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SAUNDERS
An Imprint of Elsevier Science
The Curtis Center
Independence Square West
Philadelphia, PA 19106

ASSISTED VENTILATION OF THE NEONATE 0-7216-9296-6


Copyright © 2003, Elsevier, Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including
photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher.
Permissions may be sought directly from Elsevier’s Health Sciences Rights Department in Philadelphia, PA, USA: phone
(+1) 215 238 7869, fax: (+1) 215 238 2239, e-mail: [email protected]. You may also complete your request
on-line via the Elsevier Science homepage (http://www.elsevier.com), by selecting ‘Customer Support’ and then ‘Obtaining
Permissions’.

NOTICE

Medical Assisting is an ever-changing field. Standard safety precautions must be followed, but as new
research and clinical experience broaden our knowledge, changes in treatment and drug therapy may
become necessary or appropriate. Readers are advised to check the most current product information
provided by the manufacturer of each drug to be administered to verify the recommended dose, the method
and duration of administration, and contraindications. It is the responsibility of the treating physician,
relying on experience and knowledge of the patient, to determine dosages and the best treatment for each
individual patient. Neither the Publisher nor the author assume any liability for any injury and/or damage
to persons or property arising from this publication.

Previous editions copyrighted 1996, 1988, 1981

Library of Congress Cataloging-in-Publication Data

Assisted ventilation of the neonate / [edited by] Jay P. Goldsmith, Edward H. Karotkin.–
4th ed.
p. ; cm.
Includes index.
ISBN 0-7216-9296-6
1. respiratory therapy for newborn infants. 2. Artificial respiration. I. Goldsmith, Jay P.
II. Karotkin, Edward H.
[DNLM: 1. Infant, Newborn, Diseases—therapy. 2. Respiration,
Artificial–methods—Infant, Newborn. WS 420 A848 2003
RJ312.A87 2003
615.8’36’0832–DC21 2003041523

Acquisitions Editor: Judith Fletcher


Development Director: Lynne Gery
Production Manager: Mary Stermel

Printed in the United States of America

Last digit is the print number: 9 8 7 6 5 4 3 2 1


DEDICATION

To all babies and their heroic families who have consented to participate in randomized controlled
trials of various drugs, therapies and devices, not knowing if they were assigned to the control or treatment
group, and whose contributions have brought us in great measure to our present art of practice and paved
the way for the care of infants in the future.
JPG
EHK
CONTRIBUTORS

STEVEN H. ABMAN, MD JUDD BOLOKER, MD


Professor, Department of Pediatrics, University of Colorado Children’s Hospital at Oakland,
School of Medicine; Director, Pediatric Heart Oakland, California
and Lung Center, The Children’s Hospital, Denver, Colorado Blood Gases: Technical Aspects and Interpretation
Special Ventilatory Techniques and Modalities III:
Inhaled Nitric Oxide Therapy DAVID J. BURCHFIELD, MD
Professor of Pediatrics and Physiology, Pediatrics
NAMASIVAYAM AMBALAVANAN, MD, MBBS Department, University of Florida, Gainesville, Florida
Assistant Professor, Department of Pediatrics, Division of Pharmacologic Adjuncts I
Neonatology, University of Alabama at Birmingham,
Birmingham, Alabama WALLY CARLO, MD
Ventilatory Strategies Edward M. Dixon Professor of Pediatrics
and Director, Division of Neonatology,
ROBERT MASON ARENSMAN, MD Department of Pediatrics, University of Alabama
Professor of Surgery in Pediatrics, Northwestern University; at Birmingham, Birmingham, Alabama
Chief, Pediatric Surgery, Children’s Memorial Hospital, Ventilatory Strategies
Chicago, Illinois
Extracorporeal Membrane Oxygenation GERALYNN M. CASSERLY, RRT
Surgical Management of the Airway Neonatal Critical Care Respiratory Therapist,
Respiratory Therapy Department,
W. THOMAS BASS, MD Evanston Hospital,
Associate Professor of Pediatrics, Eastern Virginia Medical Evanston, Illinois
School; Neonatologist, Pediatrics Department, Children’s Pulmonary Care
Hospital of The King’s Daughters, Norfolk, Virginia
Central Nervous System Morbidity STEVEN M. DONN, MD
Professor, Pediatrics and Communicable Diseases,
MICHAEL A. BECKER , AS, RRT University of Michigan Health System; Director,
Respiratory Care Clinical Specialist, Holden Neonatal Division of Neonatal-Perinatal Medicine,
Intensive Care Unit, Critical Care Support Services C.S. Mott Children’s Hospital, Ann Arbor, Michigan
Department, C.S. Mott Children’s Hospital/Holden Volume-Controlled Ventilation
Hospital/University of Michigan Medical Center, Ann Arbor, Special Ventilatory Techniques and Modalities I:
Michigan Patient-Triggered Ventilation
Special Ventilatory Techniques and Modalities I:
Patient-Triggered Ventilation DAVID J. DURAND, MD
Division of Neonatology, Children’s Hospital and Research
ROBERT C. BECKERMAN, MD Center of Oakland, Oakland, California
Professor of Pediatrics and Physiology and Chief, Pediatric Blood Gases: Technical Aspects and Interpretation
Pulmonology, Tulane University School of Medicine and
Tulane University Hospital for Children, New Orleans, MOHAMMAD A. EMRAN, MD
Louisiana; Medical Director, Sudden Infant Death Syndrome Surgery Department, University of Illinois Metropolitan
(SIDS) Program, State of Louisiana Group Hospitals Residency in General Surgery, Chicago,
Control of Ventilation and Apnea Illinois
Surgical Management of the Airway
EDWARD F. BELL, MD
Professor of Pediatrics, University of Iowa; Director of WILLIAM W. FOX, MD
Neonatology, Children’s Hospital of Iowa, Iowa City, Iowa Professor of Pediatrics, Division of Neonatology,
Nutritional Support University of Pennsylvania School of Medicine;
Children’s Hospital of Philadelphia, Philadelphia,
VINOD K. BHUTANI, MD, FAAP Pennsylvania
Professor, Department of Pediatrics, University of Positive-Pressure Ventilation: Pressure-Limited
Pennsylvania; Pediatrician, Pennsylvania Hospital, and Time-Cycled Ventilation
Philadelphia, Pennsylvania Special Ventilatory Techniques II: Lung Protective
Pulmonary Function and Graphics Strategies and Liquid Ventilation

vi
CONTRIBUTORS vii

MARK E. GERBER, MD BRYAN S. KING, MD


Assistant Professor of Surgery, The Feinberg Instructor in Anaesthesia, Harvard Medical School;
School of Medicine, Northwestern University, Assistant in Anaesthesia, Massachusetts General Hospital,
Chicago, Illinois Boston, Massachusetts
Surgical Management of the Airway Intraoperative Management

HARLEY G. GINSBERG, MD JOHN KINSELLA, MD


Section Head, Section of Neonatology, Professor of Pediatrics, University of Colorado School of
Ochsner Clinic Foundation, New Orleans, Louisiana Medicine; Medical Director, ECMO Service and Emergency
Cardiovascular Aspects Medical Transport Service, The Children’s Hospital, Denver,
Colorado
JAY P. GOLDSMITH, MD Special Ventilatory Techniques and Modalities III:
Clinical Professor, Department of Pediatrics, Inhaled Nitric Oxide Therapy
Tulane University School of Medicine;
Former Chairman, Department of Pediatrics, ARTHUR E. KOPELMAN, MD
and Co-Director of Nurseries, Ochsner Clinic Professor of Pediatrics/Neonatology, Pediatrics Department,
and Foundation Hospital, New Orleans, Brody School of Medicine at East Carolina University;
Louisiana Attending Neonatologist, Pediatrics Department, Pitt County
Introduction to Assisted Ventilation Memorial Hospital, Greenville, North Carolina
Resuscitation Central Nervous System Morbidity
Ventilatory Management Casebooks
SHELDON B. KORONES, MD
JAY S. GREENSPAN, MD Alumni Distinguished Service Professor of Pediatrics
Professor and Vice Chairman, Director of Neonatology, and Obstetrics and Gynecology, the University of Tennessee
Department of Pediatrics, Thomas Jefferson University, health Science Center; Director, Newborn Center, Pediatrics
A.I. duPont Hospital for Children, Wilmington, Delaware Department, Regional Medical Center at Memphis, Memphis,
Positive-Pressure Ventilation: Pressure-Limited Tennessee
and Time-Cycled Ventilation Complications
Special Ventilatory Techniques II: Lung Protective
Strategies and Liquid Ventilation FAWN C. LEWIS, MD
Clinical Instructor in Surgery, Department of Surgery,
JOSEPH HAGEMAN, MD Pediatric Surgery, Northwestern University Medical School;
Associate Professor of Pediatrics, Feinberg School Attending Physician, Pediatric Surgery Critical Care
of Medicine, Northwestern University; Medical Director Department, Children’s Memorial Hospital, Chicago, Illinois
of Inpatient Pediatrics, Department of Pediatrics, Extracorporeal Membrane Oxygenation
Evanston Hospital, Evanston, Illinois and Children’s
Memorial Hospital, Chicago, Illinois VICTOR W. LUCAS, JR., MD
Pulmonary Care Pediatric Cardiologist, Department of Pediatrics, Ochsner
Clinic Foundation, New Orleans, Louisiana
HARRIET HAWKINS, RN, CCRN Cardiovascular Aspects
Resuscitation Education Coordinator,
Clinical Education Department, CAROLYN HOUSKA LUND, RN, MS, FAAN
Children’s Memorial Hospital, Assistant Clinical Professor, Department of Family Health
Chicago, Illinois Care Nursing, University of California, San Francisco, San
Pulmonary Care Francisco, California; Neonatal Clinical Nurse Specialist,
Intensive Care Nursery, Children’s Hospital Oakland,
M. GARY KARLOWICZ, MD Oakland, California
Professor of Pediatrics, Eastern Virginia Medical School; Nursing Care
Children’s Hospital of The King’s Daughters, Norfolk,
Virginia MARK C. MAMMEL, MD
Resuscitation Professor of Pediatrics, University of Minnesota,
Minneapolis, Minnesota; Director, Newborn Research
EDWARD H. KAROTKIN, MD and Education, Neonatology Department,
Professor of Pediatrics, Eastern Virginia Medical School; Children’s Hospital—St. Paul, St. Paul, Minnesota
Medical Director, Neonatal-Perinatal Outreach High-Frequency Ventilation
Center of Virginia and North Carolina;
Community Outreach Medical Coordinator, GERALD B. MERENSTEIN, MD
Children’s Hospital of The King’s Daughters, Professor of Pediatrics and Senior Associate Dean,
Norfolk, Virginia Education, University of Colorado School of Medicine,
Introduction to Assisted Ventilation Aurora, Colorado
Resuscitation Transport of Ventilated Infants
viii CONTRIBUTORS

JAY M. MILSTEIN, MD THOMAS SHAFFER, III, PhD


Department of Pediatrics, University of Professor Emeritus of Physiology and Pediatrics
California-Davis, Davis, California and Director, Physiology Research Section,
Pharmacologic Adjuncts I Temple University School of Medicine;
Professor of Pediatrics, Thomas Jefferson University,
CHERYL MARCO NAULTY, MD Philadelphia, Pennsylvania; Associate Director of Biomedical
Associate Professor, Department of Pediatrics, Research and Director, Office of Technology Transfer,
Uniformed Services University of the Health Sciences, and Director, Nemours Research Lung Center,
Bethesda, Maryland; Medical Director, Exceptional Family A. I. duPont Hospital for Children, Wilmington,
Member Program, Department of Pediatrics, Walter Reed Delaware
Army Medical Center and North Atlantic Regional Medical Special Ventilatory Techniques II: Lung Protective
Command, Washington, DC Strategies and Liquid Ventilation
Pulmonary Outcome and Follow-Up
NARONG SIMAKAJORNBOON, MD
JOHN J. PARIS, SJ, PhD Assistant Professor of Pediatrics, Tulane University School
Walsh Professor of Bioethics, Department of Theology, of Medicine; Medical Director, Comprehensive Sleep
Boston College, Waltham, Massachusetts Medicine Center, Tulane University Hospital and Clinics,
Ethical and Legal Issues in Assisted Ventilation New Orleans, Louisiana
of Newborns Control of Ventilation and Apnea

GARY PETTETT, MD SUNIL K. SINHA, MD, PhD, FRCP, FRCPCH


Chair, Institutional Review Board and Director, Professor, School for Health, University of Durham,
Truman Medical Center Nurseries, United Kingdom; Consultant Paediatrician
Department of Neonatology, and Neonatologist, The James Cook University Hospital,
Children’s Mercy Hospital and Clinics, Middlesbrough, United Kingdom
Kansas City, Missouri Volume-Controlled Ventilation
Transport of Ventilated Infants
EMIDIO SIVIERI, MS
BARRY PHILLIPS, MD Biomedical Engineer, Section on Newborn Pediatrics,
Medical Director, Neonatal Intensive Care Unit, Pennsylvania Hospital, University of Pennsylvania
Children’s Hospital at Oakland, Oakland, California School of Medicine, Philadelphia, Pennsylvania
Blood Gases: Technical Aspects and Interpretation
KAREN SLOTARSKI, RRT
FRANK E. REARDON, JD, MPh Neonatal Critical Care Respiratory Therapist,
Partner, Hassan & Reardon, P.C., Boston, Massachusetts Respiratory Therapy Department, Evanston Hospital,
Ethical and Legal Issues in Assisted Ventilation Evanston, Illinois
of Newborns Pulmonary Care

MARLETA REYNOLDS, MD ROGER F. SOLL, MD


Professor of Surgery, Department of Pediatric Surgery, Professor of Pediatrics, University of Vermont College
Northwestern University Medical School; of Medicine, Burlington, Vermont
Attending Physician, Department of Pediatric Surgery, Pharmacological Adjuncts II: Exogenous Surfactants
Children’s Memorial Hospital, Chicago, Illinois
Extracorporeal Membrane Oxygenation ALAN R. SPITZER, MD
Professor of Pediatrics, State University of New York
THERESA P. ROCA, MD at Stony Brook; Chief, Division of Neonatology
Pediatric Cardiologist, The Heart Group, Mobile, Alabama and NICU Director, Department of Pediatrics,
Ventilatory Management Casebooks Stony Brook University Hospital, Stony Brook,
New York
ROBERT L. SCHELONKA, MD Positive-Pressure Ventilation: Pressure-Limited
Assistant Professor of Pediatrics, University of Alabama and Time-Cycled Ventilation
at Birmingham, Birmingham, Alabama Special Ventilatory Techniques II: Lung Protective
Ventilatory Strategies Strategies and Liquid Ventilation

MICHAEL D. SCHREIBER, MD PINCHI SRINIVASAN, MD


Associate Professor, Department of Pediatrics, Department of Pediatrics, Wyckoff Heights
University of Chicago, Chicago, Illinois Medical Center, Brooklyn,
Ethical and Legal Issues in Assisted Ventilation New York
of Newborns Continuous Positive Airway Pressure
CONTRIBUTORS ix

GAUTHAM K. SURESH, MD, DM, MS THOMAS E. WISWELL, MD


Assistant Professor, Neonatal Division, Professor of Pediatrics, State University of New York
Pediatrics Department, University of Vermont College at Stony Brook; Director of Neonatal Research,
of Medicine, Burlington, Vermont Stony Brook University Hospital, Stony Brook, New York
Pharmacological Adjuncts II: Exogenous Surfactants Continuous Positive Airway Pressure

MICHAEL D. WEISS BRIAN R. WOOD, MD


Department of Pediatrics, University of Neonatologist, Department of Pediatrics/Neonatology,
Florida College of Medicine, Mission-St. Joseph’s Health System, Asheville,
Gainesville, Florida North Carolina
Pharmacologic Adjuncts I Physiologic Principles
FOREWORD

“. . . I, that am curtail’d of this fair proportion, sick full-term babies, science, or art, or both?1 In the past,
Cheated of feature by dissembling Nature, neonatologists believed that “EBM” meant expressed breast
Deform’d, unfinished, sent before my time milk. Today, we think of “evidence-based medicine.”
Into this breathing world, scarce half made up, We are realizing that there are certain limits to what we can
And that so lamely and unfashionable do. Embryonic, fetal, and postnatal lung development have
That dogs bark at me as I halt by them” been described anatomically and physiologically. We are able
to ventilate babies in the saccular phase of lung development.
—William Shakespeare, Richard III, I, I, 18 Can we, or should we, approach the canalicular stage with the
same fervor? Better understanding of gas exchange, the poten-
This passage from the opening soliloquy of Shakespeare’s tial to implant type II cells, and the development of new venti-
famous play depicts the type of patient that neonatologists deal lators and ventilation strategies may lead us to focus just on the
with every day. I can remember in 1967, as an intern in the respiratory system and not the total baby. We no longer
“sick nursery,” staring at the long green tubing (often several describe a “neonatal team.” It is now the “multidisciplinary
feet) connecting a baby to a ventilator. Neonatology was in its health provider team.” The concept of family-oriented care has
infancy. Therapies were anecdotal and untested. It seemed as if reduced the sterility of the neonatal intensive care unit and has
there were no limits to the future of neonatal care. stimulated family interaction. Caring intensively and intensely
This is the fourth edition of Assisted Ventilation of the has softened the beeps and flashing lights of the newest tech-
Neonate. Many of the chapters retain the same titles but are nological equipment. Ethical considerations focusing on prena-
expanded appropriately as our knowledge has increased. The tal consultation and resuscitation decisions have become as
expansion of cellular biology, genetics, infectious diseases, important as choosing an appropriate ventilator setting. The
pharmacology, nutrition, and pulmonary function has enabled adjunctive therapies that we use may ultimately affect morbid-
the “neonatal team” to save babies of lower gestational age. As ity as we save infants of lower gestational age.
new therapies have emerged, controversies have abounded. Jay Goldsmith, Edward Karotkin, and the many contributors
The use of sedation, the use and misuse of nitric oxide and to this fourth edition have remained abreast of current
postnatal steroids, and the employment of conventional versus approaches to ventilatory care of the newborn. Understanding
nonconventional ventilatory strategies are only a few of the that “just because we can does not mean that we should” has
hot topics that have been discussed. Is ventilatory management, led to a more global approach to neonatal intensive care. These
which is essential to the survival of premature infants and physicians are doing what they do best … taking care of babies.

Gilbert I. Martin, M.D.


Medical Director, NICU
Citrus Valley Medical Center
Clinical Professor of Pediatrics
The University of California (Irvine)
Emeritus Editor, The Journal of Perinatology
PEDIATRIX Medical Group

1. Mariani GL, Carlo WA. Ventilatory management in neonates. Science or art?


Clinic Perinat 1998; 25:33–48.

xi
PREFACE

For nearly four decades we have had a tool for treating The incidence of chronic lung disease subsequent to venti-
neonates with respiratory failure: ventilatory assist devices. At lation in the neonatal period has not decreased since the intro-
first, our goal was to improve survival, especially of the duction of exogenous surfactant in 1990. Strategies to decrease
severely immature baby with surfactant deficiency. Over the prematurity have not worked, and basic science research has
years, smaller and more immature-gestation infants were yet to identify the molecular mediators of lung injury and their
rescued; often, however, they were doomed to lead a life of potential therapies. But for the clinician at the bedside, the keys
handicap and hardship. In the early 1990s, we hit the wall—the to prevention of chronic lung disease are effective ventilatory
gestational age at which conventional gas exchange could not devices, strategies for ventilatory assistance, and support pro-
adequately occur because of the anatomic and physiologic tocols that will decrease barovolutrauma to the immature lung.
immaturity of the premature infant’s lung. Controversy exists Thus this text is no longer a “how-to” manual of the mechanics
as to where that line is: 22 to 24 weeks’ gestation, 400 to for utilizing ventilatory assistance and its supportive compo-
600 grams? Biologic variability allows that the line need not be nents. Survival is no longer the goal; survival without handicap
drawn too sharply, so that each baby can be evaluated individ- must be our new paradigm.
ually for viability and suitability for aggressive intervention. In In 1999, L. D. Hudson wrote that “…the concept of ventila-
the late 1990s the decades-long trend of improving outcomes tory induced lung injury (VILI) has come of age” (JAMA).
for babies of 500 to 1500-gram birth weight also leveled off. However, over 250 years earlier, Fothergill recognized the
In recent years, emphasis has shifted from pushing back the potential for VILI from mechanical assistance of lung function:
envelope of gestational age and birth weight viability to “Mouth to mouth resuscitation may be better than using a
improving functional outcomes of those babies who had the mechanical bellows to inflate the lung because … the lungs of
potential to be treated effectively. Despite anecdotal evidence one man may bear, without injury, as great as those of a man
of survival of the smallest and most immature babies without can exert, which by the bellows can not always be determined”
handicaps, most healthcare providers have been disturbed by (J Philos Trans Royal Society, 1745).
the high incidence of handicap in infants who have been Thus, the theme for this Fourth Edition has shifted from the
“saved” by our therapies. A large inter-institutional variance in “why” and “how” of neonatal ventilation to “how best” to
the incidence of the two most recognizable sequelae of our support the newborn’s respiratory system to achieve optimal
treatment regimes—chronic lung disease and central nervous outcomes without sustaining damage from the known sequelae
system injury—has led to an evidence-based search for the best of ventilatory devices. Perhaps the best treatment is no treat-
therapies and protocols. ment at all: that is, not to intervene when the infant is too
With particular reference to the topic of the text—assisted immature or has no reasonable chance of intact survival. Or if
ventilation—we continue to search for ways to ventilate intervention is chosen, to follow the “Columbia approach” of
infants without causing harm. We know that the vast majority respiratory assistance and attempt to not intubate or mechani-
of lung injury is manmade. However, until there are social, cally ventilate the infant. This is accomplished by early use of
molecular and technological solutions to prematurity and its nasal continuous positive airway pressure (CPAP), permissive
associated diseases, we must continue to use the tools we hypercapnia, and a variety of other strategies that are discussed
have, despite their potentially damaging side effects. In this in the text.
regard, the words of Dr. George Cassidy, writing in 1988 in the If ventilatory assistance is necessary and used in neonatal
Foreword to the second edition of this text, are worth repeat- intensive care units, the following principles (borrowed heavily
ing: “The managements and techniques described in this text from Evan Richards, RRT) should be followed.
are nearly all empiric. . . . Since the methods proposed are These are called the LOVE principles—the Laws Of
those used by the experts, one might assume that these are the Ventilatory Efficiency.
methods that work best. Not so. . . . Until we’ve had the oppor-
1. Know thy ventilator and disease pathology.
tunity to compare the ‘best therapies’ with each other, we’ll
2. Develop a specific strategy for the pathophysiology
continue to have uncertain truths to guide us. Awareness of
in each individual infant.
this uncertainty makes us better doctors.” Over the last fifteen
3. Change the ventilatory strategy as the pathophy-
years many of the “best therapies” have been evaluated and
siology changes.
compared with other forms of treatment. Evidence evaluation,
4. Always strive to wean the patient off of ventilatory
Cochrane meta-analysis reviews, and other studies in the field
assistance (i.e., have an exit strategy).
of neonatal pulmonary medicine have helped guide us to the
treatment modalities that we use today. However, many thera- This Fourth Edition of Assisted Ventilation of the Neonate
pies are still empiric, and the application of even “standard” attempts to follow these principles by offering the reader
therapies is so varied that inter-institutional outcomes are quite evidence-based recommendations and empiric opinions where
divergent. insufficient data exists. In this edition, all previous chapters

xiii
xiv PREFACE

have been updated to reflect the most recent data available. ments of these devices or drugs, and exclusion is not meant to
New chapters on ethical considerations, nitric oxide, and venti- be viewed as criticism.
latory strategies expand limited sections of previous editions. Over the four editions and 22-year span of this textbook, we
Eight ventilatory management casebooks comprise the last have seen our specialty grow and we have learned much about
chapter and reflect the same subjects that were presented in the our capabilities and limitations. We hope each successive
second edition (1988). However, the management of these edition has reflected that growth and a maturation of the prac-
common neonatal respiratory cases (drawn from actual clinical titioners in this very unique field of medicine. Our failures con-
files) has changed so dramatically in the last fifteen years as to tinue to frustrate us and the temptation to adopt new and
warrant a reprise. unproven therapies is great. However, we must continue to rely
While pathophysiology and pulmonary mechanics are dis- on evidence-based therapies and apply rigorous scientific prin-
cussed as integral to the mechanics of ventilatory assistance, ciples to our research. Hopefully, this book will stimulate you
the reader is referred to other textbooks for detailed descrip- and your colleagues to continue in that pursuit. As we wait for
tions of the pathologic conditions and the radiographic findings the solution(s) to prematurity, we should remember the wisdom
of neonatal pulmonary disorders that lead to respiratory failure. of an old editorial. “The tedious argument about the virtues of
As in previous editions, authors have used brand names respirators not invented over those readily available can be
and given representative examples of specific devices and ended now that it is abundantly clear that the success of
drugs when necessary to illustrate treatment protocols and such apparatus depends on the skill with which it is used”
approaches. However, these representations are not endorse- (Lancet 2:1227,1965).

J.P.G.
E.H.K.
1 INTRODUCTION TO ASSISTED
VENTILATION

J A Y P. G O L D S M I T H , M D
EDWARD H. KAROTKIN, MD

DEFINITION AND PURPOSE HISTORY

Dramatic reductions in both neonatal and infant mortality And he went up, and lay upon the child, and put his mouth
have occurred over the past 50 years. A variety of medical upon his mouth, and his eyes upon his eyes, and his hands upon
advances have been responsible for this improvement, includ- his hands; and he stretched himself upon the child and the flesh
ing better obstetric care, improved pharmacologic agents, waxed warm.
development of respiratory support devices, micromethods for II Kings 4:34
measuring a variety of parameters in the neonate, and use of
surfactant. This chapter presents an introduction to neonatal From the earliest recorded description of mouth-to-mouth
assisted ventilation for medical personnel involved in this area resuscitation in the Old Testament (one by Elijah, I Kings
of patient care. A brief overview of the history of neonatal 17:17, and another quoted in the preceding passage by Elisha),1
medicine hopefully provides the perspective to better appreci- we have been fascinated with the idea of sustaining respiration
ate the contributions neonatal assisted ventilation has made to by artificial means. The medical literature of the past several
the field of newborn care. thousand years contains many references to early attempts.
Assisted ventilation can be defined as the movement of Hippocrates (circa 400 BC) was the first investigator to record
gas into and out of the lung by an external source connected his experience with intubation of the trachea to support pul-
directly to the patient. The external source may be a resuscita- monary ventilation.2 His preliminary work was ignored for
tion bag, a continuous distending pressure device, or a mechan- almost 2000 years, until Paraclesus (1493–1541) reported the
ical ventilator. Attachment to the patient can be via a face mask, use of bellows and an oral tube in this endeavor.2
endotracheal tube, nasal prongs, or tracheostomy. Although
not in general use today in modern intensive care nurseries,
negative-pressure ventilation can be applied by an apparatus
The 16th and 17th Centuries
surrounding the infant’s thorax. The scientific renaissance in the 16th and 17th centuries
In the neonate, assisted ventilation is a measure for support- rekindled interest in the physiology of respiration and in tech-
ing pulmonary function until the patient can breathe adequately niques for tracheostomy and intubation. By 1667, simple forms
without help. In more recent years, with the increased survival of continuous and regular ventilation had been developed.2
of babies born at the lower limits of gestational age, infants are With these developments, the emergence of a better under-
requiring prolonged assisted ventilation for months and, in the standing of the basic physiology of pulmonary ventilation can
case of patients with severe chronic lung disease, years. The be seen.
purposes of mechanical ventilation are to facilitate alveolar
ventilation and carbon dioxide removal, provide adequate
The 19th Century
tissue oxygenation, and reduce the work of breathing. This is
accomplished through the use of a device that augments or In the early 1800s, interest in resuscitation and mechanical
replaces the bellows action of the respiratory musculature. ventilation of newborn infants flourished. In 1800, the first
Mechanical ventilation of the neonate is a complex and report describing nasotracheal intubation as an adjunct to
highly invasive procedure and must not be undertaken in a mechanical ventilation was published by Fine in Geneva.3 At
casual manner. Effective ventilation of the diseased lung about the same time, the principles for mechanical ventilation
requires that the clinician understand the normal pulmonary of adults were established; the rhythmic support of breathing
physiology, as well as the pathophysiology of pulmonary was accomplished with mechanical devices, and, on occasion,
diseases in the neonate. The clinician also must correlate the ventilatory support was carried out with tubes passed into the
type of therapy to the stage of pulmonary growth and develop- trachea.
ment and to the severity of the disease. In addition, he or she In 1806, Vide Chaussier, a professor of obstetrics in the
must understand the basic mechanical principles of the specific French Academy of Science, described his experiments with
ventilator in use. The beneficial effects of ventilatory therapy are the intubation and mouth-to-mouth resuscitation of asphyxi-
dependent on a strong knowledge of these subjects, skill, and ated and stillborn infants.4 The work of his successors led to the
experience in management, combined with constant vigilance development in 1879 of the aerophore pulmonaire (Fig. 1-1),
by medical, nursing, and respiratory personnel during treatment. the first device specifically designed for the resuscitation and
1
2 1 / INTRODUCTION TO ASSISTED VENTILATION

Figure 1-1. Aerophore pulmonaire of Gairal. (From DePaul. Dictionnaire


Encyclopédique, vol. XIII, 13th series.)

short-term ventilation of newborn infants.2 This device was a


simple rubber bulb connected to a tube. The tube was inserted
into the upper portion of the infant’s airway, and the bulb was
alternately compressed and released to produce inspiration and
passive expiration. Subsequent investigators refined these early
attempts by designing devices that were used to ventilate labo-
ratory animals.
Charles-Michel Billard (1800–1832) wrote one of the finest
medical texts dealing with clinical-pathologic correlations of
pulmonary diseases in newborn infants. Dr. Billard’s book,
Traite des Maladies des Enfants Nouveau-Nes et a la Mamelle,
was published in 1828.5 His concern for the fetus and intrauter-
ine injury is evident as he writes: “During intrauterine life man
often suffers many affectations, the fatal consequences of
which are brought with him into the world . . . children may be
born healthy, sick, convalescent, or entirely recovered from
former diseases.”5 His understanding of the difficulty newborns
may have in establishing normal respiration at delivery is well
illustrated in the following passage: “. . . the air sometimes
passes freely into the lungs at the period of birth, but the san- Figure 1-2. Fell-O’Dwyer apparatus for provision of intermittent positive-
pressure ventilation. (From Northrup. M & S Rep Presbyterian Hospital,
guineous congestion which occurs immediately expels it or New York, 1896.)
hinders it from penetrating in sufficient quantity to effect a
complete establishment of life. There exists, as is well known,
between the circulation and respiration, an intimate and recip- weight, temperature, and breast milk intake were plotted daily.
rocal relation, which is evident during life, but more particu- He also published survival data and established follow-up pro-
larly so at the time of birth. . . . The symptoms of pulmonary grams for his high-risk newborn patients.6 As a result of these
engorgement in an infant are, in general, very obscure, and con- initiatives, he may well be regarded as the “father of neonatol-
sequently difficult of observation; yet we may point out the fol- ogy.” (How ironic he was an obstetrician.)
lowing: the respiration is laboured; the thoracic parietes are not These advances were followed by the work of Dr. Ballantyne,
perfectly developed; the face is purple; the general color indi- an Edinburg obstetrician who emphasized the importance of pre-
cates a sanguineous plethora in all the organs; the cries are natal care and recognized that syphilis, malaria, typhoid, tuber-
obscure, painful and short; percussion yields a dull sound.”5 It culosis, and maternal ingestion of toxins such as alcohol and
seems remarkable that these astute observations were made opiates were detrimental to the development of the fetus.6
more than 170 years ago. Better understanding of pulmonary physiology led to further
The advances made in the understanding of the pulmonary refinements in ventilation. O’Dwyer7 reported the first success-
physiology of the newborn and the devices designed to support ful use of long-term positive-pressure ventilation in a large
a newborn’s respiration undoubtedly were stimulated by the series of children when he published the results of his studies in
interest shown in general newborn care that emerged in the 1887 (Fig. 1-2). Shortly thereafter, Egon Braun and Alexander
latter part of the 19th century and continued into the first part Graham Bell independently developed intermittent body-
of the 20th century.6 In France in 1880, Dr. Eteinne Tarnier, an enclosing devices for the negative-pressure/positive-pressure
obstetrician and leading figure in the European Infant Welfare resuscitation of newborns.8,9
Movement, appreciated the importance of keeping the prema-
ture infant warm and introduced a closed water-jacketed incu-
The 20th Century
bator. In 1884 he introduced and popularized gavage feedings
for the “debile” and “weakling.”6 A few years later, his col- In the early 20th century in the United States, three princi-
league Pierre Budin developed the principles of neonatal med- ples of public health emerged that led to further improvements
icine and stressed the importance of weekly physician in newborn survival. (1) Saving of infant lives is best achieved
examinations of the newborn, maternal education, and steril- by protection and education of mothers before and after preg-
ized milk. In 1892 Budin opened his “consultation for nancy. (2) Infant mortality rate is the best available index of the
nurslings.” The experience he gained in the care of premature overall health and welfare of a community. (3) Infant mortality
infants resulted in a book on the subject. Budin was the first to is related to multiple factors, and multiple interventions are
dignify the newborn with a separate hospital chart in which necessary to lower the rate.6
1 / INTRODUCTION TO ASSISTED VENTILATION 3

In the 1920s, obstetrics became a full-fledged surgical dis-


cipline and pediatricians assumed the care for all children. One
of Budin’s students, Courney, took advantage of the public
fascination with premature infants and displayed them at the
Chicago Exposition in 1914. A similar display featuring
warming incubators was a popular venue at the World’s Fair in
1939. Shortly thereafter, Dr. Julius Hess opened the first
Premature Center at the Michael Reese Hospital in Chicago
and other centers soon followed. Modern neonatology was
born with the recognition that premature infants required par-
ticular attention with regard to temperature control, administra-
tion of fluids and nutrition, and protection from infection. In the
1930s and 1940s premature infants were given new stature, and
it was acknowledged that their death was the greatest contribu-
tion to the infant mortality rate.6
The early years of the second half of the 20th century were
marked by soaring birth rates, the proliferation of labor and Figure 1-3. Commercial Plexiglas version of the positive-pressure oxygen
delivery services, antibiotics, positive-pressure resuscitators, air lock. Arrival of the unit at the Dansville Memorial Hospital, Dansville,
miniaturization of laboratory determinations, x-ray facilities, New York, June 1952. (Photo courtesy of James Gross and the Dansville
Breeze, June 26, 1952.)
and microtechnology that made intravenous therapy possible
for neonatal patients. These advances and a host of other
advances heralded the modern era of neonatal medicine. type negative-pressure ventilators of the Drinker design.16 The
Improvements in intermittent negative-pressure and positive- success of these machines with children encouraged physicians
pressure ventilation devices in the early 20th century led to the to try modifications on neonates, with some anecdotal success.
development of a variety of techniques and machines for sup- However, initial efforts to apply intermittent positive-pressure
porting ventilation in infants. In 1929, Drinker and Shaw10 ventilation (IPPV) to premature infants with respiratory dis-
reported the development of a technique for producing constant tress syndrome (RDS) were disappointing overall. Mortality
thoracic traction to effect an increase in end-expiratory lung was not demonstrably decreased, and the incidence of compli-
volume. In the early 1950s, Bloxsom11 reported the use of a cations—particularly that of pulmonary air leaks—seemed to
positive-pressure air lock (AL) for resuscitation of infants with increase.17 During this period, clinicians were hampered by the
respiratory distress in the delivery room.12 This device was types of ventilators that were available and by the techniques
similar to an iron lung; it alternately created positive and nega- for their use.
tive pressure in a tightly sealed cylindrical steel chamber that In accordance with the findings of Cournand et al. in adult
was infused with warmed humidified 60% oxygen. Clear plastic studies conducted in the late 1940s, standard ventilatory tech-
versions of the AL quickly became commercially available in nique often required that inspiratory positive-pressure times be
the United States in the early 1950s (Fig. 1-3). However, a study very short. Cournand et al. had demonstrated that prolongation
by Apgar and Kreiselman in 195312a on apneic dogs and another of the inspiratory phase of the ventilator cycle in patients with
study by Townsend in 150 premature infants12b demonstrated normal lung compliance could result in impairment of thoracic
that the device could not adequately support the apneic venous return, a decrease in cardiac output, and the unaccept-
newborn. The linkage of oxygen administration and retinopathy able depression of blood pressure. To minimize cardiovascular
of prematurity and a randomized controlled trial of the AL effects, they advocated that the inspiratory phase of a mechan-
versus care in an Isolette at Johns Hopkins University12c ical cycle be limited to one third of the entire cycle.18 Some
revealed no advantage to either study group and heralded the ventilators manufactured in this period even were designed
hasty decline in the use of Bloxsom’s device. with the inspiratory-to-expiratory ratio fixed at 1:2.
In the late 1950s, body-tilting devices were designed that Unfortunately, the findings of Cournand et al. were not
shifted the abdominal contents in order to create effective applicable to patients with significant pulmonary parenchymal
movements of the diaphragm. Phrenic nerve stimulation13 and disease and with reduced lung compliance, such as premature
the use of intragastric oxygen14 also were reported in the liter- infants with RDS. Neonates with pulmonary disease, which is
ature but had little clinical success. In the 1950s and early generally characterized by increased chest wall compliance and
1960s, many centers also used bag and face mask ventilation to terminal airway and alveolar collapse, did not generally
support infants for relatively long periods of time. respond to IPPV techniques that had worked well in adults and
The modern era of mechanical ventilation for infants can older children. Thus, clinicians were initially disappointed with
be dated back to the 1953 report of Donald and Lord,15 who the outcome of neonates treated with assisted ventilation using
described their experience with a patient-cycled, servocon- these techniques.
trolled respirator in the treatment of several newborn infants The birth of a premature son to President John F. Kennedy
with respiratory distress. They claimed that three or possibly and Jacqueline Kennedy on August 7, 1963, focused the world’s
four infants were successfully treated with their apparatus. attention on prematurity and the treatment of hyaline mem-
In the decades following Donald and Lord’s pioneering brane disease. Patrick Bouvier Kennedy was born by cesarean
efforts, the field of neonatal ventilation made dramatic section at 34 weeks’ gestation. He weighed 2.1 kg. He was
advances; however, the gains were accompanied by several transported from Cape Cod, Massachusetts, to Boston, where
temporary setbacks. Because of the epidemic of poliomyelitis he died at 39 hours of age (Fig. 1-4). The Kennedy baby was
in the 1950s, experience was gained with the use of the tank- treated with the most advanced therapy of the time, hyperbaric
4 1 / INTRODUCTION TO ASSISTED VENTILATION

Figure 1-4. Front page of The New York Times, August 8, 1963.
(Copyright © 1963 by The New York Times Co. Reprinted by permission.)

Figure 1-5. Ayre’s T-piece forms the mechanical basis of most neonatal
oxygen,19 but he died of progressive hypoxemia. In response to ventilators currently in use. A, Continuous gas flow from which an infant
his death, The New York Times reported: “About all that can be can breathe spontaneously. B, Occlusion of one end of the T-piece diverts
done for a victim of hyaline membrane disease is to monitor the gas flow under pressure into an infant’s lungs. The mechanical ventilator
infant’s blood chemistry and try to keep it near normal levels.” incorporates a pneumatically or electronically controlled time-cycling
mechanism to occlude the expiratory limb of patient circuit. Between
The Kennedy tragedy, followed only 3 months later by the sequential mechanical breaths, the infant can still breathe spontaneously.
President’s assassination, stimulated further interest and The combination of mechanical and spontaneous breaths is intermittent
research in neonatal respiratory diseases and resulted in mandatory ventilation. (From Kirby RR: Mechanical ventilation of the
increased federal funding in these areas. newborn. Perinatol Neonatol 5:47, 1981.)

Breakthroughs in Ventilation rebreathing of dead air. In 1971, a new prototype neonatal ven-
A breakthrough occurred in 1971 when Gregory et al.20 tilator was developed by Kirby and coworkers. This ventilator
reported on clinical trials with continuous positive airway pres- used continuous gas flow and a timing device to close the
sure (CPAP) for the treatment of RDS. Recognizing that the exhalation valve modeled after the Ayre’s T-piece used in
major physiologic problem in RDS was the collapse of alveoli anesthesia (Fig. 1-5).15,23,25 Using the T-piece concept, the ven-
during expiration, they applied positive pressure to the airway tilator provided continuous gas flow and allowed the patient to
via an endotracheal tube during both expiration and inspiration; breathe spontaneously. Occlusion of the distal end of the T-
dramatic improvement was achieved. Although infants receiv- piece diverted gas flow under pressure to the infant. In addi-
ing CPAP breathed spontaneously during the initial studies, tion, partial occlusion of the distal end generated CPAP. This
later combinations of IPPV and CPAP in infants weighing less combination of mechanical and spontaneous breathing under
than 1500 g were not as successful.20 Nonetheless, the concept continuous gas flow was called intermittent mandatory venti-
of CPAP was a major advance. It was later modified by lation (IMV).
Bancalari et al.21 for use in a constant distending negative- IMV became the standard method of neonatal ventilation
pressure chest cuirass and by Kattwinkel et al.,22 who devel- and has been incorporated into all infant ventilators. One of its
oped nasal prongs for the application of CPAP without the use advantages was the facilitation of weaning by progressive
of an endotracheal tube. reduction in IMV rate, which allowed the patient to gradually
Meanwhile, Reynolds and Taghizadeh,23,24 working inde- increase spontaneous breathing against distending pressure.
pendently in Great Britain, also recognized the unique patho- Clinicians no longer needed to paralyze or hyperventilate
physiology of neonatal pulmonary disease. Having experienced patients to prevent their “fighting the ventilator.” Moreover,
difficulties with IPPV similar to those noted by clinicians in the because patients continued to breathe spontaneously and lower
United States, Reynolds and Taghizadeh suggested prolonga- cycling rates were used, mean intrapleural pressure was
tion of the inspiratory phase by delaying the opening of the reduced and venous return was less compromised than with
exhalation valve. This “reversal” of the standard inspiratory-to- IPPV.26
expiratory ratio, or “inflation hold,” allowed sufficient time for From 1971 to 1995, myriad new ventilators specifically
the recruitment of atelectatic alveoli with lower inflating pres- designed for neonates were manufactured and sold. The first
sures and gas flows, which, in turn, decreased turbulence and generation of ventilators included the BABYbird I; the Bournes
limited the effect on venous return. The excellent results of BP 200; and a volume ventilator, the Bournes LS 104/150. All
Reynolds and Taghizadeh could not be duplicated uniformly in operated on the IMV principle and were capable of incorporat-
the United States, perhaps because their American colleagues ing CPAP into the respiratory cycle [known as positive end-
used different ventilators. expiratory pressure (PEEP) when used with IMV].27
Until the early 1970s, ventilators used in neonatal intensive The BABYbird I and the Bournes BP 200 used a solenoid-
care units (NICUs) were modifications of adult devices; these activated switch to occlude the exhalation limb of the gas
devices delivered intermittent gas flows, thus generating circuit in order to deliver a breath. Pneumatic adjustments in
IPPV. The ventilator initiated every mechanical breath, and the inspiratory-to-expiratory ratio and rate were controlled by
clinicians tried to eliminate the infants’ attempts to breathe inspiratory and expiratory times, which had to be timed with a
between IPPV breaths (“fighting the ventilator”), which led to stopwatch. A spring-loaded pressure manometer monitored
1 / INTRODUCTION TO ASSISTED VENTILATION 5

peak inspiratory pressure and PEEP. These early mechanics originally developed for use in premature infants with RDS,
created time delays within the ventilator, resulting in problems exogenous surfactant therapy has been proposed for patients
in obtaining short inspiratory times (<0.5 second). with other diseases (e.g., meconium aspiration syndrome, pneu-
In the next generation of neonatal ventilators, the incor- monia) that cause neonatal respiratory failure.34 Unresolved
poration of electronic controls, microprocessors, and micro- questions remain regarding the best formulation of surfactant,
circuitry allowed the addition of light-emitting diode (LED) timing of administration (prophylactic vs rescue), number of
monitors and provided clinicians with faster response times, doses needed, technique of administration, and quantity to be
greater sensitivity, and a wider range of ventilator parameter administered. Nonetheless, it was obvious that a new era of
selection. These advances were incorporated into ventilators treatment of neonatal pulmonary disease had arrived. The bio-
such as the Sechrist 100 and Bear Cub to decrease inspiratory chemistry and physiology of surfactant and surfactant replace-
times to as short as 0.1 second and to increase ventilatory rates ment therapy are discussed in detail in Chapter 20.
to 150 breaths per minute. Monitors incorporating micro- Assisted ventilation represents the hallmark of neonatal
processors measured inspiratory and expiratory times and intensive care. Improvements in devices, the appearance of
calculated inspiratory-to-expiratory ratios and mean airway new techniques and better support systems, and the develop-
pressure. Ventilator strategies abounded, and controversy ment of exogenous surfactant and other pharmacologic agents
regarding the best (i.e., least harmful) method for assisting all have contributed to improving weight-specific survival rates
neonatal ventilation arose. High-frequency positive-pressure for infants with neonatal respiratory failure. A report in the
ventilation with the use of conventional ventilators was pro- mid 1970s of all neonates ventilated from 1966 to 1969 proudly
posed as a beneficial treatment of RDS.28 announced a survival rate of 33%.35 A more recent study
Meanwhile, extracorporeal membrane oxygenation (ECMO) looking at the outcome of infants born in the United States in
and true high-frequency ventilation (HFV) were being devel- the 1990s reports survival rates of 0% to 21% for infants born
oped at a number of major medical centers.29,30 These tech- at 22 weeks’ gestation, 5% to 46% for infants born at 23 weeks’
niques initially were offered as rescue therapy for infants who gestation, 40% to 59% for infants born at 24 weeks’ gestation,
did not respond to conventional mechanical ventilation. The 60% to 82% for infants born at 25 weeks’ gestation, and 75%
favorable physiologic characteristics of HFV led some investi- to 93% for infants born at 26 weeks’ gestation.36 It is generally
gators to promote its use as an initial treatment of respiratory recognized that survival rates for infants born at 32 weeks’ ges-
failure, especially RDS.31 tation afforded modern neonatal intensive care are essentially
A third generation of neonatal ventilators began to appear in the same as those of infants born at term.
the early 1990s. Advances in microcircuitry and microproces- Unfortunately, complications associated with infants born at
sors, developed as a result of the space program, allowed new the lower extremes of viability (bronchopulmonary dysplasia,
dimensions in neonatal assisted ventilation. The use of syn- blindness, and neurodevelopmental disability) remain signi-
chronized IMV, assist/control mode ventilation, and pressure ficant. The data on the incidence of major disabilities are much
support ventilation—previously used in the ventilation of only more difficult to analyze, but it appears that the variation in
older children and adults—became possible in neonates reported disability rates varies more than survival rates for a
because of the very fast ventilatory response times. Although given gestational age.36 Approximately 75% of premature
problems with sensing a patient’s inspiratory effort sometimes infants who survive the neonatal period will be free of disabil-
limited the usefulness of these new modalities, the advances ity. However, between 20% and 25% of survivors will have at
gave hope that ventilator complications could be limited and least one major disability-impaired mental development, cere-
that the need for sedation or paralysis during ventilation could bral palsy, blindness, or deafness. The most common disability
be decreased. Direct measurement of some pulmonary func- is impaired mental development (17%–21%), followed by
tions at the bedside became a reality and allowed the clinician cerebral palsy (12%–15%); blindness and/or deafness affect
to make ventilatory adjustments based on physiologic data less than 8% of survivors. Studies examining surviving infants
rather than on a “hunch.” born weighing between 750 and 1000 g report that approxi-
mately another half will have one or more subtle neurodevel-
opmental disabilities that will become apparent later in
Surfactant Replacement Therapy childhood.36 In a recent publication, Horbar et al.37 report that
Perhaps the most important advance in treating RDS in the the significant advances in obstetric and neonatal care that
last 40 years was the development of surfactant replacement occurred during the early 1990s have been associated with
therapy. The discovery by Avery and Mead32 in 1959 that sur- decreased mortality and morbidity for very-low-birth-weight
factant deficiency was the critical factor in neonatal RDS was infants born during the first half of that decade. Unfortunately,
the first step in a tremendous 40-year research effort that this group concludes that since 1995 there have been no addi-
culminated in the licensing of two exogenous surfactant pre- tional improvements in mortality or morbidity and that neona-
parations in the United State in the early 1990s. (In 1990, the tal mortality and morbidity rates have reached a plateau. The
United States Food and Drug Administration approved exoge- survival rate of ventilated infants weighing between 1000 and
nous surfactant for general use, heralding a new era in the treat- 1249 g after surfactant therapy is greater than 90%.38 The sur-
ment of neonatal respiratory failure.) Surfactant replacement vival rate for similar infants weighing between 750 and 999 g
therapy has clearly been shown to improve lung function and is greater than 80%.38 These statistics represent considerable
mechanics in premature infants with RDS. Most studies have improvements in survival compared with those of the presur-
demonstrated decreased duration of assisted ventilation, lower factant era of the late 1980s.38 Unfortunately, increased sur-
fractions of inspired oxygen (FIO2), lower peak inflating pres- vival rates have not resulted in a corresponding improvement in
sures, and decreases in morbidity and mortality associated with long-term neurodevelopmental outcome, which has remained
its use in infants weighing from 600 to 1500 g.33 Although stable for the past 30 years.36
6 1 / INTRODUCTION TO ASSISTED VENTILATION

Most morbidity and mortality occur among infants with plement of pediatric subspecialists, and 24-hour-per-day,
birthweights less than 1000 g. In the infant weighing less than 7-day-per-week in-house coverage by staff physicians (i.e.,
750 g, surfactant may have a lesser effect because of the struc- neonatologists/hospitalists); pediatric house officers; and/or
tural immaturity of the pulmonary system. Liquid ventilation neonatal nurse practitioners.
with perfluorochemicals has been shown to improve oxygena- Thirty years ago the vast majority of neonatal intensive care
tion, promote lung expansion, and increase blood flow to the was provided in large teaching hospitals or large community
lung without systemic effects and with minimal barotrauma.39 hospitals. Today, sophisticated neonatal care is provided in
Although still in the experimental stage, this exciting new tech- many tertiary medical centers, as well as in many smaller hos-
nique has been touted as a future potential treatment of “micro- pitals that may not fulfill the expectations implied by Downes40
premies” who are at greatest risk for morbidity and mortality. in 1971. The proliferation of NICUs in hospitals with relatively
Certainly, the treatment of neonatal respiratory failure has small delivery services or limited ancillary services that
improved dramatically over the last three decades, and many provide care for infants with the most complex of conditions is
exciting developments are on the horizon. Better ventilators, a consequence of the “deregionalization of perinatal care.” This
improvement of surfactant formulation, and advances in moni- has necessitated the development and maintenance of neonatal
toring equipment can be expected in the coming years. The transport systems capable of transporting the “sickest” infants
goal of future care is the application of effective therapy to NICUs in which the full array of pediatric subspecialists,
without iatrogenic consequences. experienced NICU nurses, respiratory therapists, and labora-
In all probability, improvements in neonatal and infant mor- tory and diagnostic services is available to support these
tality will continue to occur with improved intensive care. patients.
However, further dramatic reductions in both neonatal and Concurrent with the tremendous advances in perinatal tech-
infant mortality and decreases in low-birthweight-associated nology, innovation, and knowledge and the movement of
morbidity will not occur until many of the societal and eco- neonatal services away from the larger medical centers to
nomic disparities in our society are rectified so that the dispro- smaller facilities (deregionalization), there is an attempt to pre-
portionately high number of low-birthweight infants born in serve the regionalized approach to prenatal care. A comprehen-
these disadvantaged, high-risk groups of pregnant women is sive report by the Committee on Perinatal Health41 and the
lowered. more recent publication of the March of Dimes, Toward
Improving the Outcome of Pregnancy: The 90s and Beyond,42
promote the concept of designating certain hospitals for the
care of high-risk newborns based on each hospital’s ability to
FIVE W’S OF ASSISTED VENTILATION provide a certain level of care. Such regionalization programs
were advanced under three assumptions: that the region-
Who: Which infants are candidates for ventilation? Who is alization of prenatal care (1) increased the availability of
an inappropriate candidate? What are the ethical and medical services; (2) decreased morbidity and mortality; and
legal considerations? (3) decreased costs. Hospitals were traditionally designated in
Where: Which hospital should undertake assisted ventilation terms of three levels of prenatal care.41
of the neonate? What equipment and personnel are
Level I: Hospitals that provide services primarily for
necessary? What is meant by regionalized perinatal care?
uncomplicated maternity and newborn patients.
When: When is a patient in respiratory failure? What are the
Level II: Large urban and suburban hospitals at which the
causes of inadequate ventilation?
majority of deliveries occur. Because they have a highly
Why: What are the neurologic and physical outcomes
trained staff and modern equipment, these facilities are
of babies who are ventilated? What are the financial
capable of treating most perinatal complications.
ramifications?
Level III: Hospitals that serve a delivery population of 8,000
What: What are the types and classifications of ventilators?
to 12,000 births annually and are capable of treating all
In the previous editions of Assisted Ventilation of the types of maternal-fetal and neonatal illnesses. A level III
Neonate, the questions Who and Why were briefly presented as hospital also is responsible for the education of medical
part of this section. In view of the amount of new literature and providers, transport of critically ill neonates or mothers,
information that has been written on these two topics, the and evaluation of the overall quality of perinatal care in
editors believe that they deserved to be covered in a separate its region. Typically level III centers are designated the
chapter on Ethical Considerations (Chapter 5). perinatal center for a region.
Therefore, the remaining three questions Where, When, and
In the past few years, some centers providing ECMO and/or
What are discussed in this chapter.
heart transplantation have adopted the term level IV centers or
regional level III centers. These centers have also been respon-
sible for continuing education of their region and, in some cases,
Where: Regionalization of Perinatal Care regionalized transport systems and quality assurance review.
The National Center for Health Statistics defines an NICU The American Academy of Pediatrics is now considering
as a “hospital facility or unit staffed and equipped to provide a subdivision of level III NICUs into A, B, C, and D. The
continuous mechanical ventilatory support for more than definitions proposed are as follows:
24 hours.” The complex techniques involved in the treatment of
respiratory failure of the newborn require an NICU staffed by Level IIIA
specially trained nurses; a geographically accessible full-time Hospital or state-mandated restriction on type and/or dura-
staff of physicians composed of neonatologists, the full com- tion of mechanical ventilation
1 / INTRODUCTION TO ASSISTED VENTILATION 7

Level IIIB sumer value. Using their purchasing power, the group hopes to
No restrictions on type or duration of mechanical ventilation encourage members to have half of their enrollees’ hospitaliza-
No major surgery (see below) tions in facilities that meet their criteria by December 31, 2004.
Level IIIC The tremendous growth in the number of NICUs in com-
Major surgery performed on site (e.g., omphalocele repair, munity hospitals has occurred for a number of reasons. The
tracheoesophageal fistula or esophageal atresia repair, growing number of neonatologists graduating from more than
bowel resection, myelomeningocele repair, ventricu- 100 fellowship training programs in the United States has
loperitoneal shunt, myelomeningocele closure) increased the availability of such physicians to community hos-
No surgical repair of serious congenital heart anomalies that pitals. Experience in some well-prepared and well-staffed com-
require cardiopulmonary bypass and/or ECMO munity hospitals has demonstrated results with ventilated
Level IIID babies that are similar to those reported by university centers.44
Major surgery Neonatal care is a highly visible activity that generates good
Surgical repair of serious congenital heart anomalies that public relations; thus, community hospitals, which operate in a
require cardiopulmonary bypass and/or ECMO for competitive environment, wish to demonstrate to their potential
medical conditions consumers that all services can be provided. Obstetricians not
wishing to transfer high-risk expectant mothers to other facili-
In some states such as Virginia, numerical designations, ties have put pressure on hospital administrators to hire neo-
which may be confusing or misleading, have been replaced by natologists at level II and community level III centers.45
more descriptive terminology: Moreover, if indigent patients are excluded (or at least limited),
NICUs can be highly profitable for individual hospitals and
General: Newborn service that provides care to low-risk
private practicing physicians.
newborns weighing at least 2000 g or who have com-
Medicolegal considerations have undoubtedly caused many
pleted 34 weeks of gestation.
obstetricians to demand hospital administrators provide deliv-
Intermediate level: Newborn service that provides care for
ery room coverage by neonatologists for cesarean sections or
moderately ill neonates or stable-growing, low-birth-
unexpected high-risk deliveries. However, in response to the
weight neonates. Intermediate nurseries have the ability
changing patterns of reimbursement that started in the 1990s,
to insert and maintain umbilical arterial catheters,
there may be a shift away from the concept of deregionalization
monitor blood gases, and care for infants in environments
because small hospitals that provide expensive neonatal care
of not more than 40% oxygen.
are finding it difficult to compete with larger institutions
Specialty level: Service that provides care for high-risk
because of low census and high staffing costs.
neonates who may require central and/or peripheral arte-
Providers in level I hospitals argue that if they transfer all
rial lines with constant pressure monitoring; insertion
sick newborns to level II and level III centers, they will lose the
and maintenance of chest tubes; and administration of
skills necessary for the management of neonatal respiratory
pressors, surfactant, support CPAP, and short-term venti-
emergencies.45 Moreover, on occasion, no beds are available at
lation.
the perinatal center or conditions preclude transport. Under
Subspecialty level: Service that provides care for high-risk,
such circumstances, the level I hospital must ventilate infants
critically ill neonates with complex neonatal illness. In-
until transport can be arranged. This dilemma does not have an
house neonatology is available constantly, with a full
easy solution, but the following basic principles may apply:
range of pediatric medical and surgical subspecialties
available. 1. All hospitals with delivery services should have resources to
intubate infants and maintain ventilation for up to 8 hours.
If these guidelines are applied, prolonged assisted ventila-
2. No infant should be more than 4 hours away from neonatal
tion should be limited to level III units B to D and subspecialty
intensive care with appropriate transport.
NICUs. However, for many reasons, a deregionalization of care
3. Every infant should have access to optimal respiratory care,
with a proliferation in the number of NICUs,43—all of which
regardless of financial or geographic considerations.
want to offer a full array of neonatal services, including
assisted ventilation—has been observed since the mid-1980s The skills necessary to successfully carry out prolonged
and has persisted into the new millennium. assisted ventilation cannot be learned easily, nor can they be
Recently, certain powerful chief executive officers from the maintained with limited numbers of ventilatory cases. All per-
largest companies in the United States have formed an advisory sonnel (physicians, nurses, and respiratory therapists) must be
group (Leapfrog Group) that, among other issues, has tried to extensively trained for all aspects of ventilatory assistance so
mobilize health care purchasers to reward improvements in that optimal outcome can be achieved.
patient safety and consumer value in health care. The Leapfrog Data collected in 1980 confirmed that hospitals ventilating
Evidence-Based Hospital Referral (EHR) standards were fewer than 50 babies per year demonstrated twice the mortality
developed after review of published outcomes research and of level III larger centers in the same area (all level III hospi-
consultation with experts on neonatal intensive care. Their tals at that time ventilated more than 50 babies per year). These
initial criteria would require that an infant less than 32 weeks’ data have been validated by more recent studies that docu-
gestation or with an expected birthweight of less than 1500 g, mented enhanced survival and fewer morbidities for infants
or who has a prenatal diagnosis of a major congenital anomaly, cared for in level III perinatal centers.46,47
be delivered at or transferred to a facility that is a regional The responsibility for improved pregnancy outcome rests
NICU maintaining an average daily census of 15 or more. with obstetricians, as well as with pediatricians. Responsible
Although controversial, the Leapfrog Group believes such prenatal health care professionals should encourage the transport
“regulation” would improve outcome, patient safety, and con- of a high-risk mother and her unborn fetus to a level III center
8 1 / INTRODUCTION TO ASSISTED VENTILATION

for the delivery and subsequent care of the neonate. Studies of skilled personnel. A person able to perform endotracheal
comparing very-low-birthweight infants (<1500 g) born outside intubation, chest tube placement, and cardiopulmonary resusci-
level III centers with those born in level III hospitals have shown tation must be in the hospital at all times.53 Complications such
shorter hospital stays,48 lower costs per survivor,48 and reduced as dislodgment of the endotracheal tube or pulmonary air leaks
morbidity and mortality49,50 for the inborn infants. These differ- occur suddenly, often without warning, and require immediate
ences are accentuated when patients require assisted ventilation. correction. Often, a patient cannot wait for a physician to be
Spitzer et al.51 evaluated out born and inborn infants with RDS summoned from the office or home. Assigning the responsibil-
and found that inborn infants had significantly lower mean ity for such emergencies to untrained or uncertified staff nurses,
maximal FIO2, decreased duration of required O2 administration, respiratory therapists, or inexperienced emergency room physi-
lower peak inspiratory pressure, and shorter duration of IPPV. cians is not justified at the present time, when more appropriate
The qualifications of personnel and types of equipment nec- resources are available.
essary to maintain infants on assisted ventilation are the sub- Further information regarding what personnel and equip-
jects of considerable discussion. Guidelines have been written ment requirements a hospital should satisfy if it is to provide a
and debated throughout the country. A modified rating system certain level of perinatal and neonatal care can be found in the
initially devised by Indyk and Cohen52 (Table 1-1) describes most recent editions of Toward Improving the Outcome of
some of the necessary qualifications of units that are to under- Pregnancy: The 90s and Beyond42 and Guidelines for Perinatal
take intensive care measures such as mechanical ventilation. A Care, Fifth Edition,54 published by The American College of
unit should score 25 points or better in this system if it is to be Obstetricians and Gynecologists and the American Academy of
considered adequately prepared to care for ventilated infants. Pediatrics in 2002.
Although in 2003 this rating system appears outdated, nonaca- Transport systems are equipped and staffed to be capable of
demic hospitals nonetheless should review the requirements stabilizing infants in referring hospitals and moving them to
before pursuing a course to establish a high-cost, high-intensity health care centers safely. Hospital, community, and physician
neonatal intensive care program. The most important aspect of pride or economic considerations should not prevent the provi-
prolonged ventilatory care, however, is the continuous presence sion of optimal care to all infants.

TABLE 1-1. Modified Indyk-Cohen (INCO) Rating System for Regional Newborn Units*

Category Two Points One Point No Points

Nursing ratio (patients:nurses 1:1 2:1 or 3:1 4:1 or less


for infants being ventilated)
Nursing education Full-time in-service coordinator; formal Infrequent formal courses given Apprentice system
courses given routinely
Director of unit Board-certified neonatologist with no Physician with other responsibilities Part-time director
other responsibilities
Respiratory care Respiratory therapist(s) assigned Respiratory therapist in hospital Less than full-time coverage
exclusively to unit at all times
Working relationship between 24-hr availability of immediate pediatric 24-hr availability of general Less than full-time coverage
neonatologist and surgeon surgical care surgeon
In-house personnel Physician or neonatal nurse practitioner Nurse or respiratory therapist No formal plan
responsibilities (gases, in unit on 24-hr basis. Can run for these functions
radiography, ventilation) ventilators, read radiographs,
interpret gases
Enthusiasm and awareness of Up-to-date, with studies ongoing Aware, not innovative; no No awareness or activity
new ideas research
Availability of monitoring Virtually unlimited, including capability One respiration and heart rate Fewer than one monitor
to perform pulse oximetry monitor per two patients; no per two patients
pulse oximetry
Availability of subspecialists 24-hr availability of all specialists Some subspecialists available No pediatric subspecialty
(e.g., pediatric neurologists, coverage
cardiologists)
Type of monitoring Respiration, heart, blood pressure, Lacking one type Lacking two or more types
equipment temperature, central venous pressure,
and oxygen saturation monitoring
Data collection and analysis Computer records, quality Some mechanism of statistical No collection and follow-up
improvement program collection
Laboratory services (blood gases) Available in the unit Available within 15 min at all times Available after 15 min
Radiography Radiography machine in unit; Quickly available from central Slow and infrequently used
radiography files easily accessible service
Facilities (O2, air suction, power, Everything available; adequate Lacking one utility or incomplete Use of extension cords,
air-O2 blender at each bed) emergency power power coverage, or both 3/2 adapters
Transport Send staff member(s) with a transporter Infant brought in No special neonatal
(two-way transport) unaccompanied (one-way transport scheme
transport)

* Units performing prolonged ventilation should have a score of >25 points.


Modified from Indyk L, Cohen S: Newborn intensive care in the United States: East and West. Clin Pediatr 10:320, 1971.
1 / INTRODUCTION TO ASSISTED VENTILATION 9

When: Causes of Respiratory Failure and TABLE 1-2. Causes of Respiratory Failure
Indications for Ventilation
Problem Area Possible Causes
Although there are many reasons for beginning assisted ven-
tilation in neonates, the most common is respiratory failure. In Pulmonary Respiratory distress syndrome
any infant, this condition may take one of two forms. The first is Aspiration syndromes
Pneumonia
apnea, a condition in which mechanical ventilation is necessary Pulmonary hemorrhage
because a patient does not breathe. If the lungs are normal, the Pulmonary alveolar proteinosis
cause most often is related to the control of respiration by the Wilson-Mikity syndrome
central nervous system. Potential causes include apnea of pre- Bronchopulmonary dysplasia
maturity, asphyxia, intracranial hemorrhage, and drug overdose. Pulmonary insufficiency of prematurity
Pneumothorax
In the second form of respiratory failure, the mechanism of Tumor
pulmonary gas exchange has been compromised. The cause Diaphragmatic hernia
most often is a primary lung disease or an airway disease (e.g., Chylothorax
RDS). In these instances, physiologic alterations in gas Congenital malformations (lobar emphysema,
cystic adenomatoid malformation,
exchange cause acidosis, hypercapnia, and hypoxemia. If organ lymphangiectasis)
damage or death is to be prevented, mechanical assistance is Airway Laryngomalacia
required. Choanal atresia
The classic constellation of findings in respiratory failure Pierre Robin syndrome
consists of an acute increase in the partial pressure of arterial Micrognathia
Nasopharyngeal tumor
carbon dioxide (PaCO2) and a decrease in pH. The presence of Subglottic stenosis
hypoxemia by itself does not indicate respiratory failure, as Abnormalities of Phrenic nerve palsy
illustrated by patients with cyanotic congenital heart disease. muscles of Spinal cord injury
Respiratory failure may be caused by the failure of organ respiration Myasthenia gravis
Werdnig-Hoffmann syndrome
systems other than the central nervous system and the lungs Central problems Apnea of prematurity
(Table 1-2). When the lungs are primarily responsible, however, Drugs: morphine, magnesium sulfate,
it is important to make a simplistic distinction between two mepivacaine, meperidine
physiologic types of lung disease: atelectatic disease and Seizures
obstructive disease (Table 1-3). Birth asphyxia
Hypoxic encephalopathy
An atelectatic disease is characterized by decreased lung Intracranial hemorrhage
volume and decreased functional residual capacity. Examples Ondine’s curse
are RDS and pneumonia. Increased lung volumes and Rapid eye movement sleep
increased functional residual capacity, as seen in aspiration Miscellaneous Congestive heart failure
Persistent fetal circulation
syndromes and bronchopulmonary dysplasia, characterize an Postoperative anesthesia/sedation
obstructive disease. In many pulmonary conditions, both types Tetanus neonatorum
of disease exist (e.g., RDS in combination with pulmonary air Extreme immaturity
leaks). Even though the physiologic distinction is not absolute, Shock
it may be important for the clinician to make such a distinction Sepsis
Hypoglycemia
before he or she addresses the criteria for the initiation of Electrolyte abnormalities
assisted ventilation, the choice of ventilator, or the parameters Acid-base imbalance
of ventilator control. Infant botulism
The physician can make a diagnosis of respiratory failure Hydrops fetalis
guided by both clinical manifestations and the results of blood

TABLE 1-3. Theoretical Classification of Neonatal Pulmonary Disorders

Atelectatic Obstructive

Example Respiratory distress syndrome Meconium aspiration syndrome


Physiology ↓ Lung volume ↑ Lung volume
↓ Compliance ↓ Compliance
↓ Functional residual capacity ↑ Functional residual capacity
Normal airway resistance ↑ Airway resistance
Normal time constant ↑ Time constant
Clinical appearance Severe retractions; pectus excavatum ↑ Anteroposterior diameter
Prematurity—common Term or post term—common
Management Early positive-pressure ventilation Avoid positive-pressure ventilation
Correct hypoventilation Avoid overventilation
Pulmonary air leaks: 10%–15% Pulmonary air leaks: ≥30%
Persistent pulmonary hypertension—rare Persistent pulmonary hypertension—common

↓, decrease; ↑, increase.
10 1 / INTRODUCTION TO ASSISTED VENTILATION

SILVERMAN-ANDERSON RETRACTION SCORE

UPPER LOWER XIPHOID NARES EXPIR.


CHEST CHEST RETRACT. DILAT. GRUNT
GRADE 0

SYNCHRONIZED NO RETRACT. NONE NONE NONE


GRADE 1

LAG ON INSP. JUST VISIBLE JUST VISIBLE MINIMAL STETHOS. ONLY


GRADE 2

SEE-SAW MARKED MARKED MARKED NAKED EAR

Figure 1-6. Index designed to provide continuous evaluation of an infant’s respiratory status. An index of respiratory distress is determined by grading
each of five arbitrary criteria: chest lag, intercostal retraction, xiphoid retraction, nares dilatation, and expiratory grunt. The “retraction score” is computed
by adding the values (0, 1, or 2) assigned to each factor that best describes the infant’s condition at the time of a single observation. A score of zero indi-
cates the absence of respiratory distress; a score of 10 indicates severe respiratory distress. DILAT, dilatation; EXPIR, expiratory; INSP, inspiration; RETRACT,
retraction; STETHOS, stethoscope. (Adapted from Silverman WE, Andersen DH: Controlled clinical trial of effects of water mist on obstructive respiratory
signs, death rate and necroscopy findings among premature infants. Pediatrics 171:1,1956, with permission of Pediatrics.)

gas analysis. Clinically, the physician should look for the fol-
lowing signs:
1. Increase in respiratory rate
2. Decrease in respiratory rate accompanied by increasing
effort or increasing retractions
3. Prolonged apnea with cyanosis, bradycardia, or both
4. Cyanosis not relieved by O2 administration
5. Hypotension, pallor, and decrease in peripheral perfusion
6. Tachycardia (leading to bradycardia)
7. Periodic breathing with prolonged respiratory pauses
8. Gasping, and the use of accessory respiratory muscles
The Silverman-Anderson55 retraction score has also been
helpful in evaluating respiratory distress (Fig. 1-6). A score of
7 or greater indicates impending respiratory failure.
Blood gas analysis can be used to identify candidates for
assisted ventilation. The selection of criteria differs from center
to center. As the ability to use assisted ventilation has improved
and resulted in the enhancement of outcomes and a decrease
in complications, indications have become less rigid. For
example, the indications of Gregory et al.20 for CPAP adminis-
tration in 1971 was PaO2 less than 50 mm Hg in 100% O2.
Today, most centers would begin CPAP or assisted ventilation Figure 1-7. Graph for estimating the shunt at different inspired O2 mix-
tures. Calculations were based on an assumed hemoglobin concentration
when infants cannot maintain PaO2 greater than 50 mm Hg in of 16 g per 100 mL, arteriovenous difference of 4 vol %, respiratory
60% O2. Although there is general consensus that PaO2 less than quotient of 0.8, and PaCO2 of 40 mm Hg. The graph was constructed with
50 mm Hg is unsatisfactory, there is considerable debate the aid of a Severinghaus nomogram.
on what maximal inspired O2 should be used before CPAP or
mechanical ventilation is initiated. A level of 60% FIO2 is
chosen for two reasons. First, O2 toxicity to the lungs increases
with higher inspired O2 concentration, and “early” respiratory the shunt is greater than 30%, an increase in FIO2 from 60% to
assistance may allow the use of lower O2 concentrations and 100% should have very little effect on PaO2 (Fig. 1-7).58
decrease the total duration of O2 therapy.56,57 Second, in most The infant’s age, weight, and disease are factors that should
infants with respiratory failure, intrapulmonary and intracardiac be considered in the determination of criteria for respiratory
right-to-left shunting are the primary causes of hypoxemia. If failure. Generally, pH less than 7.25, PaO2 less than 50 mm Hg,
1 / INTRODUCTION TO ASSISTED VENTILATION 11

and PaCO2 greater than 60 mm Hg in 60% O2 indicate the need assistance early in the course of progressive atelectatic disease
for some form of respiratory assistance. However, the normal to reduce the work of breathing and, theoretically, to conserve
intrauterine umbilical artery pH is approximately 7.25.59 Thus, surfactant by alveolar stabilization before absolute criteria are
blood gases obtained immediately after birth must be inter- met. Very-low-birthweight infants may be intubated and placed
preted with awareness of the normal physiologic adaptation on assisted ventilation before criteria are met so that exogenous
process. In infants weighing less than 1500 g, PaCO2 criteria for surfactant therapy can be initiated immediately after birth.
ventilatory assistance may be modified to values greater than Furthermore, clinical judgment and the experience of the clini-
50 mm Hg, because respiratory acidosis may increase the inci- cian may dictate when intubation and mechanical ventilation
dence of intraventricular hemorrhage.60 A contrary view is held are initiated. The criteria for the initiation of artificial surfactant
by many neonatologists and researched by the group at therapy are discussed in detail in Chapter 20.
Columbia University, where pH is allowed to decrease to 7.25
or lower and PaCO2 to increase to 55 to 60 mm Hg (permissive What: Types and Classification of Mechanical
hypercapnia), resulting in no apparent increase in intraventric-
ular hemorrhage or neurologic sequelae.61 This concept is dis-
Ventilators
cussed more fully in Chapter 15. CPAP failure, and thus the The classification of ventilators can be confusing because
need for mechanical ventilation, is indicated by the presence of it may be based on the pressure relationship to the patient,
PaCO2 greater than 55 to 60 mm Hg in 100% O2 and distending the cycling mode, the power source, or the ventilatory rate
pressure of 10 to 12 cm H2O (depending on the CPAP system). (Table 1-5). The following approach, although somewhat sim-
Our criteria are also modified by the pathophysiology of plistic, should serve as an introduction to Chapters 2 through 29.
the disease process. In atelectatic disease with decreased lung Mechanical ventilation can be achieved through the use of
volume (e.g., RDS), CPAP or IMV may be initiated early to intermittent negative-pressure or positive-pressure devices.
increase lung volume, provide alveolar stabilization, and Negative-pressure ventilators are mainly of historical interest
increase functional residual capacity. In such diseases, some and represent only a small percentage of machines currently
physicians initiate CPAP at birth.61,62 However, in obstructive in use in the United States. Negative-pressure respirators can
disease (e.g., aspiration syndrome), we try to avoid positive provide assisted ventilation without the need for endotracheal
pressure and provide ambient O2 up to 100% before intubation intubation; thus, trauma to the airway is avoided and the risk of
is considered. The incidence of pulmonary air leaks can be infection is reduced. They can also provide effective contin-
extremely high when infants with obstructive lung disease are uous negative pressure.64 The only commercially available
ventilated.63 A scoring system used for the selection of infants equipment for newborns, the Isolette Respirator (Airshields,
based on the results of blood gas analysis is shown in Table 1-4. Inc., Hatboro, PA, USA), is no longer manufactured. In the
Indications for assisted ventilation are (1) a score of 3 or greater, early 1990s, this form of ventilation experienced a minor resur-
(2) PaO2 less than 50 mm Hg in 60% O2, or (3) CPAP failure gence of interest because of reported success in the ventilation
(i.e., CPAP ≥10 cm H2O at 100% FIO2). of infants with persistent pulmonary hypertension who met
Decisions to institute assisted ventilation should be made ECMO cannulation criteria.65 The Isolette Respirator has not
after the risks and benefits have been evaluated; they should not been proven effective in the ventilation of very-low-birth-
be based strictly on blood gas criteria. Even in the presence of weight infants, who represent the largest group of the NICU
near-normal blood gas values, certain conditions may necessi- population. Comparison of the advantages and disadvantages
tate ventilator support. A trend of deterioration may indicate of negative-pressure ventilators is presented in Table 1-6.
the need for respiratory assistance, even though severe hyper- Positive-pressure devices are most commonly classified
capnia and acidosis are not yet present. In addition, repeated based on cycling mode (i.e., usually the way in which the inspi-
episodes of prolonged apnea unresponsive to other measures ratory cycle is terminated). There are six basic types of
(i.e., theophylline administration, cutaneous stimulation) and cycling66:
associated with bradycardia or cyanosis should be treated with
1. Volume cycling: Inspiration ends when a certain volume is
assisted ventilation. Many infants may be placed on ventilatory
reached
2. Pressure cycling: Inspiration ends when a preset pressure is
reached
TABLE 1-4. Blood Gas Scoring System for Assisted 3. Time cycling: Inspiration ends when a preset time is reached
Ventilation*† 4. Flow cycling: Inspiration ends when flow has reached a crit-
ical low level
Points 5. Mixed cycling: Two or more independent cycling mechan-
isms are present in the same ventilator
0 1 2 3 6. High-frequency ventilators: Ventilators capable of cycling at
PaO2 (mm Hg) >60 50–60 <50‡ <50‡ rates greater than 150 breaths per minute
pH >7.30 7.20–7.29 7.1–7.19 <7.1
PaCO2 (mm Hg) <50 50–60 61–70 >70
TABLE 1-5. Classification of Neonatal Ventilators
*A score of 3 or more indicates need for CPAP or IMV.
†Ambient ocygen failure → CPAP

CPAP failure (CPAP 10 cm H2O and 100% FIO2) → IMV


By pressure relationship to patient (positive or negative)
‡May indicate need for CPAP or IMV by itself, if cyanotic heart disease is not By cycling mode (at termination of inspiration)
present. By power source
CPAP, continuous positive airway pressure; IMV, intermittent mandatory By rate
ventilation.
12 1 / INTRODUCTION TO ASSISTED VENTILATION

The vast majority of positive-pressure neonatal ventilators airway opening and produces a minimum of bulk gas flow.
fall under the first three categories. Chapter 9 discusses pressure- HFV is not a specific type of ventilator but rather a pattern of
cycled and time-cycled ventilators, and Chapter 10 addresses ventilation that uses very high rates such that tidal volumes are
volume-cycled ventilators. less than or equal to the patient’s anatomic dead space.67 This
A surge of interest that began in the 1980s has led to the mode of ventilation is discussed in Chapter 11.
development of a new class of ventilators that cannot be In pressure-cycled, time-cycled, and volume-cycled ventila-
classified based on conventional mechanical ventilation crite- tion, compliance varies pressure and volume as independent
ria. Because of respiratory complications, including oxygen variables. Compliance equals that unit of volume change pro-
toxicity, barotrauma, and cardiovascular compromise, HFV has duced by a unit of pressure change (cm3/cm H2O). In volume-
been tried as an alternative to conventional mechanical ventila- cycled ventilation, identical volumes delivered to two infants
tion when the latter has failed. HFV now is being used in many generate greater pressure in the infant with poorer compliance.
centers in the United States. Currently, there are three major In pressure-cycled ventilation, identical peak inspiratory pres-
types of HFV: high-frequency positive-pressure ventilation, sures delivered to two infants result in greater tidal volumes in
which is produced by conventional or modified conventional the infant with better compliance; also, the infant with poor
mechanical ventilators operating at rapid rates; high-frequency compliance has a shorter inspiratory time. If time-cycled venti-
jet ventilation, which is produced by ventilators that deliver a lators are not pressure limited, the volume of gas delivered to
high-velocity jet of O2 or gas directly into the airway; and high- the infant is determined by inspiratory time and gas flow. Long
frequency oscillation, which moves air back and forth at the inspiratory times and high gas flows generate increased
volumes and pressures. In the case of identical inspiratory
times and gas flow in two infants, the infant with the poorer
compliance receives less volume and greater pressure, as
TABLE 1-6. Negative-Pressure Ventilators
shown in Figure 1-8.68 Physiologic principles of mechanical
Advantages Disadvantages ventilation are discussed in Chapter 2.
Devices can be added to the ventilator that prevent exces-
Less pulmonary O2 toxicity High cost sive pressure or volume as the compliance of an infant’s lung
(bronchopulmonary Patient inaccessible for routine changes. A pressure-limiting device regulates the maximal
dysplasia) procedures and resuscitation
Doubles as an incubator Cooling of infants pressure by means of a pop-off valve. A volume-limiting device
Decrease in pulmonary Neck abrasions allows the ventilator to deliver less (but never more) than a
infections Monitoring of pulmonary status specified amount. In all three types of positive-pressure venti-
Decrease in atelectasis based on blood gas analysis is lators, tidal volume is determined by lung compliance and, if
Decrease in pulmonary air more difficult
leaks Patient usually removed for
present, a pressure-limiting device.
Decrease in airway trauma radiography Ventilators also can be classified according to the manner in
May be effective in Decreased airway patency in which they control ventilation, often termed the ventilator
persistent pulmonary neurologically depressed infants mode. To start inspiration, the machine can be triggered by the
hypertension of the Compression of trunk during patient (assistor type), by the ventilator only (controller type),
newborn inspiration decreases effectiveness
Not effective for very-low-birthweight or by both the patient and the ventilator (assistor-controller
infants (<1500 g) type). In assistor-controller ventilators, a device allows the
patient to initiate some respirations; however, it also has a pre-

VOLUME CYCLED PRESSURE CYCLED TIME CYCLED

Infant A Infant B Infant A Infant B Infant A Infant B


Good Poor Good Poor Good Poor
Compliance Compliance Compliance Compliance Compliance Compliance
PRESSURE

PRESSURE

PRESSURE
VOLUME

VOLUME

VOLUME

COMMENT COMMENT COMMENT


1. Ventilators set to deliver 1. Ventilators set at equal 1. Ventilator inspiratory time
equal volumes to infants pressures for infants A and flow equal for infants
A and B. and B. A and B.
2. Pressures related to 2. Pressures as preset. 2. Pressure unlimited. Figure 1-8. Diagrammatic pressure and volume curves
compliance. 3. Volume delivered Pressures related to lung generated in infants with different compliance on volume-
3. Preset volumes delivered. proportionate to lung compliance. cycled, pressure-cycled, and time-cycled ventilators. (From
compliance. 3. Volume delivered
Proportionate to lung Gottschalk SK, King B, Schuth CR: Basic concepts in positive
compliance. pressure ventilation of the newborn. Perinatol Neonatol 4:15,
1980.)
1 / INTRODUCTION TO ASSISTED VENTILATION 13

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man. Am J Physiol 152:162, 1948.
7. The ventilator should possess a low compliance system 19. Cochran, WD, Levison, H, Muirhead, DM, et al: A clinical trial on high
both inside and outside. oxygen pressure for the respiratory distress syndrome. N Engl J Med
8. The conventional ventilator should accurately deliver a 212:347, 1965.
wide range of tidal volumes (<5–200 mL). 20. Gregory GA, Kitterman, JA, Phibbs RH, et al: Treatment of the idiopathic
respiratory-distress syndrome with continuous positive airway pressure.
9. The ventilator should have a quick response time. N Engl J Med 284:1333, 1971.
10. The device should have an alarm system(s) (visual and 21. Bancalari E, Garcia OL, Jesse MJ: Effects of continuous negative pressure
audible) to warn about mechanical failures or patient dis- on lung mechanics in idiopathic respiratory distress syndrome. Pediatrics
connects. 51:485, 1973.
11. The system should offer user-variable flow rates that 22. Kattwinkel J, Fleming D, Cha CC, et al: A device for administration of con-
tinuous positive airway pressure by nasal route. Pediatrics 52:131, 1973.
remain constant at a set flow. 23. Reynolds EOR: Pressure waveform and ventilator setting for mechanical
12. The ventilator should be able to adequately humidify and ventilation in severe hyaline membrane disease. Int Clin Anesthesiol
heat inspired gas (60% humidity at 37°C). 12:269, 1974.
13. Variable-pressure or volume-limiting devices should be 24. Reynolds EOR, Taghizadeh A: Improved prognosis of infants mechani-
cally ventilated for hyaline membrane disease. Arch Dis Child 49:505,
available. 1974.
14. The device should offer a wide range of pressure or 25. Kirby R, Robison E, Schulz J, DeLemos RA: Continuous flow ventilation
volume capacities. as an alternative to assisted or controlled ventilation in infants. Anesth
15. The ventilator should have the capacity to digitally read Analg 51:871, 1972.
out a variety of pulmonary function parameters. 26. Kirby RR: Intermittent mandatory ventilation in the neonate. Crit Care
Med 5:18, 1977.
Appendix 1 compares commonly used ventilators classified 27. Cassani VL III: We’ve come a long way baby! Mechanical ventilation of
the newborn. Neonatal Netw 13:63, 1994.
by pressure characteristic, cycling mode, power source, and 28. Bland RD, Sedin EG: High frequency mechanical ventilation in the
rate and comments on principles of operation, advantages, and treatment of neonatal respiratory distress. Int Anesthesiol Clin 21:125,
disadvantages. 1983.
14 1 / INTRODUCTION TO ASSISTED VENTILATION

29. Slutsky AS, Drazen FM, Ingram RH Jr, et al: Effective pulmonary ventila- 51. Spitzer AR, Fox WW, Delivoria-Papadopuolos M: Respiratory distress
tion with small-volume oscillations at high frequency. Science 209:609, syndrome: The perinatal center versus infant transport in relation to sever-
1980. ity of disease [abstract]. Pediatr Res 15:4, 1981.
30. Pesenti A, Gottinoni L, Bombino L: Long-term extracorporeal respiratory 52. Indyk L, Cohen S: Newborn intensive care in the United States, East and
support: 20 years of progress. Intern Ext Care Digest 12:15, 1993. West. Comments on representative facilities and programs, and a proposed
31. Frantz ID III, Werthammen J, Stark AR: High-frequency ventilation in new point scoring system for evaluation. Clin Pediatr 10:320, 1971.
premature infants with lung disease: Adequate gas exchange at low tra- 53. Louisiana Perinatal Commission: Maternal and neonatal guidelines for
cheal pressure. Pediatrics 71:483, 1983. regionalization of perinatal care in the state of Louisiana. New Orleans,
32. Avery ME, Mead J: Surface properties in relation to atelectasis and hyaline La., Department of Health and Human Resources, 1980, p 26.
membrane disease. Am J Dis Child 17:517, 1959. 54. Guidelines for Perinatal Care, 5th ed. Elk Grove Village, Ill., American
33. Jobe AH: Pulmonary surfactant therapy. N Engl J Med 328:861, 1993. Academy of Pediatrics and American College of Obstetrics and
34. Brown DL, Pattishall EN: Other uses of surfactant. Clin Perinatol 20:761, Gynecologists, 2002.
1993. 55. Silverman WE, Andersen DH: Controlled clinical trial of effects of water
35. Johnson JD, Malachowski NC, Grobstein R, et al: Prognosis of children mist on obstructive respiratory signs, death rate and necropsy findings
surviving with the aid of mechanical ventilation in the newborn period. among premature infants. Pediatrics 17:1, 1956.
J Pediatr 84:272, 1974. 56. Gerard P, Fox WW, Outerbridge EH, Beaudry PH: Early versus late intro-
36. Lorenz JM: The outcome of extreme prematurity. Semin Perinatol 25:348, duction of continuous negative pressure in the management of idiopathic
2001. respiratory distress syndrome. J Pediatr 87:591, 1975.
37. Horbar, JD, Badger, GJ, Carpenter JH, et al: Trends in mortality and morbid- 57. Gregory GA: Devices for applying continuous positive airway pressure. In
ity for very low birthweight infants, 1991–1999. Pediatrics 110:143, 2002. Thibault DW, Gregory GA (eds): Neonatal Pulmonary Care. Reading,
38. Schwartz RM, Luby AM, Scanlon JW, Kellogg RJ: Effect of surfactant on Mass., Addison-Wesley, 1979, p 187.
morbidity, mortality, and resource use in newborn infants weighing 500 to 58. Pontoppidan H, Geffin B, Lowenstein E: Acute respiratory failure in the
1500 g. N Engl J Med 330:1476, 1994. adult. 2. N Engl J Med 287:743, 1972.
39. Greenspan JS: Liquid ventilation: A developing technology. Neonatal 59. Avery ME, Fletcher BD, Williams RG: The Lung and Its Disorders in the
Netw 12:23, 1993. Newborn Infant, 4th ed. Philadelphia, WB Saunders, 1981, pp 40, 69.
40. Downes JJ: Mechanical ventilation of the newborn. Anesthesiology 60. Wigglesworth JS: A new look at intraventricular hemorrhage. Contemp
34:116, 1971. Obstet Gynecol 98, 1985.
41. Committee on Perinatal Health, National Foundation–March of Dimes: 61. Transwell AK, Clubb RA, Smith BT, Boston RW: Individualized continu-
Toward Improving the Outcome of Pregnancy. White Plains, NY, March ous distending pressure applied within 6 hours of delivery in infants with
of Dimes, 1976. respiratory distress syndrome. Arch Dis Child 55:33, 1980.
42. March of Dimes Birth Defects Foundation: Toward Improving the 62. Avery ME, Tooley WH, Keller JB, et al: Is chronic lung disease in low
Outcome of Pregnancy: The 90s and Beyond. White Plains, NY, March of birthweight infants preventable? A survey of eight centers. Pediatrics
Dimes, 1993. 79:26, 1987.
43. Goldsmith JP, Graf MA: A modest proposal [editorial]. J Perinatol 8:1, 1988. 63. Gregory GA, Gooding CA, Phibbs RH, Tooley WH: Meconium aspiration
44. Perl H: Can a community hospital NICU measure up? Contemp Pediatr, syndrome in infants: A prospective study. J Pediatr 85:848, 1974.
2:38, 1985. 64. Outerbridge EW, Stern L: Negative pressure ventilators. In Goldsmith JP,
45. Garrett FF, Goldsmith JP: Perinatal-neonatal regionalization: A view from Karotkin EH (eds): Assisted Ventilation of the Neonate. Philadelphia,
the outlying hospital. Respir Care 23:873, 1978. WB Saunders, 1981, p 161.
46. Cordero L, Zuspan FP: Very low-birth weight infants: Five years experi- 65. Sills JH, Cvetnic WG, Pietz J: Continuous negative pressure in the treat-
ence of a regional perinatal program. Ohio Med 84:976, 1988. ment of pulmonary hypertension and respiratory failure. J Perinatol 9:43,
47. Rosenblatt RA, Mayfield JA, Hart LG, Baldwin LM: Outcomes of region- 1989.
alized perinatal care in Washington State. West J Med 149:98, 1988. 66. Williams TJ: Mechanical ventilation. In Williams TJ, Hill JW (eds):
48. Levy DL, Noelke K, Goldsmith JP: Maternal and infant transport program Handbook of Neonatal Respiratory Care. Riverside, Calif., Bourns, 1971,
in Louisiana. Obstet Gynecol 57:500, 1981. p 91.
49. Harris TR, Isaman J, Giles HR: Improved neonatal survival through 67. O’Rourke PP, Crone RK: High-frequency ventilation: A new approach to
maternal transport. Obstet Gynecol 52:294, 1978. respiratory support. JAMA 250:2845, 1983.
50. Moore TR, Resnick R: Special problems of VLBW infants. Contemp 68. Gottschalk SK, King B, Schuth CR: Basic concepts in positive pressure
Obstet Gynecol, June 23, 1984, p. 174. ventilation of the newborn. Perinatol Neonatol 4:15, 1980.
2 PHYSIOLOGIC PRINCIPLES

BRIAN R. WOOD, MD

I t is the responsibility of those who care for critically ill infants oxygen into the blood, convective flow of blood to the tissues,
to have an understanding of respiratory physiology and the diffusion of oxygen into the cells, and finally diffusion into the
functional limitations imposed on gas exchange by anatomic mitochondria. The driving force for these transfer processes is an
and developmental constraints. The first tenet of the oxygen pressure gradient, which drives this cascade from the air
Hippocratic Oath states “primum non nocere” (“first do no outside the body to intracellular mitochondria (Fig. 2-1).
harm”). The respiratory system of the premature infant is The lungs of the newborn infant transfer oxygen to the blood
fragile. In clinical practice we are faced with the difficult task by diffusion, driven by the oxygen pressure gradient. For gas
of supporting adequate gas exchange in an immature respira- exchange to occur efficiently, the infant’s lungs must remain
tory system, using powerful tools that by their very nature expanded, the lungs must be both ventilated and perfused, and
perturb ongoing developmental processes, often resulting in the ambient partial pressure of oxygen in the air must be greater
alterations in end-organ form and function. than the partial pressure of oxygen of the blood. The efficiency
In our efforts to provide ventilatory support, the infant’s of the newborn infant’s respiratory system is determined by both
lungs and airways are subjected to forces that lead to acute and structural and functional constraints; therefore, the clinician must
chronic tissue injury. This results in alterations in the way the be mindful of both aspects when caring for the infant.
lungs develop and the way they respond to subsequent noxious The infant’s cells require energy in order to function. This
stimuli. Injury leads to alterations in lung development, which energy is obtained from high-energy phosphate bonds (e.g.,
result in alterations in lung function as the infant’s body ATP) formed during oxidative phosphorylation. Only a small
attempts to heal and continue to develop. Superimposed on this amount of ATP is stored within the cells. Muscle cells contain
is the fact that the ongoing development of the respiratory an additional store of ATP, but in order to meet metabolic needs
system is hampered by the healing process itself, which further beyond those that can be provided for by the stored ATP, new
complicates the situation. ATP must be made by phosphorylation of adenosine diphos-
This complexity makes caring for infants with respiratory phate (ADP). This can be done anaerobically through glycoly-
failure both interesting and challenging. To effectively provide sis, but this is an inefficient process and leads to the formation
support for these patients, the clinician must have an under- of lactic acid. Long-term energy demands must be met aerobi-
standing not only of respiratory physiology but also of respira- cally through ongoing oxidative phosphorylation within the
tory system development, growth, and healing. mitochondria, which is a much more efficient process and
results in the formation of carbon dioxide and water.
There is a hierarchy of how energy is used by the infant.
During periods of high-energy demand, muscles initially draw
BASIC BIOCHEMISTRY OF RESPIRATION: upon the available stores of ATP, then use glycolysis to make
OXYGEN AND ENERGY more ATP from ADP, and then use oxidative phosphorylation to
supply the infant’s ongoing energy requirements. Oxidative
phosphorylation and oxygen consumption are so closely linked
The energy production required for a newborn infant to
sustain his or her metabolic functions is dependent upon the
availability of oxygen and its subsequent metabolism. During
the breakdown of carbohydrates, oxygen is consumed as
carbon dioxide and water are produced. The energy derived
from this process is generated as electrons are transferred from
electron donors to electron acceptors. Oxygen has a high elec-
tron affinity and therefore is a good electron acceptor. The
energy produced during this process is stored as high-energy
phosphate bonds, primarily in the form of adenosine triphos-
phate (ATP). The enzyme systems within the mitochondria
couple the transfer of energy to oxidation in a process known
as oxidative phosphorylation.1
For energy production to occur, oxygen must be available to
the mitochondria. The transfer of oxygen from the air outside the
infant to the mitochondria, within the infant’s cells, involves a Figure 2-1. Transfer of oxygen from outside air to intracellular mitochon-
series of steps: convection of air into the lung, diffusion of dria via an oxygen pressure gradient.

15
16 2 / PHYSIOLOGIC PRINCIPLES

to the newborn infant’s energy requirements that total oxygen Terminal sac phase (weeks 26–36): refinement of acini.
consumption is a reasonably good measure of the total energy The rudimentary primary saccules divide into subsaccules and
needs of the infant. When the infant’s workload is in excess alveoli during the terminal sac phase. The interstitium con-
of that which can be sustained by oxidative phosphorylation tinues to dissipate. Capillary invasion leads to an increase in
(aerobic metabolism), the muscle cells will revert to anaerobic alveolar–blood barrier surface area. The development of the
glycolysis to produce ATP. This anaerobic metabolism results surfactant system occurs during this phase.
in the formation of lactic acid, which accumulates in the blood Birth during the terminal sac phase may result in
and causes a decrease in pH (acidosis/acidemia).
• Transient tachypnea of the newborn
• Respiratory distress syndrome (RDS)
• Pulmonary interstitial emphysema (PIE)
ONTOGENY RECAPITULATES PHYLOGENY: Alveolar phase (week 36–3 years): alveolar proliferation
A BRIEF OVERVIEW OF DEVELOPMENTAL and development. Subsaccules become alveoli as a result of
ANATOMY the thinning of the acinar walls, dissipation of interstitium, and
invagination of alveoli by pulmonary capillaries during the
alveolar phase. The alveoli attain a polyhedral shape.
Lung Development
The tracheobronchial airway system begins as a ventral out-
pouching of the primitive foregut, which leads to the formation
of the embryonic lung bud. The lung bud subsequently divides
MECHANICS
and branches, penetrating the mesenchyma and progressing
toward the periphery. Lung development is divided into five The lung has a variety of functions, but we will concern
phases.2 ourselves here with its primary function, that of gas exchange.
The respiratory system is composed of millions of air sacs that
are connected to the outside air via airways. The lung behaves
Phases of Lung Development like a balloon in that it is in an expanded state by the intact
thorax and will deflate should the integrity of the system be
• Embryonic phase (weeks 3–6)
compromised. The interior of the lung is partitioned so as to
• Pseudoglandular phase (weeks 6–16)
provide a large surface area to facilitate efficient gas diffusion.
• Canalicular phase (weeks 16–26)
The lung is expanded by forces generated by the diaphragm
• Terminal sac phase (weeks 26–36)
and the intercostal muscles. It recoils secondary to elastic and
• Alveolar phase (week 36–3 years)
surface tension forces. This facilitates the inflow and outflow
Embryonic phase (weeks 3–6): development of proximal of respiratory gases required to allow the air volume contained
airways. The lung bud arises from the foregut 21 to 26 days within the lung to be ventilated. During inspiration the dia-
after fertilization. phragm contracts. The diaphragm is a “dome-shaped” muscle
Aberrant development during the embryonic phase may at rest. As it contracts, the diaphragm flattens, and the volume
result in of the chest cavity is enlarged. This causes the intrapleural
pressure to decrease and results in gas flow into the lung.3
• Tracheal agenesis
During unlabored breathing the intercostal and accessory
• Tracheal stenosis
muscles serve primarily to stabilize the rib cage as the dia-
• Tracheoesophageal fistula
phragm contracts, countering the forces resulting from the
• Pulmonary sequestration (if an accessory lung bud develops
decrease in intrapleural pressure during inspiration. This limits
during this period)
the extent to which the infant’s chest wall is deformed inward
Pseudoglandular phase (weeks 6–16): development of during inspiration.
lower conduction airways. During this phase the first 20 gen- Although in the premature infant the chest wall is very com-
erations of conducting airways develop. The first 8 generations pliant, the rib cage offers some structural support, serves as an
(the bronchi) ultimately acquire cartilaginous walls. Generations attachment point for the respiratory muscles, and limits lung
9 to 20 comprise the nonrespiratory bronchioles. Lymph vessels deflation on end-expiration. The elastic elements of the respira-
and bronchial capillaries accompany the airways as they grow tory systems, the connective tissue, are stretched during inspi-
and develop. ration and recoiled during exhalation. The air–liquid interface
Aberrant development during the pseudoglandular phase in the terminal air spaces and respiratory bronchioles generates
may result in surface tension that opposes lung expansion and supports lung
deflation. The conducting airways, which connect the gas
• Bronchogenic cysts
exchange units to the outside air, provide greater resistance
• Congenital lobar emphysema
during exhalation than during inspiration. The abdominal
• Congenital diaphragmatic hernia
muscles can aid in exhalation by active contraction if required,
Canalicular phase (weeks 16–26): formation of gas- but because expiration is generally passive, they make little
exchanging acini. The formation of respiratory bronchioles contribution during unlabored breathing. The respiratory
(generations 21–23) occurs during the canalicular phase. The rel- system is designed to be adaptable to a wide range of work-
ative proportion of parenchymal connective tissue diminishes. loads; however, in the newborn infant, several structural and
The development of pulmonary capillaries occurs. Gas exchange functional limitations make the newborn susceptible to respira-
is dependent upon the degree of acinus–capillary coupling. tory failure.
2 / PHYSIOLOGIC PRINCIPLES 17

Differences between the shape of a newborn infant’s chest terminal air spaces and relatively more stroma (cells and inter-
and that of an adult put the infant at a mechanical disadvantage. stitial fluid). This is manifested by a low ratio of lung volume
Unlike the adult’s thorax, which is ellipsoid in shape, the to lung weight. Although in absolute terms airway resistance is
infant’s thorax is more cylindrical and the ribs are more hori- elevated in the newborn infant, when corrected to lung volume
zontal rather than oblique. Because of these anatomic differ- (specific conductance, which is the reciprocal of resistance per
ences, the intercostal muscles in infants have a shorter course unit lung volume) the relative resistance is lower than in adults.
and provide less mechanical advantage for elevating the ribs It is important to remember that because of the small diameter
and increasing intrathoracic volume during inspiration than of the airways in the lungs of the newborn infant, even a modest
do those of adults. Also, because the insertion of the infant’s narrowing will result in a marked increase in resistance. That
diaphragm is more horizontal than in the adult, the lower ribs the newborn’s bronchial tree is short and that inspiratory flow
tend to move inward rather than upward during inspiration. The velocities are low are teleologic advantages for the newborn
compliant chest wall of the infant exacerbates this inward because both of these factors decrease airway resistance.
deflection with inspiration. This is particularly evident during Overcoming the elastic and resistive forces during ventila-
rapid eye movement (REM) sleep, when phasic changes in tion requires energy expenditure and accounts for the work of
intercostal muscle tone are inhibited. Therefore, instead of breathing. The normal work of breathing is essentially the
stabilizating the rib cage during inspiration, the intercostal same for newborns and adults when corrected for metabolic
muscles are relaxed. This results in inefficient respiration, rates.5 When the work of breathing increases, as it does in
which may be manifested clinically by intercostal and subster- response to various disease states, the newborn is at a decided
nal retractions associated with abdominal breathing. The disadvantage. The newborn infant lacks the strength and
endurance capacity of the diaphragm is determined primarily endurance to cope with a significant increase in ventilatory
by muscle mass and the oxidative capacity of muscle fibers. workload. An increase in ventilatory workload can lead to
Infants have low muscle mass and a low percentage of type 1 respiratory failure.
(slow twitch) muscle fibers compared to adults.4 In order to Elastic and resistive forces of the chest, lungs, abdomen,
sustain the work of breathing, the diaphragm must be provided airways, and ventilator circuit oppose the forces exerted by the
with a continuous supply of oxygen. Respiratory muscle fatigue respiratory muscles and/or ventilator. The terms elastic recoil,
is a common cause of respiratory failure in premature infants. flow resistance, viscous resistance, and work of breathing are
During expiration the main driving force is elastic recoil. used to describe these forces. The terms elasticity, compliance,
Elastic recoil depends on the surface tension produced by the and conductance characterize the properties of the thorax,
air–liquid interface, the elastic elements of tissue, and the bony lungs, and airways. The static pressure-volume curve illustrates
development of the rib cage. Expiration is largely passive. the relationships between these forces at different levels of lung
Because the chest wall of premature infants is compliant, it expansion. Dynamic pressure-volume loops illustrate the pres-
offers little resistance against expansion upon inspiration and sure-volume relationship during inspiration and expiration
little opposition against collapse upon expiration. This collapse (Figs. 2-2 to 2-4).
at end-expiration can lead to the development of atelectasis. In Elastic recoil refers to the tendency of stretched objects to
premature infants the largest contributor to elastic recoil is return to their original shape. When the inspiratory muscles
surface tension. Surfactant serves to reduce surface tension and relax during exhalation, the elastic elements of the chest wall,
stabilize the terminal airways. In circumstances where surfac- diaphragm, and lungs, which were stretched during inspiration,
tant is deficient, the terminal air spaces have a tendency to recoil to their original shapes. These elastic elements behave like
collapse or become atelectatic. RDS is caused by a primary sur- springs (Fig. 2-5). The surface tension forces at the air–liquid
factant deficiency. Mechanical ventilation and the administra- interfaces in the distal bronchioles and terminal airways
tion of exogenous surfactant directly into the lung is the decrease the surface area of the air–liquid interfaces (Fig. 2-6).
treatment of choice for moderate-to-severe RDS. Pressure in At some point, the forces that tend to collapse are counterbal-
the form of peak inspiratory pressure (PIP), positive end-expi- anced by those that resist further collapse. The point at which
ratory pressure (PEEP), or continuous positive airway pressure these opposing forces balance is called the resting state of the
(CPAP) may be applied to the infant’s airway to counter the respiratory system and corresponds with FRC (Fig. 2-7; see also
tendency toward collapse and the development of atelectasis. Fig. 2-2). Because the chest wall of the newborn infant is com-
The application of airway distending pressure also serves to pliant, it offers little opposition to collapse at end-expiration;
stabilize the chest wall. thus, the newborn, especially the premature newborn, has a rel-
Lung compliance and airway resistance are related to lung atively low FRC and thoracic gas volume, even when the
size. The smaller the lung, the lower the compliance and the newborn does not suffer from primary surfactant deficiency.
greater the resistance. If, however, lung compliance is cor- This low FRC and the relative underdevelopment of the con-
rected to lung volume (specific compliance), the values are ducting airways structural support explain the tendency for early
nearly identical for term infants and adults.5 In term infants, airway closure and collapse with resultant gas trapping in pre-
immediately after delivery, specific compliance is low but nor- mature infants. The respiratory system’s resting volume is very
malizes as fetal lung fluid is absorbed and a normal functional close to the closing volume of the lung. The closing volume is
residual capacity (FRC) is established. In premature infants, the volume at which dependent lung regions cease to ventilate
specific compliance remains low, due in part to persistent because the airways leading to them have collapsed. In new-
atelectasis and failure to achieve a normal FRC. Chest wall borns, closing volume may occur even above resting volume
compliance is very high in the newborn. (see Fig. 2-2).6 Gas trapping related to airway closure has been
The resistance within lung tissue during inflation and demonstrated experimentally by showing situations in which the
deflation is called viscous resistance. Viscous resistance is ele- thoracic gas volume is greater than the FRC. For this to occur,
vated in the newborn. In small lungs, there are relatively fewer the total gas volume measured in the chest at end-expiration is
18 2 / PHYSIOLOGIC PRINCIPLES

Figure 2-2. Static pressure-volume curves for the chest wall, the lung, Figure 2-4. Comparison of the pressure-volume curve of a normal infant
and sum of the two for a normal newborn infant. Functional residual (solid line) with that of a newborn with respiratory distress syndrome
capacity (FRC) or rest volume (<20% of total lung capacity) is the point at (dotted line). Note that very little hysteresis (i.e., the difference between
which collapsing and distending pressures balance out to zero pressure. the inspiratory and expiratory limbs) is observed in the respiratory distress
The lung would empty to residual volume if enough collapsing pressure syndrome curve because of the lack of surfactant for stabilization of the
(forced expiration) was generated to overcome chest wall elastic recoil in alveoli after inflation. The wide hysteresis of the normal infant’s lung curve
the opposite direction. The premature infant has an even steeper chest reflects changes (reduction) in surface tension once the alveoli are opened
wall compliance curve than that shown here, whereas his or her lung com- and stabilized. RDS, respiratory distress syndrome.
pliance curve tends to be flatter and shifted to the right, depending on the
degree of surfactant deficiency.

Figure 2-3. Extended compliance or lung expansion curve with Figure 2-5. Elastic recoil is the tendency of elements in the chest wall and
“flattened” areas (A and C) at both ends. Area A represents the situation lungs that are stretched during inspiration to snap back or recoil (arrows)
in disease states leading to atelectasis or lung collapse. Area C represents to their original state at the end of expiration. At this point (functional
the situation in an overexpanded lung, as occurs in diseases involving residual capacity or rest volume), the “springs” are relaxed and the struc-
significant air trapping (e.g., meconium aspiration) or in the excessive ture of the rib cage allows no further collapse. Opposing forces of the
application of distending pressure during assisted ventilation. FRC, func- chest wall and elastic recoil balance out, and intrathoracic and airway pres-
tional residual capacity. sures become equal (this further defines functional residual capacity or rest
volume; see also Fig. 2-2).
2 / PHYSIOLOGIC PRINCIPLES 19

Figure 2-6. Diagrammatic illustration of the Laplace relationship and the effects of surfactant film (A) and alveolar radius (B) on wall or surface tension.
The degree (reflected in the size of the open arrows) of airway or intra-alveolar pressure (P) needed to counteract the tendency of alveoli to collapse
(represented by the solid arrows) is directly proportional to double the wall or surface tension (ST) and inversely proportional to the size of the radius (r).
Distending airway pressure applied during assisted ventilation can be likened to a “pneumatic splint.”

lung is primarily governed by the presence or absence of sur-


factant. Surfactant is a surface active material released by type
II pneumocytes. It is composed mainly of dipalmitoyl phos-
phatidylcholine. Surfactant has a variety of unique properties
that enable it to decrease surface tension at end-expiration and
thereby prevent further lung deflation below resting volume
and allow an increase in surface tension upon lung expansion
that facilitates elastic recoil at end-inspiration. In addition,
surfactant reduces surface tension when lung volume is
decreased.7 A reduction in the quantity of surfactant results in
an increase in surface tension and necessitates the application
of more distending pressure to counter the tendency of the
bronchioles and terminal air spaces to collapse (Fig. 2-6A). As
can be seen from the Laplace relationship, the larger the radius
of curvature of the terminal bronchioles or air spaces, the less
pressure is needed to hold them open or to expand them further
(Fig. 2-6B). The smaller the radius of curvature (e.g., in pre-
mature infants), the more pressure is required to hold the
airways open. Surfactant helps this situation throughout the
Figure 2-7. Pressure-volume loop showing the compliance line (AC, respiratory cycle. As the radii of the air–liquid interfaces
joining points of no flow); work done in overcoming elastic resistance
(ACEA), which incorporates the frictional resistance encountered during
become smaller during exhalation, the effectiveness of surfac-
expiration (ACDA); work done in overcoming frictional resistance during tant in reducing surface tension increases; as the radii become
inspiration (ABCA); and total work done during the respiratory cycle larger, its effectiveness decreases.
(ABCEA, or the entire shaded area). Infants with RDS must generate high negative intrapleural
pressures in order to expand and stabilize their distal airways
and alveoli (see Fig. 2-4). The lung volumes achieved with the
greater than the amount of gas that is in communication with the high opening pressures during inspiration are rapidly lost as the
upper airway (FRC). lung collapses to its original resting volume during expiration.
The main contributor to lung elastic recoil in the newborn is In untreated RDS, each breath requires significant energy
surface tension. The pressure required to counteract the ten- expenditure. If the burden imposed by this large work of
dency of the bronchioles and terminal air spaces to collapse is breathing outstrips the infant’s ability to maintain this level of
described by the Laplace relationship: output, the infant develops progressive respiratory failure. In
order to expand atelectatic lungs, relatively high ventilator
P = 2 ST / r pressures may be required. Once the lungs are expanded, the
inspiratory pressures should be quickly reduced because once
Simply stated, this relationship illustrates that the pressure the lungs are inflated, the radii of the bronchioles and terminal
(P) needed to stabilize the system is directly proportional to air spaces are larger and less pressure is required to hold them
twice the surface tension (2ST) and inversely proportional to open or to expand them further. If one fails to reduce the inspi-
the radius of curvature (r). (In infants, the relationship must be ratory pressure once a normal lung volume has been estab-
modified because there is an air–liquid interface on only one lished, overdistention and dilation of the conducting airways
side of the terminal lung unit, so P = ST/r more accurately may result. This overdistention (volutrauma) is thought to be a
describes the situation in the infant.) The surface tension in the factor in the development of the proliferate airway lesions that
20 2 / PHYSIOLOGIC PRINCIPLES

characterize chronic lung disease (CLD).8 Lung overdistention tionship. The pressure-volume loop allows one to quantify the
also may lead to air leak conditions such as PIE and pneu- work done to overcome airway resistance and to determine
mothorax (see Chapter 21). lung compliance (Figs. 2-4 and 2-7). Figure 2-3 shows a static
lung compliance curve upon which three pressure-volume
loops are superimposed. Each of the loops shows a complete
Compliance respiratory cycle, but each is taken at a different lung volume.
Compliance is a measure of the change in volume resulting The overall compliance curve is sigmoidal. At the lower end of
from a given change in pressure. the curve (at low lung volume), the compliance is low, that is,
there is a small change in volume for a large change in pressure
CL = ΔV / ΔP (see Fig. 2-3, region A). This correlates with underinflation.
Pressure is required to open up terminal airways and atelectatic
where ΔV is change in volume and ΔP is change in pressure. terminal air spaces before gas can move into the lung. The lung
volume is starting below critical opening pressure. At the
center of the curve, the compliance high; there is a large change
Static Compliance in volume for a small change in pressure. This is where normal
When measured under static conditions, compliance reflects tidal breathing should occur (see Fig. 2-3, region B). This is the
only the elastic properties of the lung. Static compliance also position of maximum efficiency in a mechanical sense. At the
is referred to as elastance, the pressure required to stretch the upper end of the curve (at high lung volume), the compliance
system. It is the inverse of elastic recoil. Static compliance low; again, there is a small change in volume for a large change
measures are obtained by measuring the transpulmonary pres- in pressure (see Fig. 2-3, region C). This correlates with a lung
sure before and after inflating the lungs with a known volume of that already is overinflated. Applying additional pressure yields
gas. Transpulmonary pressure is the pressure difference little in terms of additional volume but may contribute
between alveolar pressure and pleural pressure. It is approxi- significantly to airway injury. The steeper the slope of the curve
mated by measuring pressure at the mouth and in the esophagus. connecting the points of zero flow, the greater the compliance.
To generate a pressure-volume curve, pressure measurements Compliance is reduced at both high and low lung volumes.
are made at several different volumes (see Fig. 2-2, “Lung Low lung volumes are seen in restrictive lung diseases such
Curve”). If one measures the difference between pleural pres- as primary surfactant deficiency (e.g., RDS), whereas high
sures (esophageal) and atmospheric pressures (transthoracic) at lung volumes are seen in obstructive lung diseases such as
different levels of lung expansion, the plotted curve will be a CLD. Reductions in both specific compliance and thoracic
chest wall compliance curve (see Fig. 2-2, “Chest Wall Curve”). gas volume have been measured in infants with RDS.11,12
This kind of plot shows the elastic properties of the chest wall. Teleologically, premature infants with surfactant deficiency can
In the newborn, the chest wall is very compliant; thus, large compensate for chest wall instability to a certain extent by
volume changes are achieved with small pressure changes. breathing rapidly, which results in gas trapping that tends to
Taking the lung and chest wall compliance curves together gives normalize their FRC. They also use end-expiratory grunting as
the total respiratory system compliance (see Fig. 2-2, “Total”). a method of expiratory retardation or braking to help normalize
FRC. In RDS, serial measurements of FRC and compliance
have been shown to be sensitive indicators of illness severity.13
Dynamic Compliance Dynamic lung compliance has been shown to decrease as
If one measures compliance during spontaneous breathing, the clinical course worsens and to improve at the recovery
the result is called dynamic compliance. Dynamic compliance phase begins. When ventilation is used in infants with non-
reflects the elastic recoil of the lungs. Although this is the com- compliant lungs due to surfactant deficiency, elevated distend-
pliance that is generally measured during infant pulmonary ing pressures may be required initially in order to establish a
function testing in the clinical setting, it should be understood reasonable FRC. Figure 2-4 shows the pressure-volume loop of
that interpretation can be problematic.9 If the patient is breathing a normal infant and that of an infant with RDS. A higher pres-
rapidly, the instant of zero flow may not coincide with the point sure is required to establish an appropriate lung volume in the
of lowest pressure. This is because compliance is rate dependent. infant with RDS than in the normal infant. Mechanical ventila-
Dynamic compliance may underestimate static compliance, tion without PEEP can lead to a reduction in lung compliance.
especially in infants who are breathing rapidly and those with Positive-pressure ventilation without the use of PEEP results is
obstructive airway disease. Two additional factors further com- a decrease in surfactant production, and the repeated cycling
plicate the interpretation of compliance measurements. In pre- of the terminal airways from below critical opening pressure
mature infants, REM sleep is associated with paradoxical chest leads to cellular injury and inflammation (atelectatrauma). This
wall motion, so pressure changes recorded from the esophagus results in alveolar collapse, atelectasis, interstitial edema, and
may correlate poorly with intrathoracic or pleural pressure elaboration of inflammatory mediators. The resulting atelecta-
changes. Chest wall distortion generally results in underestima- sis leads to a further reduction in lung compliance, which
tion of esophageal pressure changes.10 Also, because lung com- necessitates higher inspiratory pressures and further compro-
pliance is related to lung volume, measured compliance is mises surfactant production. Atelectatrauma leads to an
dependent on the initial lung volume above which the compli- increased diffusion barrier, which necessitates increased levels
ance measure is made. Ideally comparisons should be normal- of mean airway pressure (Paw) and/or increased levels of
ized to the degree of lung expansion, for example, to FRC. Lung inspired oxygen (FIO2). The increase in FIO2 may lead to oxida-
compliance divided by FRC is specific lung compliance. tive injury and further cellular dysfunction. Early establishment
Some clinicians use simultaneously recorded pressure and of an appropriate FRC, administration of surfactant, use of
volume changes to examine the dynamic pressure-volume rela- CPAP or PEEP to avoid the repeated collapse and reopening of
2 / PHYSIOLOGIC PRINCIPLES 21

small airways (atelectatrauma), avoidance of overinflation molecules and the wall of the respiratory system (e.g., trachea,
caused by using supraphysiologic tidal volumes (volutrauma), bronchi, bronchioles). The clinician must be aware of both
and avoidance of use of more oxygen than is required (oxida- types of resistance, as well as the resistance to flow as gas
tive injury) all are important to achieve the best possible passes through the ventilator circuit and the endotracheal tube.
outcome and long-term health of patients.14 In infants, viscous resistance may account for as much as 40%
The level of PEEP at which static lung compliance is maxi- of total pulmonary resistance.21 The relatively high viscous
mized has been termed best or optimum PEEP. This is the level resistance in the newborn is due to increases in tissue density
of PEEP at which O2 transport (cardiac output × O2 content) is (i.e., a low ratio of lung volume to lung weight) and the relative
greatest. If the level of PEEP is raised above the optimal level, amount of pulmonary interstitial fluid. This increase in pul-
dynamic compliance decreases rather than increasing.15 One monary interstitial fluid is especially prevalent after cesarean
hypothesis for this reduction in dynamic lung compliance is that section delivery22 and in conditions such as transient tachypnea
some alveoli become overexpanded due to the increase in pres- of the newborn or delayed absorption of fetal lung fluid. A
sure, which puts them on the “flat” part of the compliance curve reduction in tissue and airway resistance has been shown after
(see Fig. 2-3, region C). Therefore, despite the additional pres- administration of furosemide.23 Airway resistance (R) is
sure delivered, little additional volume is obtained, so the con- defined as the pressure gradient (P1 – P2) required to move gas
tribution of this “population” of alveoli may be sufficient to through the airways at a constant flow rate (V· or volume per
reduce the total lung compliance. It has been shown that unit time). The standard formula is as follows:
dynamic lung compliance was reduced in patients with congen-
R = (P1 – P2) / V·
ital diaphragmatic hernia (CDH) even though some of the
infants had normal thoracic gas volumes.11 The reduction in Airway resistance is determined by flow rate, length of the
dynamic lung compliance in patients with CDH is attributed to conducting airways, viscosity and density of the gases, and
overdistention of the lung remnant into the “empty” hemithorax inside diameter of the airways. This is true for both laminar and
after surgical repair of the defect. After repair of CDH, infants turbulent flow conditions.
have a reduction in the total number of alveoli and have areas
of pulmonary emphysema that persist at least into early child-
Time Constant
hood.16 Based on available evidence, in the treatment of CDH it
seems prudent to avoid rapid re-expansion and to attempt to The time constant of a patient’s respiratory system is a
avoid overexpansion by allowing adequate time for exhalation. measure of how quickly his or her lungs can inflate or deflate
Clinicians must be alert to any sudden improvement in lung or how long it takes for alveolar and proximal airway pressures
compliance in infants receiving assisted ventilation (i.e., imme- to equilibrate. Passive exhalation depends on the elastic recoil
diately after administration of surfactant). If inspiratory pressure of the lungs and chest wall. Because the major force opposing
is not reduced as compliance improves, cardiovascular compro- exhalation is airway resistance, the expiratory time constant
mise may develop because proportionately more pressure is (Kt) of the respiratory system is directly related to both lung
transmitted to the mediastinal structures as lung compliance compliance (CL), which is the inverse of elastic recoil, and
improves. The distending pressure that was appropriate prior to airway resistance (R):
the compliance change may become excessive and lead to alve-
Kt = CL × Raw.
olar overexpansion and ultimately air leak.17 Because the chest
wall is compliant in the premature infant, use of paralytic agents The time constants of the respiratory system are analogous to
to reduce chest wall impedance should not be necessary. Little those of electrical circuits. One time constant of the respiratory
pressure is required to expand the chest wall of a premature system is defined as the time it takes the alveoli (capacitor) to
infant (see Fig. 2-2, “Chest Wall Curve”). In studies investigat- discharge 63% of its tidal volume (VT); (electrical charge)
ing the use of paralytic agents in premature infants at risk for through the airways (resistor) to the mouth or ventilator (elec-
pneumothoraces, no change in lung compliance or resistance trical) circuit. By the end of three time constants, 95% of the VT
was demonstrated after 24 or 48 hours of paralysis, and many of is discharged. When this model is applied to a normal newborn
the infants studied required more rather than less ventilator with a compliance of 0.005 L/cm H2O and a resistance of 30 cm
support after paralysis.18,19 One study demonstrated a modest H2O/L/sec, one time constant = 0.15 second and three time con-
improvement in chest wall compliance after paralysis, but the stants = 0.45 second.24 In other words, 95% of the last VT should
lung compliance was 20- to 30-fold greater than chest wall com- be emptied from the lung within 0.45 second of when exhalation
pliance; therefore, paralysis would not likely contribute to reduc- begins in a spontaneously breathing infant. In a newborn infant
ing the need for elevated distending pressures.20 Paralysis should receiving assisted ventilation, the exhalation valve of the venti-
be restricted to larger infants who are “fighting the ventilator” or lator would have to be open for at least that length of time.
are actively expiring against it despite the use of sedation and/or The concept of time constant provides a framework for under-
analgesia.18 Many centers use synchronized intermittent manda- standing the interactions between the elastic and resistive forces
tory ventilation or assist/control modes of ventilation in these and how the mechanical properties of the respiratory system
situations and attempt to avoid paralysis whenever possible. work together to modulate the volume and distribution of venti-
lation. A working knowledge of time constants aids the clinician
in choosing the safest and most effective ventilator settings for an
Resistance individual patient at a particular point in the course of a specific
Resistance is the result of friction. Viscous resistance is disease process that necessitates the use of assisted ventilation.
the resistance generated by tissue elements moving past one Patients are at risk for incomplete emptying of previously
another. Airway resistance is the resistance that occurs between inspired breath when their lung condition involves an increase
moving molecules in the gas stream and between these moving in airway resistance without a reduction in lung compliance.
22 2 / PHYSIOLOGIC PRINCIPLES

They also are at risk when the pattern of assisted ventilation disease states. Nasal airway resistance makes up approximately
does not allow sufficient time for exhalation, that is, the lungs two thirds of total upper airway resistance; the glottis and
have an abnormally long time constant, or there is a mismatch larynx contribute less than 10%; and the trachea and first four
between the time constant of the respiratory system (time con- or five generations of bronchi account for the remainder
stant of the patient + that of the endotracheal tube + that of the (Fig. 2-8).29 Average peak inspiratory and expiratory flow rates
ventilator circuit) and the expiratory time setting on the venti- in spontaneously breathing term infants are approximately 2.9
lator. In these situations, the end result is gas trapping. This gas and 2.2 L/min, respectively.28 Maximal peak inspiratory and
trapping is accompanied by an increase in lung volume and a expiratory flow rates average about 9.7 and 6.4 L/min, respec-
build-up of pressure in the alveoli and distal airways. Weigl25 tively.30 The range of flow rates generated by spontaneously
termed this pressure build-up inadvertent PEEP. breathing newborns (including term and premature infants) is
Important clinical and radiographic signs of gas trapping approximately 0.6 to 9.9 L/min. Turbulent flow is produced in
and inadvertent PEEP include (1) radiographic evidence of standard infant endotracheal tubes whenever flow rates exceed
overexpansion (e.g., increased anteroposterior diameter of the approximately 3 L/min through 2.5-mm internal diameter (ID)
thorax, flattened diaphragms below the ninth posterior ribs, tubes or 7.5 L/min through 3.0-mm ID tubes.31 Flow rates that
intercostal pleural bulging; (2) decreased chest wall movement exceed these critical levels produce disproportionately large
during assisted ventilation; (3) hypercapnia that does not increases in airway resistance. For example, increasing the rate
respond to an increase in ventilator rate; and (4) signs of car- of flow through a 2.5-mm ID endotracheal tube from 5 to
diovascular compromise, such as mottled skin color, a decrease 10 L/min raises airway resistance from 32 to 84 cm H2O/L/sec,
in arterial blood pressure, an increase in central venous pres- more than twice its original value.31
sure, or the development of metabolic acidosis. Flow conditions are likely to be at least partially turbulent
The time constant should be considered whenever the lung (“transitional”) when ventilator flow rates exceed 5 L/min in
condition for which a baby is receiving assisted ventilation infants intubated with 2.5-mm ID endotracheal tubes or when
involves increased compliance (with normal or abnormal rates exceed 10 L/min in infants with 3.0-mm ID endotracheal
airway resistance) or increased airway resistance (with or tubes. With turbulent flow, resistance increases exponentially.
without normal compliance). For example, RDS is associated Because resistance is measured as a pressure drop, when flow is
with decreased compliance but usually normal airway resist- turbulent the pressure delivered to the baby’s alveoli is less than
ance. This means that the time constant of the respiratory indicated on the pressure manometer at the airway. The volume
system is extremely short. Equilibration or equalization of the delivered is also less than would be expected, especially if the
airway and alveolar pressures occurs very quickly (i.e., early in
the inspiratory cycle). Reynolds26 estimated that the time con-
stant in RDS may be as short as 0.05 second. This means that
95% of the pressure applied to the airway is delivered to the
alveoli within 0.15 second. Ventilator adjustments that decrease
the risk of gas trapping and inadvertent PEEP include (1)
decreasing PIP (on a pressure-preset ventilator), (2) reducing
VT (on a volume-preset ventilator), (3) shortening the I-time
(Ti), and (4) increasing PEEP. Increasing PEEP has been shown
to reduce inadvertent PEEP in a lung model.27 However, over-
expansion of the lung with PEEP decreases dynamic compli-
ance, as previously described. Decreased compliance results in
a short time constant and thus fast lung emptying. Proximal
airway PEEP level does not indicate the level of alveolar PEEP,
nor does it demonstrate the occurrence of alveolar gas trapping.
Even under conditions of zero proximal airway PEEP, alveolar
PEEP levels and the degree of gas trapping may be dangerously
high if the baby has compliant lungs, increased airway resist-
ance, or both (i.e., a prolonged time constant).
Although it is useful clinically to think of the infant’s respi-
ratory system as having a single compliance and a single resist-
ance, we know this is not really the case. The resistance and
compliance values we obtain from pulmonary function meas-
urements are essentially weighted averages for the respiratory
system. There are populations of respiratory subunits with a
range of discrete compliance and resistance values, whereas Figure 2-8. Airway resistance to gas flow (solid circles) is inversely propor-
what we measure at the airway are averaged values for those tional to the total cross-sectional area of the airways (open circles).
Approximately 80% of airway resistance is encountered in the first few gen-
populations of subunits. erations of bronchi, where total cross-sectional area is the least. Pressure
decreases exponentially in regions of high-velocity turbulent flow, whereas
pressure decreases more linearly in regions of low-velocity laminar flow
Flow Rate further out in the periphery. (Reprinted and adapted by permission of the
publisher from The Pathway for Oxygen: Structure and Function in the
Average values for airway resistance in normal, sponta- Mammalian Respiratory System by Edward R. Weibel, pp. 285–286, 295,
neously breathing newborn infants are between 20 and 30 cm Cambridge, Mass.: Copyright © 1984 by the President and Fellows of
H2O/L/sec,28 and these values can increase dramatically in Harvard College.)
2 / PHYSIOLOGIC PRINCIPLES 23

ventilator rate is high or the I-time is short. The resistance pro- bronchi decrease in diameter as they extend toward the peri-
duced by infant endotracheal tubes is equal to or higher than phery, the total cross-sectional area of the airway (see Fig. 2-8)
that in the upper airway of a normal newborn infant breathing increases dramatically.35 Because resistance increases to the
spontaneously. The increased resistance due to the endotracheal fourth power as the airway is narrowed, even mild airway con-
tube poses little problem as long as the baby receives pressure striction can cause significant increases in resistance to flow.
support from the ventilator. The machine can generate the addi- This effect is exaggerated in newborn infants compared to
tional pressure needed to overcome the resistance due to the adults because of the narrowness of the infant’s airways.
endotracheal tube. However, when the infant is being weaned Resistance during inspiration is less than resistance during expi-
from the ventilator or if the infant is disconnected from the ven- ration because the airways dilate upon inspiration (Fig. 2-9).
tilator with the endotracheal tube still in place, the infant may This is true even though gas flow during inspiration usually is
not be capable of generating sufficient effort to overcome the greater than that during expiration. There is an inverse, non-
increase in upper airway resistance created by the endotracheal linear relationship between airway resistance and lung volume,
tube.32 LeSouef et al.33 measured a significant reduction in res- because airway size increases as FRC increases. Any process
piratory system expiratory resistance after extubation in prema- that results in an increase in lung volume (other than gas trap-
ture newborn infants recovering from a variety of respiratory ping caused by airway obstruction) should in theory reduce
illnesses, including RDS, pneumonia, and transient tachypnea resistance to airflow. Any processes that cause a reduction in
of the newborn. lung volume, such as atelectasis or restriction of expansion,
should result in increases in airway resistance. At extremely
low volumes, resistance approaches infinity because the pres-
Airway or Tube Length
sure drops below the critical closing pressure as residual
The shorter the tube, the lower the resistance. Shortening volume is approached (see Fig. 2-2).
a 2.5-mm ID endotracheal tube from 14.8 cm (full length) to The preponderance of evidence suggests that application of
4.8 cm reduces the flow resistance in vitro to essentially that of PEEP and CPAP decreases airway resistance.36–38 Endotracheal
a full-length tube of the next size (3.0-mm ID endotracheal tube resistance is of considerable clinical importance. It has
tube). Shortening the length of a 3.0-mm ID endotracheal tube been shown that successful extubation is accomplished more
by 10 cm makes the tube comparable to a full-length, 3.5-mm often in infants coming directly off of intermittent mandatory
ID endotracheal tube in terms of flow resistance. These rela- ventilation (IMV) than after a 6-hour pre-extubation trial of
tionships are consistent for the range of flows generated by endotracheal CPAP.32 Nasal CPAP circuit design and the means
spontaneously breathing newborns.34 by which nasal CPAP is attached to the patient are the most
important determinants of CPAP success or failure.39
Airway or Tube Diameter
Viscosity and Density
In a single-tube system the radius of the tube is the most
significant determinant of resistance. When flow is laminar, Gas viscosity is negligible in the determination of airway
resistance can be described by Poiseuille’s Law: resistance. However, gas density can be of clinical significance.
The relationship between airway resistance and the density of
R = L / r4. the gas in turbulent flow is directly proportional and linear.
Decreasing the density of the gas by two thirds, such as occurs
Resistance is a function of the tube length divided by the when a heliox mixture of 80% helium and 20% O2 is adminis-
radius of the tube to the fourth power. Therefore, reduction in tered, reduces airway resistance to one third compared to that
the radius by half results in a 16-fold increase in the driving when room air is breathed. Heliox can be useful for reducing
pressure required to maintain a given flow. In a multiple tube upper airway resistance (and work of breathing) in patients
system, like the human lung, resistance is dependent on the total with obstructive disorders such as laryngeal edema, tracheal
cross-sectional area of all of the tubes. Although the individual stenosis, and CLD.40 Gas density is influenced by barometric

Figure 2-9. Air trapping behind particulate matter


(e.g., meconium) in an airway, which leads to alveolar
overexpansion and rupture. This illustrates the so-called
ball-valve mechanism, in which tidal gas passes the
particulate matter on inspiration, when the airways nat-
urally dilate (A), but does not exit on expiration, when
the airways naturally constrict (B). (From Harris TR,
Herrick BR: Pneumothorax in the Newborn. Tucson, AZ,
Biomedical Communications, Arizona Health Sciences
Center, 1978.)
24 2 / PHYSIOLOGIC PRINCIPLES

pressure, so airway resistance is slightly decreased at high curve where the compliance is lower (see Fig. 2-3, region B).
altitudes. Reductions in respiratory work with the application of CDP have
been shown in newborns recovering from RDS44 and in babies
after surgery for congenital heart disease.37 If the lung already is
Work of Breathing overinflated, increasing CDP will not result in a decrease in the
Breathing requires the expenditure of energy. For gas to be work of breathing (see Fig. 2-3, region C). Alveolar overdisten-
moved into the lungs, force must be exerted in order to over- tion due to excessive CDP may be accompanied by an increase
come the elastic and resistant forces of the respiratory system. in PaCO2 (indicating decreased alveolar ventilation) and a
decrease in PaO2, despite an increase in FRC.36,45
Work of breathing = Pressure (force) × Volume (displacement)

Work of breathing is the force generated to overcome the


frictional resistance and static elastic forces that oppose lung GAS TRANSPORT
expansion and gas flow into and out of the lungs during respi-
ration. The workload depends on the elastic properties of the
Mechanisms of Gas Transport
lung and chest wall, airway resistance, VT, and respiratory rate.
Approximately two thirds of the work of spontaneous breath- Ventilation or gas transport involves the movement of gas
ing is to overcome the static elastic forces of the lungs and by convection or bulk flow through the conducting airways and
thorax (tissue elasticity and compliance). Approximately one then by molecular diffusion into the alveoli and pulmonary
third of the total work is to overcome the frictional resistance capillaries. This makes possible gas exchange (oxygen [O2]
produced by the movement of gas and tissue components (air uptake and carbon dioxide [CO2] elimination) that matches the
flow and viscous).41 In healthy infants exhalation is passive. A minute-by-minute metabolic needs of the patient. The driving
portion of the energy generated by the inspiratory muscles is force for gas flow is the difference in pressure at the origin and
stored (as potential energy) in the lungs’ elastic components; destination of the gases; for diffusion, it is the difference in the
this energy is returned during exhalation. If the energy required concentrations between gases in contiguous spaces. Gas flows
to overcome resistance to flow during expiration exceeds the down a pressure gradient and diffuses down a concentration
amount of elastic energy stored during the previous inspiration, gradient. The predominant mechanism of gas transport by con-
work must be done not only during inspiration but also during vection is bulk flow, whereas the predominant mechanism of
expiration; thus, exhalation is no longer entirely passive. gas transport by diffusion is Brownian motion.
In infants, energy expenditure correlates with oxygen con- Ventilation of the alveoli is an intermittent process that
sumption. Resting oxygen consumption is elevated in infants occurs only during inspiration, whereas gas exchange between
with RDS and CLD.42 Mechanical ventilation reduces oxygen alveoli and pulmonary capillaries occurs throughout the respi-
consumption by decreasing the infant’s work of breathing.13,43 ratory cycle. This is because a portion of gas remains in the
Work of breathing is illustrated in a dynamic pressure-volume lungs at the end of exhalation (FRC); the remaining gas pro-
loop (see Fig. 2-7). Pressure changes during breathing can be vides a source for ongoing gas exchange and maintains approx-
measured with an intraesophageal catheter or balloon, and imately equal O2 and CO2 tensions in both the alveoli and the
volume changes can be measured simultaneously with a pneu- blood returning from the lungs.
motachograph. During inspiration (ascending limb of the loop) During spontaneous breathing, inspiration is achieved
and expiration (descending limb of the loop), both elastic and through active contraction of the respiratory muscles. A nega-
frictional resistance must be overcome by work. If only elastic tive pressure is produced in the interpleural space, a portion of
resistance needed to be overcome, the breathing pattern would which is transmitted via the parietal and visceral pleura through
follow the compliance line; however, because airway resistance the pulmonary interstitial space to the lower airways and
and tissue viscous resistance must also be overcome, a loop is alveoli. A pressure gradient between the outside atmospheric
formed (hysteresis). The areas ABCA and ACDA in Figure 2-7 pressure and the airway and alveoli pressures results in gas
represent the inspiratory work and the expiratory work, respec- flowing down the pressure gradient into the lungs (Fig. 2-10).
tively, performed to overcome frictional resistance. The area Interpleural pressure is more negative than alveolar pressure,
ABCEA represents the total work of breathing during a single which is more negative than mouth and atmospheric pressures.
breath. When an infant receives negative-pressure ventilation, pres-
The diaphragm is responsible for the majority of the work- sure is decreased around the infant’s chest and abdomen to sup-
load of respiration. The most important determinant of the plement the negative-pressure gradient used to move gas into
diaphragm’s ability to generate force is its initial position, the the lungs. During positive-pressure ventilation the upper
length of its muscle fibers at the beginning of a contraction. airway of the infant (Fig. 2-11) is connected to a device that
The longer and more curved the muscle fibers of the diaphragm, generates a positive-pressure gradient down which gas can flow
the greater the force the diaphragm can generate. In situations in during inspiration. The pressure in the ventilator circuit and in
which the lung is hyperinflated (overdistended), the diaphragm the upper airway is greater than alveolar pressure, which is
is flattened and thus at a mechanical disadvantage. greater than interpleural pressure, which is greater than atmos-
The application of PEEP or CPAP (continuous distending pheric pressure.
pressure, or CDP) may reduce the work of breathing for an infant Expiration [except in high-frequency oscillatory ventilation
whose breathing is on the initial flat part of the compliance curve (HFOV)] is a passive event. Part of the energy produced by the
secondary to atelectasis (see Fig. 2-3, region A). In this situation, muscles during inspiration is stored in the respiratory system’s
CDP should reduce the work of breathing by increasing FRC and elastic components. At end-inspiration, the respiratory muscles
bringing breathing to a higher level on the pressure-volume relax or the exhalation valve opens, and the lungs and chest
2 / PHYSIOLOGIC PRINCIPLES 25

Figure 2-10. Negative-pressure gradient produced upon inspiration Figure 2-11. Positive-pressure gradient produced by a ventilator.
by the descent of the diaphragm in a spontaneously breathing infant. Pressures are measured in the airway (Paw) and as shown in Figure 2-10.
Pressures are measured in the interpleural space (Pip), in the alveoli (Palv), Paw > Palv > Pip > Patm. Abbreviations as in Figure 2.10.
and at opening of mouth or atmosphere (Patm). Pip < Palv < Patm.

wall return to their resting state due to elastic recoil. Exhalation than that of the physiologic dead space. They hypothesized that
is passive in that no active muscular work is performed during low-volume inspiratory pulses of gas moved down the center of
expiration under normal circumstances. the airway as axial spikes and that these spikes dissipated at the
The amount of gas inspired in a single spontaneous breath or end of each “breath” (Fig. 2-12). The faster the inspiratory pulse,
delivered through an endotracheal tube during a single cycle of the further it penetrated down the conducting airway and the
the ventilator is called the tidal volume (VT). VT in milliliters more expansive the boundary of mixing between the molecules
(mL) multiplied by the number of breaths per minute or respi- of the incoming gas (with high O2 and low CO2) and the outgo-
rator frequency (f) is called minute ventilation (VE): ing gas (with high CO2 and low O2). During this kind of breath-
ing, both convection and molecular diffusion are enhanced or
VE = VT × f. facilitated. The provision of a greater interface or boundary area
between inspiratory and expiratory gases with their different O2
The portion of the incoming VT that fails to arrive to the and CO2 partial pressures is known as radial diffusive mixing.
level of the respiratory bronchioles and alveoli but instead During high-frequency ventilation (HFV), with each inspiration
remains in the conducting airways occupies the space known as gas molecules near the center of the airway flow further than
the anatomic dead space. Another portion of VT may be deliv- those adjacent to the walls of the airway, because the gas travel-
ered to unperfused alveoli. Because gas exchange does not take ing down the center of the airway is exposed to less resistance.
place in these units, the volume that they constitute is called Figure 2-13A illustrates the velocity profiles using vectors that
alveolar dead space. Together, anatomic dead space and alveo- demonstrate the intra-airway flow patterns of gas molecules in a
lar dead space make up total or physiologic dead space (VDS). representation of the airway during inspiration. At the end of the
The ratio of dead space to tidal volume (VDS/VT) defines inspiratory phase, the contour of the leading edge of the inspired
wasted ventilation, which reflects the proportion of tidal gas gas is cone shaped (Fig. 2-13B), having a larger diffusion inter-
delivered that is not involved in actual gas exchange. face with the preexisting gas than would be present if the leading
A number of mechanisms of gas transport other than bulk edge was disk shaped. During exhalation, the velocity profiles
convection and molecular diffusion have been described. They are more uniform across the entire lumen rather than being cone
include axial convection, radial diffusive mixing, coaxial flow, shaped (Fig. 2-13C).48 The pulse of gas originally occupying the
viscous shear, asymmetrical velocity profiles, and pendelluft lumen of the airway is displaced to the right (i.e., toward the
effect.46 patient’s alveoli), and an equal volume gas is displaced to the left
Henderson et al.47 noted that during rapid shallow breathing (Fig. 2-13D). This occurs even though the net displacement of
or panting in dogs, adequate gas exchange was maintained even the piston during a cycle of HFOV is zero. The back-and-forth
though the volume of gas contained in each “breath” was less currents of gas recalculating through units of lung are called
26 2 / PHYSIOLOGIC PRINCIPLES

pendelluft.46,49 This gas flow is produced because of local differ-


ences in airway resistance and lung compliance that are accen-
tuated under conditions of high-velocity flow. This leads to
regional differences in rates of inflation and deflation. “Fast
units” with short time constants inflate and deflate more rapidly,
emptying out into the conducting airways to be “inhaled” by
“slow units” still in the process of filling (Fig. 2-14). These
recalculating currents of gas flow within the lung result in more
homogeneous gas mixing and exchange.

Fig. 2-12. Spike theory of panting or high-frequency ventilation.


A–C, The quicker or more “energy dense” the puff (or inspiratory pulse),
the sharper the spike and the further it extends into the airway. D, If the
pulse is suddenly stopped at end-inspiration, mixing instantaneously
occurs. (Modified from Henderson Y, Chillingworth FP, Whitney JL: The
respiratory dead space. Am J Physiol 38:1, 1915.)

Figure 2-13. Viscous shear and inspiratory-to-expiratory velocity profiles


associated with respiratory cycling. A, During inspiration or movement
toward the right, the gas molecules of a cylindrical tracer bolus that are sit-
uated near the center of the tube travel further and faster than the gas
molecules near the wall, as represented by the velocity profiles arrows at
the right. B, At the end of the inspiratory half of the respiratory cycle, a
paraboloid front has formed. C, During exhalation or movement toward
the left, the velocity profiles are essentially uniform across the lumen.
D, The end result after a complete respiratory cycle (with zero net direc-
tional flow) is displacement of axial gas to the right and wall gas to the
left. (Modified with permission from Haselton FR, Scherer PW: Bronchial
bifurcations and respiratory mass transport. Science 208:69, 1980.
Copyright 1990 American Association for the Advancement of Science.)

Figure 2-14. Effects of different time constants on the uneven distribu-


tion of ventilation and the production of “pendelluft.” A, On inspiration,
the fast unit receives the majority of ventilation, whereas the slow unit fills
slowly (owing to local increase in airway resistance). B, At the beginning
of expiration, the slow unit may still be filling and actually “inspires” from
the exhaling fast unit. These effects are accentuated at higher frequencies,
with gas “pendeling” back and forth between neighboring units with
inhomogeneity of time constants. (Modified from Otis AB, McKerrow CB,
Bartlett RA, et al: Mechanical factors in distribution of pulmonary ventila-
tion. J Appl Physiol 8:427, 1956.)
2 / PHYSIOLOGIC PRINCIPLES 27

OXYGENATION

Oxygen transport in the infant depends on the oxygen carry-


ing capacity of the blood and the rate of blood flow. The con-
centration of oxygen in arterial blood is called oxygen content
(CaO2).

CaO2 = (1.34 × Hb × SaO2) + (0.003 × PaO2)

where Hb is hemoglobin concentration and SaO2 is arterial


oxygen saturation. The contribution of hemoglobin to oxygen
content is described in the first term of the equation, which
states that each gram of hemoglobin will bind 1.34 mL O2
when fully saturated with oxygen. The second term of the equa-
tion describes the contribution of oxygen dissolved in the
plasma. Oxygen is contained in the blood in two forms: (1) a
small quantity dissolved in the plasma and (2) a larger quantity
bound to hemoglobin. The total O2 content of the blood is the
sum of these two quantities. The dissolved portion of O2 in
blood is linearly related to PO2, such that an increase in PO2 is Figure 2-15. Nonlinear or S-shaped oxyhemoglobin curve and the linear
accompanied by an increase in O2 content. Oxygen content or straight-line dissolved oxygen (O2) relationships between O2 saturation
increases 0.003 mL per 100 mL of blood with every 1 mm Hg (SaO2) and O2 tension (PO2). Total blood O2 content is shown with division
increase in PO2. For an infant breathing 21% O2, the dissolved into a portion combined with hemoglobin and a portion physically dis-
portion of the blood’s O2 content is only about 2% of the total. solved at various levels of PO2. Also shown are the major factors that
change the O2 affinity of hemoglobin and thus shift the oxyhemoglobin
However, for a patient breathing 100% O2, the dissolved dissociation curve to either the left or the right (see also Appendix 10).
portion of the blood’s O2 content is approximately 10% of the (Modified from West JB: Respiratory Physiology: The Essentials, 2nd ed.
total. The hemoglobin-bound portion of O2 content is nonlinear Baltimore, Williams & Wilkins, 1979, pp. 71, 73.)
with respect to PO2. This relationship is illustrated by the oxy-
hemoglobin dissociation curve, which is sigmoid (Fig. 2-15).
The amount of O2 that binds to hemoglobin increases quickly both. For example, when pulmonary arterial blood (which is
at low PO2 values but begins to level off at PO2 values greater rich in CO2 and poor in O2) passes through the lung’s capillar-
than 40 mm Hg. After PO2 exceeds 100 mm Hg, the curve ies, it releases its CO2; this raises local pH, which increases O2
flattens. Once the hemoglobin is saturated, further increases in affinity. This allows more of the incoming O2 to be bound to
PO2 do not increase the content of bound oxygen. Oxygen binds hemoglobin while plasma PO2 is kept low, thus maximizing the
reversibly to hemoglobin. Each hemoglobin molecule can bind concentration gradient down which O2 diffuses from the alveoli
up to four molecules of O2, and each gram of hemoglobin can into the pulmonary capillary plasma. Also, when systemic arte-
carry approximately 1.34 mL of O2 when fully saturated. The rial blood (which is rich in O2 and poor in CO2) enters the tissue
total amount of O2 carried by hemoglobin depends on the capillaries, it picks up CO2 (which is in high concentration in
hemoglobin concentration of the blood and the bloods’ oxygen the tissues). As a result, pH and O2 affinity are lowered; this
saturation. Several factors affect hemoglobin’s affinity for allows the hemoglobin to release its O2 without significantly
oxygen. These factors include the (1) percentages of fetal and decreasing PO2 and thus helps to maintain the concentration
adult hemoglobin present in the patient’s blood; (2) amount of gradient down which O2 diffuses into the tissues.50
2,3-diphosphoglycerate; (3) pH; (4) PCO2; and (5) temperature. SaO2 as monitored clinically with pulse oximetry shows the
A greater percentage of fetal hemoglobin (as seen in premature percentage of hemoglobin in arterial blood that is saturated
infants), a decrease in 2,3-diphosphoglycerate content (as with O2. The normal range of SaO2 in newborn infants is dif-
occurs in premature infants with RDS), alkalization of pH (e.g., ferent from that in adults; instead of SaO2 levels of 95% or
after infusion of bicarbonate), a reduction in PCO2 (secondary greater in adults, SaO2 levels of 88% to 92% may be adequate
to hyperventilation), and a decrease of body temperature (as for newborns. This is because the hemoglobin saturation curve
occurs during open heart surgery) all increase the O2 affinity of is shifted to the left due to the high percentage of fetal hemo-
hemoglobin (shift the oxyhemoglobin dissociation curve to the globin in the infant’s blood. This means that the baby has a
left without changing its shape). This means that the same level higher PaO2 at any given level of SaO2. Generally the O2
of hemoglobin saturation can be achieved at lower PO2 values. demands of most extremely premature infants can be met by
In contrast, increased production of 2,3-diphosphoglycerate (as maintaining PaO2 levels just above 50 mm Hg or SaO2 levels
occurs in healthy newborns shortly after birth or with adapta- just above 88%.51
tion to high altitudes), a reduction of the percentage of fetal The O2 content of the blood is only one of a number of
hemoglobin (e.g., after transfusion of adult donor blood to a important factors that the clinician must keep in mind. Others
newborn infant), a more acidic pH, CO2 retention, and febrile include (1) myocardial contractility; (2) heart rate and stroke
illness each results in a reduction in O2 affinity (shift of the volume (cardiac output); (3) mean systemic blood pressure and
oxyhemoglobin dissociation curve to the right) (Fig. 2-15). peripheral vascular resistance; and (4) venous return to the
Some shifts in the oxyhemoglobin dissociation curve heart. These cardiovascular parameters demand the clinician’s
promote O2 uptake in the lungs, O2 release at the tissue level, or constant attention because assisted ventilation may have
28 2 / PHYSIOLOGIC PRINCIPLES

adverse effects on cardiac output, venous return, and pul- 66 mm Hg is obtained (instead of the approximately 100 mm
monary blood flow. The partial pressure of O2 in arterial blood Hg that would be expected at sea level). Therefore, the infant
(PaO2) is the amount of O2 physically dissolved in the arterial has about one third less available oxygen in the alveoli when
blood plasma and is expressed in millimeters of mercury (mm breathing room air in Denver compared to when breathing room
Hg) or in torr. PaO2 is measured directly as part of blood gas air at sea level. It the infant was being treated with 100% oxygen
analysis. PaO2 is a useful indicator of the degree of O2 uptake (FIO2 = 1.0), the relative deficit remains. In Denver, PAO2 while
through the lungs. The fraction of inspired O2 (FIO2) is the pro- breathing 100% oxygen would be about 503 mmHg, whereas at
portion of O2 in the inspired gas. FIO2 is measured directly with sea level PAO2 would be about 663 mmHg.
an O2 analyzer and is expressed as a percentage (e.g., 60% O2) Some blood gas derivatives are useful as clinical indicators
or in decimal form (e.g., 0.60 O2). The FIO2 in room air is 0.21. of disease severity. They include the following:
The partial pressure of O2 in alveolar gas (PAO2) is the amount
1. Arterial-alveolar O2 tension ratio (PaO2/PAO2, or the a/A ratio)
of O2 present in the gas mixture delivered to the alveoli. PAO2
2. Alveolar-arterial O2 gradient or difference (PAO2–PaO2)
relates directly to the number of O2 molecules available for dif-
3. Oxygenation index PAW × FIO2
fusion into the pulmonary capillary blood. To calculate the
absolute amount of O2 in alveolar gas, we use the alveolar gas
( PaO2 )
equation: The oxygenation index factors in the pressure cost of
achieving a certain level of oxygenation. An oxygenation index
PAO2 = (Barometric pressure – Partial pressure of water vapor) greater than 15 signifies severe respiratory compromise. An
× FIO2. oxygenation index of 40 or more on multiple occasions indi-
cates a mortality risk approaching 80%, which justifies the
At sea level, the alveolar gas equation for breathing room air need for extracorporeal membrane oxygenation in most level
is as follows: III neonatal centers.52
PAO2 = (760 – 47) × 0.21.
Effects of Altering Ventilator Settings
PAO2 is approximately 150. on Oxygenation
This value does not represent the exact quantity of oxygen Oxygen uptake through the lungs can be increased by (1)
arriving at the alveoli because the gas on its way to the alveoli increasing Pao2 (increasing the pressure gradient), or by
mixes with CO2 in an amount that is dependent upon the degree increasing the FIO2 (increasing the concentration gradient); (2)
of alveolar ventilation. Because the sum of the partial pressures optimizing lung volume (increasing the surface area for gas
of all gases within the alveoli must remain the same (i.e., equal exchange); (3) maximizing pulmonary blood flow (preventing
to barometric pressure), when PCO2 increases, PO2 must blood from flowing left-to-right through intracardiac or ductal
decrease (and vice versa). The partial pressure of CO2 in the shunts); and (4) optimizing ventilation-to-perfusion (V/Q)
alveoli, or PACO2, is nearly identical to the amount of CO2 matching in all parts of the lung.
physically dissolved in the arterial blood, or PaCO2. One addi- There are functionally three ventilator changes available to
tional correction factor must be used. This is called the respi- the clinician:
ratory quotient, which is the ratio of CO2 excretion to O2
uptake. The respiratory quotient ranges from approximately 0.8 1. Alter FIO2, PAO2, or both.
to slightly greater than 1.0, depending on diet. A high-carbohy- 2. Alter mean airway pressure (PAW).
drate diet raises the respiratory quotient, thus decreasing CO2 3. Alter the pattern of ventilation (i.e., extent and duration of
production. Generally, with a typical diet more O2 is consumed the various components of applied airway pressure).
than CO2 is eliminated, yielding a respiratory quotient of about Figure 2-16 is a graphic representation of the proximal
0.8. The alveolar air equation allows for an accurate calculation airway pressure plotted against time during a ventilation cycle
of PAO2 as follows: with a conventional ventilator. Control variables for conven-
tional mechanical ventilation include the following:
PAO2 = [(Barometric pressure – Partial pressure of water
1. Inspiratory flow
vapor) FIO2] × PACO2 / R,
2. PIP
where R is the respiratory quotient. 3. I-time (Ti)
It is important to remember that PACO2 is decreased by 4. PEEP
hyperventilation and that the decrease in PACO2 is matched by 5. Rate (f)
an equal increase in PAO2. Barometric pressure varies with Control variables for high-frequency jet ventilators are
weather conditions and altitude. To demonstrate the effect of similar to those for conventional ventilation.
altitude on the absolute amount of oxygen available at the alve- The control variables for HFOV are as follows:
olar level, let us consider an infant with PACO2 of 40 mm Hg and 1. MAP
respiratory quotient of 0.8 who is breathing room air in Denver, 2. ΔP (amplitude)
Colorado, which is located 5280 feet above sea level and has an 3. Frequency (expressed in Hertz)
average barometric pressure of approximately 600 mm Hg. 4. I-time (%)
Subtracting 47 mm Hg from 600 mm Hg yields 553 mm Hg,
which, when multiplied by 0.21, gives a value of around In order to compare HFV with conventional mechanical ven-
116 mm Hg. After subtracting the dividend of 40 mm Hg/0.8, or tilation, a composite outcome variable called the Fujuwara ratio
50 mm Hg, from 116 mm Hg, a PAO2 value in Denver of only is useful.53 It is expressed as PAO2/FIO2/MAP. This ratio is
2 / PHYSIOLOGIC PRINCIPLES 29

Figure 2-16. Five different ways to increase


mean airway pressure: (1) increase inspiratory flow
rate, producing a square-wave inspiratory pattern;
(2) increase peak inspiratory pressure; (3) reverse
the inspiratory-to-expiratory ratio or prolong the
I-time without changing the rate; (4) increase
positive end-expiratory pressure; and (5) increase
ventilatory rate by reducing expiratory time without
changing the I-time. (Modified from Reynolds EOR:
Pressure waveform and ventilator settings for
mechanical ventilation in severe hyaline membrane
disease. Int Anesthesiol Clin 12:259, 1974.)

similar to the oxygenation index and relates oxygenation (cor-


rected for different levels of ambient O2 concentration) to MAP. TABLE 2-1. Cost Benefit Considerations When
The clinician should formulate a hypothesis based on a Applying Different Degrees of Various
physiologic rationale, make a ventilator change, and observe Components of Assisted Ventilation Therapy
the response. This provides the clinician with feedback that Therapy Cost Benefit
either confirms or refutes the hypothesis. Ventilator changes
may have adverse hemodynamic effects. In addition, because High PIP Barotrauma Increase VT
ventilators are powerful tools, they can cause significant Increase MAP
Low PIP Atelectasis Less barotrauma
damage if they are not used judiciously (Table 2-1). We must High PEEP Increase MAP Less barotrauma
learn from experience (our own and that of others) and apply Decrease VT
that knowledge when making ventilator setting changes during Low PEEP Atelectasis Less barotrauma
assisted ventilation of the newborn. Increase VT
The effects of alterations in inspiratory flow rate on PaO2 High IMV Increase shearing forces Higher V·E
rate Increase airway resistance Lower VT
and right-to-left shunting (while holding frequency and VT Low IMV Larger airway distention Less shearing forces
constant) were studied in seven newborn infants with RDS and rate Lower airway resistance
two with meconium aspiration syndrome. The highest PaO2 High FIO2 Oxygen toxicity Lower MAP
values and the lowest calculated right-to-left shunt values Low FIO2 Higher MAP Less O2 toxicity
Long Ti Higher MAP Lower IMV
obtained coincided with the middle range of inspiratory flow More pressure transmitted Lower FIO2
rates (75–150 mL/sec). The investigators used a volume venti- to terminal lung regions
lator and maintained ventilator frequency constant; therefore Inadvertent PEEP
they were altering the I/E ratio (calculated to range from Short Ti Lower MAP Less pressure transmitted
1:1–1:6.5) as they increased inspiratory flow rate in increments Higher IMV rates to terminal lung
regions
of 25 mL/sec over the machine’s range of 50 to 200 mL/sec.
The highest PaO2 and the lowest calculated right-to-left shunt FIO2, fraction of O2 or O2 concentration expressed as a percentage; IMV,
values coincided with I/E ratio settings in the range from 1:3 intermittent mandatory ventilation; MAP, mean airway pressure; PEEP, positive
to 1:4.54 end-expiratory pressure; PIP, peak inspiratory pressure; Ti, inspiratory time;
VT, tidal volume.
The effects of two different I/E ratio settings (1:2 and 2:1)
on the degree of oxygenation in newborn infants receiving
assisted ventilation from conventional pressure-preset ventila-
tors for treatment of severe RDS have been studied.55 The of reverse I/E ratios as a means of improving oxygenation
authors randomly assigned 69 premature infants to one or the while lowering PIPs in newborns with severe RDS was first
other pattern of ventilation early in the course of their disease. explored many years ago.56 It was demonstrated that prolong-
Flow rates were held constant and frequency never exceeded ing IT or reversing the I/E ratio leads to higher PaO2 values and
40 breaths per minute. All other settings, such as PIP, PEEP, a reduction in calculated right-to-left shunting. It also was
and FIO2, were adjusted to keep arterial blood gas values within demonstrated that PEEP added to this method “acted synergis-
specified ranges. Results showed that the study group patients tically” to increase PaO2 and reduce PAO2.
(who were receiving the I/E ratio of 2:1) needed less time in O2 Advocates for the use of short I-times argue that in situ-
concentrations greater than 60% than did the control group. ations in which the time constant is short (as in RDS), it takes
They also required less time in PEEP greater than 3 cm H2O. very little time for pressure equilibration (or volume delivery),
There were no differences in mortality or morbidity. The idea so a long IT will needlessly “expose” the lung to pressure, thus
30 2 / PHYSIOLOGIC PRINCIPLES

predisposing the airways to stretch injury and volutrauma.


Remember that once the pressure reaches a plateau, no addi- TABLE 2-2. Specific Effects of Different Ventilator
tional volume is being delivered to the lung. Using high- Changes
frequency jet ventilation (HFJV), it was shown that ventilation Increasing PIP
(CO2 excretion) is improved by shortening IT as long as VT is 1. Increases VT and V·E
kept constant. However, oxygenation varied only slightly and 2. Adds little to MAP unless combined with a reversal of I/E ratio or
inconsistently with differing I/E ratios and inspiratory wave- prolongation of Ti
3. Affects maximal dilation of alveoli already open, contributing to
form shapes.57,58 In newborn infants receiving HFJV for severe barotrauma
restrictive lung disease, it has been shown that oxygenation 4. Opens alveoli with high critical opening pressures
improves with shortening of IT as long as PIP is held constant,
Reversing the I/E Ratio (or Lengthening Ti While the
even though MAP is thereby slightly reduced.59,60 Respiratory Rate Is Kept Constant)
The SensorMedics 3200 HFOV allows the operator to alter 1. Has little effect on VT or V·E beyond the minimum Ti needed to
I/E ratios (although in practice this is rarely done). In general, deliver VT or reach desired PIP level (or both)
most clinicians operate this high-frequency oscillator at an I/E 2. Can contribute on more than 1:1 basis to MAP, depending on
original PIP and degree of reversal of I/E ratio
ratio of 1:3 and do not attempt to improve oxygenation by alter- 3. Allows expansion of atelectatic alveoli at lower PIP
ing this parameter. In a study in which saline lung-lavaged 4. May cause inadvertent PEEP, overinflation of alveoli, and
rabbits were treated with HFOV (SensorMedics 3200), random reduction of pulmonary blood flow
alteration of the I/E ratio between 2:1 and 1:2 produced no Increasing Background CPAP or PEEP
significant effect on oxygenation, ventilation, or cardiovascular 1. Decreases VT and V·E unless significant atelectasis is overcome
function.61 The likelihood of gas trapping is assumed to be 2. Adds to MAP on a 1:1 basis
reduced when an I/E ratio of 1:3 is used, although this claim 3. Holds open alveoli and terminal airways on end-expiration, thus
raising closing volume and aiding in equal distribution of
was not directly addressed in the study by Courtney et al.61 ventilation
Several studies have investigated the role of MAP on over- 4. Reduces likelihood of inadvertent PEEP
coming atelectasis and improving oxygenation.53,62,63 It was
demonstrated that MAP is the parameter that best correlates CPAP, continuous positive airway pressure; I/E ratio, inspiratory-to-expiratory
with improvement in oxygenation in premature lambs with ratio; Ti, inspiratory time; IMV, intermittent mandatory ventilation; MAP, mean
airway pressure; PEEP, positive end-expiratory pressure; PIP, peak inspiratory
RDS delivered by cesarean section.63 Also, in human newborns pressure; V·E, expiratory minute ventilation; VT, tidal volume.
it has been demonstrated that “the shape of the airway pressure
wave per se does not appear to be particularly significant.
Rather, the shape of the wave seems important only because of best-ventilated regions and shift of more blood flow to less
the changes it causes in MAP.”62 In most circumstances, MAP well-ventilated areas.
is the major determinant of oxygenation. This appears to hold A variety of modalities of HFV, applied alone or in tandem
true for conventional ventilation,62,64,65 as well as for the with IMV, including high-frequency positive-pressure ventila-
various forms of HFV.66–68 The specific alteration of pressure tion,72 HFOV,73 HFJV,74–78 and HFOV in combination with
waveforms used to increase the MAP is a powerful means of IMV,79 have been shown to be effective in achieving compara-
achieving specific goals other than the improvement of oxy- ble levels of gas exchange at lower PIPs and at the same or
genation in the newborn infant receiving assisted ventilation. lower MAP in patients with intractable respiratory failure due
Table 2-2 lists the specific effects that can be achieved with to PIE. Significantly lower PaO2/FIO2/MAP values were demon-
alteration of the pressure waveform in various ways. Ventilator strated for the majority of patients who were switched from
setting changes that contribute to increases in MAP during con- conventional mechanical ventilation to HFJV.74,75,78
ventional ventilation produce different degrees of PaO2 increase A controlled study performed by Boros and Campbell53
per unit increase of MAP. In an elegant study performed on 20 compared the effects on oxygenation of high-frequency, low-
newborn infants treated with conventional mechanical ventila- VT ventilation with those of low-frequency, high-VT ventila-
tion for respiratory failure (due to RDS in 13), the changes in tion using a volume-preset ventilator. The best arterial
PaO2 due to change in MAP were compared.64 If an increase in oxygenation was found to occur at the combination of settings
PaO2 is the primary objective and an increase in MAP is not that produced the highest MAP, once again confirming that
contraindicated, then one can best achieve the goal first by oxygenation is predominantly related to MAP.53 Rapid-rate
increasing PEEP, then increasing PIP, and finally increasing the IMV (otherwise known as high-frequency positive-pressure
IT. Increases in PEEP to greater than 5 or 6 cm H2O produce ventilation) has become a popular modality of ventilation for
decreasing effects (per unit of change) and in some cases even certain categories of severely ill neonatal patients. A higher rate
adverse effects on oxygenation.69 Reports have been published means that less time is available for volume delivery and pres-
about patients treated for RDS with conventional IMV or CPAP sure equilibration; thus, VT may be reduced accordingly. Also,
alone who had a paradoxical or reverse response to an increase the higher the frequency or inspiratory flow rate, the greater the
in MAP.70,71 These reports indicate that PaO2 decreases instead proximal-to-distal airway pressure drop-off during inspiration
of increasing in direct proportion to further increases in MAP. due to the increased resistance produced by turbulent flow.
Nelson et al.71 observed such a reverse effect of increased Thus, the distal airways and alveoli may not be receiving the
hypoxemia and right-to-left shunting (instead of improved desired PIP (unless, again, IT adjustments are made).80
oxygenation) in fewer than 3% of all newborn infants receiving However, lengthening IT to achieve better volume and pressure
CPAP for RDS or related respiratory distress. They postulated delivery to the distal airways and alveoli as the ventilator rate
that the net effect of CPAP in these cases was overexpansion of increases means shortening the exhalation time. When insuffi-
portions of the lung leading to compression of capillaries cient time is provided for exhalation, inadvertent PEEP may
around the alveoli, thus causing a reduction in blood flow to the become a problem. Inadvertent PEEP and gas trapping could
2 / PHYSIOLOGIC PRINCIPLES 31

overexpand the lung to the point that pulmonary blood flow is sions affect the distribution of air to the gas exchange units.
compromised, thus reducing oxygenation and leading to CO2 The pulmonary arteries, like the airways, form a treelike struc-
retention. ture. The pulmonary circulation is perfused by the entire
A study reported by Gonzalez et al.81 demonstrates how cardiac output. Blood flow is determined by the pressure dif-
serious inadvertent PEEP may become when rapid-rate IMV or ference between pulmonary arteries and veins and by the vas-
high-frequency positive-pressure ventilation is used. Rabbits, cular resistance. The pulmonary circulation is a low-pressure
whose lung mechanics are similar to those of human infants, low-resistance system. The distribution of blood flow to the
were ventilated at rates of 30, 60, 90, and 120 breaths per gas exchange units depends on the distribution of resistances,
minute, while I/E ratio and proximal distending airway pres- which are affected by contraction of the smooth muscle wall of
sures were kept constant at 1:2 and 17/2, respectively. In going the arteries. In hypoxia, resistance increases. There are regional
from 30 to 60 breaths per minute under these conditions, both differences in ventilation and perfusion. The dependent por-
ventilation and oxygenation improved with only a minimal tions of the lung are better ventilated and better perfused than
increase in tracheal pressure and lung volume (FRC). However, the upper portions. Hypoxic vasoconstriction shunts blood
after the rate was increased to 120 breaths per minute, inadver- away from poorly ventilated acini, which helps to preserve V/Q
tent PEEP developed, as manifest by an increase in FRC matching. Ideally ventilation and perfusion are evenly
without an increase in PaO2. Serious concern (based mainly on matched, with a V/Q ratio of 1. When a lung or lung unit is rel-
theoretic considerations) about the possibility of inadvertent atively underventilated but normally perfused or is normally
PEEP and gas trapping has been expressed in relation to both ventilated but overperfused, it is said to have a low V/Q (<1).
HFOV82 and HFJV.24 In the case of HFOV, it is mainly the When a lung unit is overventilated and normally perfused or is
extremely high rates used (15–25 Hz, or 900–1500 cycles per normally ventilated and underperfused, the resultant V/Q is
minute) that have given cause for concern; in contrast, in the high (>1).
case of HFJV, it is the slower “passive” exhalation that worries With each breath, inspired gas is distributed by bulk flow to
clinicians. Kolton et al.83 demonstrated that the mean lung the distal airways, depending on the length of the conducting
volume of rabbits treated with HFOV was significantly greater airways and the rate of flow through them. Gas flow rates are
than that of rabbits treated with conventional mechanical ven- determined by local differences in driving pressure, flow resist-
tilation. Simon et al.82 demonstrated that proximal MAP (as ance, tissue elasticity, and compliance. For spontaneous breath-
normally monitored in neonatology) is an underestimation of ing, the driving pressure is the interpleural pressure swings
mean alveolar pressure. Actual measurement of inadvertent generated during inspiration; during assisted ventilation, the
PEEP with the use of the proximal airway occlusion technique transpulmonary pressure swings are produced by the forces
performed by Bryan and Slutsky84 on lung-lavaged rabbits and exerted by the ventilator (see Figs. 2-10 and 2-11). In the
on nine newborn infants with either RDS or persistent pul- healthy lung, local differences in interpleural or transpul-
monary hypertension (PPHN) being treated with HFOV monary pressure are responsible for most of the regional dif-
revealed no significant trapping of air with rates of 15 to 25 Hz, ferences in ventilation. In the sick lung, local differences in
which is the range usually applied to newborns. compliance and airway resistance (time constants) are the
major contributors to uneven distribution of ventilation. The
distribution of ventilation can be measured by having a patient
breathe an inert radioactive gas such as xenon-133. Because
VENTILATION xenon is inert and therefore is not reabsorbed, it simply fills the
ventilated airways and alveoli. Scintillation counters can be
For gas exchange to occur efficiently, ventilation and perfu- used to locate and quantify the areas of ventilation. Bryan et
sion must be well matched. Gas is distributed through the lung al.85 showed that the dependent lung regions in normal subjects
via the airways. The volume of gas moved into and out of the have a greater regional volume expansion ratio (change in
lung with each normal breath is the VT. The largest volume that volume per unit of preinspiratory volume) than do the nonde-
can be inhaled after a full exhalation is the vital capacity. The pendent regions of lung. When a patient is upright, the basal
volume of gas that remains in the lung after a normal expiration regions of the lung are ventilated to a greater extent than are the
is the FRC. The volume that remains in the lung after a apical regions. When a patient is supine, the basal and apical
maximal expiration is the residual volume. Residual volume regions are ventilated to a similar extent, but the posterior (low-
and vital capacity together are the total lung capacity. The ermost) regions are ventilated to a greater extent than the ante-
product of tidal volume and breathing frequency is the minute rior regions (uppermost). It is important to remember, however,
volume. Only a portion of our minute volume actually reaches that at the end of a normal exhalation (at FRC) the volume in
the alveoli. The volume of the conducting airways is called the the uppermost regions of the lung is greater than that of the
anatomic dead space. As respiratory rate and/or VT are dependent regions (Fig. 2-17). This may appear contradictory,
increased, minute ventilation increases. Alveolar ventilation but these differences can be explained on the basis of regional
increases even more than minute ventilation because the interpleural pressure differences (Fig. 2-18). Interpleural pres-
anatomic dead space remains constant. The dimensions of the sure at end-expiration is more negative in the uppermost por-
airway system influence ventilation. With progressive dichoto- tions than in the dependent portions of the lung. Converting the
mous branching moving toward the lungs periphery, the overall interpleural pressures to transpulmonary pressures, one can
cross-sectional area of the airways increases, so airflow velo- plot a pressure-volume curve (lower right of Fig. 2-18). When
city decreases, as does resistance. the lungs are inflated starting from FRC, the dependent lung
The dimensions of the airways determine resistance to units will receive proportionately more of the inspired gas and
airflow; resistance falls toward the periphery of the lungs as the the nondependent units will receive proportionally less as the
cross-sectional area increases. Differences in airway dimen- height above the dependent units increases. The basilar units
32 2 / PHYSIOLOGIC PRINCIPLES

Figure 2-17. Although the upper parts of the lung are more expanded or
hold a greater volume at end-expiration or the functional residual capacity
level of expansion than do the lower parts, the latter show greater volume
changes (i.e., ventilation changes) than do the former during tidal breath-
ing. This occurs because the lower parts are situated on a steeper portion of
the compliance or pressure-volume curve and achieve a greater ΔV per unit
of ΔP. (Reprinted and adapted by permission of the publisher from The
Pathway for Oxygen: Structure and Function in the Mammalian Respiratory
System by Edward R. Weibel, pp. 285–286, 295, Cambridge, Mass.: Copyright
© 1984 by the President and Fellows of Harvard College.)

Figure 2-18. Effect of the interpleural pressure gradient up


the lung upon the distribution of ventilation. The greatest
negative pressure is at the top owing to the gravitational tug
(weight) of the lung through its visceral pleura on the parietal
pleura. Because the upper and lower areas are on different
parts of the pressure-volume curve, different amounts of
volume (ventilation) are achieved by the two areas given the
same pressure change. The steeper compliance line for the
lower area means a greater increase in volume per unit pres-
sure change. (Modified from West JB: Respiratory Physiology:
The Essentials, 2nd ed. Baltimore, Williams & Wilkins, 1979,
p. 96.)

are stretched proportionately more than the higher units FRC or rest volume actually reverses the pattern of the distribu-
because they are operating on a steeper slope of the volume- tion of ventilation.87 If inspiration is started from a low level of
pressure curve. Compliance increases progressively from the lung volume, interpleural pressures are less negative overall
highest portion of the lung to the most dependent portion or (because elastic recoil is minimal at these low lung volumes) and
from high starting lung volumes to lower volumes. At the even may be positive in the more dependent regions of the lung.
beginning of a gradual inflation from FRC, the more dependent When regional interpleural pressure exceeds (is more positive
lung regions operate on a steeper part of the compliance curve than) airway pressure, then airway closure occurs and no gas
than the less dependent regions, so ventilation is greater in the enters that segment for the first portion of inspiration or until
dependent regions. regional interpleural pressure decreases to below airway pressure
Lung units that contain collapsed airways require large pres- further along into inspiration. Thus, ventilation is reduced in
sure changes before the airways open to permit gas transfer. dependent regions and is redirected to the upper lung regions,
These units are not ventilated as well as units in which the making them the better-ventilated areas; this is a reversal of
airways are patent from the start. Units with high resistance are the usual pattern. During assisted ventilation, inflation at end-
ventilated poorly regardless of their position, because these units inspiration is uniform, as evidenced by the observation of alveoli
have low compliance for any given transpulmonary pressure. of equal size throughout the lung.88 At end-expiration or FRC
In newborn infants, airway closure may be present in the resting level, however, alveoli in the uppermost regions of the lung are
VT range, unlike older individuals in which pleural surface pres- found to have a volume fourfold that of alveoli at the base.
sure at FRC is substantially subatmospheric throughout the lung, Moderate levels of PEEP (<6 cm H2O) increase FRC more in
thus preventing airway closure while the lung is at operational dependent regions than in upper regions of the lung because the
volume.86 Starting inspiration from a lung volume that is below former are less well expanded initially and are at a lower and
2 / PHYSIOLOGIC PRINCIPLES 33

more favorable point on their compliance curve. If significant area makes that lung less compliant than the normal lung; thus,
basilar atelectasis pre-exists, the addition of PEEP or CPAP the affected lung receives less volume per unit pressure than do
should help the most in the more dependent areas, opening them the unaffected areas. Differences in distal airway resistance
for improved regional ventilation. All forms of CDP favor uni- may be caused by local narrowing secondary to either obstruc-
formity of ventilation because they expand airways and thus tion or compression. For example, partial obstruction of a
lower resistance and because they prevent airway closure and bronchus with meconium increases airway resistance and
gas trapping during forced exhalation. reduces alveolar ventilation in the area behind the partial
Gravitational effects on the distribution of ventilation have obstruction (see Fig. 2-14). Many disease processes common in
been exploited in adult patients with or without ventilatory premature infants involve nonuniform regional compliance.
assistance who have unilateral lung disease89 or who have During conventional mechanical ventilation, distribution of the
undergone thoracotomy.90 Improved gas exchange in these inspired gas is largely controlled by regional variations in com-
patients can be accomplished if they are positioned with their pliance. During HFV, the distribution of inspired gas is more
“good” side down. This technique increases ventilation to the dependent on the mechanical properties of the central airways
dependent lung regions, which also receive relatively greater and chest wall (resistance, inertance) and less so on the com-
blood flow, resulting in better V/Q matching in the good lung. pliance of lung tissue. If inspiratory pressure is increased
Body position affects ventilation and gas exchange in infants in slowly (low inspiratory flow rate), the volume of gas delivered
the opposite way. When infants with unilateral lung disease are depends mainly on the compliance of the lung. If inspiratory
placed in the lateral decubitus position, the uppermost “good” pressure is increased quickly (high inspiratory flow rate), the
lung receives a greater portion of ventilation than the depend- distribution of gas depends mainly on local airway resistance.
ent lung. This may be the case for infants with restrictive lung Consequently, the largest volumes are delivered to areas with
disease such as unilateral PIE. In cases of unilateral PIE, one the least resistance. This information is useful to the clinician
sees ideal circumstances for the occurrence of airway closure in trying to decide how best to ventilate a patient with meconium
the “bad” lung when it is placed in the dependent position. In aspiration syndrome. One would like to be able to ventilate the
patients with unilateral tension PIE, interpleural pressure on the patient’s unobstructed lung regions while minimizing air trap-
bad side already is elevated secondary to the presence of high ping and overdistention in areas behind partially obstructed
(positive) interstitial pressure due to gas trapping outside of the airways (see Fig. 2-9). One approach is to use rapid rates (high
terminal air spaces. Positioning patients with this side down inspiratory flows) and short ITs. In this fashion, only regions of
adds the additional weight of the mediastinal structures, which the lung with short (or normal) time constants are given
causes the interpleural pressure to exceed local airway pressure sufficient time for pressure equalization (volume delivery);
and results in airway collapse. This airway closure in the thus, these areas are being ventilated while overdistention of
dependent (bad lung) often facilitates resolution of unilateral lung regions with long time constants is avoided. In cases of
PIE, while the infant’s gas exchange needs are met by the non- pulmonary air leak (pneumothorax or bronchopleural fistula), a
dependent lung.91,92 strategy incorporating short IT and a high rate often is effective
The pattern of diaphragmatic motion plays a role in the dis- in decreasing the magnitude of the leak. Several reports have
tribution of ventilation in the newborn infant. When the described the successful application of HFV in adults with
diaphragm is paralyzed and the patient is supine, mechanical airway disruption or bronchopleural fistulae96,97 and in new-
ventilation tends to produce greater motion of the superior than borns with persistent air leaks through pneumothoraces.98 In
of the inferior portion of the diaphragm because the superior cases of PIE, the use of low rates and long ITs might worsen the
portion is less constrained by the abdominal contents and medi- clinical situation. Because the lung regions with PIE have long
astinal structures. Therefore, there is preferential ventilation of time constants (due to elevated compliance and resistance),
the upper (anterior) segments of the lung.93 Because perfusion they could become further overdistended with this mode of
still is likely to be better in the dependent regions secondary to ventilation. If ventilated with a conventional ventilator using
gravitational effects, paralysis may result in V/Q mismatch high rates and short ITs or if ventilated with an HFV, lung areas
with hypoxemia. The improvement in oxygenation achieved with long time constants would be less likely to become over-
after adults with acute respiratory failure94 or premature infants distended. As the PIE resolved and the compression effects on
with respiratory insufficiency95 are switched from the supine to the surrounding lung tissue were alleviated, the distribution of
the prone position is attributable to the enhancement of V/Q ventilation would more homogeneous.74,75 The clinician’s
ratios (or an increase in ventilation to a level that better choice of strategy and mode of ventilation can be important
matches the existing degree of perfusion). In premature infants determinants of the distribution of ventilation, particularly in
the prone position affords better distribution of ventilation situations of nonhomogeneous lung disease.
throughout the lung, especially to the dependent regions that During assisted ventilation, to minimize risk to the infant the
are better perfused.95 The most common causes of uneven dis- minimal pressure required to achieve adequate gas flow and
tribution of ventilation are conditions characterized by local alveolar ventilation should be used. Enough distending pressure
differences in lung compliance, airway resistance, or both. If should be applied to prevent airway collapse and enough driving
the patient is receiving assisted ventilation and is faced with pressure should be applied so as to achieve an appropriate VT.
local differences in either lung tissue elasticity or airway resist-
ance, the distribution of gas delivered during the inspiratory Effects of Altering Ventilator Settings
phase is influenced by the mode of ventilation chosen. Local or
regional (lobar) variations in compliance are determined by (1) on Ventilation
local tissue water content; (2) presence or absence of surfac- During conventional ventilation, increasing VT or increasing
tant; (3) presence of volume loss; or (4) presence of gas trap- the ventilator rate are the two primary methods for increasing
ping or overexpansion. For example, pneumonia in one lung ventilation (enhancing CO2 removal). The ventilator rate is
34 2 / PHYSIOLOGIC PRINCIPLES

controlled either directly or by altering the I/E ratio. VT is con- the lung with a gas,111 (2) increase in PaO2,113 (3) increase in
trolled in different ways depending on the type of ventilator. PAO2,112 (4) increase in pH,110 and (5) elaboration of vasoactive
With “volume ventilators,” VT can be manipulated directly. substances such as bradykinin,109 the prostaglandins [PGE1,
With time-cycled pressure-limited devices, adjustments that PGA1, PGI2 (prostacyclin),114,115 and PGD2116], and endothe-
increase ΔP (difference between PIP and PEEP) generally will lium-derived relaxing factor,117 which subsequently was shown
increase VT. For example, if one increases PIP and leaves PEEP to be the gas NO.118 Blood flow through the pulmonary circuit
alone, VT will increase. To control ventilation or CO2 elimina- is directly proportional to the pressure gradient across the pul-
tion during HFJV, the operator manipulates basically the same monary vessels and the total cross-sectional area of the vessels
parameters in the same direction as during conventional venti- that make up the pulmonary vascular bed. Blood flow is
lation.57–59,99–103 Ventilation during HFOV is generally con- inversely proportional to the blood’s viscosity. Increased blood
trolled by altering the amplitude, which controls the stroke viscosity interferes with gas exchange by reducing pulmonary
length of the piston. The larger the amplitude, the greater the perfusion.
CO2 removal. VT delivered during HFOV is frequency depend- As the lung expands after birth, pulmonary vascular resist-
ent and decreases as the operating frequency increases.104 This ance decreases and pulmonary blood flow increases.111 With
means that in the unusual clinical setting in which amplitude inflation of the lungs, some “straightening out” of pulmonary
settings are maximized, frequency may need to be reduced if an vessels occurs. The larger vessels are pulled open by traction of
improvement in ventilation is desired. At the other extreme, the lung parenchyma that surrounds them. The perialveolar cap-
when VT or amplitude settings are approaching minimum illary lumens enlarge due to the action of surface tension pro-
levels, operating frequency may have to be increased in order to duced by the newly established air–fluid interfaces. There are
decrease CO2 removal.105,106 two types of pulmonary blood vessels: alveolar vessels, which
are composed of capillaries and the slightly larger vessels in the
alveolar walls (these vessels are exposed to alveolar pressure);
and extra-alveolar vessels, which include the arteries and veins
PERFUSION that run through the lung parenchyma but are surrounded by
interstitial tissue rather than alveoli (Fig. 2-19).119 The diameter
Before delivery, only 8% to 10% of cardiac output flows to of alveolar vessels is determined by the balance between the
the lungs.107 In the fetus, pulmonary vascular resistance is high alveolar pressure and the hydrostatic pressure within the vessel.
and systemic vascular resistance is low. Most of the blood The vessel walls contain little elastic tissue and virtually no
coming out of the fetal heart flows from right to left through the muscle fibers. Alveolar vessels collapse if alveolar pressure
foramen ovale and ductus arteriosus, thus bypasseing the lungs. exceeds pulmonary venous pressure. Extra-alveolar vessels
Under normal circumstances after delivery, a rapid transition to have structural support in their walls and are not significantly
the adult pattern of circulation occurs, after which virtually all
right-sided heart output goes through the lungs, then the left
side of the heart, and out the aorta. Key to this transition is a
decrease in pulmonary vascular resistance and an increase in
pulmonary blood flow preceding closure of the fetal shunts.
Experiments carried out on fetal lambs108–113 and investigations
into the actions of certain mediators,109,114–116 including nitric
oxide (NO) (Table 2-3),117,118 have demonstrated a number of
factors that contribute to the decrease in pulmonary vascular
resistance that occurs at birth. These include (1) expansion of

TABLE 2-3. Factors Affecting Pulmonary Blood Flow

Increasing Flow Decreasing Flow

1. Volume expansion of the 1. Lung atelectasis


lungs
2. Increase in PAO2 2. Decrease in PAO2
3. Increase in PaO2 3. Hypoxemia (reduction in PaO2)
4. Alkalosis (repiratory or 4. Acidosis (respiratory or
metabolic) metabolic)
5. Release of mediator 5. Mast cell degranulation with
substances (e.g., bradykinin, release of histamine
prostaglandins) Figure 2-19. Effects of lung volume on pulmonary vascular resistance
6. Left-to-right shunting 6. Right-to-left shunting (PVR, solid curved line). A, “Extra-alveolar” vessels pose high resistance
(intracardiac or ductal) (intracardiac or ductal) (dotted curved line) at low and high lung volumes, at the former because
7. Endogenous production of 7. Systemic hypotension (when they become narrow and at the latter because they become stretched.
NO or endothelium-derived right-to-left shunting is B, “Alveolar” vessels pose the least resistance (dashed curved line) when
releasing factor already present) they are open widest at the functional residual capacity (FRC) lung volume
8. Inhalation of exogenous NO 8. Lung overexpansion level, but they become compressed under conditions of lung overinflation.
RV, residual volume; TLC, total lung capacity. (Modified from West JB:
NO, nitric oxide; PaO2; partial pressure of oxygen in arterial blood; PAO2, partial Respiratory Physiology: The Essentials, 2nd ed. Baltimore, Williams &
pressure of oxygen in the alveoli. Wilkins, 1979, p. 39.)
2 / PHYSIOLOGIC PRINCIPLES 35

influenced by alveolar pressure. The vessel diameter of extra- vascular resistance. Its action reduces pulmonary vasoconstric-
alveolar vessels is affected by lung volume, because expanding tion, thereby increasing pulmonary blood flow.117,118,125–127
the lung tends to pull these vessels open. If an airless lung is Endogenous NO is generated in vascular endothelial cells by
inflated to total lung capacity, pulmonary vascular resistance enzymatic cleavage of the terminal nitrogen from L-arginine;
shows a U-shaped response, with high resistance at the low production is accelerated at birth due to the increase in PO2. NO
and high ends of inflation and low resistance in the middle (see diffuses into the vascular smooth muscle cells and stimulates
Fig. 2-17). Resistance is high at low lung volumes because the the production of cyclic guanosine monophosphate (cGMP),
extra-alveolar vessels are narrowed (they are not being pulled which causes smooth muscle relaxation.
open). Resistance is high at high inflation volumes because the The primary factor keeping pulmonary vascular resistance
alveolar vessels are narrowed due to compression (they may high in the fetus is relative hypoxia. Because of the preferential
even collapse). The lowest pulmonary vascular resistance is perfusion of the pulmonary circuit with the most desaturated
found when the lung is neither underinflated nor overinflated. blood (venous blood returning from the fetus’s head), the PaO2
The rapid rise in oxygen tension in the alveoli (PAO2) and in of blood perfusing the lungs of a fetal lamb is around 18 to
the arterial blood (PaO2) perfusing the pulmonary vessels plays 21 mm Hg.107 Profound fetal hypoxemia causes further pul-
a major role in the circulatory adaptation that occurs during monary vasoconstriction. A decrease in pulmonary arterial PO2
transition of extrauterine life. It is the influence of PAO2 on to about 14 mm Hg diminishes pulmonary blood flow in the
adjacent arteries that exerts the greatest effect on decreasing fetus to approximately 50% its base level.128 Hypoxemic stress
pulmonary vascular resistance with the initiation of breathing produces progressively greater increases in pulmonary vascular
air.113 With the initiation of breathing air, the lung is exposed to resistance as the gestational age of a fetus advances.129 Chronic
a PO2 of approximately 100 mm Hg or greater if the infant is hypoxia in the fetus produces an increase in the medial smooth
given supplemental O2. Even if the O2 tension of the mixed muscle of the pulmonary arterioles, which may lead to pulmo-
venous blood perfusion in the pulmonary arteries is low, the nary hypertension and increased pulmonary vasoreactivity.130
arteries themselves are rich with O2 from the surrounding This may be an etiology for PPHN in the newborn infant.
alveoli as long as PAO2 is elevated. Sobel et al.112 demonstrated A variety of mediator substances are contained in mast cells,
that gas diffuses from the alveoli to the pulmonary arteries. including histamine, bradykinin, serotonin, acetylcholine,
PaO2 in the central circulation of the newborn infant rises from leukotrienes, and various prostaglandins (predominantly
the fetal range between 25 and 30 mm Hg to greater than PGD2).121,131 Mast cells are activated by different stimuli in dif-
60 mm Hg within the first hours following birth. ferent ways, both in terms of increasing the synthesis of medi-
Many mediator substances have been implicated in the pul- ator substances and their release through degranulation. The
monary vasodilation seen in the newborn infant. Bradykinin is a same mediator substance may exert opposite effects at different
vasoactive peptide that produces pulmonary vasodilation in times in the newborn period. Because the “net effect,” such as
fetal lambs.109 Bradykinin concentration increases transiently in vasoconstriction or vasodilation, is the result of many different
blood that has passed through the lungs of fetal lambs ventilated substances acting in different directions, the regulation of pul-
with oxygen, but it does not increase if the lungs are ventilated monary vascular tone is complicated and remains an active area
with nitrogen. Bradykinin stimulates the local production of of investigation.
prostacyclin, which is also a potent pulmonary vasodilator.114 Infants living at high altitudes have an increase in pul-
PGA1, PGE1, and prostacyclin decrease pulmonary vascular monary vascular resistance that persists into childhood. They
resistance by dilating both pulmonary veins and arteries.114,115,120 have relative pulmonary hypertension and are at increased risk
Prostacyclin production is stimulated by lung expansion with air for developing cor pulmonale.132 Infants with cyanotic congen-
and by mechanical ventilation. The decrease in pulmonary vas- ital heart disease and chronic hypoxemia are also at risk for
cular resistance associated with mechanical ventilation can be developing pulmonary hypertension and cor pulmonale, as are
attenuated by prior administration of a prostaglandin synthesis oxygen-dependent infants with CLD. The vasoconstriction
inhibitor (indomethacin).115 PGD2, another prostaglandin, is a response to alveolar and arterial hypoxemia is potentiated by
semiselective pulmonary vasodilator. It promotes pulmonary acidosis.110
vasodilation without causing the systemic vasodilatory effect PPHN of the newborn is associated with a variety of
produced by other prostaglandins.116 The pulmonary vasodila- conditions, including RDS, pneumonia, meconium aspiration
tory effect of PGD2 is present only during the first few days after syndrome, and CHD (see Chapter 23).133–137 It is also seen in
birth; thereafter, it becomes a pulmonary vasoconstrictor. This infants with chronic fetal distress or peripartum stress. The
observation suggests that PGD2 plays a role in the transition mechanism of PPHN is right-to-left shunting at the atrial and
from fetal to adult-type circulation after birth. PGD2, like hista- ductal levels secondary to persistent elevation of pulmonary
mine, is released through mast cell degranulation. The number vascular resistance. Infants with PPHN exhibit hypoxemia sec-
of mast cells in the lungs increases just before birth and then ondary to extrapulmonary right-to-left shunting; near-systemic
declines after delivery.121 Mast cells play an important role or suprasystemic pulmonary artery pressures; and lability in
in the pulmonary vasoconstrictive response to hypoxia.122 pulmonary artery pressure secondary to pulmonary vasoreac-
Mast cells are abundant in the lung and are ideally located tivity (Fig. 2-20). Hyperventilation of infants with PPHN has
for modulation of vascular tone. Mast cell degranulation has been shown to decrease pulmonary artery pressure.138,139 Right-
been demonstrated to occur after acute alveolar hypoxia.123 to-left shunting may occur at the foramen ovale and ductus
Pretreatment with cromolyn sodium (a mast cell degranulation arteriosus when pulmonary artery pressure exceeds systemic
blocking agent) prevents the pulmonary vasoconstriction nor- blood pressure. This results in pulmonary hypoperfusion and
mally induced by alveolar hypoxia.124 hypoxemia due to the contribution of the venous admixture
NO, previously known as endothelium-derived relaxing crossing the shunts. In PPHN it is the pressure difference (ratio
factor, plays an important role in regulating pulmonary of pulmonary arterial-to-systemic arterial pressure) that is
36 2 / PHYSIOLOGIC PRINCIPLES
The more dependent the lung region, the greater its perfu-
important, rather than any specific pressure values. A normal sion.149 The vessels in dependent regions of the lung are more
blood pressure in the systemic circulation may be inadequate to distended and thus present less resistance to flow because their
prevent right-to-left shunting if the pressure in the pulmonary transmural pressure is greater. Transmural pressure is the dif-
artery is greater than that in the systemic circulation. PAO2 – ference between the pressures inside and the pressure outside
PaO2 does not begin to decrease (indicating an improvement in the vessel wall. Inside “hydrostatic” pressure increases the
oxygenation or a reduction in shunting) until pulmonary artery more dependent a vessel’s position in the lung. Outside inter-
pressure drops below aortic pressure (systolic blood pressure). stitial pressure reflects interpleural pressure (see Fig. 2-16).
Dopamine is used clinically for treatment of PPHN. Dopamine Interpleural pressure decreases the more dependent the lung
causes an increase in systemic blood pressure (decreasing the region. Because the hydrostatic pressure increase (inside the
magnitude of right-to-left shunting) and improves myocardial vessel) is greater than the interpleural pressure decrease
contractility.140 The clinical usefulness of intravenous pul- (outside the vessel), the transmural pressure increases the more
monary vasodilators is limited because these medications are dependent the lung region. In the upright adult, the lung is
nonspecific; they dilate the systemic and the pulmonary vascu- divided into four perfusion zones (Fig. 2-21) based on up-and-
lature.141 Inhaled NO causes a dose-dependent decrease in pul- down distance and specific pressure differences.149 Zone I is the
monary vascular resistance and an increase in pulmonary blood least dependent (uppermost) region and has almost no blood
flow, without affecting systemic arterial pressure. It is a selec- flow because alveolar pressure exceeds pulmonary capillary
tive pulmonary vasodilator. When used in low concentrations pressure. This causes collapse of the capillaries around the
(<80 ppm), it is inactivated prior to entering the systemic cir- alveoli. Zone II is the upper middle region and has some flow
culation (see Chapter 14).126,127,137,142–148 because pulmonary artery pressure exceeds alveolar pressure.
Zone III is the lower middle region, where flow is determined
by the difference in pressure between the pulmonary arteries
and pulmonary veins. Zone IV is the most dependent region,
where interstitial pressure is great enough to cause narrowing
of extra-alveolar vessels and, thus, reduce blood flow due to
increased pulmonary vascular resistance. In infants, under
normal circumstances the entire lung is considered to have
zone III characteristics from a physiologic standpoint. In some
situations, as in the presence of air trapping or alveolar overdis-
tention, a portion of the lung may behave as zone I or II, with
a decrease in pulmonary blood flow. In other conditions such as
interstitial edema (fluid overload; left-sided heart failure, as in
congenital heart disease or significant patent ductus arteriosus;
capillary leakage following hypoxic insult or asphyxia; CLD),
much of the dependent portion of the lung behaves like zone
IV, with increased vascular resistance and decreased pul-
monary blood flow. In this clinical situation, fluid restriction,
Figure 2-20. Vicious circle touched off by hypoxemia that reverts transi-
administration of a diuretic, or both may result in significant
tional circulation back to the fetal type, as seen in persistent pulmonary improvements in gas exchange due to an improvement in
hypertension. pulmonary blood flow (as well as an improvement in lung

Figure 2-21. Various intraluminal and extraluminal pressure


effects on the alveolar vessels of the lung in relation to blood
flow in the four perfusion zones. Alveolar vessels represent
“Starling resistors,” which consist of collapsible tubes in pres-
sure chambers. Note the situation in zone II, where there is a
constriction in the “downstream end” of the collapsible vessel.
Here, chamber (alveolar) pressure exceeds intraluminal down-
stream (venous) pressure and the vessel collapses; pressure
inside the tube at the constriction is equal to the chamber (alve-
olar) pressure. Flow is thus determined by the arterial–alveolar
pressure difference rather than by the usual arterial–venous
pressure difference. (Modified from West JB, Dollery CT,
Naimark A: Distribution of blood flow in isolated lung: relation
to vascular and alveolar pressures. J Appl Physiol 19:713, 1964.)
2 / PHYSIOLOGIC PRINCIPLES 37

compliance and a decrease in airway resistance). Conditions in tractility and resistance to fatigue are other effects of methyl-
which significant left-to-right shunting and pulmonary hyper- xanthines.161,162 A further discussion on the control of ventila-
perfusion occur tend to abolish the unevenness of blood flow in tion can be found in Chapter 3.
the lungs.85
Regional hypoventilation produces local pulmonary vaso-
constriction that diverts blood flow away from underventilated
areas. This is a protective mechanism that decreases the perfu-
CONCLUSION
sion of nonventilated or poorly ventilated areas of the lung.
Term newborn and premature lambs are capable of redirecting Based on an understanding of the physiologic principles of
blood flow away from hypoxic regions produced by atelectasis assisted ventilation, we know that ventilator strategies must be
or bronchial obstruction.150,151 The flow directed away from individualized for each patient. We also know that the strategy
atelectatic and hypoxic lung segments is directly proportional used to provide mechanical ventilatory support is more impor-
to the amount of lung volume loss.152 Lung scans in infants tant than the specific type of device used to deliver that support.
have identified perfusion deficits in areas of atelectasis.153 Each time we encounter an infant in respiratory distress, we
Alveolar overdistention secondary to air trapping may reduce must determine what level of support is required: CPAP,163
area blood flow by collapsing surrounding capillaries. noninvasive ventilation, some form of HFV,164–167 liquid ven-
When CPAP or positive-pressure ventilation is used to tilation,168,169 conventional ventilation,170–174 or perhaps some
recruit atelectatic lung units, improvement in both local venti- combination.175
lation and perfusion may result in those regions. However, We must be cognizant of how our strategies and techniques
those areas of the lung, which already are well expanded, may of providing assisted ventilation to infants impact their long-
be further inflated, which can increase rather than decrease pul- term outcomes. Repeated cycling of the terminal airways from
monary vascular resistance in those areas. The overall effect on below critical opening pressure leads to cellular injury and
pulmonary blood flow produced by positive-pressure ventila- inflammation (atelectatrauma). This results in alveolar col-
tion depends on the initial lung volume status of the various lapse, atelectasis, interstitial edema, and elaboration of
functional lung regions and the net result of the therapy on inflammatory mediators. The resulting atelectasis leads to a
global pulmonary blood flow. further reduction in lung compliance that necessitates higher
inspiratory pressures, which further compromises surfactant
production. Atelectatrauma leads to increased diffusion barrier,
which necessitates increased levels of mean airway pressure
CONTROL OF VENTILATION (Paw) and/or increased levels of inspired oxygen (FIO2). The
increase in FIO2 may lead to oxidative injury and further cellu-
In the newborn infant, neurologic and chemical control of lar dysfunction. There are more questions than answers. We
respiration differs in several ways from that in the adult. First, know that mechanical ventilation causes lung injury that leads
the central respiratory control center is immature and therefore to inflammatory response176; oxygen exposure is harmful177,178;
more easily influenced by medications, acid/base status, sleep lung overdistention (volutrauma) causes lung injury179; lung
state, temperature, hypoxia, and other variables. Second, the injury and inflammation exacerbate the deleterious effects of
central and peripheral chemoreceptors that respond to changes oxygen toxicity and volutrauma180; and atelectatrauma is a
in arterial O2 and CO2 tensions act both quantitatively and qual- source of lung injury.181
itatively different from those in adults. Third, a set of chest wall Establishment of an appropriate FRC, administration of sur-
stretch proprioceptors is able to reflexively inhibit or drive factant, avoidance of mechanical ventilation (if possible), use
respiration.154–157 REM sleep also has a significant effect on the of adequate PEEP to avoid the repeated collapse and reopening
control of respiration in the newborn infant. During REM of small airways, avoidance of lung overinflation caused by
sleep, the normal phasic tone changes in the intercostal using supraphysiologic tidal volumes, and avoidance of use of
muscles, which are important for stabilizing the rib cage during more oxygen than is necessary all are important in order to
inspiration, are inhibited. Because the intercostal muscles fail achieve the best possible outcomes and long-term health of our
to tighten with inspiration, the infant’s chest wall deforms patients. While caring for your patients, always remember the
during inspiration. Contraction of the diaphragm worsens the words of Hippocates, “first do no harm.”
paradoxical movement, increases its O2 consumption measured
during REM sleep, and may lead to fatigue-induced apnea.156
Application of CPAP or PEEP causes the infant’s respiratory REFERENCES
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ing and apneic episodes.158,159 The distending pressure sta- in late gestation and in the neonate. Am Rev Respir Dis 129:607–613,
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Febiger, 1975, p. 83. 149:1327–1334, 1994.
3 CONTROL OF VENTILATION
AND APNEA

NARONG SIMAKAJORNBOON, MD
ROBERT C. BECKERMAN, MD

Assisted ventilation often is used to treat respiratory control Preterm Infants


disorders in neonates. The basic knowledge of sleep and control In the preterm infant, active sleep is prominent and accounts
of breathing in infants is important for understanding the patho- for 90% of total sleep time at 31 weeks of gestation. The
physiology of apnea in these patients. Intrauterine breathing amount of active sleep decreases to 50% at term. Irregular
patterns have been observed in a sheep fetus as early as 5 to 14 breathing and apnea are common and occur primarily during
weeks of gestation (20 weeks term).1 The irregular breathing active sleep.9 Premature infants have greater breath-to-breath
movements in the human fetus have been detected as early as variability in minute ventilation compared to term infants. In
11 weeks of gestation, with a rate ranging from 30 to 70 move- contrast to term infants, preterm infants respond to hypoxia
ments per minute and lasting between 55% and 99% of the day.2 with a sustained decrease in ventilation with no initial hyper-
The breathing pattern is altered from a periodic non–air-breath- pnea, which may reflect an immaturity of the central nervous
ing pattern in the fetus to a continuous air-breathing pattern in system involved in breathing control.10,11 The reduced hyper-
infants. Sleep and breathing patterns in infants undergo a signi- capnic response may indicate reduced CO2 sensitivity of the
ficant maturation change during the first year of life. Prematurity central chemoreceptors, and the response increases progres-
profoundly affects the respiratory pattern with highly irregular sively with gestational age to the adult level at term.12 In addi-
and frequent apnea. Understanding this developmental change tion, stimulation of irritant receptors in the carina in preterm
in sleep and breathing patterns is important for the neonatologist infants leads to apnea; term infants respond to the same stimuli
and pediatrician in the diagnosis and management of apnea and with increased respiratory efforts. This paradoxical response to
respiratory dysrhythmias in neonates. Adequate establishment of respiratory stimuli may be related to immaturity of vagal
functional residual capacity (FRC) in newborns is essential if myelination.13 Chest wall instability in preterm infants may
their lungs are to meet the metabolic demands placed on them. contribute to apnea secondary to intermittent airway closure
Although premature infants maintain their FRC through the and decreased FRC.14 Increasing lung volume by continuous
tonic activity of the diaphragm and intercostal muscles during
expiration, babies born at term combine prolonged postinspira-
tory muscle activity with laryngeal control of the expiratory
TABLE 3-1. Anatomic Classification of Respiratory
flow. An infant who is unable to maintain an adequate FRC may
Control: Disorders in the Neonate
progress to respiratory insufficiency and require mechanical
ventilatory support, which is associated with an obvious risk of Brainstem
morbidity and mortality. Infection
In this chapter, the development of sleep and respiratory Infarction
control is reviewed. The pathophysiology, diagnosis, and man- Hemorrhage
Trauma
agement of common conditions that cause abnormal control of Apnea of prematurity
breathing in neonates and infants are discussed (Table 3-1). Congenital central hypoventilation syndrome
Spinal Cord
Trauma
Spinal muscular atrophy
DEVELOPMENTAL ASPECT OF SLEEP Myoneural Junction
AND RESPIRATORY CONTROL Congenital myasthenia gravis
Familial infantile myasthenia gravis
Muscle
Fetus Myotonic dystrophy
Chest wall, airways, and lung
The fetal respiratory center is active in utero as evidenced by Congenital scoliosis
phrenic nerve activity; however, this activity is minimal and has Skeletal dysplasias
a different pattern than that present after birth.3,4 In the human Craniofacial anomalies
Airway anomalies
fetus, breathing movement can be identified at the 10th to 12th Bronchopulmonary dysplasia
week of gestation.5,6 By 20 to 28 weeks of gestation, rhythmical
Miscellaneous
breathing activity is observed in utero and is characterized by Gastroesophageal reflux
long silent periods with no respiratory movement alternating with Inborn error of metabolism
active periods.7 This cycle varies between 40 and 60 minutes.8
41
Exploring the Variety of Random
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The Project Gutenberg eBook of Farewell
message
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Title: Farewell message

Author: David Mason

Release date: June 19, 2024 [eBook #73869]

Language: English

Original publication: New York, NY: Royal Publications, Inc, 1958

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*** START OF THE PROJECT GUTENBERG EBOOK FAREWELL


MESSAGE ***
FAREWELL MESSAGE

By DAVID MASON

V'gu found Earth primitive and crude.

Its hydrogen bombs, for instance....

[Transcriber's Note: This etext was produced from


Science Fiction Adventures April 1958
Extensive research did not uncover any evidence that
the U.S. copyright on this publication was renewed.]
There was the alien spaceship. It squatted in the middle of the
airfield's main runway, in the way of every plane landing and taking
off, to the complete confusion of traffic control.
The airport people had asked V'gu, politely, to move it. He had
looked at them with blank indifference, and gone on making notes
on Terran marriage rites.
Nobody had suggested forcing V'gu to move his ship. The ship
looked as heavy as a battle cruiser—it probably was armed—and it
did not look as if it could be moved by anything short of a hydrogen
bomb. V'gu, when told about hydrogen bombs, had smiled and
implied that such weapons were about on par with stone axes.
The governments of the world treated V'gu with respect, and
informed their peoples that he was merely a visiting student, with no
intention of harming them, and should be given every courtesy,
according to the best traditions of hospitality to strangers. So far, he
had not become angry at anyone.
It was not too difficult to be courteous to V'gu. He looked reasonably
pleasant: the standard number of arms and legs, one head, and only
a slight tint of green to the skin. The green tint had caused one
restaurant in the southern United States some debate before they
would permit him a table, but V'gu had not been angered; he had
merely smiled and noted it down in his notes about taboos.
In fact, the only thing that made it slightly difficult to be courteous
to V'gu was his air of superiority. He paid for services and sample
objects and information by trading strange gadgets which could do
fabulous things, and which were immediately patentable by the
lucky owners, but he passed out the priceless gadgets with the air of
a civilized man handing out glass beads and useless gimcracks to
savages.
It was a question how long before someone felt enough insulted by
this air of superiority to lose his temper and kill the alien being. The
governments of the world were nervously protective of V'gu, trying
to postpone and prevent any such murder. They were afraid of a
space fleet or police force that might come to inquire what had
happened to him, if he came to harm.
At last, to the relief of governments, and to the joy of the traffic
control department of the airport where his ship still obstructed
traffic, V'gu was about to go home. His ship was filled with
photographs, notes and souvenirs. He announced that he had spent
enough years in a tour of strange planets to complete his course of
study. He announced a farewell speech.
Photographers brought cameras to focus on him standing on the
lowered gangplank of his ship, and color TV projected his image to
the screens of the world—a tallish person, only a little strange and
ugly, with a smooth greenish tint to his skin. The photographers
finished flashing stills, and the TV sound booms moved in to pick up
his voice.

The oldest reporter there was named McCann, and experience had
made him leathery and cynical. He already knew what V'gu would
say—the alien's superior attitude had made it only too clear.
Someone reminded V'gu respectfully that he had promised a speech.
"Yes indeed," he replied sonorously. His English was perfect. He had
spent all of three hours in learning to speak it.
"You may write in your history books that I think Earth is a pleasant
little planet," he went on, "but sadly backward and primitive in many
respects. I believe that this is caused by the numerous wars, and the
generally quarrelsome behavior of your species." He said this
without anger, and looked at the crowd and the cameras with a kind
of superior pity and compassion in his gaze. "If you could only stop
this bickering among yourselves, with a planet as green and pleasant
as this you could attain a harmony and pleasure of life equal to any
of the truly civilized worlds of the galaxy. My home world, for
example, abolished wars generations ago. We learned a philosophy
of cooperation."
He paused, and gestured up dramatically at the starry night sky, and
again looked at the crowd with contempt. "Yes there are many
worlds out there which are peaceful, productive and cooperative. But
there are also worlds which are dead and shrunken cinders where
there had been green planets and thriving races of people who could
not give up war. For your sake I hope that you will be able to change
your path, but I think that you do not have the ability, and that at
last you will reach the end of the path you are on, and destroy each
other and perhaps your world also. Each nova that you see in the
sky marks the suicide of a race. Our knowledge of these matters is
certain: there is never a nova caused simply by accident; power
sources cannot fail this way. Each nova tells us of a war, of the death
of a culture which probably thought of itself as civilized, and yet
could not subdue its innate savagery."
The reporters scribbled and the cameras whirred. McCann closed his
notepad, bored, and gazed at the sky, prepared to suffer through
the rest of the speech. His paper could get the words of the speech
from the TV. McCann had no comment to add; he had heard such
ideas before. To the east in the sky was the distant glare of the
landing lights of an oncoming aircraft.... No. Not a plane, a star. A
star almost fantastically brilliant, brighter than the others, brighter
than Mars.
"Mr. V'gu!" a young reporter said excitedly. "Isn't that a nova,
there?" He pointed and everyone looked.
V'gu turned, his hand on the gangway rail. They waited and fidgeted
as he stood without moving, looking up. After a time long enough
for him to have memorized the entire star region, his eyes came
down again, and he looked at them blankly, as if he had forgotten
why they were there.
McCann felt a sudden electric thrill of recognition. He had seen a
similar paralyzed lack of expression on the faces of men who had
just learned that they had made some terrible mistake. He turned
abruptly and pushed through the crowd, heading for a phone.

The other reporters didn't understand. Not yet.


"This nova," one of them said. "What was it from?"
V'gu looked up at it. "A sun blew up," he muttered. "Five years ago.
The light took five years to get here." The microphones barely
picked up his voice.
"Do you know anything about the people who lived there, Mr. V'gu?"
V'gu opened his mouth as if to answer. Then he closed it again. He
looked over his shoulder into his spaceship's entrance.
A reporter asked, "What about the nova, Mr. V'gu?"
"I was—I was very well acquainted with the people who caused it,"
V'gu said slowly. "Very well acquainted. I—cannot imagine why it
happened."
"It was a war, wasn't it, Mr. V'gu?"
"A war?" V'gu looked up again and hesitated. "Yes, I suppose it
was."
A moment later he added, apparently without reason, "I've been
away from home a long time."
"How long will it take you to get back home, Mr. V'gu?"
"Get back?" V'gu looked around vaguely, his shoulders slumped. He
looked less alien, somehow, and more like the men around him, and
more likeable. He looked back to his questioner. "Oh. Oh yes, I'm ...
I've changed my mind. You may tell your papers that I've—ah—
decided to extend my stay with you. For—for some time, I think."
The youngest reporter asked suddenly, "Did the nova have anything
to do with you changing your mind? With this decision, I mean."
The tall greenish man in the odd clothes came down the gangplank
and entered the crowd, peering about as if he had forgotten the
microphones and the cameras he was supposed to be speaking to.
Then he saw his object and went through the crowd to him. It was
an airfield official.
"Sir," said V'gu to the official, humbly—and suddenly everyone
watching knew how well V'gu had known the people of the nova
world. "Sir, I believe this spaceship is in your way. Where would you
like me to park it?"
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