Pediatric critical care medicine, volume 2 respiratory, cardiovascular and central nervous systems, 2e (2014)

We describe the develop-mental mechanics of breathing, with particular reference to elastic properties of the lung and chest wall, compliance of the lung and chest wall, airway resistanc

Pediatric Critical Care Medicine

123

Derek S Wheeler Hector R Wong Thomas P Shanley

Editors

Volume 2:

Respiratory, Cardiovascular and Central Nervous Systems

Second Edition

Pediatric Critical Care Medicine

Derek S Wheeler , MD, MMM

Division of Critical Care Medicine

Cincinnati Children's Hospital Medical Center

University of Cincinnati College of Medicine

Cincinnati, OH

USA

Hector R Wong , MD

Division of Critical Care Medicine

Cincinnati Children's Hospital Medical Center

Cincinnati, OH

USA

Thomas P Shanley , MD University of Michigan Medical School Ann Arbor, MI

USA

DOI 10.1007/978-1-4471-6356-5

Springer London Heidelberg New York Dordrecht

Library of Congress Control Number: 2014939299

The use of general descriptive names, registered names, trademarks, service marks, etc in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use

While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may

be made The publisher makes no warranty, express or implied, with respect to the material contained herein Printed on acid-free paper

“You don’t choose your family They are God’s gift to you…”

Desmond Tutu

The practitioner of Pediatric Critical Care Medicine should be facile with a broad scope of

knowledge from human developmental biology, to pathophysiologic dysfunction of virtually every organ system, and to complex organizational management The practitioner should select, synthesize and apply the information in a discriminative manner And fi nally and most importantly, the practitioner should constantly “listen” to the patient and the responses to inter-ventions in order to understand the basis for the disturbances that create life-threatening or severely debilitating conditions

Whether learning the specialty as a trainee or growing as a practitioner, the pediatric sivist must adopt the mantle of a perpetual student Every professional colleague, specialist and generalist alike, provides new knowledge or fresh insight on familiar subjects Every patient presents a new combination of challenges and a new volley of important questions to the receptive and inquiring mind

A textbook of pediatric critical care fi lls special niches for the discipline and the student of the discipline As an historical document, this compilation records the progress of the spe-cialty Future versions will undoubtedly show advances in the basic biology that are most important to bedside care However, the prevalence and manifestation of disease invariably will shift, driven by epidemiologic forces, and genetic factors, improvements in care and, hopefully, by successful prevention of disease Whether the specialty will remain as broadly comprehensive as is currently practiced is not clear, or whether sub-specialties such as cardiac- and neurointensive care will warrant separate study and practice remains to be determined

As a repository of and reference for current knowledge, textbooks face increasing and imposing limitations compared with the dynamic and virtually limitless information gateway available through the internet Nonetheless, a central standard serves as a defi ning anchor from which students and their teachers can begin with a common understanding and vocabulary and thereby support their mutual professional advancement Moreover, it permits perspective, punctuation and guidance to be superimposed by a thoughtful expert who is familiar with the expanding mass of medical information

Pediatric intensivists owe Drs Wheeler, Wong, and Shanley a great debt for their work in authoring and editing this volume Their effort was enormously ambitious, but matched to the discipline itself in depth, breadth, and vigor The scientifi c basis of critical care is integrally woven with the details of bedside management throughout the work, providing both a satisfy-ing rationale for current practice, as well as a clearer picture of where we can improve The coverage of specialized areas such as intensive care of trauma victims and patients following congenital heart surgery make this a uniquely comprehensive text The editors have assembled

an outstanding collection of expert authors for this work The large number of international contributors is striking, but speaks to the rapid growth of this specialty throughout the world

We hope that this volume will achieve a wide readership, thereby enhancing the exchange

of current scientifi c and managerial knowledge for the care of critically ill children, and lating the student to seek answers to fi ll our obvious gaps in understanding

The specialty of pediatric critical care medicine continues to grow and evolve! The modern PICU of today is vastly different, even compared to as recently as 5 years ago Technological innovations in the way we approach the diagnosis and treatment of critically ill children have seemingly changed overnight in some cases Efforts at prevention and improvements in care of patients prior to coming to the PICU have led to better outcomes from critical illness The out-comes of conditions that were, even less than a decade ago, almost uniformly fatal have greatly improved Advances in molecular biology have led to the era of personalized medicine – we can now individualize our treatment approach to the unique and specifi c needs of a patient

We now routinely rely on a vast array of condition-specifi c biomarkers to initiate and titrate therapy Some of these advances in molecular biology have uncovered new diseases and condi-tions altogether! At the same time, pediatric critical care medicine has become more global

We are sharing our knowledge with the world community Through our collective efforts, we are advancing the care of our patients Pediatric critical care medicine will continue to grow and evolve – more technological advancements and scientifi c achievements will surely come

in the future We will become even more global in scope However, the human element of what pediatric critical care providers do will never change “For all of the science inherent in the specialty of pediatric critical care medicine, there is still art in providing comfort and solace

to our patients and their families No technology will ever replace the compassion in the touch

of a hand or the soothing words of a calm and gentle voice [1].” I remain humbled by the gifts that I have received in my life And I still remember the promise I made to myself so many years ago – the promise that I would dedicate the rest of my professional career to advancing the fi eld of pediatric critical care medicine as payment for these gifts It is my sincere hope that the second edition of this textbook will educate a whole new generation of critical care professionals, and in so-doing help me continue my promise

Cincinnati , OH , USA Derek S Wheeler , MD, MMM

Reference

1 Wheeler DS Care of the critically ill pediatric patient Pediatr Clin North Am 2013; 60:xv–xvi Copied with permission by Elsevier, Inc

Promises to Keep

The fi eld of critical care medicine is growing at a tremendous pace, and tremendous advances

in the understanding of critical illness have been realized in the last decade My family has directly benefi ted from some of the technological and scientifi c advances made in the care of critically ill children My son Ryan was born during my third year of medical school By some peculiar happenstance, I was nearing completion of a 4-week rotation in the Newborn Intensive Care Unit The head of the Pediatrics clerkship was kind enough to let me have a few days off around the time of the delivery – my wife Cathy was 2 weeks past her due date and had been scheduled for elective induction Ryan was delivered through thick meconium- stained amni-otic fl uid and developed breathing diffi culty shortly after delivery His breathing worsened over the next few hours, so he was placed on the ventilator I will never forget the feelings of utter helplessness my wife and I felt as the NICU Transport Team wheeled Ryan away in the transport isolette The transport physician, one of my supervising 3rd year pediatrics residents during my rotation the past month, told me that Ryan was more than likely going to require ECMO I knew enough about ECMO at that time to know that I should be scared! The next 4 days were some of the most diffi cult moments I have ever experienced as a parent, watching the blood being pumped out of my tiny son’s body through the membrane oxygenator and roller pump, slowly back into his body (Figs 1 and 2 ) I remember the fear of each day when

we would be told of the results of his daily head ultrasound, looking for evidence of nial hemorrhage, and then the relief when we were told that there was no bleeding I remember the hope and excitement on the day Ryan came off ECMO, as well as the concern when he had

intracra-to be sent home on supplemental oxygen Today, Ryan is happy, healthy, and strong We are thankful to all the doctors, nurses, respiratory therapists, and ECMO specialists who cared for Ryan and made him well We still keep in touch with many of them Without the technological

Fig 1

advances and medical breakthroughs made in the fi elds of neonatal intensive care and pediatric

critical care medicine, things very well could have been much different I made a promise to

myself long ago that I would dedicate the rest of my professional career to advancing the fi eld

of pediatric critical care medicine as payment for the gifts that we, my wife and I, have been

truly blessed It is my sincere hope that this textbook, which has truly been a labor of joy, will

educate a whole new generation of critical care professionals, and in so-doing help make that

fi rst step towards keeping my promise.

Fig 2

With any such undertaking, there are people along the way who, save for their dedication, inspiration, and assistance, a project such as this would never be completed I am personally indebted to Michael D Sova, our Developmental Editor, who has been a true blessing He has kept this project going the entire way and has been an incredible help to me personally through-out the completion of this textbook There were days when I thought that we would never fi n-ish – and he was always there to lift my spirits and keep me focused on the task at hand I will

be forever grateful to him I am also grateful for the continued assistance of Grant Weston at Springer Grant has been with me since the very beginning of the fi rst edition of this textbook

He has been a tremendous advocate for our specialty, as well as a great mentor and friend

I would be remiss if I did not thank Brenda Robb for her clerical and administrative assistance during the completion of this project Juggling my schedule and keeping me on time during this whole process was not easy! I have been extremely fortunate throughout my career to have had incredible mentors, including Jim Lemons, Brad Poss, Hector Wong, and Tom Shanley All four are gifted and dedicated clinicians and remain passionate advocates for critically ill children, the specialties of neonatology and pediatric critical care medicine, and me! I want to personally thank both Hector and Tom for serving again as Associate Editors for the second edition of this textbook Their guidance and advice has been immeasurable I have been truly fortunate to work with an outstanding group of contributors All of them are my colleagues and many have been my friends for several years It goes without saying that writing textbook chapters is a diffi cult and arduous task that often comes without a lot of benefi ts Their exper-tise and dedication to our specialty and to the care of critically ill children have made this project possible The textbook you now hold in your hands is truly their gift to the future of our specialty I would also like to acknowledge the spouses and families of our contributors – participating in a project such as this takes a lot of time and energy (most of which occurs outside of the hospital!) Last, but certainly not least, I would like to especially thank my fam-ily – my wife Cathy, who has been my best friend and companion, number one advocate, and sounding board for the last 22 years, as well as my four children – Ryan, Katie, Maggie, and Molly, to whom I dedicate this textbook and all that I do

Part I The Respiratory System in Critical Illness and Injury

1 Applied Respiratory Physiology 3

J Grant McFadyen, Douglas R Thompson, and Lynn D Martin

2 Life-Threatening Diseases of the Upper Respiratory Tract 19Derek S Wheeler

3 Congenital Airway Anomalies 41Michael J Rutter and Matthew J Provenzano

4 Status Asthmaticus 49Derek S Wheeler and Riad Lutfi

5 Bronchiolitis 75Kentigern Thorburn and Paul Stephen McNamara

6 Pneumonia 87Carrie I Morgan and Samir S Shah

7 Acute Lung Injury (ALI) and Acute Respiratory Distress

Syndrome (ARDS) 101

Waseem Ostwani and Thomas P Shanley

8 Mechanical Ventilation 127

Alik Kornecki and Derek S Wheeler

9 Therapeutic Gases in the Pediatric ICU 163

Brian M Varisco

10 High Frequency Oscillatory Ventilation 175

Kathleen M Ventre and John H Arnold

11 Surfactant Therapy 195

Neal J Thomas, Robert F Tamburro Jr., Douglas F Willson,

and Robert H Notter

12 Extracorporeal Life Support 215

Richard T Fiser

13 Ventilator-Induced Lung Injury 237

Shinya Tsuchida and Brian P Kavanagh

14 Neonatal Lung Diseases 249

Thordur Thorkelsson and Gunnlaugur Sigfusson

15 Pulmonary Hypertension 263

Peter Oishi, Sanjeev A Datar, and Jeffrey R Fineman

16 Neuromuscular Respiratory Failure 283

R Paul Boesch and Hemant Sawnani

Part II The Cardiovascular System in Critical Illness and Injury

17 Applied Cardiovascular Physiology in the PICU 303

Katja M Gist, Neil Spenceley, Bennett J Sheridan, Graeme MacLaren,

and Derek S Wheeler

Ganga Krishnamurthy, Eva W Cheung, and William E Hellenbrand

21 Cyanotic CHD Lesions with Decreased Pulmonary Blood Flow 359

John M Costello and Peter C Laussen

22 Cyanotic Lesions with Increased Pulmonary Blood Flow 377

Nazima Pathan and Duncan J Macrae

23 Congenital Heart Disease: Left Ventricular Outfl ow Tract Obstruction 387

John R Charpie, Dennis C Crowley, and Ranjit Aiyagari

24 Single Ventricle Lesions 397

Katja M Gist, Steven M Schwartz, Catherine D Krawczeski,

David P Nelson, and Derek S Wheeler

25 Long-Term Outcomes in Congenital Heart Disease 417

Haleh C Heydarian, Nicolas L Madsen, and Bradley S Marino

26 Ventricular Assist Device Support in Children 441

Sanjiv K Gandhi and Deirdre J Epstein

27 Arrhythmias 451

David S Cooper and Timothy K Knilans

28 Infl ammatory Diseases of the Heart 467

Mary E McBride and Paul A Checchia

29 Cardiomyopathies in Children 483

Angela Lorts, Thomas D Ryan, and John Lynn Jefferies

30 Acute Decompensated Heart Failure 497

Shilpa Vellore, Jennifer L York, and Avihu Z Gazit

31 Diseases of the Pericardium 509

Katja M Gist and Derek S Wheeler

32 Hypertensive Emergencies 523

Amanda B Hassinger and Denise M Goodman

Part III The Central Nervous System in Critical Illness and Injury

33 Molecular Biology of Brain Injury: 2012 535

Michael J Whalen, Phoebe Yager, Eng H Lo, Josephine Lok, Heda Dapul,

Sarah Murphy, and Natan Noviski

34 Tumors of the Central Nervous System 555

Robert F Tamburro Jr., Raymond Barfi eld, and Amar Gajjar

35 Intracranial Hypertension 569

Andrew C Argent and Anthony Figaji

36 Stroke 589

Brandon A Zielinski and Denise Morita

37 Infl ammatory Brain Diseases 601

Marinka Twilt, Dragos A Nita, and Susanne M Benseler

38 Abusive Head Trauma 617

Rachel P Berger and Michael J Bell

39 Toxic Metabolic Encephalopathy 627

Jorge S Sasbón and Hugo Arroyo

40 CNS Infections 643

Simon Nadel and Mehrengise Cooper

41 Status Epilepticus 675

Robert C Tasker and Ryan Wilkes

42 Diseases of the Peripheral Nervous System 695

Matthew Pitt

43 Movement Disorders in the ICU 711

Dragos A Nita and Teesta B Soman

Index 721

Ranjit Aiyagari , MD Department of Pediatrics , C.S Mott Children’s Hospital,

University of Michigan , Ann Arbor , MI , USA

Andrew C Argent , MBBCh, MD(Paediatrics), FCPaeds(SA), FRCPCH(UK)

Paediatric Intensive Care, School of Child and Adolescent Health , Red Cross War

Memorial Children’s Hospital, University of Cape Town , Cape Town , South Africa

John H Arnold , MD Division of Critical Care Medicine , Children’s Hospital ,

Boston , MA , USA

Hugo Arroyo , MD Department of Neurology , Hospital de Pediatria “Dr J P Garrahan”,

Ciudad Autonoma de Buenos Aires , Buenos Aires , Argentina

Raymond Barfi eld , MD, PhD Department of Pediatric Hematology/Oncology ,

Duke University , Durham , NC , USA

Michael J Bell , MD Critical Care Medicine , University of Pittsburgh , Pittsburgh , PA , USA Susanne M Benseler , MD, MSCE, PhD Division of Pediatric Rheumatology,

Department of Pediatrics , Alberta Children’s Hospital , Calgary , Alberta , Canada

Rachel P Berger , MD, MPH Department of Pediatrics , Children’s Hospital

of Pittsburgh of UPMC , Pittsburgh , PA , USA

R Paul Boesch , DO, MS Department of Pediatrics and Adolescent Medicine,

Pediatric Pulmonology , Mayo Clinic , Rochester , MN , USA

Ronald A Bronicki , MD Department of Pediatrics , Baylor College of Medicine ,

Houston , TX , USA

Cardiovascular Intensive Care Unit , Texas Children’s Hospital , Houston , TX , USA

John R Charpie , MD, PhD Department of Pediatrics and Communicable Diseases ,

C.S Mott Children’s Hospital, University of Michigan , Ann Arbor , MI , USA

Paul A Checchia , MD Department of Pediatrics , Texas Children’s Hospital ,

Houston , TX , USA

Eva W Cheung , MD Department of Pediatric Cardiology , Children’s Hospital

of New York Presbyterian, Columbia University College of Physicians and Surgeons , New York , NY , USA

David S Cooper , MD, MPH Cardiovascular Intensive Care Unit,

Heart Institute, Division of Cardiology , Cincinnati Children’s

Hospital Medical Center , Cincinnati , OH , USA

Department of Pediatrics , University of Cincinnati College of Medicine ,

Cincinnati , OH , USA

Mehrengise Cooper , MRCPCH Pediatric Intensive Care Unit ,

St Mary’s Hospital , London , UK

John M Costello , MD, MPH Division of Cardiology , Ann and Robert H Lurie

Children’s Hospital of Chicago , Chicago , IL , USA

Dennis C Crowley , MD Department of Pediatrics , C.S Mott Children’s Hospital ,

Ann Arbor , MI , USA

Heda Dapul , MD Pediatric Critical Care Medicine and Neuroscience Center ,

Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA

Sanjeev A Datar , MD, PhD Department of Pediatrics , University of California

San Francisco, Benioff Children’s Hospital , San Francisco , CA , USA

Ali Dodge-Khatami , MD, PhD Department of Cardiovascular Surgery ,

University of Mississippi Medical Center, University of Mississippi Children’s

Heart Center, Batson Children’s Hospital , Jackson , MS , USA

Deirdre J Epstein , BSN Division of Cardiothoracic Surgery ,

St Louis Children’s Hospital, Washington University School of Medicine ,

St Louis , MO , USA

Anthony Figaji , MBChB, MMed, FCS (Neurosurgery), PhD Department

of Neurosurgery , University of Cape Town, Red Cross War Memorial Children’s Hospital ,

Cape Town , South Africa

Jeffrey R Fineman , MD Department of Pediatrics , University of California

San Francisco, Benioff Children’s Hospital , San Francisco , CA , USA

Richard T Fiser , MD Department of Pediatrics , University of Arkansas

for Medical Science , Little Rock , AR , USA

Amar Gajjar , MD Department of Oncology , St Jude Children’s Research Hospital ,

Memphis , TN , USA

Sanjiv K Gandhi , MD Department of Pediatric Cardiothoracic Surgery ,

British Columbia Children’s Hospital , Vancouver , BC , Canada

Avihu Z Gazit , MD Department of Pediatrics , Saint Louis Children’s Hospital ,

St Louis , MO , USA

Katja M Gist , DO, MA, MSCS Department of Pediatrics,

Division of Critical Care Medicine , Cincinnati Children’s Hospital Medical Center ,

Cincinnati , OH , USA

Denise M Goodman , MD, MS Department of Pediatrics ,

Children’s Memorial Hospital, Chicago , Chicago , IL , USA

Amanda B Hassinger , MD Department of Pediatrics , Women’s and Children’s

Hospital of Buffalo , Buffalo , NY , USA

William E Hellenbrand , MD Department of Pediatrics , Yale New Haven Children’s

Hospital/Yale University’s School of Medicine , New Haven , CT , USA

Haleh C Heydarian , MD Department of Pediatrics – Division of Cardiology ,

Cincinnati Children’s Hospital Medical Center , Cincinnati , OH , USA

John Lynn Jefferies , MD, MPH Department of Cardiology ,

Cincinnati Children’s Hospital Medical Center , Cincinnati , OH , USA

Brian P Kavanagh , MB, FRCPC, FFARCSI (hon) Critical Care Medicine – Physiology

and Experimental Medicine , Hospital for Sick Children, Dr Geoffrey Barker Chair

in Critical Care Medicine , Toronto , ON , Canada Department of Anesthesia , University of Toronto , Toronto , ON , Canada

Timothy K Knilans , MD Heart Institute/Department of Pediatrics,

Division of Cardiology , Cincinnati Children’s Hospital Medical Center/University

of Cincinnati College of Medicine , Cincinnati , OH , USA

Alik Kornecki , MD Department of Pediatric Critical Care ,

London Health Sciences Centre, Children’s Hospital , London , ON , Canada

Catherine D Krawczeski , MD Department of Critical Care Medicine ,

Stanford University School of Medicine , Palo Alto , CA , USA

Ganga Krishnamurthy , MBBS Department of Pediatrics , Children’s Hospital

of New York Presbyterian, Columbia University Medical Center , New York , NY , USA

Peter C Laussen , MBBS Department of Critical Care Medicine ,

The Hospital for Sick Children , Toronto , Canada

Eng H Lo , PhD Neuroscience Center , Massachusetts General Hospital,

Harvard Medical School , Charlestown , MA , USA

Josephine Lok , MD Pediatric Critical Care Medicine and Neuroscience Center ,

Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA

Angela Lorts , MD The Heart Institute, Cincinnati Children’s Hospital Medical Center ,

Cincinnati , OH , USA

Riad Lutfi , MD Division of Critical Care Medicine , Riley Hospital for Children ,

Indianapolis , IN , USA

Graeme MacLaren , MBBS, DipEcho, FCICM, FCCM Paediatric ICU ,

National University Health System , Singapore , Singapore Paediatric ICU , Royal Children’s Hospital, Melbourne , Parkville , VIC , Australia

Duncan J Macrae , MB ChB, FRCH, FRCPCH Department of Pediatric Intensive Care ,

Royal Brompton and Harefi eld NHS Foundation Trust , London , UK

Nicolas L Madsen , MD, MPH Department of Pediatrics – Division of Cardiology ,

Cincinnati Children’s Hospital Medical Center , Cincinnati , OH , USA

Bradley S Marino , MD, MPP, MSCE Department of Pediatrics,

Divisions of Cardiology and Critical Care Medicine , Cincinnati Children’s Hospital Medical Center , Cincinnati , OH , USA

Lynn D Martin , MD, MBA Department of Anesthesiology and Pain Medicine ,

Seattle Children’s Hospital , Seattle , WA , USA

Mary E McBride , MD Department of Pediatrics , Ann and Robert H Lurie Children’s

Hospital of Chicago , Chicago , IL , USA

J Grant McFadyen , MBChB, FRCA Department of Anesthesiology and Pain Medicine ,

Seattle Children’s Hospital , Seattle , WA , USA

Paul Stephen McNamara , MBBS, MRCPCH, PhD Institute of Translational

Medicine (Child Health) , The University of Liverpool , Liverpool , Merseyside , UK Paediatric Respiratory Medicine , Alder Hey Children’s Hospital , Liverpool , Merseyside , UK

Carrie I Morgan , MD Department of Pediatrics, Division of Critical Care Medicine ,

Blair E Batson Children’s Hospital , Jackson , MS , USA

Denise Morita , MD Division of Pediatric Neurology , Primary Children’s Medical Center,

University of Utah , Salt Lake City , UT , USA

Sarah Murphy , MD Pediatric Critical Care Medicine and Neuroscience Center ,

Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA

Simon Nadel , FRCP Pediatric Intensive Care Unit , St Mary’s Hospital , London , UK

David P Nelson , BS, PhD, MD Department of Cardiology , Cincinnati Children’s Hospital

Medical Center , Cincinnati , OH , USA

Dragos A Nita , MD, PhD, FRCPC Division of Neurology, Department of Pediatrics ,

The Hospital for Sick Children , Toronto , ON , Canada

Robert H Notter , MD Department of Pediatrics , University of Rochester ,

Rochester , NY , USA

Natan Noviski , MD Pediatric Critical Care Medicine , Massachusetts General Hospital,

Harvard medical School , Boston , MA , USA

Peter Oishi , MD Department of Pediatrics , University of California San Francisco,

Benioff Children’s Hospital , San Francisco , CA , USA

Waseem Ostwani , MD Pediatric Critical Care Medicine, Department of Pediatric

and Communicable Diseases , C S Mott Children’s Hospital , Ann Arbor , MI , USA

Nazima Pathan , FRCPCH, PhD Department of Paediatrics , University of Cambridge ,

Cambridge , UK

Matthew Pitt , MD, FRCP Department of Clinical Neurophysiology ,

Great Ormond Street Hospital for Children NHS Foundation Trust , London , Middlesex , UK

Matthew J Provenzano , MD Division of Pediatric Otolaryngology –

Head and Neck Surgery , Cincinnati Children’s Hospital Medical Center ,

Cincinnati , OH , USA

Michael J Rutter , FRACS Division of Pediatric Otolaryngology – Head and Neck Surgery ,

Cincinnati Children’s Hospital Medical Center , Cincinnati , OH , USA

Thomas D Ryan , MD, PhD The Heart Institute, Cincinnati Children’s Hospital Medical

Center , Cincinnati , OH , USA

Jorge S Sasbón , MD Pediatric Intensive Care , Hospital de Pediatria “Dr J P Garrahan” ,

Ciudad Autonoma de Buenos Aires , Buenos Aires , Argentina

Hemant Sawnani , MBBS, MD Division of Pulmonary Medicine ,

Cincinnati Children’s Hospital Medical Center , Cincinnati , OH , USA

Steven M Schwartz , MD, MS, FRCPC Department of Critical Care Medicine ,

The Hospital for Sick Children , Toronto , ON , Canada

Samir S Shah , MD, MSCE Department of Pediatrics , Cincinnati Children’s Hospital

Medical Center and the University of Cincinnati College of Medicine , Cincinnati , OH , USA

Thomas P Shanley , MD MICHR , University of Michigan Medical School ,

Ann Arbor , MI , USA

Bennett J Sheridan , MBBS, FRACP, FCICM The Royal Children’s Hospital ,

Melbourne , VIC , Australia

Gunnlaugur Sigfusson , MD Department of Pediatrics , Children’s Hospital Iceland ,

Reykjavik , Iceland

Teesta B Soman , MBBS, FAAP, DIPL, ABPN, MBA Department of Pediatrics,

Division of Neurology , The Hospital for Sick Children, Neurology , Toronto , ON , Canada

Neil Spenceley , MB ChB, MRCPCH Department of Pediatric Critical Care ,

Yorkhill Children’s Hospital , Glasgow , Scotland, UK

Robert F Tamburro Jr , MD, MSc Department of Pediatrics ,

Penn State Hershey Children’s Hospital , Hershey , PA , USA

Robert C Tasker , MBBS, MD, FRCP Departments of Neurology

and Anaesthesia (Pediatrics) , Boston Children’s Hospital , Boston , MA , USA

Neal J Thomas , MD, MSc Penn State CHILD Research, Division of Pediatric

Critical Care Medicine , Penn State Children’s Hospital, Pennsylvania State University College of Medicine , Hershey , PA , USA

Douglas R Thompson , MD Department of Anesthesiology and Pain Medicine ,

University of Washington, Seattle Children’s Hospital , Seattle , WA , USA

Kentigern Thorburn , MBChB, MMed, MD, FCPaed, FRCPCH, MRCP, DCH Pediatric Intensive Care, Alder Hey Children’s Hospital and Department of Clinical

Infection, Microbiology and Immunology , The University of Liverpool, Alder Hey Children’s Hospital , Liverpool , Merseyside , UK

Thordur Thorkelsson , MD, MS Department of Neonatology ,

Children’s Hospital Iceland , Reykjavik , Iceland

Shinya Tsuchida , MD Department of Pediatrics , The University of Tokyo,

Tokyo University Hospital , Tokyo , Japan

Marinka Twilt , MD, MSCE, PhD Department of Pediatric Rheumatology ,

Aarhus University Hospital , Aarhus , Denmark

Brian M Varisco , MD Department of Pediatrics , Cincinnati Children’s Hospital

Medical Center , Cincinnati , OH , USA

Shilpa Vellore , MD Department of Pediatrics , Saint Louis Children’s Hospital ,

Saint Louis , MO , USA

Kathleen M Ventre , MD Department of Pediatrics , Children’s Hospital

Colorado/University of Colorado , Aurora , CO , USA

Michael J Whalen , MD Department of Pediatrics , Massachusetts General Hospital ,

Charlestown , MA , USA

Derek S Wheeler , MD, MMM Division of Critical Care Medicine ,

Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine , Cincinnati , OH , USA

Ryan Wilkes , MD Department of Cardiology , Children’s Hospitals of Atlanta ,

Atlanta , GA , USA

Douglas F Willson , MD Department of Pediatrics , Medical College of Virginia ,

Richmond , VA , USA

Phoebe Yager , MD Pediatric Critical Care Medicine and Neuroscience Center ,

Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA

Jennifer L York , MD Department of Pediatrics , Saint Louis Children’s Hospital ,

Saint Louis , MO , USA

Brandon A Zielinski , MD, PhD Division of Pediatric Neurology ,

Primary Children’s Medical Center, University of Utah , Salt Lake City , UT , USA

The Respiratory System

in Critical Illness and Injury

D.S Wheeler et al (eds.), Pediatric Critical Care Medicine,

DOI 10.1007/978-1-4471-6356-5_1, © Springer-Verlag London 2014

Abstract

Understanding and managing respiratory failure remains a cornerstone of critical care tice, as over half of all admissions to pediatric critical care units are related to respiratory issues The unique aspects of a developing pulmonary system demand an in-depth knowl-edge of these changes and their impact on diagnostics and therapeutics Only by under-standing the normal function of the respiratory system is the critical care physician able to begin to formulate mechanisms for supporting a failing physiology

prac-In this chapter, we describe the developmental anatomy of the lung, with emphasis on the fact that the number of alveoli continues to increase long after birth We describe the develop-mental mechanics of breathing, with particular reference to elastic properties of the lung and chest wall, compliance of the lung and chest wall, airway resistance, and lung volumes Next,

we describe the physiologic effects of mechanical ventilation Factors that affect the nance of oxygenation are discussed, and the alveolar gas equation is introduced We describe the maintenance of alveolar ventilation with a discussion of the included components of tidal volume, dead space and respiratory frequency This knowledge is applied to a simplified model of the lung allowing an examination of the mechanics of ventilation Using the single compartment model of the lung, the derivation of the equation of motion for the respiratory system and its implications for artificial mechanical ventilation are explored Developmental anatomy and physiology of the pulmonary circulation is reviewed including physiologic and pharmacologic factors affecting pulmonary vascular pressures, resistances and the resultant changes in blood flow A brief discussion of ventilation and perfusion relationships including the difference between shunt and venous admixture concludes this chapter

mainte-Keywords

Mechanics of breathing • Alveolar gas equation • Equation of motion • Work of breathing •Ventilation perfusion relationships

Applied Respiratory Physiology

J Grant McFadyen, Douglas R Thompson, and Lynn D Martin

1

D.R Thompson, MD

Department of Anesthesiology and Pain Medicine,

Seattle Children’s Hospital, 4800 Sand Point Way N.E

critical care physician able to begin to formulate mechanisms

for supporting a failing physiology This chapter will serve to

introduce the developmental aspects of anatomy and

physi-ology as they relate to the respiratory system, discuss

pulmo-nary circulation and ventilation/perfusion inequality, and

discuss the physiologic effects of mechanical ventilation

Developmental Anatomy

During the embryonic period, the airways first appear as a

ventral outpouching of the primitive foregut The lung

devel-ops through five stages (Fig.1.1), beginning with the

embry-onic stage in the 4th week during which the two main bronchi

are formed By the end of the pseudoglandular stage (week

16) all major conducting airways have formed, including the

terminal bronchioles [1] The canalicular stage is

character-ized by the development of respiratory bronchioles and the

initiation of surfactant production [2] During the saccular

and alveolar stages the respiratory system continues to

mature, with decreased interstitial tissue, thinning distal

air-way walls, the formation of alveoli and increasing surfactant

production The pulmonary vasculature develops in tandem

with the airways, eventually resulting in the completion of the extensive pulmonary capillary network by the alveolar stage Since the process of lung development is a continuum beginning early in embryonic life and progressing through to adolescence, factors that interfere with any of the phases of development may result in altered lung function and/or increased risk of disease in later life [3]

Close to term, the human fetal lung secretes approximately 0.5 L of fluid a day The lung contains approximately 30 mL/

kg of fetal lung liquid just prior to birth [4] At birth, the lung epithelium switches from a secretory to absorptive epithe-lium This switch involves increased expression of the epithe-lial sodium channel and of the sodium pump, and also changes

in expression of lung aquaporins [5] At birth, most of the lung fluid is expelled mechanically, but some will remain to

be absorbed during the first postnatal days In premature infants this ability of lung to reabsorb water is often impaired.Over the remainder of childhood, the lung will continue

to grow and mature and the 20 million alveolar saccules present at birth [6], will increase to 300 million alveoli by 8 years of age [7] The increase in alveoli parallels the increase

in alveolar surface area from 2.8 m2 at birth, to 32 m2 at

8 years of age, and 75 m2 by adulthood [7] Alveolar

Saccular

Alveolar

Alveoli saccules Extra-callular matrix

Expansion of gas exchange area nerves and capillaries

Continued cellular proliferation Lung growth and expansion Surfactant synthesis

Postnatal

In utero

Neural network maturation Primitive alveoli

Conducting airways

Lung bud differentiation

trachee and bronchi

Pulmonary vein and artery

Terminal bronchioles Immature neural networks

Pre-acinar blood vessals

Type I, Type II cells

Birth Fig 1.1 Stages of lung development (Reprinted from Kajekar [3 ] With permission from Elsevier)

multiplication appears to be the major mechanism for lung

growth, although some growth has also been attributed to the

growth of individual alveoli

The adult lung contains anatomic channels that permit

ventilation distal to an area of obstruction (Fig 1.2) Two

channels have been identified in normal human lungs:

inter-alveolar (pores of Kohn) and bronchiointer-alveolar (Lambert’s

channels) Inter-bronchiolar channels are not found in

healthy lungs, but develop during disease processes Pores of

Kohn appear as holes in alveolar walls in the first and second

year of life [8] Lambert’s channels are found after 6 years of

age [9] The absence of these collateral pathways places

infants and children at risk for the development of atelectasis

and resulting ventilation/perfusion inequality [10]

Developmental Mechanics of Breathing

Elastic Properties of the Lung and Chest Wall

The lung is an elastic structure and has a natural tendency to

decrease its size The chest wall, which, in contrast to the

lung, pulls outward at low volumes and inward at high

vol-umes, counteracts this tendency [11] Lung recoil has been

shown to increase with age in children over 6 years of age

[12] and may relate to elastin deposition [13] The presence

of an air-liquid interface increases the elastic recoil of the

lung, due to surface tension Surface tension is the force that

acts across the surface of a liquid, since the attractive forces

between liquid molecules are stronger than the forces between liquid and gas molecules [14] In early surface tension experi-ments in the 1920s, Von Neergaard demonstrated that saline filled lung units, in which the surface tension forces had been abolished, were far more compliant than air filled lung units (Fig 1.3) It is likely that the decrease in surface tension forces resulted in a reduction in lung elastic recoil [14] Surfactant, a phospholipid-protein complex, has been shown

to lower surface tension profoundly The intermolecular repulsive forces oppose the normal attractive forces and this effect is amplified at lower lung volumes, with compression

of the surfactant complex Traditional understanding of face tension notes the significant role that surfactant plays in lung stabilization in accordance with the law of Laplace, stat-ing that the pressure across a surface (P) is equal to 2 timesthe surface tension (T) divided the radius (r):

sur-P= 2 / T rHowever, this probably does not explain lung stabilization

in its entirety The interdependence model of the lung, in which lung units share planar rather than spherical walls, gives cre-dence to tissue forces playing a role (Fig.1.4) In all likelihood, lung stability results from a combination of these two forces

Compliance of the Lung and Chest Wall

The pressure-volume curve of the air-filled lung is depicted

in Fig 1.3 The slope of the curve, volume (V) change per

Interbronchiolar

alveolar

Bronchiole-Interalveolar

Fig 1.2 The various pathways for collateral ventilation (Reprinted

Copyright © 2012 American Thoracic Society Official journal of the

American Thoracic Society)

Saline inflation 200

Fig 1.3 Pressure-volume curves of air and saline Open circles

repre-sent inflation and closed circles reprerepre-sent deflation The compliance of

the saline filled lung is greater than the air filled lung (Reprinted from

unit pressure (P), is equal to the compliance (C) of the lung

(C =∆V/∆P) Normally the lung is quite compliant However,

at the extremes of lung inflation and deflation, as seen from

the graph, that compliance is reduced Lung compliance

depends both on the elasticity of the tissue and the original

lung volume before inflation, as much larger pressures are

needed to inflate lungs from lower lung volumes Compliance

measured at zero airflow is termed static compliance Lung

compliance may also be measured during slow breathing;

this value is termed dynamic compliance Dynamic

compli-ance also reflects the intrinsic elastic properties of the lung,

though it is influenced by the respiratory rate and level of

airway resistance [15]

Plateau Pressure Positive End E

− xxpiratory Pressure C

Tidal Volume correctedPeak Inspiratory Pressure Pos

− iitive End Expiratory Pressure

The compliance of the respiratory system depends both

on the compliance of the lung as well as the compliance of

the chest wall During the first year of life, the compliance of

the respiratory system (CT) increases by as much as 150 %

[16] The increase in lung compliance is responsible for the

majority of the gain, outstripping the decrease in chest wall

compliance The compliance of the chest wall (CCW) is sured by examining the difference between the esophageal/pleural pressure (PPL) and atmospheric pressure (PA) per change in volume (CCW= V/([PA − PPL])) The infant chest wall is remarkably compliant and chest wall compliance decreases with increasing age The elastic recoil of an infant’s chest wall is close to zero and with age it increases due to the progressive ossification of the rib cage and increased intercostal muscle tone [17] In addition, the mov-ing of the abdominal compartment caudally with the attain-ment of an upright posture has also been theorized to play a role in increasing outward recoil of the adult chest The decreased recoil of the infant chest wall increases the possi-bility of lung collapse in the setting of lung disease The excessive compliance of the infant chest wall requires the infant to perform more work than an adult to move a propor-tionally similar tidal volume During an episode of respira-tory distress an infant will develop severe chest wall retractions during its efforts to maintain ventilation and oxy-genation However, a significant portion of the energy gener-ated is wasted through the distortion of the highly compliant rib cage during negative pressure generation from diaphrag-matic contraction [18] It has been observed that some infants will stop breathing from fatigue when faced with excessive respiratory demands This clinical impression of diaphrag-matic fatigue and failure has been confirmed through electro-myographic measurements of the diaphragms of fatiguing infants who become apneic in the face of increased work of breathing [19]

Fig 1.4 (a) Classic model of the distal lung, in which individual alveoli

are controlled by Laplace’s law Small alveoli would empty into large

alveoli (b) Interdependence model of the lung, in which alveoli share

common planar and not spherical walls Any decrease in the size of one alveolus would be stabilized by the adjacent alveoli (Reprinted from

Airway Resistance

In order for air to move in and out of the lungs, gas must flow

from an area of higher pressure to one of lower pressure

According to Ohm’s law, the pressure gradient (P) that faces

a substance (gas or liquid) is equal to the product of the flow

rate (V) times the resistance to flow (R) (P = V × R) The

components of pulmonary resistance to gas flow include: (i)

the inertia of the respiratory system (effectively negligible);

(ii) the frictional resistance of the chest wall tissue

(negligi-ble); (iii) the frictional resistance of the lung tissue (20 % of

pulmonary resistance); and (iv) the frictional resistance of

the airways to the flow of air (majority of pulmonary

resis-tance) [20]

The extent of the pressure drop and its relationship to the

airflow rate depend on the pattern of flow, either laminar or

turbulent In laminar flow, air travels down a tube in parallel

to the side of the tube; however, when variation in the flow

rate develops due to a sudden rise in gas flow rate, a

narrow-ing of the tube or the encounternarrow-ing of an acute angle, the flow

becomes turbulent Laminar flow of air is governed by the

Hagen-Poiseuille law (also known as Poiseuille’s law),

where P = (V) (8lη/πr4); in this equation, l is the length of the

tube, r is the radius of the tube and η is the viscosity of the

gas Through rearranging the terms, it can be noted that

resistance is mostly determined by the radius of the tube, in

that R = P/V = 8lη/πr4 Turbulent flow has different properties

to laminar flow, as it is proportional to the square of the flow

rate: P = KV2 and becomes more dependent on the gas

den-sity instead of the viscoden-sity [21] Clinical attempts to exploit

the properties of turbulent gas flow have been made in the

patients with both upper and lower airway obstruction (i.e.,

croup and asthma) In both of these settings, the introduction

of helium-oxygen admixtures is an attempt to introduce

helium, a gas with a lower density than oxygen, in order to

promote airflow in turbulent airways

The main site of airway resistance in the adult is the upper

airway; however, it has been shown that peripheral airway

resistance in children under 5 years of age is four times higher

than in adults [22] This may explain the high incidence of

lower airway obstructive disease in infants and young

chil-dren, especially when considering Poiseuille’s law and the

dramatic increase in resistance that is seen with only a small

amount of airway obstruction Within the bronchial tree,

direct measurements of the pressure drop have found that the

major site of resistance is the medium-sized bronchi and that

little of the total resistance to airflow is determined by the

smaller airways The resistance of these bronchi is

deter-mined by the presence of exogenous materials, autonomic

regulation of bronchial smooth muscle, and lung volume As

lung volume increases, radial traction is imparted to the

sur-rounding lung tissue, which increases the intraluminal caliber

of these bronchi and reduces their resistance (Fig.1.5) [23]

During illness, airway resistance can be increased from either intraluminal obstruction or extrinsic compression Extrinsic compression can occur from a variety of etiologies,including the occurrence of airway collapse during forced expiration, secondary to dynamic compression of the airway During normal exhalation there is a pressure drop from the alveolus to the mouth, which allows for air flow A continued favorable transmural pressure gradient and cartilaginous support maintain airway patency (transmural pressure gradi-ent = intraluminal pressure − pleural pressure) On the con-trary, during a forced expiration maneuver, the pleural pressure raises significantly, decreasing the transmural pres-sure gradient, causing the airway caliber to narrow At some location along the airway during the forced expiration maneuver, the intraluminal pressure will equal the intrapleu-ral pressure This is termed the equal pressure point (EPP).Beyond this point, forces favoring airway collapse exceed those favoring patency (tethering action of lung tissue andrigid cartilage), resulting in airway collapse [24] In the pres-ence of bronchopulmonary dysplasia, bronchomalacia and tracheomalacia, these mechanisms are amplified, leading to earlier symptoms of airway collapse [25]

Segmental bronchi 02

Airway generation

Fig 1.5 The relationship of airway resistance (AWR) with lung

vol-ume Conductance, the reciprocal of AWR, is a straight line (Reprinted

treating infants and children with respiratory disease

Volumes and capacities of the lungs are affected by several

factors, specifically muscle strength, static-elastic

character-istics of the chest wall and lungs, and patient age [26] A

traditional spirometric tracing is shown in Fig 1.6, depicting

tidal breathing followed by maximal inspiratory and

expira-tory efforts There are five lung volumes depicted on the

fig-ure Tidal volume is defined as the amount of gas moved

during normal breathing and residual volume is defined as

the amount of gas that remains in the lung after a maximal

expiration Four capacities, which are composed of multiple

volumes, are also shown on the figure Vital capacity is

defined as the volume of gas that may be exhaled from the

lung following a maximal inspiration Functional residual

capacity (FRC) is defined as the gas that remains in the lung

at the end of a tidal breath This gas serves as a reservoir of

oxygen during expiration and accordingly is a very

impor-tant construct in the understanding of respiratory

pathophys-iology and will now be considered at length

FRC in a normal lung is the same as the end expiratory

lung volume (EELV); however, in diseased or injured lung,

EELV may be greater or less than FRC FRC is determined

by the static balance between the outward recoil of the chest

wall and the inward recoil of the lung However, in infants,

the outward recoil is quite small, while the inward recoil is

only slightly less than that in adults [27] Accordingly, the

static balance of forces results in a low ratio of FRC to total

lung capacity (TLC) (approximately 10–15 %), limiting gas

exchange However, when measured in the dynamic state,

that ratio of FRC/TLC in infants approximates the adult

value of 40 % [28] Therefore, the dynamic end-expiratory

lung volume of infants is much greater than that predicted by

the static balance of forces

The mechanism for this difference in static versus

dynamic FRC/TLC ratio in infants relates to the mechanism

of breath termination Adults cease expiration at low flow rates, while infants will abruptly terminate expiration [29] at high flow rates (Fig.1.7) Infants utilize two mechanisms to end expiration; post-inspiratory activity of the diaphragm and expiratory laryngeal braking [30, 31] The expiratory braking mechanism is an active process in which the resis-tance in the upper airway is increased by laryngeal narrow-ing during expiration This generates positive end-expiratory pressure (PEEP), which results in an EELV that is aboveFRC and prevents lung derecruitment during times of acute respiratory illness These mechanisms are dependent on both sleep state and gestational age During REM sleep in prema-ture infants, both post-inspiratory activity of the diaphragm and laryngeal braking are reduced, though braking appears preserved during non-REM sleep [32, 33] This may exacer-bate the loss of oxygen stores, resulting in apnea that pres-ents with the clinical findings of significant desaturation and bradycardia in premature infants

The final volume and capacity to consider are closing ume and closing capacity The closing capacity is comprised

vol-of residual volume and closing volume and is defined as the volume of gas that remains in the lung when small alveoli and airways in dependent regions of the lung are collapsed or considered closed When closing capacity exceeds FRC, by definition, some lung units are closed during a portion of tidal breathing If closing capacity exceeds tidal volume, then these lung units will be closed during all phases of tidal breathing These concepts are important in pediatrics, as children younger than 6 years of age have a closing capacity greater than FRC in the supine position [34] This finding has been attributed to reduced inward recoil of the lung This concept becomes clinically important in critically ill infants and children, in which elevated closing capacity leading to areas of collapse results in ventilation and perfusion inequal-ity, resulting in pathophysiologic intrapulmonary shunting,

VITAL CAPACITY

INSPIRATORY CAPACITY MAXIMAL INSPIRATION

END-EXPIRATION

MAXIMAL EXPIRATION

CLOSING VOLUME RESIDUAL

VOLUME

EXPIRATORY RESERVE VOLUME

DEFINITION OF STANDARD STATIC LUNG VOLUMES

FUNC–

TIONAL RESID–

UAL CAPACITY

CLOSING CAPACITY

Fig 1.6 Typical spirometric

tracing that depicts tidal breathing

followed by a maximal

inspiration and then a maximal

expiration Five volumes and five

capacities are shown (Reprinted

With permission from Charles

C Thomas Publishers, Ltd)

especially in the supine position in bed

Ventilation/perfu-sion (V/Q) matching will be discussed at length later in the

chapter

Physiologic Effects of Mechanical Ventilation

Since the introduction of mechanical ventilation into the

intensive care unit, there has been an explosion of new

venti-lators and ventilatory techniques to treat patients with

respi-ratory failure Physicians contemplating the use of

mechanical ventilation must be familiar with these

therapeu-tic options and their potential benefits and associated risks A

detailed understanding of the physiologic and

pathophysio-logic effects of mechanical ventilation is crucial to improve

the outcomes of patients with respiratory failure

Maintenance of Oxygenation

The partial pressure of oxygen in the alveolus (PAO2) is one

of the primary determinants of arterial oxygen tension and is

the chief target of alterations in mechanical ventilation The

PAO2 is determined by the alveolar gas equation:

PAO2= PiO2 − PACO2, where PiO2 is the partial pressure of

inspired oxygen and PACO is the partial pressure of alveolar

carbon dioxide The PiO2 is determined by the fraction of inspired oxygen, the barometric pressure (Pb= 760 mmHg atsea level), and the partial pressure of water vapor (PH2O= 47 mmHg) Thus the PiO2= FiO2* (Pb − PH2O) = 150mmHg in room air at sea level For clinical purposes, PACO2

is assumed to equal the partial pressure of arterial carbon dioxide (PaCO2= 40 mmHg) divided by the respiratory quo-tient (RQ; determined by the mix of metabolic substrates andusually estimated to be approximately 0.8) resulting in

50 mmHg Substituting these values for PiO2 and PACO2, respectively, into the previous equation yields the classic alveolar gas equation: PAO2= FiO2* (Pb–PH2O)–PaCO2/RQ.The latter equation yields a PAO2of 100–120 mmHg at roomair and sea level The alveolar gas equation reveals three eti-ologies for hypoxemia (Table1.1): (i) low FiO2(i.e., hypoxicgas mixture); (ii) low barometric pressure (i.e., high alti-tude); and (iii) hypoventilation The first two are rarelycauses of hypoxemia and an important principle of the alveo-lar gas equation can be gleaned by examining the last situa-tion A decrease in alveolar ventilation by 50 % in room air

at sea level will yield a PAO2 of 50 mmHg, a clinically nificant level of hypoxemia However, with the administra-tion of 25 % inspired oxygen, the PAO2 increases to

sig-78 mmHg, a non-hypoxemic concentration Thus, a very small increase in inspired oxygen tension will easily over-come hypoxemia due solely to hypoventilation

The difference between the partial pressure of oxygen in the alveolus (PAO2) and that in the pulmonary capillary (PaO2), approximately 10 mmHg under normal conditions, is caused by the diffusion barrier of the alveolar-capillary membrane and the overall V/Q ratio of the lung While theformer is easily overcome by increasing the inspired oxygen concentration and is rarely a cause for clinically significant hypoxemia, the same cannot be said for the latter The prin-cipal etiology for clinically significant hypoxemia is pulmo-nary pathology associated with decreased lung volumes, reduced lung compliance, and an increased proportion of low V/Q compartments of the lung [35] Under severe

Fig 1.7 Passive flow-volume curve in an infant, that demonstrates the

abrupt onset of inspiration much above passive FRC (Reprinted from

Copyright © 2012 American Thoracic Society Official journal of the

American Thoracic Society)

Table 1.1 Alveolar partial pressures of oxygen under various

Normoxic, hypoventilation at sea level

conditions, areas of the lung may become completely

atelec-tatic and lead to right-to-left intrapulmonary shunting One

of the primary objectives of mechanical ventilation is to

restore normal lung volumes and mechanics through the

application of continuous positive airway pressure (CPAP)

A useful clinical index of the effect of changes of ventilation

variables is mean airway pressure (Paw) [36] Mean airway

pressure is defined by the following equation:

Paw= (Peak Inspiratory Pressure (PIP)–Positive End‐Expirat

ory Pressure(PEEP)) * (Ti/Ti + Te) + PEEP, where Ti is

inspiratory time and Te is expiratory time

Accordingly, alterations in peak inspiratory and end-

expiratory pressure, ventilator rate, and inspiratory to

expira-tory (I:E) ratio can increase Paw, which can recruit atelectatic

or poorly ventilated alveolar units, thereby restoring normal

V/Q matching and decreasing intrapulmonary shunt [37]

The restoration of lung volumes frequently allows a dramatic

reduction in the inspired oxygen concentration as well as

improving respiratory mechanics and decreasing the work of

breathing These improvements may allow for the partial or

complete restoration of spontaneous ventilation, which is

associated with several possible advantages (improved V/Q

matching, decreased risk of barotrauma, diminished adverse

effects of continuous positive pressure ventilation) [38]

From the previous discussion, the major etiologic factors

producing hypoxemia can be listed as: (i) hypoxic gas

mix-ture; (ii) hypoventilation; (iii) ventilation-perfusion

mis-match; (iv) diffusion abnormalities of the alveolar-capillary

membrane; (v) high altitude and (vi) true shunt related to

cyanotic congenital heart disease

Maintenance of Alveolar Ventilation

A second goal of mechanical ventilation is to augment or

con-trol alveolar ventilation Respiratory failure is frequently

defined in terms of PaCO2, which is inversely related to

alve-olar ventilation (VA): PaCO2∞ VCO2/VA, where VCO2 is carbon

dioxide production Alveolar ventilation is also defined (at

normal ventilator frequencies) as: VA= f*(VT − VD), where VT

is tidal volume, VD is dead space volume, and f is the

respira-tory frequency Alterations in VT and/or f, which are the

com-ponents of minute ventilation (VE), will result in changes in

PaCO2 Clinicians may fail to account for the third

compo-nent in these equations, namely VD The relationship between

VE and PaCO2 can be described by the following equation:

PaCO2= 0.863 VCO2/[VE(1 − VD/VT)], where VCO2 is the

meta-bolically produced carbon dioxide at standard temperature

and pressure Most of VD in normal individuals is the result of

the volume of the conducting airways (anatomic VD) Since

the anatomic dead space is relatively constant, with an

increasing VT, VD/VT tends to decrease and rarely exceeds 0.3 In patients with intrinsic lung disease undergoing mechanical ventilation, VD/VT has been found to exceed 0.6 and is primarily due to continued ventilation of poorly per-fused regions of the lungs (alveolar VD) In this setting, increases in VT may not decrease VD/VT since higher alveolar pressures as a result of increases in VT may result in a decrease

in pulmonary perfusion and therefore increase alveolar VD The effect of changes in VT on VD/VT can be assessed with capnography and use of the Bohr equation: VD/VT= (PaCO2 − PETCO2)/PaCO2, where PETCO2 is the partial pres-sure of carbon dioxide in exhaled gas, commonly referred to

as end-tidal carbon dioxide In summary, three factors must

be considered when changes in PaCO2occur: (i) changes inmetabolic VCO2; (ii) alterations in VE as a result of increases or decreases in VTand f; and (iii) modifications of VD

Mechanics of Ventilation

A simplified single-compartment model of the lungs posed of a single, cylindrical flow-conducting tube (i.e., con-ducting airways) connected to a single, spherical elastic compartment (i.e., alveoli) is frequently used to describe pul-monary mechanics (Fig.1.8) In this model, the lungs are con-sidered as a homogeneous assembly of units with uniform pressure-volume (compliance) and pressure-flow (resistance)characteristics derived from this single representative unit To achieve inflation, a transrespiratory pressure (Ptr) composed of two components is required The first component, the trans-thoracic pressure (Ptt), is defined as the pressure required to deliver the tidal volume against the elastic recoil of the lungs and chest wall, while the second component, the transairway pressure (Pta), is the pressure necessary to overcome airflow resistance This is described mathematically by the equation

com-Ptr=Ptt + Pta, where Ptr=airway minus body surface pressure,

Ptt=alveolar minus body surface (atmospheric) pressure, and

Pta=airway minus alveolar pressure The pressure required forinspiration may come from the respiratory muscles (Prm) and/

or the ventilator (Ptr), giving us the equation:Prm + Ptr=Ptt + Pta Since the ventilator measures pressure relative to atmosphere,

Ptr is equal to the Paw displayed on the ventilator, allowing the substitution: Prm + Paw=Ptt + Pta

The single-compartment model assumes a linear ship between pressure and volume and between pressure and flow The change in Ptt is directly proportional to the corre-sponding change in lung volume and the constant of propor-tionality is the slope (∆P/∆V) of the pressure-volume curve (i.e., the reciprocal of compliance [C]) Similarly, the change

relation-in Ptais proportional to the change in flow rate (F) and theconstant of proportionality (∆P/∆F) is resistance (R).Substituting ∆P/∆V for Ptt and ∆P/∆F for Pta yields the equation of motion of the respiratory system for inspiration:

Prm + Paw= V/C + (F) * (R), where V is the volume inspired or

expired, C is the compliance of the respiratory system, F is

the inspiratory or expiratory flow rate, and R is the resistance

of the respiratory system For passive expiration, the

equa-tion of moequa-tion of the respiratory system is defined as:

V/C = − (F) * (R), where the elastic components of the lungs

(PA= V/C) provides the pressure to drive the expiratory flow

rate In situations where respiratory muscles are relaxed,

measurement of pressure, volume and flow allow calculation

of total respiratory system compliance and resistance

The relationships represented in the equation of motion

can be graphically represented for both constant inspiratory

flow (i.e., volume-limited ventilation) and constant

inspiratory-pressure (i.e., pressure-limited ventilation) as

shown in Fig 1.9 During constant inspiratory flow

ventila-tion (Fig.1.9, left), the initial increase in pressure is related

to the resistance and flow rate while the slope of the pressure

rise is inversely proportional to compliance, tidal volume,

resistance, and inspiratory flow rate Lung pressure (PL) is

expressed as PL= (F) * (t)/C, where F is inspiratory flow rate,

t is the inspiratory time, and C is the compliance of the

respiratory system Lung volume (VL) can be represented as

VL= (F) * (t) During constant inspiratory pressure ventilation

(Fig 1.9, right), the PL, VL, and F during inspiration are

exponential functions of time derived from the equation of motion as PL=∆P(1−℮ − t/τ), VL= C(∆P)(1−℮ − t/τ), and

F =∆P/R (℮ − t/ τ), where ∆P is equal to peak inspiratory sure minus end-expiratory pressure, t is the inspiratory time,

pres-℮ is the natural logarithm (≈ 2.72), and τ is the time constant

of the respiratory system

The time constant (τ) is the product of compliance ume/pressure) and resistance (pressure x time/volume) and

(vol-is measured in seconds Exhalation during any form ofmechanical ventilation is passive Therefore, the P, V, and F can also be derived from the equation of motion as:

PL=∆P(℮ − t/ τ), VL= C(∆P)(℮ − t/ τ), and F = −∆P/R (℮ − t/ τ), where t is the expiratory time and τ is the expiratory time constant Note that all variables are measured relative to their value at end-expiration, the PL is pressure above positive-end expiratory pressure (PEEP) and VL is the volume above end- expiratory volume When inspiratory and expiratory times are between zero and infinity, the shapes of the lung pressure and lung volume curves are defined by the τ By plotting these curves over time in units of τ, clinically useful princi-ples emerge (Fig.1.10) Irrespective of the specific values of resistance and compliance, after 1 τ 63 % of lung inflation or deflation occurs, 95 % after 3 τ, and for all practical pur-poses, complete equilibration after 5 τ

Fig 1.8 The simplified single compartment model of the lungs

com-posed of a flow-resistive element adjoined in series with a compliance

from Blackwell Publishing Ltd)

Inspiration expiration 30

20

10

0 0

Fig 1.9 Graphic representation of the equation of motion for constant

inspiratory flow (left) and constant inspiratory pressure (right) breaths

Pressure, volume and flow are measured relative to their respective end-

expiratory values The shaded areas represent equal geometric areas

proportional to the pressure required to overcome lung elastic recoil

The dotted line represents mean airway and lung pressure Note the

higher peak and lower mean airway pressures with the constant

inspira-tory flow breath (left) compared to the constant inspirainspira-tory pressure

Blackwell Publishing Ltd)

The equation of motion is a useful means to more closely

examine the differences between constant flow volume-

limited ventilation, and constant pressure ventilation with a

decelerating inspiratory flow waveform Peak airway

pres-sures are higher for a constant flow pattern compared to the

constant pressure pattern However, peak alveolar pressures

depend only on the compliance and tidal volume, thereby

making peak lung pressures independent of the pattern of

ventilation Second, at any point time, airway pressure is

equal to the volume/compliance plus the resistance/flow The

pressure required to overcome flow resistance (shaded area

in Fig 1.9) is constant with fixed inspiratory flow while it

decreases exponentially with the decelerating flow pattern

In the example depicted, the area is equal for both patterns,

since tidal volume and inspiratory times are equal Third, the

more rapid approach to the pressure limit during constant

pressure decelerating flow ventilation leads to a higher Paw

compared to constant flow ventilation Since all shaded areas

are equal, the total area under the airway curve is equal to the

total area under the lung pressure curve for each pattern

Therefore, the Paw is equal to mean PL, a finding that has been

verified in animals [36]

The final feature of pulmonary mechanics that must be

appreciated is the sigmoidal shape of the static pressure-

volume (compliance) relationship of the respiratory system

(Fig.1.11) The respiratory system is most compliant in the

mid-volume range, becoming progressively less compliant at

high (near total lung capacity) and low (approaching residual

volume) volume extremes Tidal ventilation near total lung

capacity occurs under two conditions: (i) when total lungvolume and/or vital capacity are decreased secondary to intrinsic lung disease, and (ii) when end-expiratory volume

is decreased Conversely, ventilation near residual volume with a decrease in compliance also occurs under two condi-tions: (i) when obesity and/or abdominal distention increaseresidual volume and encroach on the lower range of vital capacity, and (ii) when intrinsic lung disease results in air-way or alveolar closure at end-expiratory volume

The relationship between end-expiratory lung volume and closing capacity is critical Conditions that decrease FRC below closing capacity or increase closing capacity above FRC, result in maldistribution of ventilation and perfusion, and adversely affect the mechanics of breathing (Table1.2)

In the school-aged child and in the adult, FRC is normally well above closing capacity However, the relationship is more precarious in young infants, as noted previously, in whom studies suggest that closing capacity exceeds FRC [39] A primary goal of mechanical ventilation is restoration

of the normal relationship between FRC and closing ity Conditions associated with a decrease in FRC (e.g., pul-monary edema, pneumonitis, infant respiratory distress syndrome [(IRDS)] and acute respiratory distress syndrome[(ARDS)] are treated with PEEP to increase FRC back tonormal levels Situations associated with increased closing

Fig 1.10 Exponential lung pressure or volume curves as a function of

time constant during inspiration (solid line) and expiration (dotted line)

Fig 1.11 A hypothetical static pressure-volume curve of the

respira-tory system Note the sigmoidal shape of the inspirarespira-tory limb with high compliance in the midvolume range and low compliance at either high

or low lung volumes Inflection points denote the change from low to

per-mission Blackwell Publishing Ltd)

capacity, such as bronchiolitis and reactive airway disease,

are treated with bronchodilators and measures to improve

airway clearance in order to reduce closing capacity and

maintain airway patency

Work of Breathing

The pressure-volume (compliance) and pressure-flow

(resis-tance) characteristics of the respiratory system determine the

work of breathing which, in actuality, represents the afterload

on the respiratory muscles [40] The work of breathing

over-comes two major sources of impedance: (i) elastic recoil of

the lung and chest wall (Fig.1.12, areas A, C and D), and (ii)

the frictional resistance to gas flow in the airways (Figs.1.1,

1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11, and 1.12, areas

A, B and C) The total work of breathing (Fig.1.12, areas A

through D) is increased by a decrease in respiratory

compli-ance and/or an increase in respiratory resistcompli-ance properties

When total work of breathing against compliance and

resis-tance is summated and plotted against respiratory frequency,

an optimal respiratory frequency exists that minimizes the

total work of breathing (Fig.1.13) In patients with low lung

compliance (restrictive lung diseases) such as pulmonary

edema, pneumonia, IRDS, or ARDS, the optimal frequency is

increased, leading to rapid, shallow breathing In contrast, in

obstructive lung diseases with increased resistance such as

bronchiolitis or asthma, the optimal frequency is decreased leading to slow, deep breathing

Developmental Anatomy and Physiology of the Pulmonary Circulation

The development of the lungs and the pulmonary vasculature are closely related, as adequate blood flow is essential for the formation of the lungs, and preacinar arteries develop in utero with conducting airways [41] The arterial tree under-goes complex remodeling in the peripheral portions of the pulmonary circulation, due in part to changes in wall stress [42] Muscularization of the pulmonary vasculature occurs throughout infancy and reaches adult levels by adolescence Pulmonary vascular muscle thickness is a function of gesta-tional age and blood flow which explains why in patients with congenital heart disease, increased pulmonary blood flow leads to long-standing pulmonary hypertension due to smooth muscle proliferation in the pulmonary vessels [43] Premature infants are born with less arterial smooth muscle than full term infants, this smooth muscle regresses earlier and therefore predisposes to early congestive heart failure in the setting of left-right shunts

Table 1.2 Conditions predisposing to convergence of closing and

functional residual capacities

Elevation of closing capacity

Pressure (cm H2O)

Fig 1.12 Inspiratory and expiratory pressure-volume curve recorded

during a complete respiratory cycle Total work of breathing (pressure

× volume) is defined as the sum of resistive work (area defined by ABC) plus the elastic work (area defined by ACD) Total work (defined by area ABCD) is increased by either an increase in resistive properties of

the respiratory system or by a decrease in compliance (slope of line

from Blackwell Publishing Ltd)

Pulmonary Vascular Pressures

Pressures within the pulmonary circulation are quite low,

despite the fact that the entire cardiac output is designed to

flow through it Following the initial decrease after birth,

pulmonary arterial pressures remain fairly constant in the

disease-free state throughout life, with systolic, diastolic

and mean pressures of 25, 8 and 15 mmHg, respectively

Pulmonary venous pressure is routinely just above that of

left atrial pressure, near 5 mmHg The transpulmonary

pressure is determined by subtracting the left atrial pressure

from the mean pulmonary arterial pressure and is

approxi-mately 10 mmHg in the healthy subject The pressure

within the pulmonary capillaries is uncertain, though

experimental evidence in animals suggests it may range

from 8 to 10 mmHg The pulmonary vascular pressures

vary based on gravity and may range from near 0 mmHg at

the apex of the lung and increase to 25 mmHg at the base

[44]; the consequences resulting from this gradient will be

discussed below

The pressure within the pulmonary capillaries plays an

important role in their patency as they are surrounded by gas

and receive little support from the alveolar epithelial cells

(Fig.1.14) The pressure within the capillaries is fairly close

to alveolar and when the transmural pressure is positive, the

capillaries collapse As the lung expands, the extra-alveolar

vessels are pulled open by the radial traction of the elastic

lung parenchyma In addition, this expansion results in a

negative intrapleural pressure which also helps maintain the

patency of the alveolar vessels (Fig.1.15)

Distribution of Blood Flow

Blood flow in the lung is influenced by gravity whether supine or upright In the upright lung, blood flow decreases almost linearly from the base to the apex The uneven distri-bution is explained by hydrostatic pressure differences within the blood vessels In order to explain the effects of the hydrostatic forces, one may consider the lung as being com-prised of distinct units or zones (Fig.1.16) At the apex of the lung, zone 1, alveolar pressure exceeds both pulmonary arte-rial and venous pressure, resulting in collapse of the alveolar

Fig 1.13 Hypothetical diagrams

showing work done against

elastic and resistance, separately,

and summated to indicate total

work at different respiratory

frequencies For a constant

minute volume, minimum work is

performed at higher frequencies

with restrictive (low compliance)

disease and at lower frequencies

when airflow resistance is

increased (Reprinted from Martin

Blackwell Publishing Ltd)

Fig 1.14 Alveolar vessels Microscopic section of dog lung showing

per-mission from Wolter Kluwers Health)

vessels This zone is ventilated, but not perfused and is

termed alveolar dead space In the mid-region of the lung,

zone 2, pulmonary arterial pressure exceeds alveolar

pres-sure Blood flow here is determined by the difference

between alveolar and arterial pressures in this zone and is not

impacted by venous pressure At the base of the lung, zone 3,

venous pressure exceeds alveolar pressure and flow is

deter-mined by the usual arterial-venous pressure difference At

low lung volumes, zone 4 arises at the base of the lung where

the low lung volume reduces the size of extra-alveolar

ves-sels, increasing their resistance and reducing blood flow

Pulmonary Vascular Resistance

The resistance within any system may be described by a variation of the previously described Ohm’s law, where:

Resistance Input pressure Output pressure

Alveolar vessels Alveolus

Fig 1.15 Alveolar and extra-alveolar vessels Alveolar vessels are

predominantly capillaries exposed to alveolar pressure Extra-alveolar

vessels are pulled open by the radial traction of the lung parenchyma,

resulting in a lower external pressure that promotes vascular patency

vessels or there is an increase in the number of blood vessels

This concept is key to understanding the ability of the

pul-monary vasculature to decrease its resistance in response to

increases in arterial or venous pressure (Fig.1.17) During

periods of increased blood flow, the initial mechanism to

reduce resistance, is via the recruitment of capillaries with

low or no blood flow If this mechanism is not sufficient and

pressures begin to rise, the pulmonary capillaries then

dis-tend, which increases the total cross sectional area that blood

may pass through, thereby decreasing the pressure

An additional mechanism that alters pulmonary

resis-tance is the volume of the lung, though this relationship is

complex as illustrated below A change is lung volume has

opposite effects on the resistances of extra-alveolar versus

the alveolar vessels During lung inflation, the radial traction

as noted above pulls open extra-alveolar vessels; however,

this same increase in lung volume increases the resistance to

flow through alveolar vessels (Fig.1.18) It can be seen from

Fig 1.18 that there is a lung volume where pulmonary

resis-tance is at a minimum It has been concluded that this lung

volume, where pulmonary resistance nadirs, is FRC [45]

Neurogenic stimuli, vasoactive substances, and chemical

mediators have been demonstrated to alter PVR in the setting

of elevated PVR in adults However, in adults with normal

PVR these agents do not appear to significantly alter

resis-tance Interestingly, the neonate appears to respond to a variety

of vasodilating agents, including acetylcholine, β-adrenergic

agonists, bradykinin, prostaglandin E, prostacyclin, bosentan,

calcium channel blockers, and nitric oxide [46] The ability of the pulmonary vasculature to constrict is not age dependent and even newborns with only a small amount of arterial mus-cularization are able to induce significant pulmonary vasocon-striction, as noted in neonates with persistent pulmonary hypertension (PPHN) There are numerous vasoconstrictors,including endothelin, carbon dioxide, leukotrienes, hypoxia and platelet activating factor [47, 48]

Ventilation-Perfusion Relationships

Matching ventilation to perfusion (V/Q) depends to someextent on gravity Both ventilation and perfusion increase with increasing distance towards the base of the lung; how-ever, perfusion increases more than ventilation which accounts for the variability in V/Q from apex to base(Fig 1.19) The apical regions are usually underperfused, V/Q = 3, while the base is underventilated in relation to per-fusion, V/Q = 0.6 [49] In the discussion and explanation to follow, it is important to recognize the difference between shunt and venous admixture Shunt refers to the anatomic shunt that occurs when venous blood travels to the arterial side of the circulation without encountering ventilated lung Examples include bronchial and Thebesian circulation, right

to left shunting in cyanotic congenital heart disease and blood flow through completely atelectatic lung segments

Increasing venous pressure

Fig 1.17 Pulmonary vascular resistance decreases with increases in

either pulmonary arterial or venous pressure During decreases in

arte-rial pressure, venous pressure was held constant and vice versa

Kluwers Health)

120

Capillary

Extra-alveolar vessel

Fig 1.18 Effects on pulmonary vascular resistance as lung volume

changes At low lung volumes, the extra-alveolar vessels are narrow and at high volumes, the capillaries are stretched, reducing their caliber Both of these effects, increase pulmonary vascular resistance (Reprinted

Venous admixture, in contrast, is the amount of venous blood

that needs to be added to the pulmonary end-capillary blood

to produce the actual arterial oxygen content Venous

admix-ture is a calculated value and not an anatomic construct

Lung units with low V/Q ratios contribute to venous

admix-ture They are differentiated from lung units with V/Q ratios

of 0, by the fact that the administration of supplemental

oxy-gen will increase the saturation of blood emerging from their

end-capillaries

V/Q mismatching lowers arterial pO2 and results in

desat-uration through the addition of mixed venous blood to

pul-monary end-capillary blood There are two additional

reasons that V/Q mismatching results in lower arterial pO2

(i) More blood will flow through lung units with low V/Q

ratios than through high V/Q units, resulting in a greater

amount of venous admixture (ii) Due to the sigmoidal shape

of the oxyhemoglobin dissociation curve, lung units with

low V/Q ratios have lower pO2 values and accordingly lie on

the steep portion of the curve, and will have a

disproportion-ately greater drop in saturation This is in contrast to high

V/Q units, who reside on the flat part of the curve and even

large increases in pO2 will have minimal impact on

satura-tion The net result is arterial desaturation, as the slightly

higher oxygen content from high V/Q units cannot

counter-act the significantly lower oxygen content from the low V/Q

units

The difference between mixed venous pCO2(46 mmHg)

and pulmonary end-capillary pCO2(40 mmHg) is not very

great Accordingly, even a significant amount of venous

admixture will only produce a very small increase in arterial

pCO2 The presence of dead space ventilation, on the other

hand, will have a much larger impact on arterial pCO2 For

example, an infant with bronchiolitis may have a large

por-tion of their lung comprised of lung units with high V/Q

ratios In this setting, additional increases in ventilation will

be ineffective at eliminating pCO2, as these units are already maximally ventilated in relation to their perfusion

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Fig 1.19 The distribution of pulmonary blood flow, ventilation and

the ventilation/perfusion ratio as found between apex and base in an

Wolters Kluwers Health)