centers in
the brainstem and are tightly regulated with multiple feedback
systems that match the level of alveolar ventilation to the
metabolic needs. These feedback mechanisms include central and
peripheral chemoreceptors, stretch receptors in the airways and
lung parenchyma with vagal afferenta, and segmental reflexes in
the spinal cord regulated by muscle spindles.60
Respiratory neurons in the medulla have inherent rhythmicity
even without the rostral brain or sensory afferents. Respiratory
neurons are concentrated in two bilaterally symmetrical areas
(dorsal and ventral groups) near the level of the obex in the
medulla. The dorsal respiratory group (DRG) of respiratory
neurons is located in the dorsomedial medulla and contains
mostly inspiratory neurons. The ventral respiratory group (VRG)

Figure 9-5. Schematic representation of the respiratory neurons on the


dorsal surface of the brainstem. Cross-hatched areas contain predominantly inspiratory neurons, blank areas contain predominantly expiratory neurons, and dashed areas contain both inspiratory and expiratory
neurons. Bt C = Btzinger complex; C1 = first cervical spinal nerve;
CP = cerebellar peduncle; DRG = dorsal respiratory group; 4th Vent =
fourth ventricle; IC = inferior colliculus; NA = nucleus ambiguus; NPA
= nucleus para-ambigualis; NPBL = nucleus parabrachialis lateralis;
NPBM = nucleus parabrachialis medialis; NRA = nucleus retroambigualis; PRG = pontine rerspiratory group; VRG = ventral respiratory
group. Courtesy of Dr. M. Tabatabai.

of neurons is located in the ventrolateral medulla. It consists of


both inspiratory and expiratory neurons61 (Figure 95).
The respiratory rhythm or cycle generated by the respiratory
neurons is composed of three phases: inspiration, postinspiration
(or early expiration), and late expiration. During the inspiration
phase, inspiratory neurons, which are premotor to the phrenic and
intercostal motor nuclei, display an augmented discharge.60 At the
end of the inspiratory phase, inspiratory neurons receive a
transient inhibition (off-switch) that terminates the increase of
inspiratory neuronal activity.61 Afferent inputs to the inspiratory
neurons, especially those from the pulmonary stretch receptors,
which are highly concentrated in the upper trachea, affect the
timing of the off-switch. The larger the airway inflation or tidal
volume (VT), the shorter the duration of inspiration62. During the
postinspiration (or early expiration) phase, the inspiratory
neurons receive both excitatory and inhibitory impulses associated
with active braking of expiratory airflow as the contraction of the
diaphragm gradually diminishes.60 After the postinspiration phase
of the respiratory cycle, lung volume decreases passively to the
preinspiratory level or to FRC. Under certain conditions, such as
during exercise or during the administration of inhalational
anesthetic agents, expiratory muscles may undergo active contractions. In this phase of the respiratory cycle, inspiratory neurons
receive inhibitory postsynaptic potentials in an augmented
pattern. Throughout the expiratory phase of the respiratory cycle,

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decreasing inhibitions of the onset of subsequent inspiration exist.


In addition, various afferent inputs affect the onset of inspiration
or prolong the duration of expiration. More specifically, respiratory neurons are grouped together as follows:

DRG of Neurons
The DRG is spatially associated with the tractus solitarius, the
principal tract for the 9th and 10th cranial nerves. These nerves
carry afferent fibers from the airways and lungs, heart, and
peripheral arterial chemoreceptors. The DRG functions as an
important primary and possibly secondary relay site for visceral
sensory inputs via the glossopharyngeal and vagal afferent fibers.
Furthermore, because many of the inspiratory neurons in the DRG
project to the ipsilateral and contralateral spinal cord and make
excitatory connections with phrenic motor neurons, the DRG
serves as a source of inspiratory drive to phrenic and possibly
external intercostal motor neurons.63

VRG of Neurons
The VRG extends from the rostral to the caudal end of the medulla
and has three subdivisions (see Figure 95). The Botzinger
complex, located in the most rostral part of the medulla in the
vicinity of the retrofacial nucleus, contains mostly expiratory
neurons. These neurons send inhibitory signals to DRG and
VRG neurons and project into the phrenic motor neurons in the
spinal cord, causing inhibition and contributing to the inspiratory
off-switch mechanism.64,65 The middle portion of the VRG is
occupied by the nucleus ambiguus (NA) and nucleus paraambigualis (NPA), which are located side by side. Axons of the
motor neurons originating at the NA project along with other
vagal nerve fibers and innervate laryngeal abductor (inspiratory)
and adductor (expiratory) muscles via the recurrent laryngeal
nerve.66 The NPA contains mostly inspiratory neurons, which
respond to lung inflation. The axons of these neurons project to
both the phrenic and the external intercostal motor neurons in
the spinal cord. The nucleus retroambigualis occupies the caudal
portion of the VRG and contains expiratory neurons whose axons
project into the spinal motor neuron pools of the internal
intercostal and abdominal expiratory muscles.67 The inspiratory
neurons of the DRG send collateral fibers to the inspiratory
neurons of the NPA in the VRG. These connections may provide
ipsilateral synchronization of the inspiratory activity between the
neurons in the DRG and those in the VRG. Furthermore, the
neurons in the NPA send collateral fibers to the contralateral NPA,
and vice versa.65 These connections may be responsible for the
bilateral synchronization of the medullary inspiratory motor
neuron output.

Pontine Respiratory Group of Neurons


An additional group of inspiratory and expiratory neurons exists
in the dorsolateral portion of the rostral pons, although their
function appears to be secondary or ancillary to DRG and VRG of
the medulla. Inspiratory neurons are concentrated ventrolaterally
in the region of the nucleus parabrachialis lateralis, whereas the
expiratory neurons are located more medially in the vicinity of the
nucleus parabrachialis medialis.68 These respiratory neurons are
referred to as the pontine respiratory group (PRG), which, in the
past, was called the pneumotaxic center, a term now considered
obsolete. There are reciprocal projections between the PRG

neurons and the DRG and VRG neurons in the medulla. Electrical
stimulation of the PRG produces rapid shallow breathing, whereas
transection of the brainstem at a level caudal to the PRG results
in prolonged inspiratory time (TI) or apnea with sustained
inspiration (apneusis).63 The PRG probably plays a secondary role
in modifying the inspiratory off-switch mechanism.69

Respiratory Rhythm Generation


Rhythmic breathing can be maintained without the brain rostral
to the pons and in the absence of feedback from peripheral
chemoreceptors. Thus, respiratory rhythmogenesis apparently
takes place in the brain stem. The PRG, DRG, and VRG have all
been considered as possible sites of the central respiratory
pacemaker or pattern generator.70,71 The prevailing view is that
rhythmicity is a property of the synaptic interactions among the
various groups of respiratory, motor, and sensory neurons in the
network.60,72 Studies in neonatal and fetal rats have indicated that
respiratory rhythm is generated in the small cluster of pacemaker
neurons in the ventrolateral medulla near the Boetzinger (preBoetzinger) complex.73,74 Such respiratory rhythmogenesis may be
uniquely needed for the fetus to initiate and maintain breathing
activities when there is little or no feedback from chemoreceptors
to the medulla.

Pulmonary and Thoracic Receptors


The respiratory tract (the upper airways, trachea, and bronchi),
lung, and chest wall have a number of sensory receptors that
respond to mechanical and chemical stimuli. These receptors affect
not only ventilation but also circulatory and other nonrespiratory
functions.

Upper Airway Receptors


The major role of the receptors in the pharynx is associated with
the swallowing function. It involves the inhibition of breathing,
closure of the larynx, and coordinated contractions of the
pharyngeal muscles.75 The larynx has a rich concentration of
various receptors. Activation of these receptors can cause apnea,
coughing, closure of the glottis, laryngospasm, and changes in the
ventilatory pattern.76 These reflexes, which affect the patency of
the upper airway, respond to transmural pressure or airflow
changes. Three types of receptors stimulate the superior laryngeal
nerve: pressure receptors, drive (irritant) receptors, and flow
(or cold) receptors.77 The laryngeal flow receptors produce
inspiratory modulation while breathing room air, but become
silent when inspired air is warmed and fully saturated. The activity
of pressure receptors increases markedly with upper airway
obstruction.77,78
Newborn animals are particularly sensitive to the stimulation
of the superior laryngeal nerve either directly or through the
receptors, which results in ventilatory depression or apnea. In
puppies anesthetized with pentobarbital, water in the laryngeal
lumen produced apnea whereas normal saline with neutral pH did
not. The principal stimulus for the apneic reflex was reduced or
absent chloride ion concentrations.79 The strong inhibitory
responses of various upper airway receptors in the newborn have
been attributed to immaturity of the central nervous system.79
Infants, particularly premature neonates, exhibit a clinically
important airway protective reflex response to fluid at the entrance

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to the larynx.80,81 This reflex seems to trigger prolonged breathholding and apnea in neonates and young children during
inhalation induction of anesthesia. When a small quantity of
warmed saline solution is dripped into the nasopharynx in
sleeping neonates, it pools in the piriform fossa and then overflows
into the interarytenoid space at the entrance to the larynx. This
area is densely populated with various nerve endings and
receptors. The most common response to fluid accumulation is
swallowing. These neonates also respond by central apnea, with
the glottis either open or gently closed. Coughing or awakening
may also occur, but these are infrequent. An apneic response is
more prominent with water than with normal saline solution.80
These findings appear clinically relevant and particularly
important in pediatric anesthesia. During inhalation induction,
pharyngeal reflexes (swallowing) are abolished while laryngeal
reflexes remain intact.82 Secretions would, therefore, accumulate in
the hypopharynx without swallowing, which would cause breathholding or central apnea. Positive-pressure breathing with a mask
and bag, in an attempt to support ventilation, instead of suctioning
the secretions in the larynx, would push secretions further down
into the larynx, stimulating the superior laryngeal nerve and
triggering true laryngospasm.39
The upper airway protective mechanism involves both the
pharynx and the larynx and includes sneezing, swallowing,
coughing, and laryngeal closure. Laryngospasm is a sustained tight
closure of the vocal cords caused by contraction of the adductor
(cricothyroid) muscles that persists beyond the removal of the
initial stimulus triggering the glottic closure. In puppies, it is
elicited by repetitive stimulation of the superior laryngeal nerve.83
By contrast, hyperventilation and hypocapnia as well as light
anesthesia increase the activity of adductor neurons and reduce
the mean threshold of the adductor reflex.75 Hyperthermia and
decreased lung volume also facilitate laryngospasm elicited by
the stimulation of the superior laryngeal nerve.83 By contrast,
hypoventilation and hypercapnia, positive intrathoracic pressure,
and deep anesthesia depress excitatory adductor after-discharge
activity and increase the threshold of the reflex that precipitates
laryngospasm.84 It is interesting to note that hypoxia (PaO2 <
50 mmHg) also increases the threshold for laryngospasm. These
findings are consistent with clinical impressions that laryngospasm occurs most frequently under light anesthesia and that it can
be broken by deepening anesthesia or by awakening the patient. In
addition, laryngospasm can also be broken when the patient
becomes severely hypoxemic, suggesting a fail-safe mechanism by
which asphyxia tends to prevent sustained laryngospasm.39
Furthermore, in puppies, positive upper airway pressure inhibits
the glottic closure reflex and laryngospasm. This finding also
supports the clinical observation that, during emergence from
anesthesia in infants and young children, the maintenance of
positive end-expiratory pressure (PEEP) and inflation of the lung
at the time of extubation seem to reduce both the incidence and
the severity of laryngospasm.39

Tracheobronchial and Pulmonary Receptors


There are three types of major receptors: slowly adapting (pulmonary stretch) receptors (SARs) and rapidly adapting (irritant)
receptors (RARs), both of which are innervated by myelinated
vagal afferents, and unmyelinated C fiber endings or J (juxtaalveolar) receptors.

Respiratory Physiology 113

SARs
SARs are mechanoreceptors that lie within the submucosa of
smooth muscles in the membranous posterior wall of the trachea
and major bronchi.85 SARs are stimulated by the distention of the
airways during inspiration (periodic lung inflation). They inhibit
inspiratory activity (Hering-Breuer inflation reflex) and show little
response to steady levels of lung inflation. Although SARs are
predominantly mechanoreceptors, hypocapnia stimulates and
hypercapnia inhibits their discharge.86
The inflation reflex is important in human newborn infants
as well as in cats in adjusting the pattern of breathing.62,87 In
anesthetized cats, TI is decreased with increasing VT with
hypercapnia, indicating the presence of the inflation reflex in the
normal VT range. Vagotomy abolishes this reflex and TI is
prolonged (Figure 96). In the human adult, TI is independent
of VT until the latter increases to about twice the normal VT, when
the inflation reflex appears. Apnea that is often observed in adult
patients during the emergence from general anesthesia with the
endotracheal tube cuff inflated may be related to the inflation
reflex, because deflation of the cuff often establishes rhythmic
breathing. The upper trachea has a high concentration of stretch
receptors.

RARs
RARs are located within the airway epithelial cells and are most
concentrated in the regions of the carina and large bronchi.88 RARs
react to both mechanical and chemical stimuli and, unlike SARs,
respond rapidly to large inflation, deflation, and distortion of
the lung. In addition, RARs are stimulated by cigarette smoke,

Figure 9-6. Relation between tidal volume (VT) and inspiratory time
(TI) as ventilation is increased in response to respiratory stimuli. Note
that in region I, VT increases without changes in TI. Also shown as
dashed lines are the VT trajectories for three different tidal volumes
in region II. From Berger AJ: Control of breathing. In: Murray JF,
Nadel JA, editors. Textbook of Respiratory Medicine. Philadelphia:
WB Saunders; 1988, with permission.

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ammonia, and other irritant gases, including inhaled anesthetics,


with considerable interindividual variability. RARs are more
consistently stimulated by histamine, prostaglandins, and leukotrienes, suggesting their role in response to pathologic states,
such as bronchial asthma.63 The stimulation of RARs in the large
airways may be responsible for reflexes such as coughing, bronchospasm, and tracheal mucus secretion. Activation of RARs in
the periphery of the airways may produce hyperpnea.
When the vagal afferents are partially blocked by cold temperature, inflation of the lung produces a sustained contraction of the
diaphragm and prolonged inflation of the lung (the paradoxical
reflex of Head). This reflex is most likely mediated by RARs. It may
also be related to the sigh mechanism, which may be triggered by
the collapse of some parts of the lung with quiet breathing and
increasing surface force. In the neonate, mechanical inflation of
the lung initiates a deep, gasping breath, which may be related
to the paradoxical reflex, and helps expand unaerated portions of
the lung.89

C Fiber Endings (J Receptors)


Most afferent axons arising from the lung, heart, and abdominal
viscera are slow-conducting unmyelinated vagal fibers. Studies by
Paintal90 have suggested the presence of such receptors located near
the pulmonary or capillary wall (juxtapulmonary or J receptors).
C fiber endings are stimulated by pulmonary congestion, edema,
or microemboli as well as irritant gases, including inhalational
anesthetic agents. Such stimulation of J receptors causes apnea
followed by rapid shallow breathing as well as bronchoconstriction,
hypersecretion, hypotension, and bradycardia. In addition, stimulation of C fiber endings can provoke severe reflex contraction of
the laryngeal muscles, which may be partially responsible for the
laryngospasm observed during inhalational induction with isoflurane or desflurane. Inhalation of irritant gases or particles causes
a sensation of tightness of the chest, or dyspnea, probably by
activation of pulmonary receptors. Bilateral vagal blockade in some
patients with lung disease abolishes dyspneic sensation and
increases breath-holding time.91

of isolated upper airways to halothane resulted in depression


of respiratory-modulated pressure receptors, whereas irritant
receptors and cold (flow) receptors were consistently stimulated in
a dose-dependent manner.75 Laryngeal pressure receptors may be
a part of the feedback mechanism that maintains the patency of
the upper airways. The depression of this feedback mechanism,
together with the activation of irritant receptors, may play an
important role in the collapse of the upper airways during the
induction of inhalational anesthesia.

Chemical Control of Breathing


Regulation of alveolar ventilation and maintenance of normal
PaCO2 within a very narrow range are the principal functions of
the central (medullary) and peripheral (carotid) chemoreceptors.

Central Chemoreceptors
The central or medullary chemoreceptors, located near the surface
of the ventrolateral medulla, are spatially separated from the
medullary respiratory centers. The central chemoreceptors
respond primarily to changes in hydrogen ion concentration in
the adjacent interstitial fluid and cerebrospinal fluid (CSF), rather
than to changes in PaCO2.93 Because CO2 rapidly passes through
the blood-brain barrier into the CSF, which has a poor buffering
capacity, central chemoreceptors are readily stimulated by
increases in PaCO2. By contrast, ventilatory responses to acute
metabolic acidosis and alkalosis are limited because changes in
hydrogen ion concentration are not rapidly transmitted to CSF.
In chronic acid-base disturbances, the pH of CSF surrounding
the chemoreceptors is generally maintained close to the normal
value of approximately 7.3, regardless of arterial pH.94 Under these
circumstances (patients with chronic obstructive pulmonary
disease or high altitude dwellers), the maintenance of alveolar
ventilation becomes more dependent on the hypoxic stimulation of
the peripheral chemoreceptors (see Peripheral Chemoreceptors).

Peripheral Chemoreceptors
Chest Wall Receptors
The chest wall muscles, especially intercostal muscles (and, to a
lesser extent, the diaphragm), contain various types of mechanoreceptors that can produce respiratory reflexes.92 The two types of
receptors most extensively studied are muscle spindles, which lie
parallel to the extrafusal muscle fibers, and the Golgi tendon
organs, which lie in series with the muscle fibers.63 The muscle
spindles are slowly adapting mechanoreceptors and are innervated
by motor neurons that excite intrafusal fibers of the spindle. The
arrangement of muscle spindles is appropriate for the respiratory
muscle load-compensation mechanism.63 The Golgi tendon
organs are located at the point of insertion of the muscle fiber into
its tendon and are also a slowly adapting mechanoreceptor.

Anesthetic Effects on the Upper Airway Receptors


Inhalation induction of anesthesia in children is often associated
with reflex responses such as breath-holding and laryngospasm.
Studies in animals have demonstrated that inhaled anesthetic
agents stimulate upper airway receptors directly and affect
breathing. In dogs under urethane-chloralose anesthesia and
breathing spontaneously through a tracheostomy, the exposure

The primary site of peripheral chemoreceptors affecting ventilation is in the carotid bodies, located at the bifurcation of the
common carotid artery. Peripheral chemoreceptors react rapidly
to changes in PaCO2 and pH. Their contribution to the ventilatory
drive has been estimated to be about 15% of resting ventilation,
but may be much larger when ventilation is increased.95 The
carotid body has three types of neural components: type I
(glomus) cells, type II (sheath) cells, and sensory nerve fiber
endings.96 Sensory nerve fibers originate at the terminals in
apposition to the glomus cells and travel through the carotid
nerve, which enters the glossopharyngeal nerve. The sheath cells
envelope both the glomus cells and the sensory nerve terminals.63
The carotid bodies are perfused with an extremely high level of
blood flow through a very short artery arising directly from the
internal carotid artery. They rapidly respond to an oscillating
PaCO2, rather than to a constant PaCO2. This mechanism may, in
part, be responsible for exercise-induced hyperventilation.97
The primary and unique role of peripheral chemoreceptors,
however, is their response to decreases in PaO2. Moderate-tosevere hypoxemia (PaO2 < 60 mmHg) results in significant increases in ventilation in a dose-dependent fashion.98 Ventilatory
stimulation, however, is absent in certain hypoxemic or hypoxic

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states, such as moderate-to-severe anemia and carbon monoxide
poisoning. Under these conditions, as PaO2 is kept near normal,
the chemoreceptors are not stimulated despite decreased arterial
O2 content and possible tissue hypoxia. In neonates during the
first several weeks of age, ventilation is depressed, rather than
stimulated, by hypoxemia caused by direct hypoxic suppression or
depression of medullary respiratory centers, although peripheral
chemoreceptor activities are present (see Central Chemoreceptors).
In acute hypoxemia, the ventilatory response via the carotid
chemoreceptors is partially opposed by the effect of hypocapnia
and respiratory alkalosis, which suppresses the central chemoreceptors. Acidification of the CSF by means of medication, such
as acetazolamide, restores hyperventilation (the method used for
acute ascent to high altitude by mountain rescuers). When a
hypoxic environment persists for more than several days or
weeks, for example, during a sojourn to high altitude, ventilation
increases further as CSF bicarbonate decreases and pH returns
toward normal despite continuous hypocapnia.99 In chronic
hypoxemia lasting for years, the carotid bodies gradually lose their
hypoxic response. In high-altitude-dwelling natives of the Andes
and Himalayas, the blunted response of carotid chemoreceptors
to hypoxemia takes 10 to 15 years to develop and is sustained for
a long time.100,101 In cyanotic heart disease in children, the hypoxic
response is lost within a few years, but returns after surgical
correction of right-to-left shunts and restoration of normoxia.102
In patients with chronic respiratory insufficiency and hypercapnia, hypoxemic stimulation of carotid chemoreceptors provides the primary stimulation of the medullary respiratory
centers. If these patients are given O2 and PaO2 increases rapidly,
as in the immediate postoperative period, stimulus by hypoxemia
is removed, ventilation may decrease or cease, and PaCO2
increases further. This is particularly the case in patients with
chronic hypercapnia. These patients may become comatose with
extremely high PaCO2 values (CO2 narcosis), and cardiorespiratory catastrophe may follow. Instead of O2 therapy alone, these
patients need their ventilation improved artificially with or without added O2.

Respiratory Physiology 115

CO2 Response Curve

Figure 9-7. Effect of acute hypoxemia on the ventilatory response to


steady-state arterial carbon dioxide pressure (PaCO2) in one subject.
Inspired oxygen was adjusted in each experiment to keep arterial oxygen pressure (PaO2) constant at the level as indicated. From reference
98, with permission.

The graphic presentation of the relationship


arterial or
. between
.
end-tidal PCO2 and minute ventilation (VI or VE) is commonly
known as the CO2 response curve. This curve normally reflects the
response or sensitivity of the medullary respiratory centers to
PCO2. The CO2 response curve is a useful and practical means for
evaluating the chemical control of breathing, provided that the
mechanical properties of the respiratory system, including
neuromuscular transmission, the respiratory muscles, chest wall
and lungs, and airways, are intact. Normally, ventilation increases
linearly with increasing PCO2, up to 10% or so, when ventilation
starts to decrease (CO2 narcosis). Under hypoxemic conditions,
the CO2 response is potentiated, primarily by the stimulation of
carotid chemoreceptors, resulting in the shift to the left of the
curve (Figure 97).98 An exception is during the newborn period
when hypoxemia causes respiratory depression and the rightward
shift of the curve (see Figure 93).40 By contrast, inhalational
anesthetic agents, opioids, and sedatives in general depress the
medullary respiratory centers and result in the rightward shift of
the CO2 response curve (Figure 98).103

Depression or a shift to right of the CO2 response curve occurs


in patients whose carotid bodies have been removed.104 This may
also occur in patients with lung disease in whom increases in
intact neural stimulation cannot be translated into increased
ventilation. Under these circumstances, it had long been difficult
to separate out neural components from mechanical failure of
the respiratory apparatus.105 In 1975, Whitelaw and coworkers
demonstrated that negative mouth pressure generated against
occlusion (occlusion pressure) at 0.1 s (P0.1) correlates well with
neural (phrenic) impulse and is unaffected by the mechanical
properties of the respiratory system.106 Milic-Emili and Grunstein
proposed that the ventilatory response to CO2 be analyzed not as
the product of tidal volume (VT) and respiratory rate (f) but rather
in terms of the product of mean inspiratory flow rate (VT/TI,
where TI is inspiratory time), as an indication of neural drive, and
the duty cycle of breathing (TI/TTOT, where TTOT is the respiratory
cycle duration) as follows107:
.
VI = VT f = VT/TI TI/T TOT

Assessment of Respiratory Control

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Anesthetic Effect on Respiratory Muscles

Figure 9-8. CO2 response curve with halothane. Family of steadystate CO2 response curves in one subject awake and at three levels of
halothane anesthesia. Note progressive decrease in ventilatory response
to PaCO2 with increasing anesthetic depth (minimum alveolar concentration [MAC]). The ventilatory response in awake state was measured
in response to end-tidal carbon dioxide pressure (PCO2). Courtesy of
Dr. Edwin S. Munson; data based on reference 103.

The distinct advantage of analyzing the ventilatory response in


this way is that VT/TI is an index of the inspiratory drive,
independent of the timing element. Conversely, VT is time
dependent, because VT = VT/TI TI. The second parameter,
TI/TTOT, is a dimensionless index of effective timing (respiratory
duty cycle) that is determined by the vagal afferent and central
inspiratory off-switch mechanism.108 It is apparent from this
equation that a reduction in ventilation in a patient under general
anesthesia or with lung disease is caused either by changes in the
drive (VT/TI) or the timing component (TI/TTOT) or both.

Anesthetic Effects on Respiratory Control


Anesthetic Effect on the CO2 Response Curve
Most anesthetic agents, opioids, and sedatives depress ventilation,
either by themselves or in combination
. with other agents. They
invariably affect minute ventilation (V I) and its components, VT,
frequency, VT/TI, TI/T TOT, or their combinations. All inhaled
anesthetics (perhaps with the exception of diethyl ether, which has
not been in clinical use since the 1970s) depress ventilation
profoundly in a dose-dependent fashion (see Figure 98). This
subject has been extensively studied in adults.109 Information on
the effects of anesthetic agents on the CO2 response in infants and
children, however, has been limited.

Under normal circumstances, inspiration of air into the lung is


produced by coordinated contractions of inspiratory muscles and
exhalation is accomplished passively by the elastic recoil of the
lung and chest wall. General anesthesia affects ventilation by
decreasing the intensity of motor neuron impulses to inspiratory
muscles, but with different degrees of depression. Three groups
of muscles coordinate the inspiratory phase of breathing: the
diaphragm, the external intarcostal muscles (pump muscles), and
the upper airway muscles, which maintain the patency of the
pharynx and larynx during inspiration. In quiet breathing, the
contraction of the diaphragm is the primary force producing tidal
ventilation, whereas the intercostal muscles stiffen the chest wall
and resist negative intrathoracic pressure from sucking the thorax
inward, which would result in thoracoabdominal asynchrony, as
seen in the neonate with labored breathing with or without upper
airway obstruction. By contrast, an increase in ventilation during
exercise or hypercapnia is accomplished primarily by increased
intercostal activity.
Sensitivity to anesthetics differs among various inspiratory
muscles and their neurons. Froese and Bryan were the first to
compare the depressant effects of anesthesia on the diaphragm
and intercostal muscles in children and adults.110 Using twodimensional magnetometers to measure chest wall and abdominal
circumferences, they demonstrated that light halothane anesthesia
depressed intercostal muscle activities disproportionately more
than it did the diaphragm. Subsequently, Ochiai and colleagues,
in their electromyographic studies in cats, demonstrated that the
phasic inspiratory activity of the genioglossus muscle (which
moves the tongue anteriorly and maintains the patency of the
pharyngeal airway) was most sensitive to the depressant effect of
halothane at a given concentration.111 The diaphragm was most
resistant or least sensitive whereas the sensitivity of the intercostal
muscles to halothane was intermediate (Figure 99). Furthermore,
the same group of investigators found that, in kittens, phasic
activity of the genioglossus was more readily depressed than in
adult cats.112
Unlike the laryngeal airway, the pharyngeal airway is not
supported by a rigid cartilaginous or bony structure. Its wall
consists of soft tissues surrounded by the upper airway muscles
and is kept patent with sustained and cyclic contractions of the
pharyngeal dilator muscles (the genioglossus, geniohyoid, tensor
palatine, and others).39,113 Anesthesia-induced depression of these
pharyngeal dilator muscles seems responsible for upper airway
obstruction that is often seen in infants and young children.
The work of breathing increases significantly in anesthetized
children breathing spontaneously without an oral airway when
compared with those with an oral airway or laryngeal mask airway in place, thereby indicating the presence of partial upper
airway obstruction. The addition of low continuous positive
airway pressure (CPAP of 56 cmH2O) further decreases the work
of breathing even in those with an oral airway or laryngeal mask
airway.114
In healthy awake patients, exhalation of VT is produced
passively by elastic recoil of the lung and chest wall. Under
halothane anesthesia, however, there have been reports of active
contractions of abdominal expiratory muscles.115 If this active
expiration occurs in anesthetized, spontaneously breathing
patients, it would further contribute to the reduction of FRC at
end-expiration, airway closure, and possibly, increased venous
admixture.

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Respiratory Physiology 117

Figure 9-10. Total lung capacity (TLC) and lung volume subdivisions.
ERV = expiratory reserve volume; FRC = functional residual capacity;
IC = inspiratory capacity; IRV = inspiratory reserve volume; RV =
residual volume; VC = vital capacity; VT = tidal volume.
Figure 9-9. Decrease in phasic inspiratory muscle activity, expressed
as peak height of moving time average (MTA), in percent change from
control (1% halothane), during halothane anesthesia in adult cats. Values
are mean sem. *P < .05 compared with the diaphragm (DI); **P <.05
compared with the genioglossus muscle (GG). From reference 111.

LUNG VOLUMES AND


MECHANICS OF BREATHING
Lung Volumes
Total lung capacity (TLC) is the maximum lung volume during
inspiration with maximal contraction of inspiratory muscles. TLC
is subdivided into inspiratory capacity (IC) and FRC. IC and FRC
are further subdivided as shown in Figure 910. FRC is the lung
volume at the end of normal expiration when inspiratory muscles
are totally relaxed. It is normally about 50% of TLC (FRC/TLC
ratio, 0.5) in the upright position and 40% of TLC in the supine
position. Residual volume (RV) is the amount of air remaining in
the lung after maximum expiration and is roughly 25% of TLC
(RV/TLC ratio, 0.25). FRC is determined by the balance between
the outward recoil (expansion) of the thorax and the inward
recoil of the lung. The two opposing forces result in a negative
interpleural pressure of approximately 5 cmH2O in older children
and adults. In infants, interpleural pressure is at or slightly below
the atmospheric pressure.
In infants, the chest wall is extremely compliant (outward recoil
is low) whereas the inward recoil of the lung is only mildly lower
than that of adults.19,116 Consequently, FRC or relaxation volume
(VR) of young infants at complete relaxation (such as central
apnea, general anesthesia, or the use of neuromuscular blocking
agents) decreases to a mere 10 to 15% of TLC.116 This low VR is
substantially below the closing capacity (CC) and results in small
airway closure, atelectasis, ventilation/perfusion imbalance, and
hemoglobin desaturation.

TLC measured with the tracer gas washout technique


was reported to be relatively small (~60 mL/kg) in infants,
although air spaces in the lung might not have been fully
recruited (the lung inflated with relatively low pressure of 2025
cmH2O).117 TLC in children who are older than 18 months
(measured with an adequate inflation pressure of 3540 cmH2O)
increases with growth until 5 years of age, when it reaches
90 mL/kg, the value for older children and adults.117 In normal
children and adolescents, lung volume is correlated well with body
size, especially height.39

Elastic Properties
Compliance of the Lung, Thorax,
and Respiratory System
In order to expand the lung and achieve tidal ventilation by
contraction of the inspiratory muscles (or with positive pressure
applied to the airway system), one has to overcome the elastic
recoil of the lung and thoracic structures, which resist the
expansion. This elastic recoil pressure is fairly constant over the
range of normal V T, but it increases at the extremes of lung
inflation or deflation. The elastic recoil pressures of the lung, chest
wall, or respiratory system (lung and thorax) are expressed
as compliance of the lung (CL), thorax or chest wall (CW), or
respiratory system (CRS) and are expressed in units of lung volume
per units of pressure change as follows:
CL = V/
P
where V is usually the VT and P is the transpulmonary
pressure (pressure difference between the airway and the
interpleural pressure). In the case of CW, P is the pressure
difference across the chest wall (interpleural and atmospheric
pressures) and for CRS, the pressure difference between the airway

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and the atmospheric pressures. The reciprocal of compliance is


elastance (E = 1/C) and E can be added as follows:
ERS = EL + EW
1/CRS = 1/CL + 1/CW
The measurement of compliance is usually made at the extreme
of tidal breath where there is no airflow (static compliance, CST(L),
CST(W), and CST(RS)). Even without any inherent changes in
the pressure-volume characteristics of the lung, compliance of
the lung (CL) (or that of the respiratory system, CRS) decreases as
the end-expiratory volume increases from the midpoint of TLC
(as with air-trapping or with excessive levels of PEEP). CL also
decreases when FRC decreases to below normal at the midpoint of
TLC (as with general anesthesia or administration of neuromuscular blocking agents, see Effects of Anesthesia on Respiratory
Mechanics). Therefore, the measurement of the pressure-volume
relationship over the entire range of TLC provides a more accurate
description of the elastic properties of the lung and respiratory
system39 (Figure 911).
In normal lungs, compliance measured during the respiratory
cycle (dynamic compliance [CDYN]) is approximately the same as
static compliance. Conversely, when there is airway obstruction
with an increased pressure swing during tidal ventilation, CDYN
is relatively decreased, whereas static compliance is relatively
unaffected. This difference between static compliance and CDYN
increases with increasing respiratory frequency (frequency
dependence of compliance) and is a sign of airway obstruction.118
After several days of postnatal adaptation with the concomitant
removal of lung fluid, lung compliance of the neonate is extremely
high (elastic recoil, low),21 because of poorly developed elastic
fibers119 (Figure 912). These functional characteristics of pressurevolume relationships are not too dissimilar to those of geriatric
patients with pulmonary emphysema with the loss of functioning

elastic fibers (Figure 913). At both extremes of human life (e.g.,


neonatal and geriatric), the lung is prone to premature airway
closure.18 Elastic recoil pressure of the lung at 60% of TLC increases
from approximately 1 cmH2O to 7 cmH2O at 7 years and as high
as 9 cmH2O during the latter half of the teenage years.119,120

Developmental Changes in Compliance


of the Lung and Thorax
In infants, outward recoil of the thorax is extremely low (compliance, high)116 because of the soft cartilagenous rib cage and
poorly developed thoracic musculature. In comparison, inward
recoil of the lung is only mildly diminished compared with that
in adults. In the neonate, the CW is three to six times higher than
CL. Consequently, static balance of these opposing forces would
shift and decrease FRC to very low levels. This decrease in FRC
would make parenchymal airways unstable and prone to collapse.
This situation does occur under general anesthesia or muscle
paralysis and, to a lesser extent, during apnea and active (REM)
sleep when inspiratory muscles are relaxed.117,121,122
When does the chest wall of infants become stiffer and
CW decrease to the level of CL? Papastamelos and associates
have shown that the development of the chest wall occurs much
sooner than was previously believed.123 In their study, both CL
and CW were very high in young infants and CW was two to three
times higher than CL. However, the chest wall developed rapidly
with increasing rigidity and, by 9 to 12 months of age, CW
decreased to the level of CL. Both CW and CL continued to
decrease (elastic recoil, increase) thereafter for the entire study
period of 3 years. This rapid development of the chest wall (with
resultant stiffening and a decrease in CW) in young infants was
attributed to the shift from the horizontal to the upright posture
in early infancy, which presumably requires stronger thoracic
musculature.123

Figure 9-11. Schematic representation of the pressure volume (P-V) curve and compliance of the respiratory system. At the midpoint of the P-V curve
(indicated as FRC awake), the slope and compliance
(Crs = P/
V) is the highest. When functional
residual capacity (FRC) is decreased to the lower,
flatter portion of the P-V curve under general anesthesia or paralysis (indicated as FRC anesthetized),
Crs decreases even without changes in the mechanics
of the lung.

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Respiratory Physiology 119

Figure 9-12. Pressure-volume curves obtained from excised lungs at autopsy. Data are grouped by postnatal
ages as shown by symbols. It is evident that elastic recoil pressure (horizontal distance between nil distending
pressure and the curve at a given distending volume) increases with postnatal development of the lungs.
Based on data from references 17 and 119, with permission.

Figure 9-13. Static pressure-volume curves (deflation limbs) of the lungs in various conditions as
indicated. From Bates DV, editor: Respiratory Function in Disease: An Introduction to the Integrated
Studies. 3rd ed. Philadelphia: WB Saunders; 1989. p. 558.

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The breathing pattern of infants younger than 6 months of age


is predominantly diaphragmatic (abdominal) and the intercostal
(rib cage) contribution to VT is relatively less than that in adults.
After 9 months of age, the rib cage portion of V T increases to
approximately 50%, the level seen in older children and adults,
This increase in the thoracic portions of VT is brought about by
changes in the shape of the rib cage (from a horizontal to a V
shape) and the maturation of the thoracic musculature.124

airways, the tissue viscoelastic resistance or the resistance of


the lung and thoracic tissues themselves to deformation, and
inertial resistance (inertance) resulting from the movement of
gas molecules within the airways, especially at high velocities.
By contrast to compliance (or elastance), which is measured at
points of no flow, flow resistance is present only when the lung is
in motion.

Airway Resistance
Maintenance of FRC in Infants
In spite of an excessively compliant chest wall and the tendency
for static FRC (VR) to fall, dynamic FRC in awake, spontaneously
breathing infants is well maintained near the values seen in older
children and adults because of a number of mechanisms that
prevent FRC from collapsing. These mechanisms include
1. Breaking of expiration with continual (although diminishing) diaphragmatic activity in the early expiratory phase.
2. Tachypnea with short expiratory time and the initiation of
inspiration before the end of passive expiration. The resultant
intrinsic PEEP (PEEPi) maintains dynamic FRC higher than
relaxed FRC or VR.
3. Sustained tonic activities of the inspiratory muscles throughout
the respiratory cycle (especially external intercostal muscles).
How long does dynamic FRC continue postnatally? A study by
Colin and coworkers has demonstrated that the transition from
dynamic to relaxed FRC in infants occurs between 6 and 12 months
of age.125 By 1 year of age, the breathing pattern is predominantly
that of relaxed end-expiratory volume, as in older children and
adults. Perhaps the most important of all these mechanisms that
sustain FRC is the tonic activity of the external intercostal muscles,
the diaphragm, and other inspiratory muscles,126 the diaphragm,
and other inspiratory muscles. This mechanism effectively stiffens
the chest wall and maintains higher levels of FRC at end-expiration.

Anesthetic Effect on FRC


General anesthesia with or without muscle relaxants markedly
diminishes or abolishes inspiratory muscle tone and results in
a reduction in FRC. In healthy young adults, a reduction in
FRC following the induction of anesthesia has been reported
to be between 9 and 25%.127,128 In older individuals, the average
reduction in FRC is greater (30%), probably due to decreased
elastic recoil of the lung.129 The effect on FRC of general anesthesia
is more pronounced in infants and young children because their
thorax is more compliant,130 as discussed in more detail in the
section Effects of Anesthesia on Respiratory System Mechanics.
A reduction in FRC is not limited to general anesthesia or muscle
paralysis alone.131 Henderson-Smart and Read have reported a
30% reduction in thoracic gas volume (FRC measured with body
plethysmograph) in infants when their sleep pattern changed from
quiet (non-REM) to active (REM) sleep with the relaxation of
respiratory muscles.129

Dynamic Properties
Breathing involves cyclic contractions of respiratory muscles and
the generation of force, which must overcome resistive and elastic
properties of the lung and chest wall. The resistive properties of the
respiratory system include the resistance to airflow within the

The pressure required to overcome frictional resistance and


produce flow between the airway opening (Pao) at the mouth and
alveoli (PALV) is proportional to flow rate.132 Airway resistance
(Raw) is expressed as pressure gradient across the airways:
.
(P = Pao PALV) per unit flow (V):
.
Raw = P/V (cmH2O/L/s)
If the respiratory system is assumed to have a single
compartment with a constant elastance or compliance (E = 1/C)
and a constant resistance (R), the equation of forces acting on the
respiratory system can be expressed:
.
.
.
P = EV + RV + IV
where inertance (I) is very small in tidal breathing and can be
ignored. During normal tidal breathing, approximately 90% of the
pressure gradient required is needed to overcome the elastic forces
and the remaining 10% of the pressure is expended to counter the
flow resistance.133
Flow resistance is related to the length (l), the radius of the tube
(r), and the viscosity of the gas () as follows:
r = 8l/r4
Assuming a laminar flow (as seen in small or peripheral
airways), it is apparent from this equation (Poiseuilles law) that
the most important factor affecting flow resistance is the change
in the radius of the tube (airways), because resistance is inversely
proportional to the fourth power of the radius. When the flow is
turbulent, as occurs in large airways, the flow resistance increases
approximately with r5. Therefore, R aw in infants with smaller
airway diameters is much higher, in absolute terms, than Raw in
older children and adults. In terms of body size, however, the
caliber of airways in general is wider and Raw is lower in infants
and children than in adults.21,23

Upper Airway Resistance


The airway system extends from the airway opening at the naris or
the mouth to the alveolar duct at the periphery of the lung.
Functionally, the airway system can be subdivided into the upper
(extrathoraic) and lower (intrathoracic) airways. During quiet
breathing, airflow resistance through the nasal passages accounts
for approximately 65% of total Raw in adults.134 Stocks and Godfrey
found that nasal resistance accounted for approximately 49%
of the total Raw in European infants, whereas it was significantly
less in infants of African origin (31%).135 Overall, upper R aw is
approximately two thirds of the total Raw.
Except when crying, newborn infants are obligatory nasal
breathers. The cephalad position of the epiglottis and the close
approximation of the soft palate to the tongue and epiglottis in
neonates may be a reason why mouth breathing is more difficult
than nasal breathing.136 When the nasal airway is occluded, some

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infants, especially during REM sleep, do not respond sufficiently
to initiate adequate mouth breathing and OSA ensues. In infants,
insertion of a nasogastric tube significantly increases total
resistance by as much as 50% and may compromise breathing.137
If the upper airway is narrowed by either compression, increased
wall thickness (inflammation), or luminal obstruction (secretions),or their combinations, the resultant increase in Raw would
be far greater in infants than in adults. Life-threatening upper
airway obstruction, such as croup (laryngotracheobronchitis)
and epiglottitis (supraglottitis), are seen almost exclusively in
infants.

Lower Raw
Between the trachea and the alveolar duct, there are an average of
23 airway generations138 (Figure 914). As gas molecules move
from the trachea toward the terminal airways during inspiration,
the radius of the successive generations of airways becomes
smaller and, therefore, the resistance to flow is expected to
increase. In reality, however, the total cross-sectional area of the
airway segments increases dramatically toward the periphery,
although the diameter of successive single airways decreases.
This is because the number of airways increases markedly
and, consequently, the resistance to flow of the airways decreases
toward the periphery138 (see Figure 914). Indeed, using a retrograde catheter technique, Macklem and Mead demonstrated that
the peripheral airways, less than about 1 mm in diameter (around
the 14th generation), contribute less than 10% of the lower Raw or
3% of the total Raw.139
On the basis of physiologic studies of the lungs using the
retrograde technique at autopsy, Hogg and colleagues reported
that peripheral airways in children younger than 6 years of age

Respiratory Physiology 121

were disproportionately small and Raw high, compared with


adults.140 They postulated that the diameters of peripheral airways of the same generation were disproportionately smaller
in infants than in older children and adults. However, Motoyama has demonstrated in healthy infants and children under
general anesthesia that the conductance of the upstream segment,
normalized for lung volume, is disproportionately high (parenchymal Raw, low) in infants and decreases with age.21 This study,
based on the measurements of maximum expiratory flow-volume
curves, indicated that lower Raw toward the periphery of the lung
parenchyma is relatively lower in infants during the early postnatal
years than in adults. A later study in children has also confirmed
these findings.141

Tissue Viscoelastic Resistance


It has been assumed for a long time that the majority of the forces
necessary to overcome the total respiratory system resistance
during breathing were expended by airway (frictional) resistance.
The pressure needed to overcome tissue viscous resistance during
inspiration was estimated to be about 35% in adults and 28% in
children.19 However, studies since the mid-1980s on mechanical
ventilation, in both animals and humans, have indicated that
viscoelastic resistance, or the energy required to counter the lung
and chest wall tissues hysteresis or viscoelasticity, contributed a
significantly greater proportion of the total resistance than
previously assumed.142 Furthermore, flow and volume dependence
of viscoelastic resistance (Rvis or R) behaves very differently and
is opposite that of flow resistance. Raw increases with increasing
flow because of higher turbulence, whereas Raw decreases with
increasing lung volume because airway caliber also increases with
volume. The traditional view has been that the total resistance

Figure 9-14. A: Diagrammatic representation of the sequence of elements in the conductive, transitory, and respiratory zones
of the airways. AD = alveolar ducts; AS = alveolar sacs; BL = bronchioles; BR = bronchi; RBL = respiratory bronchioles; T = terminal generation; TBL = terminal bronchioles; z = order of generation of branching. B: Total airway cross-sectional area, A(z),
in each generation, z. A and B: From reference 138, with permission.

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Figure 9-15. Flow and volume dependence


of respiratory system resistance (Rrs) and its
subdivisions, resistive component (Rint or airway
resistance [Raw]) and viscoelastic component
(
Rrs) (Rrs = Rint + Rrs). IA: Average relationship of Rrs and Rint with increasing inspiratory
flow at a constant inspiratory volume (0.47 L)
in 16 anesthetized and paralyzed adult subjects.
IB: Similar relationship between Rrs with variable inspiratory flow. IIA: Average relationship
of Rrs and Rint with variable inspiratory volume
at a constant inspiratory flow (0.56 L/s1) in same
subjects as IA. IIB: Similar relationship in terms
of Rrs. Bars, 1 standard deviation (sd). Modified
from D'Angelo E, Calderini G, Torri F, et al.
Respiratory mechanics in anesthetized paralyzed
humans: effects of flow, volume, and time. J Appl
Physiol. 1989;67:255664.

followed the same direction of flow and volume dependence.


Paradoxically, Rvis decreases with increasing flow while the volume
is kept constant, and while the flow rate is kept constant, Rvis
increases with increasing lung volume143 (Figure 915). Furthermore, the direction of changes in total resistance followed that
of Rvis, but not Raw. A study in anesthetized and ventilated children
has shown the same flow and volume dependence of Rvis as in
adults; that is, opposite the direction of changes in Raw122,144 (Figure
916). This new evidence on the behavior of Rvis has important
clinical implications. Traditionally, the patient with airway
obstruction has been treated with large VTs and a slow respiratory
rate, to allow complete exhalation in order to avoid PEEPi and air
trapping. With the new understanding, it makes more sense to
breathe with smaller VT and higher respiratory rate in order to
minimize both Rvis and total respiratory system resistance and
decrease the work of breathing.145

markedly in patients breathing through an ET tube under general


anesthesia.

Time Constant of the Respiratory System

In awake adults, FRC is maintained with the rigid thorax and


sustained inspiratory muscle tone throughout the respiratory
cycle. Sustained inspiratory muscle tone is especially important in
infants because of the extremely compliant cartilaginous thoracic
cage with poorly developed thoracic muscles. Turning from the
upright to the supine position alone reduces FRC about 10% of
TLC (0.70.8 L in adults) even in awake individuals. Anesthesia
with or without muscle paralysis reduces FRC further by abolishing the inspiratory muscle tone (the diaphragm and intercostals). FRC under general anesthesia (called relaxation volume,
VR) is decreased 9 to 25% in healthy young adults, bringing FRC
closer to the level of RV in the awake state.127,128 In older patients,
the average reduction in FRC was reported to be greater (30%),
probably because of decreased elastic recoil of the lung and airway
closure.148
The effect of general anesthesia on FRC is more pronounced
in infants and young children because of their thorax is more

When the lung is allowed to empty passively from end-inspiration


to FRC, the speed of lung deflation is determined by the product
of respiratory system resistance and compliance (R C or R/E),
which is a unit of time (time constant, ). If the respiratory system
is considered as a single compartment with a constant resistance
and compliance within the VT range of breathing (which is a
reasonable assumption in healthy individuals):
= RC
Under these conditions, the volume-time profile can be
represented by an exponential decay and at 1 time constant (1 ),
VT is reduced by 63%. In healthy children and adults, is 0.4 to 0.5
s, whereas it is considerably shorter in neonates (0.20.3 s).19 In
patients with obstructive lung disease, such as bronchial asthma,
is increased because of an increase in Raw. It is also increased

Effects of Anesthesia on Respiratory Mechanics


General anesthesia significantly affects respiratory mechanics
and alters pulmonary gas exchange. The single most important
mechanism causing a cascade of changes in respiratory mechanics
in anesthetized infants and children appears to be the relaxation of
inspiratory muscles by anesthetics. This muscle relaxation, in turn,
results in a reduction in FRC, cephalad displacement of the
diaphragm, airway closure and atelectasis of dependent lung segmen